CN111747954B

CN111747954B - Pyrazine compounds and uses thereof

Info

Publication number: CN111747954B
Application number: CN202010656947.3A
Authority: CN
Inventors: 齐长河; 徐汉忠; 曾庆北; 杨振帆; 张小林
Original assignee: Dizhe Jiangsu Pharmaceutical Co Ltd
Current assignee: Dizhe Jiangsu Pharmaceutical Co Ltd
Priority date: 2018-08-17
Filing date: 2019-08-16
Publication date: 2021-08-24
Anticipated expiration: 2039-08-16
Also published as: CN111747954A

Abstract

The present disclosure relates to novel pyrazine compounds that target adenosine receptors (particularly a1 and A2, specifically, A2 a). The disclosure also relates to pharmaceutical compositions comprising one or more of said compounds as an active ingredient, and the use of said compounds in the treatment of Adenosine Receptor (AR) related diseases, for example cancer such as NSCLC, RCC, prostate cancer and breast cancer.

Description

Pyrazine compounds and uses thereof

The application is a divisional application of Chinese patent application with the application number of 201980006428.8, the application date of 2019, 8 and 16, and the invention name of pyrazine compound and application thereof. The original application is a national phase application with an international application number of PCT/CN2019/100996, and the international application requires the priority of a PCT patent application with an application number of PCT/CN2018/101006 and an application date of 8-17.2018. All of the above applications are incorporated by reference into this application.

Technical Field

The present disclosure relates to novel pyrazine compounds that target adenosine receptors (particularly a1 and A2, specifically, A2 a). The disclosure also relates to pharmaceutical compositions comprising one or more of the compounds as an active ingredient, and the use of the compounds in the treatment of Adenosine Receptor (AR) related diseases, for example cancer such as non-small cell lung cancer (NSCLC), Renal Cell Carcinoma (RCC), prostate cancer and breast cancer.

Background

Adenosine is a naturally occurring nucleoside that elicits a variety of physiological responses by interacting with a class of adenosine receptors. Based on their biochemical and pharmacological properties, such as ligand binding characteristics, glycosylation and function, four adenosine receptor subtypes have been classified in humans (a1, A2a, A2b and A3).

The inflammatory response helps to eliminate harmful agents from the body, but inflammation is also a non-specific reaction that can harm healthy tissue. There is a wide variety of pathogenic lesions that can trigger inflammatory responses including infections, allergens, autoimmune stimuli, immune responses to transplanted tissue, toxic chemicals and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal trauma, and tumor growth.

Adenosine receptors are reported to play a non-redundant role in down-regulating inflammation in vivo by acting as a physiological "STOP" (termination mechanism) that can limit the immune response and thus protect normal tissues from excessive immune damage during the onset of different diseases. Adenosine receptors such as A2a, A2b, and A3 were shown to down-regulate immune responses during inflammation and protect tissues from immune damage. Inhibition of signaling via adenosine receptors can be used to enhance and prolong immune responses. Adenosine inhibits long-term inflammation acting via the A2a adenosine receptor (Ohta et al, Nature 2001; 414: 916-. The A2b Adenosine receptor is involved in regulating cell growth (see Adenosine A2b receptor (Adenosine A2b Receptors as Therapeutic Targets), Drug development research (Drug Dev Res)45: 198; Feoktisov et al, Trends in pharmacology sciences (Trends Pharmacol Sci)19: 148-.

Therefore, compounds targeting adenosine receptors are needed as pharmacological tools and are of high interest as drugs for the treatment of adenosine receptor-related diseases, such as cancer (e.g., NSCLC, RCC, prostate or breast cancer), parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive disorders, HIV, ADA-SCID, AHF and chronic heart failure, Chronic Obstructive Pulmonary Disease (COPD) or asthma.

Disclosure of Invention

In one aspect, the present disclosure provides a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein X, Ring A, Ring B, W, V, Y, R₁、R₂M and n are as defined herein.

In one aspect, the present disclosure provides a compound represented by formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein ring a, ring B, Z, Y, R₁、R₂M and n are as defined herein.

In one aspect, the present disclosure provides a compound represented by formula (Ia-i):

or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring Q, R₁、R₂、R₃、R₇M, n and i are as defined herein.

In one aspect, the present disclosure provides a compound represented by formula (Ia-ii):

or a pharmaceutically acceptable salt thereof, wherein ring A, Z, Y, R₁And m is as defined herein.

In one aspect, the present disclosure provides a compound represented by formula (Ib):

In another aspect, the present disclosure also relates to a pharmaceutical composition comprising one or more of the compounds or pharmaceutically acceptable salts thereof as an active ingredient, and the use of the compounds or pharmaceutically acceptable salts thereof for the treatment of Adenosine Receptor (AR) related diseases, for example cancer such as NSCLC, RCC, prostate cancer or breast cancer.

Detailed Description

In one aspect, the present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

x is selected from amino, halogen, hydroxyl, cyano, C_1-12Alkoxy, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino group, C_1-12An alkanoylamino group;

ring A is a 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group;

ring B is selected from 3-12 membered saturated or unsaturated carbocyclic group or 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group;

w is-C_1-12alkylene-or-C (O) -which may be via hydroxyl, C_1-12Alkyl radical, C_1-12Alkoxy or C_1-12alkyl-OH is mono-or independently poly-substituted;

v is-NH-, -NH-C_1-12Alkylene-, -NH-C (O) -or N-linked pyrrolidinyl, which may be via hydroxy, C _1-12Alkyl radical, C_1-12Alkoxy, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino or C_1-12alkyl-OH is mono-or independently poly-substituted;

y is hydrogen, halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbonyl, carbamate, sulfonyl, C_1-12Alkyl radical, C_1-12Alkoxy radical、C_1-12Alkanoyl radical, C_1-12alkyl-OH, C_1-12Alkyl-cyano, C_1-12Haloalkyl, C_1-12Haloalkoxy, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C_1-12Alkylsulfonyl radical, C_1-12Alkanoylamino, 3-12 membered saturated or unsaturated carbocyclic or 3-12 membered saturated or unsaturated heterocyclic, optionally via R₃Monosubstituted or independently polysubstituted therewith;

each R₁Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C_1-12Alkanoylamino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is₁Optionally further via R₄Monosubstituted or independently polysubstituted therewith;

Each R₂Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C_1-12Alkanoylamino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is₂Optionally further via R₅Monosubstituted or independently polysubstituted therewith;

each R₃Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonylRadical, phosphate radical, phosphoryl radical, phosphinyl radical, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_3-12Cycloalkyl) amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl group, (C)_1-12Alkyl) sulfonyl, (C)_1-12Alkyl) phosphinyl, (C)_1-12Alkyl radical)₂Phosphinyl, (C)_1-12Alkyl) phosphoryl, (C)_1-12Alkyl radical)₂Phosphoryl, C_1-12Alkanoylamino group, N- (C)_1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is ₃Optionally further via R₆Monosubstituted or independently polysubstituted therewith;

wherein each R₄、R₅Or R₆Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, phosphinyl, urea, carbamate, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl group, (C)_1-12Alkyl) sulfonyl, (C)_1-12Alkyl) phosphinyl, (C)_1-12Alkyl radical)₂Phosphinyl group, C_1-12Alkanoylamino group, C_1-12Alkylsulfonyl and C_1-12A haloalkoxy group;

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

n is 0, 1, 2, 3 or 4.

In some embodiments, X is selected from amino, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino or C_1-12An alkanoylamino group.

In some embodiments, X is amino.

In some embodiments, ring a is a 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2, or 3 heteroatoms selected from N, O or S.

In some embodiments, ring a is a 6-10 membered unsaturated monocyclic or polycyclic heterocyclic group.

In some embodiments, ring a is selected from

In some embodiments, ring a is selected from

In some embodiments, each R is₁Independently selected from hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxetanyl or 1, 1-dioxothietanyl, which may optionally be further reacted via R ₄Mono-or independently poly-substituted therewith, wherein each R₄Independently selected from halogen, hydroxy, cyano, amino, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy or C_1-12A haloalkoxy group.

In some embodiments, each R is₁Independently selected from amino, chloro, methyl, difluoromethyl, trifluoromethyl, aminomethyl, ethyl, hydroxyethyl, isopropyl, hydroxypropyl, methoxyethyl, 2-hydroxy-n-propyl, cyclopropyl and oxetanyl. In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, m is 2.

In some embodiments, m is 3.

In some embodiments, m is 4.

In some embodiments, m is 0, 1, or 2.

In some embodiments, ring B is a 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2, or 3 heteroatoms selected from N, O or S.

In some embodiments, ring B is selected from:

in some embodiments, ring B is selected from:

in some embodiments, each R is₂Independently selected from halogen, hydroxy, amino, C_1-12Alkyl or C_1-12Haloalkyl, wherein each R₂Optionally further via R₅Mono-or independently poly-substituted therewith, said R₅Selected from halogen, hydroxy, cyano, C _1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy or C_1-12A haloalkoxy group.

In some embodiments, each R is₂Independently selected from cyano, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, ethoxy, methoxy, difluoromethoxy, trifluoromethoxy, methylamino, dimethylamino, ethylamino, isopropylamino, hydroxymethyl, or hydroxyethyl.

In some embodiments, each R is₂Independently fluorine or methyl.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

In some embodiments, n is 4.

In some embodiments, n is 0, 1, or 2.

In some embodiments, W is methylene or-C (O) -.

In some embodiments, when W is methylene, V is-NH-C (O) -; when W is-C (O) -V is-NH-, -NH-C_1-12Alkylene-or N-linked pyrrolidinyl, which may be via hydroxy, C_1-12Alkyl radical, C_1-12Alkoxy or C_1-12alkyl-OH is mono-or independently poly-substituted.

In some embodiments, Y is hydrogen, hydroxy, amino, cyano, carbonyl, carbamoyl, C _1-12Alkyl radical, C_1-12alkyl-OH, C_1-12Alkoxy, sulfonyl, (C)_1-12Alkyl) sulfonyl, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl, 3-12 membered saturated or unsaturated carbocyclic or 3-12 membered saturated or unsaturated heterocyclic group, which may optionally be substituted by R₃Monosubstituted or, independently, polysubstituted therewith.

In some embodiments, Y is a 3-12 membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl selected from:

which may optionally be via R₃Monosubstituted or, independently, polysubstituted therewith.

In some embodiments, Y is selected from:

In some embodiments, Y is hydrogen, halogen, hydroxy, cyano, or a salt thereof,Amino, carbamoyl, ureido, carbamate, sulfonyl, C_1-12Alkyl radical, C_1-12Alkoxy radical, C_1-12Alkanoyl radical, C_1-12alkyl-OH, C_1-12Alkyl-cyano, C_1-12Haloalkyl, C_1-12Haloalkoxy, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C_1-12Alkylsulfonyl, which may optionally be via R₃Monosubstituted or, independently, polysubstituted therewith.

In some embodiments, each R is₃Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C _1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_3-12Cycloalkyl) amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl group, (C)_1-12Alkyl) sulfonyl, (C)_1-12Alkyl) phosphinyl, (C)_1-12Alkyl radical)₂Phosphinyl, (C)_1-12Alkyl) phosphoryl, (C)_1-12Alkyl radical)₂Phosphoryl, C_1-12Alkanoylamino group, N- (C)_1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is₃Optionally further via R₆Monosubstituted or, independently, polysubstituted therewith. In some embodiments, each R is₃Is independently selected from

Which may optionally be further processed by R₆Monosubstituted or, independently, polysubstituted therewith.

In some embodiments, each R is₆Independently selected from halogen,Hydroxy, cyano, amino, carbamoyl, sulfonyl, urea, carbamate, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C_1-12Alkanoylamino group, C_1-12Alkylsulfonyl radical, C_1-12Haloalkoxy or C_1-12Alkyl-substituted cycloalkyl groups.

In some embodiments, each R is ₃Independently selected from: hydroxy, amino, cyano, carbamoyl, sulfonyl, phosphoryl, phosphinyl, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, ethylamino, hydroxyethyl, hydroxymethyl, hydroxyethoxy, sulfonylmethyl, aminomethyl, cyclopropyl, cyclopropylcarbonyl, cyclobutylamino, cyclopropyl, cyclobutyl, cyclohexyl, pyranyl, furyl, phenyl, pyridyl, pyrazinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 1, 4-oxacyclohexyl, bicyclo [1.1.1]Pentyl, 1, 6-diazaspiro [3.3 ]]Heptylalkyl, 2, 6-diazaspiro [3.3]Heptylalkyl, 2, 6-diazaspiro [3.4 ]]Octyl, 3, 6-diazabicyclo [3.1.1]Heptylalkyl, 2, 5-diazabicyclo [2.2.1]Heptylalkyl, and 3, 8-diazabicyclo [3.2.1]Octyl, which may optionally be further mono-or, independently, poly-substituted with fluoro, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, sulfonyl, methylsulfonyl, carbamoyl, N-methylcarbamoyl, N-dimethylcarbamoyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclopropylcarbonyl.

In some embodiments, each R is₃Independently selected from: hydroxy, cyano, fluoro, chloro, bromo, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, hydroxyethoxy, methylaminoethoxy, dimethylaminoethoxy, hydroxyethylamino, aminocarbonylmethoxy, 2-fluoro, trifluoromethyl, dimethylamino, hydroxyethyl, dimethylamino, methyl, dimethylamino, methyl, ethyl, amino, methyl, or ethyl-hydroxy-ethyl, methoxymethyl, methylsulfonyl, methylsulfonylmethyl, N-methylcarbamoyl, N-dimethylcarbamoyl, dimethylaminomethyl, hydroxymethyl, dimethylphosphoryl, methylaminocarbonyl, methylaminocarbonylmethyl, dimethylaminocarbonyl, dimethylaminocarbonylmethyl, 2-methoxy-ethyl, hydroxyethoxy, methylaminoethoxy, cyclopropyl, cyclopropylcarbonyl, 3- (dimethylamino) cyclobutylamino, phenyl, pyridin-2-yl, azetidin-1-yl, pyrrolidin-1-yl, N-morpholinyl, 3- (dimethylamino) azetidin-1-yl, 4-methylpiperazin-1-yl, 1, 6-diazaspiro [3.3 ].]Heptane-6-yl, 3-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl, 3, 8-diazabicyclo [3.2.1]Octane-8-yl, 8-methyl-3, 8-diazabicyclo [3.2.1 ]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octane-3-yl, 8-methyl-3, 8-diazabicyclo [3.2.1]Octane-3-yl, 3, 6-diazabicyclo [3.1.1]Heptane-6-yl, 3-methyl-3, 6-diazabicyclo [3.1.1]Heptane-6-yl, 2, 6-diazaspiro [3.4 ]]Ocn-2-yl, 6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl, piperidinyl, piperazin-1-yl, 1-methylpiperidin-4-yl, 3- (dimethylamino) pyrrolidine, 3- (dimethylaminomethyl) azetidin-1-yl, 2, 5-diazabicyclo [2.2.1]Heptane-2-yl, 5-methyl-2, 5-diazabicyclo [2.2.1]Heptane-2-yl, 2, 6-diazaspiro [3.3 ]]Heptane-2-yl or 3, 4-dimethylpiperazin-1-yl.

In some embodiments, Y is hydrogen, hydroxy, amino, cyano, carbonyl, carbamoyl, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, sulfonyl, methylamino, dimethylamino, methylcarbamoyl, dimethylcarbamoyl, 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl, which may optionally be substituted with R₃Mono-or independently poly-substituted therewith, wherein each R₃Independently selected from hydroxy, methyl, fluoro, cyano, dimethylamino, dimethylcarbamoyl, hydroxyethyl, hydroxymethyl, methoxy, trifluoromethyl, trifluoromethoxy, methylsulfonyl, dimethylamino, methoxymethyl, methylcarbamoyl, phenyl, pyridyl, cyclopropyl.

In some embodiments, Y is hydrogen, hydroxy, cyano, carbamoyl, methyl, methoxy, methoxymethyl, 1-methoxy-ethyl, 2-methoxy-ethyl, trifluoromethoxy, trifluoromethoxymethyl, trifluoromethoxyethyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, methoxymethyl, methoxyethyl, methylamino, dimethylamino, methylsulfonyl, methylsulfonylmethyl, methylsulfonylethyl, methylcarbamoyl, dimethylcarbamoyl, dimethylaminomethyl, or piperidin-1-yl-carbonyl.

In another aspect, the present disclosure provides compounds of formula (Ia):

or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

ring a is a 6-10 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O or S;

ring B is a 5-6 membered saturated or unsaturated carbocyclic group or a 5-6 membered saturated or unsaturated heterocyclic group;

z is-C_1-12Alkylene-or a bond;

y is hydrogen, amino, carbamoyl, carbonyl, sulfonyl, C_1-12Alkyl radical, C_1-12Alkoxy radical, C_1-12alkyl-OH, C_1-12Alkyl-cyano, C_1-12Haloalkyl, C_1-12Haloalkoxy, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C _1-12Alkylsulfonyl radical, C_1-12Alkanoylamino, 3-6 membered saturated or unsaturated carbocyclic group or 3-6 membered saturated or unsaturated heterocyclic group, which may optionally be substituted with R₃Monosubstituted or independently polysubstituted therewith;

each R₁Independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, diFluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxolanyl or 1, 1-dioxothietanyl, which may optionally be further substituted by R₄Monosubstituted or independently polysubstituted therewith;

each R₂Independently halogen, hydroxy, amino, C_1-12Alkyl or C_1-12Haloalkyl, wherein each R₂Optionally further via R₅Monosubstituted or independently polysubstituted therewith;

each R₃Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C_1-12Alkyl radical, C_1-12Haloalkyl, C _1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_3-12Cycloalkyl) amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl group, (C)_1-12Alkyl) sulfonyl, (C)_1-12Alkyl) phosphinyl, (C)_1-12Alkyl radical)₂Phosphinyl, (C)_1-12Alkyl) phosphoryl, (C)_1-12Alkyl radical)₂Phosphoryl, C_1-12Alkanoylamino group, N- (C)_1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is₃Optionally further via R₆Monosubstituted or independently polysubstituted therewith;

each R₄Independently selected from halogen, hydroxy, cyano, amino, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy or C_1-12A haloalkoxy group;

each R₅Independently selected from halogen, hydroxy, cyano, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy or C_1-12A haloalkoxy group;

each R₆Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, ureido, carbamate, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C_1-12Alkanoylamino group, C_1-12Alkylsulfonyl radical, C _1-12Haloalkoxy or C_1-12Alkyl-substituted cycloalkyl groups;

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

n is 0, 1, 2, 3 or 4.

In some embodiments, Z is a bond and Y is C_1-12Alkoxy, cyclobutyl optionally mono-substituted with methoxy.

In some embodiments, Z is ethylene and Y is methoxy.

In another aspect, the present disclosure provides compounds of formula (Ia-i):

or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

ring Q is a 3-6 membered saturated or unsaturated carbocyclic group or a 3-6 membered saturated or unsaturated heterocyclic group;

each R₁Independently selected from hydroxy, fluoro, chloro, bromoAmino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxetanyl or 1, 1-dioxothietanyl, which may optionally be further substituted by R ₄Monosubstituted or independently polysubstituted therewith;

each R₃Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_3-12Cycloalkyl) amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl group, (C)_1-12Alkyl) sulfonyl, (C)_1-12Alkyl) phosphinyl, (C)_1-12Alkyl radical)₂Phosphinyl, (C)_1-12Alkyl) phosphoryl, (C)_1-12Alkyl radical)₂Phosphoryl, C_1-12Alkanoylamino group, N- (C)_1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is₃Optionally further via R₆Monosubstituted or independently polysubstituted therewith;

each R₅Independently selected from halogen, hydroxy, cyano、C_1-12Alkyl radical, C _1-12Haloalkyl, C_1-12Alkoxy or C_1-12A haloalkoxy group;

each R₆Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, ureido, carbamate, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C_1-12Alkanoylamino group, C_1-12Alkylsulfonyl radical, C_1-12Haloalkoxy or C_1-12Alkyl-substituted cycloalkyl groups;

R₇is hydrogen, C_1-12Alkyl radical, C_1-12Alkoxy or C_1-12alkyl-OH;

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

n is 0, 1, 2, 3 or 4; and is

i is 0, 1, 2, 3 or 4.

In some embodiments, R₇Is hydrogen, methyl or ethyl.

In some embodiments, ring Q is selected from:

in some embodiments, i is 0.

In some embodiments, i is 1.

In some embodiments, i is 2.

In some embodiments, i is 3.

In some embodiments, i is 4.

In some embodiments, i is 0, 1, 2, or 3.

In yet another aspect, the present disclosure provides compounds of formula (Ia-ii):

or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

Z is-C_1-12Alkylene-or a bond;

y is hydrogen, C_1-12Alkyl radical, C_1-12Alkoxy radical, C_1-12alkyl-OH, 3-6 membered saturated or unsaturated carbocyclic group or 3-6 membered saturated or unsaturated heterocyclic group, which may optionally be substituted with R₃Monosubstituted or independently polysubstituted therewith;

each R₁Independently selected from hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxetanyl or 1, 1-dioxothietanyl, which may optionally be further reacted via R₄Monosubstituted or independently polysubstituted therewith;

each R₃Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_3-12Cycloalkyl) amino, N- (C) _1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl group, (C)_1-12Alkyl) sulfonyl, (C)_1-12Alkyl) phosphinyl, (C)_1-12Alkyl radical)₂Phosphinyl, (C)_1-12Alkyl) phosphoryl, (C)_1-12Alkyl radical)₂Phosphoryl, C_1-12Alkanoylamino group, N- (C)_1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is₃Optionally further via R₆Monosubstituted or independently polysubstituted therewith;

each R₆Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, ureido, carbamate, C_1-12Alkyl radical, C_1-12Haloalkyl, C_1-12Alkoxy radical, C_1-12Haloalkoxy, C_1-12alkyl-OH, N- (C)_1-12Alkyl) amino, N- (C)_1-12Alkyl radical)₂Amino, N- (C)_1-12Alkyl) carbamoyl, N- (C)_1-12Alkyl radical)₂Carbamoyl radical, C_1-12Alkanoylamino group, C_1-12Alkylsulfonyl radical, C_1-12Haloalkoxy or C_1-12Alkyl-substituted cycloalkyl groups; and is

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

In some embodiments, ring a is pyridonyl (pyridonyl) or azaindolizinyl (azaindolizinyl).

In some embodiments, m is 1 and R₁Is C_1-12Alkyl, optionally C _1-3Alkyl, optionally methyl.

In some embodiments, Z is a bond and Y is a cyclobutyl group monosubstituted with methoxy.

In some embodiments, Z is ethylene and Y is methoxy.

In some embodiments, Z is methylene, Y is phenyl, pyrrolidinyl, or tetrahydrofuranyl, which may optionally be optionally substituted with R₃Monosubstituted or, independently, polysubstituted therewith.

In some embodiments, R₃Is halogen or C_1-12An alkyl group.

In some embodiments, R₃Is fluorine or methyl.

In another aspect, the present disclosure provides a compound of formula (Ib):

or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R₇is hydrogen, C_1-12Alkyl radical, C_1-12Alkoxy or C_1-12alkyl-OH;

each R₁Independently selected from hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxetanyl or 1, 1-dioxothietanyl, which may optionally be further reacted via R ₄Monosubstituted or independently polysubstituted therewith;

each R₅Independently selected from halogen, hydroxy, cyano, C_1-12Alkyl radical, C _1-12Haloalkyl, C_1-12Alkoxy or C_1-12A haloalkoxy group;

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

n is 0, 1, 2, 3 or 4; and is

i is 0, 1, 2, 3 or 4.

In some embodiments, ring a is selected from

In some embodiments, each R is₁Independently selected from fluoro, chloro, amino, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxyethyl, hydroxypropyl, methoxyethyl, 2-hydroxypropyl, cyclopropyl or oxetanyl.

In some embodiments, m is 0, 1 or 2.

In some embodiments, ring B is selected from:

in some embodiments, R₂Is methyl or fluoro.

In some embodiments, n is 0 or 1.

In some embodiments, ring Q is selected from:

in some embodiments, each R is₃Independently selected from fluoro, chloro, bromo, cyano, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, hydroxyethyloxy, methoxyethyloxy, amino, methylamino, dimethylamino, ethylamino, isopropylamino, hydroxyethylamino, methylaminoethyloxy, dimethylaminoethyloxy, dimethylphosphino-methyl, carbamoyl, carbamoylmethoxy, azetidinyl, pyrrolidinyl, morpholinyl, pyrazinyl, dimethylaminoazetidiyl, 1-methyl-pyrazin-4-yl, 3-methyl-3, 8-diaza-bicyclo [3.2.1 ] bicyclo [3 ] methyl ]Octane-8-yl, 3-methyl-3, 6-diaza-bicyclo [3.1.1]Heptylalkyl, 8-methyl-3, 8-diaza-bicyclo [3.2.1]Octane-3-yl, 6-methyl-2, 6-diaza-spiro [3.4]Octane-2-yl or 5-methyl-2, 5-diaza-spiro [3.3]-heptane-2-yl.

In some embodiments, i is 0, 1, 2, or 3.

In one aspect, the present disclosure provides compounds of formula (I) selected from exemplary compounds 1-306 in table 1 below.

TABLE 1 exemplary Compounds 1-306

It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

In various places of the present disclosure, linking substituents are described. In the case of structures where a linking group is explicitly required, the markush variables (markush variable) listed in connection with said group are to be understood as linking groups. For example, if a structure requires a linking group and the markush group definition of the variable recites "alkyl," it is understood that the "alkyl" represents a linked alkylene.

As used herein, the term "substituted" when referring to a chemical group means that the chemical group has one or more hydrogen atoms removed and replaced with a substituent. As used herein, the term "substituent" has the ordinary meaning known in the art and refers to a chemical moiety that is covalently attached, or fused as appropriate, to the parent group. As used herein, the term "optionally substituted" or "optionally … … substituted" means that a chemical group may have no substituents (i.e., unsubstituted) or may have one or more substituents (i.e., substituted). It is understood that substitution at a given atom is limited by valence number.

As used herein, the term "C_i-j"indicates a range for the number of carbon atoms, where i and j are integers and the range for the number of carbon atoms includes the endpoints (i.e., i and j) and each integer point in between, and where j is greater than i. E.g. C_1-6A range of one to six carbon atoms is indicated, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C" or "C" refers to a compound having a structure that is similar to a structure of a cell_1-12"indicates 1 to 12, including 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.

As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated or unsaturated hydrocarbon chain, which may be further subdivided into hydrocarbon chains (alkenyl or alkynyl) having at least one double or triple bond. In some embodiments, alkyl refers to a saturated hydrocarbon chain. The above-mentioned hydrocarbon chain may be straight or branched. The term "C_i-jAlkyl "meansAlkyl groups having i to j carbon atoms. Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2, 2-trimethylbutyl and the like. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, ethynyl, propyn-1-yl, propyn-2-yl, and the like. "C_1-12Examples of alkyl groups are methyl, ethyl, propyl, isopropyl and butyl. "C_1-3Examples of alkyl groups are methyl, ethyl, propyl and isopropyl.

As used herein, the term "alkylene," whether used as part of another term or independently, refers to a divalent alkyl group. Examples of alkylene groups include, but are not limited to, methylene, 1-ethylene, 1, 2-ethylene, 1-propylene, 1, 2-propylene, 1, 3-propylene, 2-propylene, and the like.

As used herein, the terms "halo" and "halogen" refer to an atom selected from fluorine, chlorine, bromine, and iodine.

As used herein, the term "alkoxy", whether used as part of another term or independently, refers to a group of the formula-O-alkyl. The term "C_i-jAlkoxy "means that the alkyl portion of the alkoxy group has from i to j carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. "C_1-12Examples of alkoxy groups are methoxy, ethoxy and propoxy.

As used herein, the term "C_i-jalkyl-OH "means a group of the formula" -C_i-jalkyl-OH ", wherein the alkyl portion of the group has from i to j carbon atoms, and one or more hydroxyl groups may be bonded to any carbon atom in the alkyl portion. In some embodiments, "C_i-jalkyl-OH "has one hydroxyl group. "C_1-12Examples of alkyl-OH "are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-hydroxyisopropyl.

As used herein, the term "C_i-jHaloalkyl "means halo-substituted: (Mono-or polysubstituted) C_i-jAn alkyl group. "C_1-12Examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl and bromoisopropyl. An example of "difluoroethyl" is 1, 1-difluoroethyl. Examples of "trifluoroethyl" are 2,2, 2-trifluoroethyl and 1,2, 2-trifluoroethyl.

As used herein, the term "C_i-jHaloalkoxy "means halogen-substituted (mono-or poly-substituted) C_i-jAn alkoxy group. "C_i-jExamples of haloalkoxy "are fluoromethoxy, difluoromethoxy or trifluoromethoxy. Examples of "trifluoroethoxy" are 2,2, 2-trifluoroethoxy and 1,2, 2-trifluoroethoxy.

“N-(C_1-12Alkyl) amino "are exemplified by methylamino and ethylamino.

“N-(C_1-12Haloalkyl) amino "are exemplified by fluoromethylamino, difluoromethylamino, trifluoromethylamino, 2-chloroethylamino and 1-bromoisopropylamino.

“N,N-(C_1-12Alkyl radical)₂Examples of amino groups are di- (N-methyl) amino, di- (N-ethyl) amino and N-ethyl-N-methylamino.

As used herein, the term "C_i-jAlkanoyl "means C_i-jAn alkylcarbonyl group. "C_1-12Examples of alkanoyl "are propionyl and acetyl.

“C_1-12Examples of alkanoylamino "are formylamino, acetylamino and propionylamino.

“C_1-12An example of alkanoyloxy "is acetoxy.

“C_1-12Examples of alkoxycarbonyl "are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.

As used herein, the term "carbamoyl" refers to aminocarbonyl. "N- (C)_1-12Alkyl) carbamoyl "are exemplified by methylaminocarbonyl and ethylaminocarbonyl. "N, N- (C) _1-12Alkyl radical)₂Examples of carbamoyl "are dimethylaminocarbonyl and methylethylaminocarbonyl.

As used herein, the term "carbocyclyl," whether used as part of another term or independently, refers to any ring, including monocyclic or polycyclic rings (e.g., having 2 or 3 fused, bridged, or spiro rings), wherein all ring atoms are carbon and contain at least three ring-forming carbon atoms. In some embodiments, a carbocyclyl group may contain 3 to 12 ring-forming carbon atoms (i.e., 3-12 membered carbon atoms), 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, or 4 to 8 ring-forming carbon atoms. The carbocyclyl group may be saturated, partially unsaturated, or fully unsaturated. In some embodiments, the carbocyclyl group may be a saturated cyclic alkyl group. In some embodiments, a carbocyclyl group may be an unsaturated cyclic alkyl group containing at least one double bond in its ring system. In some embodiments, an unsaturated carbocyclyl group may contain one or more aromatic rings. In some embodiments, one or more of the saturated or unsaturated carbocyclic groups form a ring-CH₂The-group may be replaced by a-C (O) -group.

In some embodiments, carbocyclyl is monocyclic. In some embodiments, the carbocyclyl is a saturated monocyclic alkyl. Examples of monocyclic saturated or unsaturated carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like.

As used herein, the term "spiro" refers to a ring system in which two rings are connected by a single common atom; the term "fused ring" refers to a ring system in which two rings share two adjacent atoms; and the term "bridged ring" refers to a ring system in which two rings share three or more atoms.

A3-12, 3-10, or 5-6 "membered saturated or unsaturated carbocyclyl" is a saturated, partially unsaturated, or fully unsaturated monocyclic or polycyclic ring system having 3 to 12, 3 to 10, or 5 to 6 ring-forming carbon atoms, respectively, wherein one or more is cyclic-CH₂The-group may optionally be replaced by a-c (o) -group.

An example of "3-12 membered saturated or unsaturated carbocyclic group" is C_3-4Cycloalkyl, cyclohexyl, cyclohexenyl, cyclopentyl, phenyl, naphthyl and bicyclo [1.1.1]Pentane-1-yl. "C_3-4Examples of cycloalkyl groups "are cyclopropyl and cyclobutyl. "Examples of 5-6 membered saturated or unsaturated carbocyclic groups "are cyclopentyl and phenyl.

As used herein, the term "heterocyclyl" refers to a carbocyclic group in which one or more (e.g., 1, 2, or 3) ring atoms are replaced with a heteroatom, including but not limited to O, S, N, P and the like. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in the ring system. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl. In some embodiments, the heterocyclyl is a fully unsaturated heterocyclyl. In some embodiments, an unsaturated heterocyclyl group may contain one or more aromatic rings. In some embodiments, one or more of the heterocyclic groups form a ring-CH ₂The group may optionally be substituted by-C (O) -, -S-, -S (O) -or-S (O)₂-group replacement. In some embodiments, where the heterocyclyl contains sulfur in its ring system, the ring-forming sulfur atoms may be optionally oxidized to form S-oxides. In some embodiments, the heterocyclyl is bonded to other moieties of the compound via its ring-forming carbon. In some embodiments, the heterocyclyl is linked to the other moiety of the compound via its ring-forming nitrogen.

In some embodiments, a 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2, or 3 heteroatoms selected from N, O or S.

A "3-12, 3-10, or 5-6 membered saturated or unsaturated heterocyclyl" is a saturated, partially unsaturated, or fully unsaturated monocyclic or polycyclic ring (e.g., having 2 or 3 fused, bridged, or spiro rings) having 3 to 12, 3 to 10, or 5 to 6 ring-forming carbon atoms, respectively, at least one ring-forming atom of which is selected from nitrogen, sulfur, or oxygen, and which may be bonded to other parts of the compound via its ring-forming carbon or nitrogen unless otherwise specified, wherein one or more ring-forming-CH groups of the saturated or unsaturated heterocyclyl are₂The group may be substituted by-C (O) -, -S-, -S (O) -or-S (O)₂-group replacement, and wherein when the heterocyclyl contains sulfur in its ring system, said ring sulfur atom may be optionally oxidized to form S-oxide.

Exemplary monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1-dioxothietanylPyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thienyl, and the like,

Oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidinonyl, pyrazinonyl (pyrazinonyl), pyrimidinonyl, pyridazinonyl (pyridazinonyl), triazinonyl (triazinonyl), and the like.

Examples of spiro heterocyclic groups include, but are not limited to, spiropyranyl, spiro

Oxazine groups, and the like. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolyl, isoquinolyl, quinoxalyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1,2-a ] phenyl fused rings]Pyridyl, [1,2,4 ] or a salt thereof]Triazolo [4,3-a]Pyridyl, [1,2,3 ] ]Triazolo [4,3-a]Pyridyl, and the like. Examples of bridged heterocyclic groups include, but are not limited to, morphinyl (morphanyl), hexamethylenetetramino, 8-aza-bicyclo [3.2.1]Octane, 1-aza-bicyclo [2.2.2]Octane, 1, 4-diazabicyclo [2.2.2]Octane (DABCO), and the like.

Unless otherwise indicated, the "compounds" of the present disclosure are intended to encompass all stereoisomers, geometric isomers, and tautomers of the depicted structures.

The term "stereoisomer" refers to any of a variety of stereoisomeric configurations (e.g., enantiomers, diastereomers, and racemates) of asymmetric compounds (e.g., compounds having one or more asymmetrically substituted carbon atoms or "asymmetric centers"). Compounds of the present disclosure containing an asymmetric center may be isolated in optically active (enantiomeric or diastereomeric) or optically inactive (racemic) forms. The term "enantiomer" includes a pair of stereoisomers that are not superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic mixture". The term "diastereomer" or "diastereomer" includes stereoisomers having at least two asymmetric atoms which are not mirror images of each other. Certain compounds containing one or more asymmetric centers may give rise to enantiomers, diastereomers, or other stereoisomeric forms, which may be defined as (R) -or (S) -at each asymmetric center with respect to absolute configuration, according to the Cahn-lngold-Prelog R-S system. Resolved compounds with unknown absolute configuration may be indicated using the term "or" at the asymmetric center. Methods for how to prepare optically active forms from racemic mixtures are known in the art, such as by HPLC resolution or stereoselective synthesis.

The term "geometric isomer" or "cis and trans isomers" refers to a compound having the same formula but with its functional groups rotated to different orientations in three-dimensional space.

The term "tautomer" includes proton transfer tautomers in the isomeric protonated state of compounds having the same formula and overall charge. Examples of proton transfer tautomers include, but are not limited to, keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons may occupy two or more positions of a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2, 4-triazole, 2H-1,2, 4-triazole and 4H-1,2, 4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution. Unless otherwise specified, a compound of the present disclosure identified by name or structure as one particular tautomeric form is intended to include other tautomeric forms.

The "compounds" of the present disclosure are also intended to encompass all isotopes of atoms in the compounds. Isotopes of atoms include atoms having the same number of atoms but different mass numbers. For example, unless otherwise specified, the disclosure "compounds The hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine or iodine in the "are intended to also include isotopes thereof, such as, but not limited to¹H、²H、³H、¹¹C、¹²C、¹³C、¹⁴C、¹⁴N、¹⁵N、¹⁶O、¹⁷O、¹⁸O、³¹P、³²P、³²S、³³S、³⁴S、³⁶S、¹⁷F、¹⁹F、³⁵Cl、³⁷Cl、⁷⁹Br、⁸¹Br、¹²⁷I and¹³¹I. in some embodiments, the hydrogen comprises protium, deuterium, and tritium. In some embodiments, the term "deuterium substituted" or "deuterium substituted" replaces another isoform of hydrogen (e.g., protium) in a chemical group with deuterium. In some embodiments, the carbon comprises¹²C and¹³C. in some embodiments, a "compound" of the present disclosure encompasses only isotopes of hydrogen in the compound. In some embodiments, a "compound" of the present disclosure encompasses only isotopes of atoms in natural abundance.

It is also to be understood that the "compounds" of the present disclosure may exist in solvated as well as unsolvated forms such as, for example, hydrated forms, solid forms, and the present disclosure is intended to encompass all such solvated and unsolvated forms.

It is also understood that the "compounds" of the present disclosure may exist in the form of pharmaceutically acceptable salts.

As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, pharmaceutically acceptable compounds, materials, compositions, and/or dosage forms refer to those approved or generally recognized by regulatory agencies such as the united states Food and Drug Administration (u.s.food and Drug Administration), the chinese Food and Drug Administration (China Food and Drug Administration), or the European Drug Administration (European Medicines Agency), for use in animals and, in particular, humans, such as listed in the united states pharmacopeia (u.s.pharmacopeia), the chinese pharmacopeia (China pharmacopeia), or the European pharmacopeia (European pharmacopeia).

As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by conversion of an existing acidic moiety (e.g., carboxy, etc.) or basic moiety (e.g., amine, alkali metal, etc.) to its salt form. In many cases, the compounds of the present disclosure are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or similar groups. Pharmaceutically acceptable salts are acid and/or base salts that generally do not have a biologically or otherwise undesirable property of the parent compound in order to retain its biological effectiveness and properties. Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts, which can be derived from, for example, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) or organic acids (e.g., formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, trimesic acid, citric acid, lactic acid, phenylacetic acid, benzoic acid, mandelic acid, methanesulfonic acid, naphthalenedisulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, and the like). In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a formate salt. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a TFA salt.

Suitable pharmaceutically acceptable salts of the compounds of the present disclosure also include, for example, base addition salts, which can be derived, for example, from inorganic bases (e.g., sodium, potassium, ammonium salts and hydroxides, carbonates, bicarbonates of metals from columns I-XII of the periodic table, such as calcium, magnesium, iron, silver, zinc, copper, and the like) or organic bases (e.g., primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like). Certain organic amines include, but are not limited to, isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. It will be appreciated by those skilled in the art that addition of an acid or base for forming acid/base addition salts is possible in addition to that shown in the examples. Other lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20 th edition, Mark Publishing Company (Mack Publishing Company), Easton, Pa. (1985); and Stahl and Wermuth, handbook of pharmaceutically acceptable salts: properties, Selection and Use (Handbook of Pharmaceutical Salts, Selection, and Use) (Wiley-VCH, Weinheim, Germany, 2002). In some embodiments, suitable pharmaceutically acceptable salts of the compounds of the present disclosure are inorganic base salts.

The disclosure also includes active intermediates, active metabolites and prodrugs of the compounds of the disclosure. As used herein, "active intermediate" refers to an intermediate compound in the course of synthesis that exhibits the same or substantially the same biological activity as the final synthesized compound.

As used herein, "active metabolite" refers to a breakdown or end product of a compound of the present disclosure, or a salt or prodrug thereof, produced by metabolism or biotransformation in an animal or human body, which exhibits the same or substantially the same biological activity as the specified compound. Such metabolites may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound or salt or prodrug.

As used herein, "prodrug" refers to any compound or conjugate that releases the active parent drug when administered to an animal or human subject. Prodrugs can be prepared by modifying functional groups present in a compound in such a way that the modification is cleavable from the parent compound in routine manipulation or in vivo. Prodrugs include compounds wherein a hydroxy, amino, sulfhydryl, or carboxyl group is bonded to any group such that, when administered to a mammalian subject, it is cleaved to form a free hydroxy, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present disclosure. The preparation and use of prodrugs are discussed in t.higuchi and v.stella, "prodrugs as Novel Delivery Systems (Pro-drugs as Novel Delivery Systems)", "proceedings of the American chemical society of america (a.c.s.symposium Series) volume 14, and" Bioreversible Carriers in Drug Design "Edward b.roche eds., American society of pharmacy and bergamon publishers (American Pharmaceutical Association and Pergamon Press),1987, both of which are hereby incorporated by reference in their entirety.

Synthesis method

The synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, is illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a variety of possible synthetic routes, and thus, these schemes are merely illustrative and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. Moreover, the steps in the described schemes are for better illustration and may be changed as appropriate. The compound examples in the examples were synthesized for the purposes of study and possible submission to regulatory agencies.

The reaction for preparing the disclosed compounds can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, at a temperature in the range of from the freezing temperature of the solvent to the boiling temperature of the solvent. The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for the particular reaction step may be selected by the skilled artisan.

The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the choice of an appropriate protecting group, can be readily determined by those skilled in the art. The chemistry of protecting Groups can be found, for example, in t.w.greene and p.g.m.wuts, Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), 3 rd edition, willy & Sons, Inc., new york (1999), which is incorporated herein by reference in its entirety.

The reaction may be monitored according to any suitable method known in the art. For example, canBy spectroscopic means, e.g. nuclear magnetic resonance spectroscopy (e.g. nuclear magnetic resonance spectroscopy)¹H or¹³C) Infrared spectroscopy (IR), spectrophotometry (e.g. UV-visible), mass spectrometry, or by chromatography, such as High Performance Liquid Chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or Thin Layer Chromatography (TLC). One skilled in the art can purify compounds by a variety of methods, including High Performance Liquid Chromatography (HPLC), ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization)," Karl F.Blom, Brian Glass, Richard Sparks, Andrew P.Combs, J.Combo. chem. (J.Combi. chem.) 2004,6(6),874-883, which is incorporated herein by reference in its entirety), and normal phase silica chromatography.

The structures of the compounds in the examples were characterized by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shift (. delta.) is 10^-6(ppm) is given as unit.¹H-NMR spectra were obtained on a Bruker AVANCE NMR (300MHz or 400MHz) spectrometer using ICON-NMR (under TopSpin process control) using tetramethylsilane as internal standard and dimethylsulfoxide-d₆(DMSO-d₆) Or CDCl₃Or CD₃OD or D₂O or acetone _ d₆Or CD₃CN (from inokay (Innochem) or Sigma-Aldrich (Sigma-Aldrich) or Cambridge Isotope laboratories, Cambridge Isotope lab, Inc.).

MS measurements were performed in positive and negative ion mode using a Shimadzu 2020 mass spectrometer with an electrospray source.

High Performance Liquid Chromatography (HPLC) measurements were performed on a Shimadzu LC-20AD system or a Shimadzu LC-20ADXR system or a Shimadzu LC-30AD system using a homogenously-packed (Shim-pack) XR-ODS C18 column (3.0 x 50mm, 2.2 μm), or an Ascentis Express C18 column (2.1 x 50mm, 2.7 μm), or an Agilent Poroshell HPH-C18 column (3.0 x 50mm, 2.7 μm).

Thin layer chromatography was performed using silica gel plates of national pharmaceutical chemicals Beijing Ltd (Sinopharm Chemical Reagent Beijing co., Ltd.) and xinno Chemical (Xinnuo Chemical). Silica gel plates for Thin Layer Chromatography (TLC) were 175-225 μm. The silica gel plate used for separating and purifying the product by TLC was 1.0 mm.

The purification column uses silica gel as a carrier (100-200, 200-300 or 300-400 mesh, manufactured by Rushanshi shang xincaiiao co., Ltd.) or Rushan Taiyang Desiccant co., Ltd., or the like, available from bose, or a flash column in the agala Technologies flash system (reversed phase C18 column 20-45 μm, manufactured by agel Technologies). The size of the column is adjusted according to the amount of compound.

Known starting materials of the present disclosure may be synthesized by using or according to methods known in the art, or may be purchased from Alfa Aesar (Alfa Aesar), echeli (TCI), Sigma-Aldrich (Sigma-Aldrich), bodharma (Bepharm), bibpharma (Bide pharmatech), pharma (PharmaBlock), Enamine, ikano, and jidawei medical technology (JW & Y pharm lab), among others.

Unless otherwise specified, the reactions were all carried out under an argon or nitrogen atmosphere. By argon or nitrogen atmosphere is meant that the reaction flask is connected to a sphere of argon or nitrogen having a volume of about 1L. The hydrogenation is usually carried out under pressure. Unless otherwise specified, the reaction temperature in the examples is ambient temperature, which is from 10 ℃ to 30 ℃.

The reaction progress was monitored by TLC or/and LC-MS. Eluent systems for the reaction include a dichloromethane-methanol system and a petroleum ether-ethyl acetate system. The volume ratio of the solvent is adjusted according to different polarities of the compound.

Elution systems for column chromatography and eluent systems for TLC of purified compounds include dichloromethane-methanol systems and petroleum ether-ethyl acetate systems. The volume ratio of the solvent is adjusted according to different polarities of the compound. Small amounts of basic or acidic reagents (0.1% to 1%), such as formic acid, or acetic acid, or TFA, or ammonia may be added for adjustment.

Abbreviations for the chemicals used in the synthesis of the compounds provided herein are listed below:

pharmaceutical composition

The present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises more than one compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition comprises one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Generally, pharmaceutically acceptable carriers are conventional pharmaceutical carriers in the art, which can be prepared in a manner well known in the pharmaceutical art. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be blended with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition.

The form of the pharmaceutical composition depends on various criteria including, but not limited to, the route of administration, the extent of the disease, or the dosage to be administered. The pharmaceutical composition may be formulated for oral, nasal, rectal, transdermal, intravenous or intramuscular administration. The pharmaceutical compositions may be formulated as tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants or suppositories, depending on the desired route of administration.

In certain embodiments, the pharmaceutical composition comprises from about 1mg to about 500mg, specifically, from 1mg to about 50mg of the disclosed compound, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure, or pharmaceutically acceptable salts thereof, as a first active ingredient, and further comprises a second active ingredient. The second active ingredient can be any immunomodulatory or anti-neoplastic agent known in the art, including, but not limited to, chemotherapeutic agents, immunotherapeutic agents, cell signaling inhibitors, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, anti-hormonal agents, and the like. Examples of such immunomodulators or antineoplastic agents are platinum chemotherapeutic agents (e.g., cisplatin (DDP), Carboplatin (CBP), sulfato-1, 2-diaminocyclohexaniplatin (SHP), Nedaplatin (Nedaplatin), Oxaliplatin (OXA), leplatin (Laboplatin)), Docetaxel (Docetaxel), Paclitaxel (Paclitaxel), Doxorubicin (Doxorubicin), Etoposide (Etoposide), Mitoxantrone (Mitoxantrone), CTLA-4 inhibitors, anti-CTLA-4 antibodies, PD-1 inhibitors, PD-L1 inhibitors, anti-PD-1/PD-L1 antibodies, CD39 inhibitors, anti-CD 39 antibodies, CD73 inhibitors, anti-CD 73 antibodies, CCR2 inhibitors, anti-CCR 2 antibodies, EGFR inhibitors, 4/6 inhibitors, MELK inhibitors, 40 agonists, anti-hormone inhibitors, 4 homotyrosine kinase antibodies, CDK inhibitors, DNA methyltransferase inhibitors, Hsp90 inhibitors, FGFR inhibitors, mTOR inhibitors, aromatase inhibitors, VEGF inhibitors, LHRH antagonists, PI3K inhibitors, AKT inhibitors, aurora kinase inhibitors, MEK inhibitors, HDAC inhibitors, BET inhibitors, PIK3CA inhibitors, proteasome inhibitors, other SERDs, farnesyl transferase inhibitors, VEGF-a antibodies, ErbB3(Her3) antibodies, proteasome inhibitors, protein kinase C β inhibitors, anti-IGF-1R antibodies, anti-Her 2 antibodies, SERMs, IGF inhibitors, anti-IgG antibodies, and the like. Representative examples of antineoplastic agents for treating cancer or tumor may include, but are not limited to, cisplatin, carboplatin, SHP, nedaplatin, oxaliplatin, leplatin, docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, vincristine, vinblastine, gemcitabine (gemcitabine), cyclophosphamide, chlorambucil (chlorembecil), carmustine (carmustine), methotrexate, fluorouracil, actinomycin, epirubicin (epirubicin), anthracycline, bleomycin, mitomycin-C, irinotecan (irinotecan), topotecan (topotecan), teniposide (teniposide) interleukin, interferon, tremelimumab (tremelimumab), ipilimumab (ipilimumab), periclizumab (perlizumab), nivolumab (nivolumab), avizumab (avivalrubizumab), alutavautab (ipulatab), ipimab (ipulatab-52, ipirab, iputab, ipitabine, ipotebuclizumab (52), and ipolizumab (ipolizumab), and paclitaxel (ipolizumab), and, Proolizumab (plozalizumab), MLN1202, cetuximab (cetuximab), lapatinib (lapatinib), erlotinib (erlotinib), gefitinib (gefitinib), neratinib (neratinib), trastuzumab (trastuzumab), ado-trastuzumab emtansine (ado-trastuzumab emtansine), pertuzumab (pertuzumab), MCLA-128, anastrozole (anastrazole), raloxifene (raloxifene), G1T38, tamoxifen (tamoxifen), sertraline (goserelin), enzalutamide (enzalutamide), vorinostat (voristatintat), entinostat (entinostat), sunitinib (sunitinib), bevacizumab (bevacizumab), kutazaril (Bnetatib), netatib-c 0980), netasinib (Btuzumab), netasinib) (Btuzumab-d), kutab (kutab), kutab) (Tahitab), Tahitab (Tahitab), Tahitachib-80, Tahitab (Tahitachib) (C-D) (Tahitab), Tahitachib) (Tahitab), Tahitab (Tahitachib) (Tahitab), Tahita, Tahitachib-D) (Tahita, Tahita hita, Tab-D) (Tab, Tahita hiticib, Tab, Tahita, Tab, Tahiticib, Tahititabine (Tab, Tahita Tab, Tahiticib, Tab, Tahita Tab, Tab, Tab et Tab, Tab, Tab, Tab, Tab, Temsirolimus (temsirolimus), everolimus (everolimus), sapacitikitib (sapaniertib), AZD5363, MK2206, panitumumab (panitumumab), pericentrumab (pembrolizumab), sorafenib (sorafenib), palbociclib (palbociclib), vitricilin (abemaciclib), rebocillin (ribociclib), crizotinib (crizotinib), dorivitinib (dovitinib), tyrosine protein kinase inhibitors, azacitidine (azacitidine), CC-486, HSP90 Garitterib (HSP 8990 gaarespib), Debio 1347, idatinib (erdatin), Vitusertivibi (vitusertib), alisertib (isertinib), semetimiitinib (sarmentizitunib), evereitiib (bletezomib), evertezomib (AGRIB-58579), tipeptib (AGRIB), SARTAIB (AGRIBENZUCB), SANTRIBENZUCB (AGRIBENZUCTUTIE), SANTE (AGITRIBENZ), SANTE (AGITRITUNTILUB K), SANTILOBIUB), SANTILOBTAB (AGINB), SANTILOBTAB), SANTILOBIUB (SANTE) and so on (SANTE).

The treatment of adenosine receptor related diseases as defined hereinafter may be applied as monotherapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy or immunotherapy. Such chemotherapy may include one or more of the following chemotherapeutic agents: cisplatin (DDP), Carboplatin (CBP), sulfato-1, 2-diaminocyclohexaneproplatin (SHP), nedaplatin, Oxaliplatin (OXA), leplatin, docetaxel, paclitaxel, doxorubicin, etoposide, or mitoxantrone. Such immunotherapeutic agents may include one or more of the following antineoplastic agents: (i) anti-CTLA-4 antibodies; (ii) an anti-PD-1 antibody; (iii) anti-PD-L1 antibody; (iv) anti-CD 73 antibodies; (v) anti-CD 39 antibodies; or (vi) an anti-CCR 2 antibody.

Specifically, the anti-CTLA-4 antibody is tremelimumab (as disclosed in US 6,682,736). In another aspect of the invention, specifically, the anti-CTLA-4 antibody is ipilimumab (by Bristol Myers Squib) to

Commercially available).

Specifically, the anti-PD-L1 antibody is an antibody as disclosed in US 20130034559 (MedImmune)). In another aspect of the invention, specifically, the anti-PD-L1 antibody is an antibody as disclosed in US 2010/0203056 (gene tex (Genentech)/Roche (Roche)). In another aspect of the invention, specifically, the anti-PD-L1 antibody is an antibody as disclosed in US 20090055944 (Medarex). In another aspect of the invention, specifically, the anti-PD-L1 antibody is an antibody as disclosed in US 20130323249 (sorento Therapeutics).

Specifically, the anti-PD-1 antibody is MRK-3475 (Merck). In another aspect of the invention, specifically, the anti-PD-1 antibody is nivolumab or an anti-PD-1 antibody as disclosed in WO 2006/121168 or US 8,008,449 (Medarex). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody as disclosed in WO2009/101611 (CureTech). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody as disclosed in WO2012/145493 (amplimune). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody (Wyeth)/medical immunization) as disclosed in US 7,488,802. In another aspect of the invention, specifically, the anti-PD-1 antibody is an antibody (board of Texas university, univ.of) as disclosed in US 20130280275. In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody as disclosed in WO99/42585(Agonox), WO 95/12673 and WO 95/21915.

Specifically, the anti-CD 39 antibody is IPH52 (innote Pharmaceuticals).

Specifically, anti-CD 73 antibodies are CPI-006(Corvus Pharmaceuticals) or IPH53(Innate Pharmaceuticals).

Specifically, the anti-CCR 2 antibody is promolizumab (Takeda Pharmaceuticals International Co.)) or MLN1202 (Millennium Pharmaceuticals).

According to this aspect of the present invention there is provided a combination suitable for use in the treatment of an adenosine receptor related disease, particularly cancer, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above; and any one or more of the chemotherapeutic agents listed above and/or any one or more of the immunotherapeutic agents listed under (i) - (vi) above.

For example, the compounds of the present disclosure may be provided in combination with an anti-PD 1/PD-L1 antibody. In some particular embodiments, the compounds of the present disclosure may be provided in combination with an anti-PD 1/PD-L1 antibody and further in combination with an anti-CTLA-4, CD38, CD73, or CCR2 antibody.

According to this aspect of the present disclosure there is provided a combination suitable for use in the treatment of cancer comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof; and any of the immunomodulatory or antineoplastic agents listed above.

Thus, in another aspect of the present disclosure there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulatory or chemotherapeutic agent selected from those listed above.

Herein, when the term "combination" is used, it is understood that this term refers to simultaneous, separate or sequential administration. In some embodiments, "combination" refers to simultaneous administration. In another aspect of the disclosure, "combination" refers to separate administration. In another aspect of the disclosure, "combination" refers to sequential administration. The delay in administering the second component should not be such as to lose the beneficial effect of the combination when administered sequentially or separately.

According to another aspect of the present disclosure there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulatory or antineoplastic agent selected from those listed above, in association with a pharmaceutically acceptable diluent or carrier.

According to another aspect of the present disclosure there is provided a pharmaceutical composition for use in producing an immunomodulatory or anti-cancer effect, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with an immunomodulatory or anti-neoplastic agent selected from the group consisting of the immunomodulatory or anti-neoplastic agents listed above, in association with a pharmaceutically acceptable diluent or carrier.

According to another aspect of the present disclosure there is provided a pharmaceutical composition for use in the treatment of NSCLC, RCC, prostate or breast cancer (etc.) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulatory or antineoplastic agent selected from those listed above, in association with a pharmaceutically acceptable diluent or carrier.

According to another aspect of the present disclosure, there is provided a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antineoplastic agent selected from the immunomodulators or antineoplastic agents listed above.

According to another aspect of the present disclosure, there is provided a kit comprising:

a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a first unit dosage form;

b) an immunomodulator or antineoplastic agent selected from the immunomodulators or antineoplastic agents listed above in a second unit dosage form; and

c) a container for holding the first and second dosage forms.

In addition to being useful in therapeutic medicine, the compounds of formula (I) or pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for assessing adenosine receptor activity or expression in experimental animals such as cats, dogs, rabbits, monkeys, rats, and mice, as part of the search for novel therapeutic agents.

In the above other pharmaceutical compositions, processes, methods, uses and medicament manufacturing features, alternative and preferred embodiments of the compounds of the present disclosure described herein are also applicable.

Method of treatment

The present disclosure provides a method of treating diseases associated with adenosine receptors, including, for example, a1, A2a, and/or A2b, specifically, A2a, by administering to a subject a therapeutically effective amount of one or more compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the disclosure.

As used herein, the term "adenosine receptor-associated disease" or "AR-associated disease" refers to a disease whose onset or suffering or both are associated with genomic changes, expression, overexpression, decline or activity of AR (including, e.g., a1, A2a and/or A2b, particularly A2a), as the case may be. Examples include, without limitation, inflammatory disorders, cancer, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive disorders, HIV, ADA-SCID, Acute Heart Failure (AHF) and chronic heart failure, Chronic Obstructive Pulmonary Disease (COPD), asthma, and other diseases. In certain embodiments, AR-related diseases refer to diseases that are to be treated by inhibiting the action of adenosine receptors.

In some embodiments, the AR-associated disease is cancer, preferably an AR-expressing cancer or an AR-overexpressing cancer. "AR-expressing cancer" is a cancer involving cancer cells or tumor cells having AR proteins (e.g., A2a, A1, and/or A2b) present on their cell surface. An "AR overexpressing cancer" is a cancer that has significantly higher levels of AR proteins (e.g., A2a, A1, and/or A2b) at the cell surface of the cancer or tumor cell as compared to a noncancerous cell of the same tissue type. Such overexpression may be caused by gene amplification or increased transcription or translation. Adenosine receptor expression or overexpression can be determined in a diagnostic or prognostic assay by assessing the increase in AR protein levels present on the cell surface (e.g., by immunohistochemical analysis; IHC). Alternatively or additionally, the level of nucleic acid encoding AR in the cell may be measured, for example, by fluorescence in situ hybridization (FISH; see WO98/45479 published 10.1998), southern blot or Polymerase Chain Reaction (PCR) techniques, such as real-time quantitative PCR (RT-PCR) (Methods)132:73-80 (1990)). In addition to the above assays, a variety of in vivo assays may be used by those of skill in the art. For example, cells in a patient can be exposed to an antibody, which is optionally labeled with a detectable label (e.g., a radioisotope), and binding of the antibody to the patient's cells can be assessed, e.g., by external scanning for radioactivity or by analyzing biopsies taken from patients previously exposed to the antibody.

Specifically, cancers include, without limitation, lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, lung adenocarcinoma, large cell lung cancer, squamous cell lung cancer), Renal Cell Carcinoma (RCC), prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bone cancer, uterine cancer, colon cancer, leukemia, glioblastoma, melanoma, chondrosarcoma, brain cancer, bile duct cancer, osteosarcoma, lymphoma, adenoma, myeloma, hepatocellular carcinoma, adrenocortical cancer, pancreatic cancer, bladder cancer, liver cancer, gastric cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, nasopharyngeal cancer, or oral cancer. In some embodiments, the cancer is NSCLC, RCC, prostate cancer, or breast cancer. Unless otherwise specified, the cancer as referred to herein may be at any stage. In some embodiments, the cancer is an early stage cancer. In some embodiments, the cancer is a locally advanced cancer. In some embodiments, the cancer is a locally advanced and/or metastatic cancer. In some embodiments, the cancer is an invasive cancer. In some embodiments, the cancer is a cancer that is resistant to an existing therapy.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has efficacy in treating cancer (e.g., NSCLC, RCC, prostate cancer, breast cancer). In addition, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may also be useful in the treatment of other adenosine receptor-related diseases, such as parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive disorders, HIV, ADA-SCID, AHF and chronic heart failure, Chronic Obstructive Pulmonary Disease (COPD), or asthma.

As used herein, the term "treating" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be performed after one or more symptoms have occurred. In other embodiments, treatment may be performed in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, e.g., to prevent or delay their recurrence.

A therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as provided herein will depend on various factors known in the art, such as body weight, age, past medical history, current medications, the health status and likelihood of cross-reactions, allergies, sensitivity, and adverse side effects of the individual, as well as the route of administration and the extent of disease progression. As indicated by these and other circumstances or requirements, one of skill in the art (e.g., a physician or veterinarian) may proportionately decrease or increase the dosage.

Use of compounds

In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a medicament for treating an AR-related disease. Exemplary AR-related diseases include, but are not limited to, cancer (e.g., NSCLC, RCC, prostate cancer, or breast cancer) and other diseases.

In such cases, the present disclosure also provides a method of screening for a patient suitable for treatment with a compound or pharmaceutical composition of the present disclosure, alone or in combination with other ingredients (e.g., a second active ingredient, such as an antineoplastic agent). The method comprises sequencing a tumor sample from a patient and detecting accumulation or activation of AR.

According to another aspect of the present disclosure there is thus provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use as a medicament.

According to a further aspect of the present disclosure there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the modulation of adenosine receptors in a warm-blooded animal such as man.

The term "modulating/modulating" when used in conjunction with an adenosine receptor refers to the effect or result of altering the expression, reduction and/or activity of the adenosine receptor.

According to a further aspect of the present disclosure there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of an AR-related disease in a warm-blooded animal such as man.

According to this aspect of the present disclosure there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.

According to another feature of the present disclosure there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above in the manufacture of a medicament for use in the treatment of NSCLC, RCC, prostate or breast cancer.

According to another feature of the present disclosure there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the treatment of breast cancer.

According to another feature of this aspect of the present disclosure there is provided a method of modulating adenosine receptors in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.

According to another feature of this aspect of the present disclosure there is provided a method of treating an AR-related disease in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.

According to another feature of this aspect of the present disclosure there is provided a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.

According to another feature of this aspect of the present disclosure there is provided a method of producing an anti-cancer effect in a warm-blooded animal, such as a human, in need of such treatment which comprises (1) determining whether or not the warm-blooded animal has an AR-expressing cancer, and (2) administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, if so.

According to a further feature of this aspect of the disclosure there is provided a method of treating NSCLC, RCC, prostate cancer or breast cancer in a warm-blooded animal, such as a human, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.

According to a further aspect of the present disclosure there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in modulating AR in a warm-blooded animal such as a human being.

According to a further aspect of the present disclosure there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of an AR-related disease in a warm-blooded animal such as a human being.

According to this aspect of the present disclosure there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in the production of an anti-cancer effect in a warm-blooded animal such as man.

According to another feature of the present disclosure there is provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of NSCLC, RCC, prostate or breast cancer.

Examples of the invention

The general method of the present disclosure is further illustrated below. The compounds of the present disclosure may be prepared by methods known in the art. Specific methods for preparing preferred compounds of the present disclosure are described below. However, these in no way limit the methods of preparation of the compounds of the present disclosure.

EXAMPLE 01 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- ((3-fluoropyridin-2-yl) methyl) pyrazine-2-carboxamide (Compound 01)

Scheme 01

Step 1.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid methyl ester

To a solution of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (200mg, 0.71mmol, 1 eq.) and (2, 6-dimethylpyridin-4-yl) boronic acid (214.4mg, 1.42mmol, 2 eq.) in n-BuOH (25mL) was added xPhos (67.7mg, 0.14mmol, 0.2 eq.) and Pd (OAc) ₂(31.9mg, 0.14mmol, 0.2 equiv.), K₃PO₄(301.4mg, 1.42mmol, 2 equiv.). After stirring at 100 ℃ for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂The residue was purified with MeOH 10:1) to give methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylate (230mg, 36.8%) as a yellow solid. LCMS M/z (ESI), M + ═ 339.2

Step 2.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- [ (3-fluoropyridin-2-yl) Methyl radical]Pyrazine-2-carboxamide (Compound 01)

A solution/mixture of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (215mg, 0.64mmol, 1 eq) and 1- (3-fluoropyridin-2-yl) methylamine (96.2mg, 0.76mmol, 1.20 eq), HATU (483.2mg, 1.3mmol, 2.0 eq), DIEA (246.4mg, 1.9mmol, 3.0 eq) in DMF (10mL) was stirred at 20 ℃ under an air atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 53% B to 62% B at 7min Internal; 220/254 nm; rt: 6.1min) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- [ (3-fluoropyridin-2-yl) methyl as a pale yellow solid]Pyrazine-2-carboxamide (compound 01) (83.3mg, 29.3%). LCMS M/z (ESI), M⁺＝447.2。¹H NMR (400MHz, methanol-d)₄):δ2.4(s,6H),4.8(d,J＝1.7Hz,2H),7.1-7.2(m,4H),7.4(dt,J＝8.6,4.4Hz,1H),7.4-7.5(m,2H),7.6(ddd,J＝9.9,8.4,1.3Hz,1H),8.4(dt,J＝4.8,1.4Hz,1H)。

EXAMPLE 02 preparation of 3-amino-N- [ (2, 6-difluorophenyl) methyl ] -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxamide (Compound 02)

Scheme 02

Step 1.6-chloro-3-methyl-5- (5-methylfuran-3-yl) pyrazine-2-carboxylic acid methyl ester

Methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (1g, 4.5mmol, 1 eq.) and (5-methylfuran-2-yl) boronic acid (0.6g, 4.8mmol) and Pd (dppf) Cl₂(0.3g, 0.5mmol) and Na₂CO₃(1.0g, 9.0mmol) in bis

alkane/H₂The mixture in O (40mL) was stirred at 90 ℃ for 4 hours under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM: MeOH (1:1) (3X 10 mL). By CH₂Cl₂The filtrate was extracted (3X 10 mL). Then passing through Na₂SO₄The organic layer was dried and the solution was concentrated under reduced pressure. By preparative HPLC with the following Conditions (CH)₂Cl₂EtOAc (1:1)) to purify the crude product, yielding methyl 6-chloro-3-methyl-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (125mg, 7.1%) as a yellow solid. LCMS M/z (ESI), [ M + H ]⁺＝268.2。

Step 2.3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-base) Pyrazine-2-carboxylic acid methyl ester

Methyl 6-chloro-3-methyl-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (65mg, 0.24mmol, 1 eq.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (56.4mg, 0.24mmol, 1.00 eq.) and Pd (dppf) Cl₂(17.5mg, 0.024mmol, 0.10 eq.) and Na₂CO₃ ₍50.88mg, 0.48mmol, 2 equivalents) of beta-cyclodextrin in ethylene glycol

alkane/H₂The mixture in O (6/1, 3mL) was stirred at 90 ℃ under a nitrogen atmosphere for 10 hours. Filtering the resulting mixture with CH₂Cl₂MeOH (1:1) (3X 10mL) washed the filter cake. Using 20mL of H₂O washing the filtrate and CH₂Cl₂(3X 20mL) was extracted. With Na₂SO₄The aqueous layer was dried and concentrated under reduced pressure. The residue was then dissolved in ethyl acetate (10 mL). The precipitated solid was collected by filtration and washed with diethyl ether (3 × 3mL), and the resulting solid was dried in vacuo to give methyl 3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (55mg, 63.2%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝341.2。

Step 3.3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) Pyrazine-2-carboxylic acid

Methyl 3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (90mg, 0.3mmol, 1 eq) was in MeOH (9mL) and 1mL was taken for reaction. LiOH (25.2mg, 1.1mmol, 4.0 equiv.) and H were combined at 0 deg.C₂O (1.8mL) was added to the solution and stirred at room temperature for 6 hours. The mixture was basified to pH 6 with HCl (aqueous solution). The solution was concentrated under reduced pressure and 3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) pyrazine-2-carboxylic acid was obtained as a yellow solid (85mg, 96.6%). LCMS M/z (ESI), [ M + H]⁺＝327.1。

Step 4.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- (1-methyl-6-oxo-1, 6-dihydropyridine-3- Yl) -5- (5-Methylfuran-2-yl) pyrazine-2-carboxamide (Compound 02)

To a stirred solution of 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid (80mg, 0.3mmol, 1 equiv.) and DIEA (116.1mg, 0.9mmol, 3.00 equiv.) in DMSO (4mL) was added HAUT (342mg, 0.9mmol, 3.0 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 10 min. 1- (2, 6-difluorophenyl) methylamine (107.3mg, 0.75mmol, 2.5 equivalents) was then added dropwise and stirred at room temperature for 10 hours. The reaction was quenched by the addition of brine (30mL) at room temperature. The resulting solid was collected by filtration and passed through preparative TLC (CH) ₂Cl₂EtOAc 1:1) to give 30mg of crude product, which was purified by preparative HPLC (column: XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (10MMOL/L NH)₄HCO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 37% B to 37% B within 8 min; 220,254 nm; rt: 7.33min) to yield 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxamide (compound 02) (7.4mg, 6.49%). LCMS M/z (ESI) [ M + H ]]⁺＝452.3。¹H NMR (400MHz, methanol-d)₄)δ2.25(s,3H),3.64(s,3H),4.70(s,2H),6.18(d,J＝3.4Hz,1H),6.55(d,J＝9.2Hz,1H),6.81(d,J＝3.3Hz,1H),6.98(t,J＝7.9Hz,2H),7.39-7.28(m,1H),7.52(dd,J＝9.2,2.5Hz,1H),7.92(d,J＝2.5Hz,1H)。

Example 04: preparation of N- ((3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-yl) pyrazin-2-yl) methyl) -2, 6-difluorobenzamide (Compound 04)

Scheme 3

Step 1.3-amino-5-chloro-6- (5-methylfuran-2-yl) pyrazine-2-carbonitrile

3-amino-5, 6-dichloropyrazine-2-carbonitrile (250mg, 1.3mmol, 1 eq.) and (5-methylfuran-2-yl) boronic acid (166.6mg, 1.3mmol, 1.00 eq.) and Pd (dppf) Cl₂(96.8mg, 0.1mmol, 0.1 equiv.) and Na₂CO₃(280.4mg, 2.7mmol, 2 equiv.) in II

alkane/H₂The mixture in O (15mL) was stirred at 70 ℃ under a nitrogen atmosphere for 6 hours.

Filtering the resulting mixture with CH ₂Cl₂MeOH (1:1) (3X 10mL) washed the filter cake. Using 20mL of H₂O washing the filtrate and CH₂Cl₂(3X 20mL) was extracted. Through Na₂SO₄The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE (CH)₂Cl₂EtOAc (1:1)) (1:1) elution afforded 3-amino-5-chloro-6- (5-methylfuran-2-yl) pyrazine-2-carbonitrile as a yellow solid (130mg, 28.9%). LCMS M/z (ESI), [ M + H]⁺＝235.1。

Step 2.3- (aminomethyl) -6-chloro-5- (5-methylfuran-2-yl) pyrazin-2-amine

A mixture of 3-amino-5-chloro-6- (5-methylfuran-2-yl) pyrazine-2-carbonitrile (240mg, 1.0mmol, 1 eq) in THF (12mL) was stirred, and DMSB (155.4mg, 2.1mmol, 2.0 eq) was slowly added to the mixed solution at 0 ℃ and stirred at room temperature for 6 hours. By adding H at 0 deg.C₂The reaction was quenched with O (2mL) followed by the addition of Na₂CO₃The solution was stirred at room temperature for 30min to give 3- (aminomethyl) -6-chloro-5- (5-methylfuran-2-yl) pyrazin-2-amine (240mg, 96.34%) as a yellow liquid. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝239.2。

Step 3.N- [ [ 3-amino-5-chloro-6- (5-methylfuran-3-yl) pyrazin-2-yl]Methyl radical]Carbamic acid tert-butyl ester Esters

At room temperature toTo a solution of 3- (aminomethyl) -6-chloro-5- (5-methylfuran-2-yl) pyrazin-2-amine (238mg, 1.0mmol, 1.0 equiv.) in DCM (10mL) was added (BOC) ₂O (438.9mg, 2.0mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 10 hours. The resulting mixture was quenched with water (20mL) and CH₂Cl₂(3X 20mL) was extracted. By H₂The combined organic layers were washed with O (3X 10mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and N- [ [ 3-amino-5-chloro-6- (5-methylfuran-3-yl) pyrazin-2-yl) was obtained as a yellow solid]Methyl radical]Tert-butyl carbamate (150mg, 41.83%). LCMS M/z (ESI), [ M + H]⁺＝339.2。

Step 4.N- [ [ 3-amino-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (5-methylfuran-3- Radical) pyrazin-2-yl]Methyl radical]Carbamic acid tert-butyl ester

Reacting N- [ [ 3-amino-5-chloro-6- (5-methylfuran-3-yl) pyrazin-2-yl]Methyl radical]Tert-butyl carbamate (120mg, 0.34mmol, 1 eq.) was added to the di-tert-butyl carbamate

alkane/H₂In O (10mL), then in N₂1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (124.9mg, 0.5mmol, 1.50 equiv.) and Pd (dppf) Cl were added next₂(25.9mg, 0.1mmol) and Na₂CO₃(75.1mg, 0.7mmol, 2 equiv.) and stirred at 90 ℃ under nitrogen atmosphere for 10 hours. The reaction solution was concentrated and passed through preparative TLC (CH)₂Cl₂EtOAc 1:1) purification to yield N- [ [ 3-amino-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (5-methylfuran-3-yl) pyrazin-2-yl) as a yellow solid ]Methyl radical]Tert-butyl carbamate (35mg, 23.53%). LCMS M/z (ESI), [ M + H]⁺＝412.3。

Step 5.5- [ 6-amino-5- (aminomethyl) -3- (5-methylfuran-3-yl) pyrazin-2-yl]-1-methyl-1, 2- Dihydropyridin-2-ones

Reacting N- [ [ 3-amino-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (5-methylfuran-3-yl) pyrazin-2-yl]Methyl radical]Tert-butyl carbamate (120mg, 1 eq) was added to DCM (5mL) and TFA (2.5 mL). The resulting solution was stirred at room temperature under an air atmosphere for 10 hours. With saturated Na₂CO₃(aqueous solution) the mixture was acidified to pH 7. By CH₂Cl₂The resulting mixture was extracted (3X 30 mL). By H₂The combined organic layers were washed with O (2X 10mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives 5- [ 6-amino-5- (aminomethyl) -3- (5-methylfuran-3-yl) pyrazin-2-yl as a yellow solid]-1-methyl-1, 2-dihydropyridin-2-one (80mg, 84.58%). LCMS M/z (ESI), [ M + H]⁺＝312.2。

Step 6.N- ((3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-) Yl) pyrazin-2-yl) methyl) -2, 6-difluorobenzamide (compound 04)

To 5- [ 6-amino-5- (aminomethyl) -3- (5-methylfuran-3-yl) pyrazin-2-yl at room temperature under an air atmosphere]To a stirred solution of-1-methyl-1, 2-dihydropyridin-2-one (80mg, 0.26mmol, 1 equiv.) and 2, 6-difluorobenzoic acid (60.9mg, 0.39mmol, 1.5 equiv.) in DMSO (1mL) was added HAUT (197mg, 0.52mmol, 2.0 equiv.) and DIEA (67mg, 0.52mmol, 2.0 equiv.) in portions. The resulting solution was stirred at room temperature for 10 hours. The resulting mixture was quenched with brine (20mL) and CH ₂Cl₂The aqueous solution was extracted (3X 10 mL). Through anhydrous Na₂SO₄The organic layer was dried, filtered and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC (DCM: MeOH ═ 20:1) to give N- [ [ 3-amino-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (5-methylfuran-3-yl) pyrazin-2-yl) as a light yellow solid]Methyl radical]-2, 6-difluorobenzamide (compound 04) (112mg, 93.7%). LCMS M/z (ESI) [ M + H ]]⁺＝452.2。¹H NMR (400MHz, methanol-d)₄)δ2.22-2.33(m,3H),3.36(s,14H),3.63(s,3H),4.66(s,2H),6.12-6.20(m,1H),6.67(d,J＝3.3Hz,1H),7.09(t,J＝8.2Hz,2H),7.41-7.58(m,2H),7.85(d,J＝2.6Hz,1H)。

Example 05: 3-amino-N- (2, 6-difluorobenzyl) -6- (2, 6-dimethylpyridine-4-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 05)

Scheme 4

Step 1.3-amino-6-chloro-5-, (

Azol-2-yl) pyrazine-2-carboxylic acid methyl ester

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (500mg, 2.25mol, 1 eq) and 2- (tributylstannyl) -1,3-

Oxazole (806.5mg, 2.25mol, 1.00 eq) in 1, 4-bis

To a stirred solution in an alkane (20mL) were added LiCl (190.9mg, 4.50mmol, 2 equiv.), tricyclohexylphosphine (126.3mg, 0.45mmol, 0.2 equiv.) and Pd in portions₂(dba)₃.CHCl₃(466.2mg, 0.45mmol, 0.20 equiv.). The resulting mixture was stirred with microwave stimulation at 140 ℃ under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH) ₂Cl₂MeOH 20:1) to give 3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (160mg, 27.9%). LCMS M/z (ESI), [ M + H]⁺＝255.1。

Step 2.3-amino-6-chloro-5-, (

Azol-2-yl) pyrazine-2-carboxylic acid

To 3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (100mg, 0.4mmol, 1 eq) to a stirred solution in MeOH (10mL) and water (1mL) was added lioh₂O (49.4mg, 1.2mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH/water, 10% to 50% gradient over 35 min; detector, UV 254nm, to give 3-amino-6-chloro-5- (1, 3-) as a yellow solid

Oxazol-2-yl) pyrazine-2-carboxylic acid (50mg, 52.9%). LCMS M/z (ESI), [ M + H]⁺＝241.1，¹H NMR(300MHz,DMSO-d₆)δ7.50(d,J＝0.8Hz,1H),8.34(d,J＝0.8Hz,1H)。

Step 3.3-amino-6-chloro-N- (2, 6-difluorobenzyl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

3-amino-6-chloro-5- (1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.62mmol, 1 equiv.) and DIEA (241.7mg, 1.87mmol, 3 equiv.) in DMSO (10mL) was added 1- (2, 6-difluorophenyl) methylamine (133.9mg, 0.94mmol, 1.50 equiv.) and HATU (355.6mg, 0.94mmol, 1.5 equiv.) in portions. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH) ₂Cl₂The residue was purified with MeOH 20:1) to give 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] as a yellow solid]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 05) (140mg, 48.51%). LCMS M/z (ESI), [ M + H]⁺＝366.1，¹H NMR(300MHz,DMSO-d₆)δ9.10(t,J＝5.7Hz,1H),8.42(s,1H),7.88(s,2H),7.58(s,1H),7.49-7.28(m,1H),7.10(t,J＝8.0Hz,2H),4.57(d,J＝5.8Hz,2H)。

Step 4.3-amino-N- (2, 6-difluorobenzyl) -6- (2, 6-dimethylpyridin-4-yl) -5-, (

Oxazole-2- Yl) pyrazine-2-carboxamide (Compound 05)

To (2, 6-dimethylpyridin-4-yl) boronic acid (82.6mg, 550mmol, 2.00 equivalents) and 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl at room temperature under a nitrogen atmosphere]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (100mg, 270mmol, 1 eq) in dioxane

To a stirred mixture in an alkane (10mL) was added Pd (dppf) Cl in portions₂CH₂Cl₂(44.7mg, 0.05mmol, 0.2 eq.) and K₃PO₄₍232.2mg, 1.09mmol, 4 equivalents). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere overnight. The resulting mixture was concentrated in vacuo. By preparative TLC (CH)₂Cl₂The residue was purified with MeOH 20:1) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- (2, 6-dimethylpyridin-4-yl) -5- (1, 3-)

Oxazol-2-yl) pyrazine-2-carboxamide (compound 05) (40mg, 33.2%). LCMS M/z (ESI), [ M + H]⁺＝437.3；¹H NMR(300MHz,DMSO-d₆)δ9.12(t,J＝5.8Hz,1H),8.26(s,1H),7.95(s,2H),7.46-7.31(m,2H),7.09(t,J＝8.0Hz,2H),7.00(s,2H),4.62(d,J＝5.9Hz,2H),2.40(s,6H)。

The compounds listed in the table below were prepared using the method described for compound 05.

EXAMPLE 06.3-amino-N- (2, 6-difluorobenzyl) -6- (2, 6-dimethyl (N-morpholinyl)) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 06)

Scheme 5

Step 1.3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group]-5- (4-fluorophenyl) pyrazine-2-carboxamide

A solution/mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (1.2g, 4.48mmol, 1 equiv.) and 1- (2, 6-difluorophenyl) methylamine (1.0g, 6.99mmol, 1.56 equiv.) in DMF (25mL) was stirred at 15 ℃ under an air atmosphere for 2 h. The resulting mixture was washed with 3 x 10 volumes of water. The precipitated solid was collected by filtration and washed with diethyl ether (3X 10mL) to give 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group as a brown yellow solid]-5- (4-fluorophenyl) pyrazine-2-carboxamide (1.3g, 73.82%). LCMS M/z (ESI), [ M + H]⁺＝393.2。

Step 2.N- [ (tert-butoxy) carbonyl]-N- (5-chloro-3- [ [ (2, 6-difluorophenyl) methyl ] methyl]Carbamoyl radical]-6- (4-fluorophenyl) pyrazin-2-yl) carbamic acid tert-butyl ester

N- [ (tert-butoxy) carbonyl group was added to a 40mL sealed tube at room temperature]-N- (3- [ [ (2, 6-difluorophenyl) methyl group]Carbamoyl radical]A solution of tert-butyl-5- (2, 6-dimethylmorpholin-4-yl) -6- (4-methylphenyl) pyrazin-2-yl) carbamate (500mg, 1.27mmol, 1 eq), DMAP (13mg, 0.127mmol, 0.1 eq) and di-tert-butyl dicarbonate (687mg, 3.18mmol, 2.5 eq) in DCM (30 mL). The resulting solution was stirred at room temperature For 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:2) to give N- [ (tert-butoxy) carbonyl as a yellow solid]-N- (5-chloro-3- [ [ (2, 6-difluorophenyl) methyl ] methyl]Carbamoyl radical]-tert-butyl 6- (4-fluorophenyl) pyrazin-2-yl) carbamate (600mg, 79%). LCMS M/z (ESI), [ M + H]⁺＝593.3

Step 3.N- [ (tert-butoxy) carbonyl]-N- (3- [ [ (2, 6-difluorophenyl) methyl group]Carbamoyl radical]-5-(2,6- Preparation of dimethylmorpholin-4-yl) -6- (4-fluorophenyl) pyrazin-2-yl) carbamic acid tert-butyl ester

N- [ (tert-butoxy) carbonyl group was added to a 10mL sealed test tube at 100 ℃]-N- (5-chloro-3- [ [ (2, 6-difluorophenyl) methyl ] methyl]Carbamoyl radical]-tert-butyl 6- (4-fluorophenyl) pyrazin-2-yl) carbamate (230mg, 0.39mmol, 1 equiv.), 2, 6-dimethylmorpholine (134.0mg, 1.16mmol, 3 equiv.), Cs₂CO₃(252.7mg, 0.78mmol, 2 equiv.), 2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl (RuPhos) (36.2mg, 0.08mmol, 0.2 equiv.), 3 rd generation methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos-Palladacycle Gen.3) (32.4mg, 0.04mmol, 0.1 equiv.), and toluene (15mL) for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:2) to give N- [ (tert-butoxy) carbonyl as a yellow solid ]-N- (3- [ [ (2, 6-difluorophenyl) methyl group]Carbamoyl radical]Tert-butyl 5- (2, 6-dimethylmorpholin-4-yl) -6- (4-fluorophenyl) pyrazin-2-yl) carbamate (30mg, 11.51%). LCMS M/z (ESI), [ M-Boc + H]⁺＝572.3。

Step 4.3-amino-N- (2, 6-difluorobenzyl) -6- (2, 6-dimethyl (N-morpholinyl)) -5- (4-fluorobenzene) Yl) pyrazine-2-carboxamide (Compound 06)

N- [ (tert-butoxy) carbonyl was added to a 50mL round-bottom flask at room temperature]-N- (3- [ [ (2, 6-difluorophenyl) methyl group]Carbamoyl radical]A solution of tert-butyl-5- (2, 6-dimethylmorpholin-4-yl) -6- (4-methylphenyl) pyrazin-2-yl) carbamate (50mg, 0.07mmol, 1 eq) and TFA (2mL) in DCM (10 mL). The resulting mixture was decompressedAnd (5) concentrating. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)₄HCOO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 78% B to 78% B within 7 min; 220/254 nm; rt: 6.68min) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- (2, 6-dimethylmorpholin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 06) (2mg, 5.6%). LCMS M/z (ESI), [ M + H]⁺＝472.3。¹H(300MHz,DMSO-d₆)δ1.08(6H,s),2.35(2H,t),3.03(2H,d),3.60(2H,d),4.60(2H,d),7.03-7.15(4H,m),7.29(2H,t),7.39(1H,q),8.07(2H,t),8.57(1H,t)。

EXAMPLE 07. preparation of N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl ] methyl ] -2-fluoro-6- (trifluoromethyl) benzamide (Compound 07)

Scheme 6

Step 1.3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine

To a mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (500mg, 2.0mmol, 1 eq) in MeOH (100mL) was added NH portionwise₄OH (2mL) and Raney nickel (10mg, 0.1mmol, 0.1 equiv.). The mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. This gave 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (560mg, 87.1%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝253.1。

Step 2.N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzene Carboxamides

To a mixture of 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (210mg, 0.8mmol, 1 eq) and 2-fluoro-6- (trifluoromethyl) benzoic acid (259.4mg, 1.3mmol,1.5 equiv.) to a mixture in DCM (5mL) was added HATU (632.0mg, 1.7mmol, 2 equiv.) and Et in portions₃N (252.3mg, 2.5mmol, 3 equiv.). The mixture was stirred at room temperature under an air atmosphere for 4 hours and quenched with water (10 mL). By CH₂Cl₂The resulting mixture was extracted (3X 20 mL). By H₂The combined organic layers were washed with O (3X 10mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subsequently purified by preparative TLC (PE/EtOAc 2:1) to give N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] as a yellow solid ]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzamide (457mg, 49.7%). LCMS M/z (ESI), [ M + H]⁺＝443.1。

Step 3.N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyri dine Oxazin-2-yl]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzamide (compound 07)

To N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] under a nitrogen atmosphere]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzamide (90mg, 200mmol, 1 eq) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (167.3mg, 0.7mmol, 3.5 eq) in bis

alkane/H₂Pd (dppf) Cl was added in portions to a mixture in O (10mL)₂(44.6mg, 0.06mmol, 0.30 equiv.) and K₃PO₄(258.9mg, 1.2mmol, 6.0 equiv.). The mixture was stirred at 110 ℃ under a nitrogen atmosphere for 10 hours and concentrated in vacuo. The resulting residue was purified by preparative TLC (PE/EtOAc 5:4) to give a residue product, followed by preparative HPLC (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)₄HCOO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 34% B to 54% B within 7 min; 220/254 nm; rt: 7.08min) to give N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) as a white solid Pyrazin-2-yl radicals]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzamide (compound 07) (29mg, 27.1%). LCMS M/z (ESI) [ M + H ]]⁺＝516.1。¹H NMR (400MHz, methanol-d)₄)δ3.53(s,2H),4.71(s,1H),6.37(d,J＝9.4Hz,1H),7.13(t,J＝8.8Hz,2H),7.31(dd,J＝9.4,2.6Hz,1H),7.53(dt,J＝8.8,6.0Hz,2H),7.63(d,J＝7.6Hz,1H),7.66-7.71(m,1H),7.76(d,J＝2.5Hz,1H)。

Example 08.

Preparation of N- [ [ 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl ] methyl ] pyridine-2-carboxamide (Compound 08)

Scheme 7

Step 1.3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine

3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (500mg, 2.0mmol, 1 eq) was added to MeOH (100mL) and NH was added₄OH (2mL), followed by slow addition of raney nickel (10mg, 0.1mmol, 0.1 equiv) to the above mixture and stirring at room temperature under a hydrogen atmosphere for 10 h. The resulting mixture was concentrated under reduced pressure. This gave 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (560mg, 87.1%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝253.2。

Step 2.N- [ [ 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl]Methyl radical] Pyridine-2-carboxamides

A mixture of 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (45mg, 0.2mmol, 1 eq.) and pyridine-2-carboxylic acid (32.9mg, 0.3mmol, 1.5 eq.) and HAUT (135.4mg, 0.4mmol, 2.0 eq.) and TEA (60.9mg, 0.5mmol, 3.0 eq.) in DCM (3mL) was stirred at room temperature under an air atmosphere for 4 hours.

The resulting mixture was quenched with water (10mL) and CH₂Cl₂(3X 20mL) was extracted. By H₂O (3X 10mL) washes the combined organicsLayer of anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subsequently purified by preparative TLC (PE/EtOAc 1:2) to give N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] as a yellow solid]Methyl radical]Pyridine-2-carboxamide (53mg, 79.02%). LCMS M/z (ESI), [ M + H]⁺＝358.2。

Step 3.N- [ [ 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl]Methyl radical] Preparation of pyridine-2-carboxamide (Compound 08)

To N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] under a nitrogen atmosphere]Methyl radical]Pyridine-2-carboxamide (25mg, 0.1mmol, 1 equiv.) and (2, 6-dimethylpyridin-4-yl) boronic acid (16.2mg, 0.1mmol, 1.5 equiv.) in dioxane

alkane/H₂To the mixture in O (2.0mL) was added Pd (dppf) Cl₂(5.1mg, 0.01mmol, 0.1 equiv.) and K₃PO₄(44.5mg, 0.21mmol, 3 equiv.). The mixture was stirred at 90 ℃ under a nitrogen atmosphere for 10 hours. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give the residue product, followed by preparative HPLC (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH) ₄HCOO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 36% B to 64% B within 7 min; 220/254 nm; rt: 6.97min) to give N- [ [ 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl) -as a white solid]Methyl radical]Pyridine-2-carboxamide (Compound 08) (6.7mg, 9.4%). LCMS M/z (ESI) [ M + H ]]⁺＝429.2。¹H NMR (400MHz, methanol-d)₄)δ2.37(s,4H),4.74(s,1H),7.01-7.20(m,2H),7.43(s,1H),7.60(s,1H),8.02(d,J＝7.9Hz,1H),8.18(d,J＝7.8Hz,1H),8.69(s,1H)。

Example 09.3 preparation of amino-N- [ [6- (dimethylamino) pyridin-2-yl ] methyl ] -6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 09)

Scheme 8

Step 1.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid

To a solution of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (1g, 3.55mol, 1 eq) and (2, 6-dimethylpyridin-4-yl) boronic acid (1.1g, 7.3mol, 2.1 eq) in n-BuOH (25mL) under a nitrogen atmosphere was added x-Phos (0.3g, 0.7mmol, 0.2 eq) and Pd (OAc)₂(0.2g, 0.7mmol, 0.2 equiv.), K₃PO₄(301.4mg, 1.42mmol, 2 equiv.). The mixture was stirred at 100 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂/MeOH 10:1) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid as a yellow solid (400mg, 33.30%). LCMS M/z (ESI), [ M + H ]⁺＝339.0。

Step 2.3-amino-N- [ [6- (dimethylamino) pyridin-2-yl]Methyl radical]-6- (2, 6-dimethylpyridine-4-) Yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 09)

To a solution of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (150mg, 0.4mmol, 1 eq), 6- (aminomethyl) -N, N-dimethylpyridin-2-amine (134.1mg, 0.9mmol, 2.0 eq), HATU (337.1mg, 0.9mmol, 2 eq) in DMF (5mL) was added DIEA (171.9mg, 1.3mmol, 3 eq) dropwise over 1min at 15 ℃. The resulting mixture was stirred at 15 ℃ for a further 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃ H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 49% B to 69% B within 7 min; 254/220 nm; rt: 5.8min) to give 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl ] as a pale yellow solid]Methyl radical]-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 09) (39.0mg, 18.6%). LCMS M/z (ESI), [ M + H]⁺＝472.3，¹H NMR(400MHz,DMSO-d₆)δ2.33(s,6H),2.97(s,6H),4.48(d,J＝5.6Hz,2H),6.52(dd,J＝10.2,7.9Hz,2H),6.99(s,2H),7.16-7.26(m,2H),7.37-7.51(m,3H),9.20(t,J＝5.7Hz,1H)。

Example 11.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) -N- ((3- (trifluoromethyl) pyridin-2-yl) methyl) pyrazine-2-carboxamide (Compound 11)

Scheme 9

Step 1.3-amino-6-chloro-5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid

To 3-amino-6-chloro-5- (1, 3-)

To a solution of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (400mg, 1.57mmol, 1 eq) in MeOH (2mL) and THF (8mL) was added lioh₂O (131.8mg, 3.14mmol, 2 equiv.). The resulting mixture was stirred at 40 ℃ under a nitrogen atmosphere for 2 hours. With HCl.H₂O adjust the mixture to pH 8. The solvent was removed under reduced pressure. The residue was provided with 3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (350mg, 92.6%). LCMS M/z (ESI), [ M + H]⁺＝241.1，¹H NMR:(300MHz,DMSO-d₆)δ7.60(s,1H),7.76(s,2H),8.44(s,1H),13.68(s,1H)。

Step 2.3-amino-6-chloro-5- (1,3-

Azol-2-yl) -N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical] Pyrazine-2-carboxamides

To 3-amino-6-chloro-5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.62mmol, 1 eq) in DCM (15mL) was added 1- [3- (trifluoromethyl) pyridin-2-yl in portions]Methylamine (219.6mg, 1.25mmol, 2 equiv.), HOBT (168.5mg, 1.25mmol, 2 equiv.), and EDC.HCl (239.0mg, 1.25mmol, 2 equiv.) for 5 min. The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 3-amino-6-chloro-5- (1, 3-) as a yellow solid

Azol-2-yl) -N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (20mg, 8.1%). LCMS M/z (ESI), [ M + H]⁺＝399.1；¹H NMR:(300MHz,MeOD)δ4.93(s,2H),7.53(d,2H),8.19(m,2H),8.83(d,1H)。

Step 3.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) - N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamides (Compound 11)

To 3-amino-6-chloro-5- (1, 3-)

Azol-2-yl) -N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (20mg, 0.05mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyrazinePyridin-2-one (23.6mg, 0.10mmol, 2.00 equiv.) in 1, 4-bis

Pd (dppf) Cl was added in portions to a mixture in an alkane (5mL)₂(7.3mg, 0.01mmol, 0.20 equiv.) and Cs₂CO₃(32.7mg, 0.10mmol, 2 equiv.). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 min. The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 2 hours and concentrated in vacuo. By preparative HPLC with the following conditions (column: Xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10 MMOL/LNH)₄HCOO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 30% B to 40% B within 7 min; 254,220 nm; rt: 6.55min) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) -N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 11) (2mg, 8.5%). LCMS M/z (ESI), [ M + H]⁺＝472.3，¹H NMR:(300MHz,MeOD)δ3.66(s,3H),4.95(s,2H),6.55(d,1H),7.39(d,1H),7.54(m,2H),8.07(m,2H),8.19(d,1H),8.79(d,1H)。

EXAMPLE 13 preparation of 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl ] methyl ] -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 13)

Scheme 10

And (1). 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl- Preparation of 6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide

3-amino-6-chloro-5- (4-fluorophenyl) pyridine at 15 ℃ in air atmosphereTo a stirred mixture of oxazine-2-carboxylic acid (350mg, 1.308mmol, 1 eq) and 6- (aminomethyl) -N, N-dimethylpyridin-2-amine (296.62mg, 1.962mmol, 1.5 eq) in DMF (20mL) was added HATU (994.47mg, 2.615mmol, 2 eq) and DIEA (338.03mg, 2.615mmol, 2 eq) portionwise. The resulting mixture was stirred for 3 hours and quenched with 50mL of water. The resulting solid was collected by filtration and dried under reduced pressure to give 3-amino-6-chloro-N- [ [6- (dimethylamino) pyridin-2-yl ] as a pale yellow solid]Methyl radical]-5- (4-fluorophenyl) pyrazine-2-carboxamide (300mg, 57.23%). LCMS M/z (ESI), [ M + H]⁺＝401.2。

Step 2.3-amino-N- [ [6- (dimethylamino) pyridin-2-yl ]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl- Preparation of 6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 13)

To 3-amino-6-chloro-N- [ [6- (dimethylamino) pyridin-2-yl ] amine under a nitrogen atmosphere]Methyl radical]-5- (4-fluorophenyl) pyrazine-2-carboxamide (50mg, 0.12mmol, 1 equiv.) and (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) boronic acid (28.6mg, 0.19mmol, 1.50 equiv.) in water (0.2mL) and bis

Addition of Cs to a solution in alkane (1.8mL)₂CO₃(81.3mg, 0.25mmol, 2 equiv.) and Pd (dppf) Cl₂(9.1mg, 0.01mmol, 0.1 eq.) the resulting mixture was stirred at 90 ℃ under nitrogen for 2 h and concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃ H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 40% B to 48% B within 7 min; 254/220 nm; rt: 5.37min) to give 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl ] as a pale yellow solid]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 13) (12mg, 20.3%).

LCMS:m/z(ESI),[M+H]⁺＝474.2，¹H NMR(400MHz,DMSO-d₆)δ3.0(s,5H),3.4(s,2H),4.5(d,J＝5.9Hz,1H),6.2(d,J＝9.3Hz,1H),6.4-6.5(m,1H),7.3(t,J＝8.8Hz,1H),7.5(t,J＝7.9Hz,1H),7.5(t,J＝7.1Hz,2H),7.9(d,J＝2.5Hz,1H),9.3(s,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 13.

Example 14.3-amino-N- ((3-fluoropyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 14)

Scheme 11

And (1).3- ((di-tert-butoxycarbonyl) amino) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) - 5-(

Azol-2-yl) pyrazine-2-carboxylic acid methyl ester

3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (80mg, 0.2mmol, 1 eq.) and (Boc)₂To a stirred mixture of O (160.0mg, 0.7mmol, 3.0 equiv.) in DCM (2mL) was added DMAP (5.97mg, 0.049mmol, 0.2 equiv.) portionwise. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 20:1) to give 3- [ bis [ (tert-butoxy) carbonyl ] as a pale yellow oil]Amino group]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (84mg, 65.2%). LCMS M/z (ESI), [ M + H]⁺＝528。

And 2. step 2.3- ((di-tert-butoxycarbonyl) amino) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) - 5-(

Azol-2-ylPyrazine-2-carboxylic acid

To 3- [ bis [ (tert-butoxy) carbonyl ] group at room temperature under an air atmosphere ]Amino group]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (84mg, 0.2mmol, 1 eq) in MeOH (5mL) was added LiOH (7.6mg, 0.3mmol, 2 eq) portionwise. The resulting mixture was stirred at 50 ℃ for a further 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 20:1) to give 3- [ bis [ (tert-butoxy) carbonyl ] as a yellow solid]Amino group]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (75mg, 91.7%). LCMS M/z (ESI), [ M + H]⁺＝514.1。

And 3. step 3.(3- (((3-fluoropyridin-2-yl) methyl) carbamoyl) -5- (1-methyl-6-oxo-1, 6-dihydro Pyridin-3-yl) -6-, (

Azol-2-yl) pyrazin-2-yl) carbamic acid di-tert-butyl ester

To 3- [ bis [ (tert-butoxy) carbonyl ] group at room temperature under an air atmosphere]Amino group]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (81mg, 0.16mmol, 1 mmAmount) and 1- (3-fluoropyridin-2-yl) methylamine (39.8mg, 0.3mmol, 2.0 equivalents) to a stirred mixture of DMF (2mL) was added HATU (120.0mg, 0.3mmol, 2 equivalents) and DIEA (61.2mg, 0.47mmol, 3 equivalents) portionwise. The resulting mixture was stirred at room temperature for another 6 hours. The resulting mixture was quenched with water (20mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with water (3X 50mL) and anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives N- [ (tert-butoxy) carbonyl as a yellow solid]-N- (3- [ [ (3-fluoropyridin-2-yl) methyl)]Carbamoyl radical]-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (1,3-

Oxazol-2-yl) pyrazin-2-yl) carbamic acid tert-butyl ester (80mg, 81.6%) which was used directly in the next step without further purification. LCMS M/z (ESI), [ M-Boc + H]⁺＝522.3。

And 4. step 4.3-amino-N- ((3-fluoropyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 14)

To N- [ (tert-butoxy) carbonyl group at room temperature under an air atmosphere]-N- (3- [ [ (3-fluoropyridin-2-yl) methyl)]Carbamoyl radical]-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (1,3-

Oxazol-2-yl) pyrazin-2-yl) carbamic acid tert-butyl ester (70mg, 0.11mmol, 1 equiv.) and TFA (2mL) were added in portions to a stirred solution/mixture in DCM (2 mL). The resulting mixture was stirred at room temperature for a further 0.5 h. The resulting mixture was concentrated under reduced pressure. The residual was dispersed in MeOH (4mL) NH was added portionwise at room temperature under an air atmosphere₃.H₂O (4mL). The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (4mL). The residue was purified by preparative TLC (DCM/MeOH 20:1) to give 3-amino-N- [ (3-fluoropyridin-2-yl) methyl) as a yellow solid ]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 14) (22mg, 45.9%). LCMS M/z (ESI), [ M + H]⁺＝422.2。¹H NMR(DMSO-d₆,400MHz)δ3.5(3H,s),4.7(2H,dd),6.3(1H,d),7.3-7.5(3H,m),7.7-7.9(3H,m),8.0(1H,d),8.3(1H,s),8.4(1H,dt),9.3(1H,t)。

Example 15.3-amino-N- [ [6- (dimethylamino) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 15)

Scheme 12

Step 1.6- (dimethylamino) pyridine-2-carbonitrile

To a solution of 6-bromopyridine-2-carbonitrile (2g, 10.9mmol, 1 eq) in THF (25mL) was added dimethylamine (3.0g, 65.6mmol, 6 eq). The solution was stirred at 80 ℃ for 12 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (5:1) to give 6- (dimethylamino) pyridine-2-carbonitrile as a light yellow solid (1.1g, 68.4%). LCMS M/z (ESI), [ M + H]⁺＝148.2

Step 2.6- (aminomethyl) -N, N-dimethylpyridin-2-amine

To a solution of 6- (dimethylamino) pyridine-2-carbonitrile (1.1g, 7.5mmol, 1 eq) in MeOH (50mL), NH at room temperature₃.H₂Raney nickel (64.03mg, 0.747mmol, 0.10 equiv.) was added to a mixture of O (0.3g, 7.5mmol, 1 equiv.). The mixture was stirred at 20 ℃ under a hydrogen atmosphere for 30 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 6- (aminomethyl) -N, N-dimethylpyrazine as a yellow oil Pyridin-2-amine (1g, 88.5%). LCMS M/z (ESI), [ M + H]⁺＝152.2。

And 3. step 3. 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-di Hydropyrid-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 15)

To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.32mmol, 1 eq) and 6- (aminomethyl) -N, N-dimethylpyridin-2-amine (72.4mg, 0.48mmol, 1.5 eq) were added in portions to a mixture in DMF (3mL) with HATU (243mg, 0.64mmol, 2 eq) and DIEA (118mg, 0.96mmol, 3 eq). The mixture was stirred at 15 ℃ for 10min under an air atmosphere. The precipitated solid was collected by filtration and washed with water (3 × 10 mL). Drying the obtained solid under infrared light to obtain 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl ] as light yellow solid]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 15) (66.1mg, 46.4%).

LCMS:m/z(ESI),[M+H]⁺＝447.2。¹H NMR(400MHz,DMSO-d₆)δ2.9(s,5H),3.3(s,2H),4.4(d,J＝5.7Hz,2H),6.3(d,J＝9.3Hz,1H),6.5(dd,J＝9.2,7.9Hz,2H),7.3-7.4(m,2H),7.46(dd,J＝8.5,7.3Hz,1H),7.8(s,1H),8.0(d,J＝2.6Hz,1H),8.3(d,J＝0.8Hz,1H),9.3(t,J＝5.7Hz,1H)。

Example 16.3-amino-N- ((3- (dimethylamino) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxylic acidPreparation of amine (Compound 16)

Scheme 13

Step 1.2- (aminomethyl) -N, N-dimethylpyridin-4-amine

To a solution of 4- (dimethylamino) pyridine-2-carbonitrile (200mg, 1.4mmol, 1 eq) in MeOH (5mL) was added NH₃.H₂O (0.1mL, 2.6mmol, 1.9 equiv.). The resulting mixture was stirred at 15 ℃ under a hydrogen atmosphere for 30 min. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2- (aminomethyl) -N, N-dimethylpyridin-4-amine (190mg, 92.5%) as a brown solid. LCMS M/z (ESI), [ M + H]⁺＝152.2。

Step 2.3-amino-N- ((3- (dimethylamino) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-di Hydropyridin-3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 16)

To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.32mmol, 1 eq) and 2- (aminomethyl) -N, N-dimethylpyridin-3-amine (72.4mg, 0.48mmol, 1.5 eq) were added to a mixture in DMF (5mL) in portions HATU (242.7mg, 0.64mmol, 2 eq) and DIEA (165.12mg, 1.28mmol, 4 eq). The mixture was stirred at 15 ℃ under an air atmosphere for 60min and quenched with water (15 mL). The precipitated solid was collected by filtration and washed with water (3X 100 mL). The resulting mixture was concentrated in vacuo to give 3-amino-N- ((3- (dimethylamino) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (in the form of a yellow solid

Oxazol-2-yl) pyrazine-2-carboxamide (compound 16) (50.6mg, 35.5%). LCMS M/z (ESI), [ M + H]⁺＝447.2，¹H NMR (400MHz, methanol-d)₄)δ-0.05(s,1H),1.2(s,1H),2.7(s,6H),3.3(s,3H),4.7(d,J＝5.5Hz,2H),6.3(d,J＝9.4Hz,1H),7.3(dd,J＝8.1,4.7Hz,1H),7.3-7.4(m,2H),7.5(dd,J＝8.1,1.5Hz,1H),7.8(s,1H),8.0(d,J＝2.6Hz,1H),8.2(dd,J＝4.7,1.4Hz,1H),8.3(d,J＝0.7Hz,1H),9.3(t,J＝5.5Hz,1H)。

Example 17.3-amino-N- ((6-methoxypyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 17)

Scheme 14

Step 1.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrile Oxazine-2-carboxylic acid esters

3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1g, 3.93mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (1.8g, 7.85mmol, 2 equiv.) in 1, 4-bis

Cs was added in portions to a stirred mixture in an alkane (50mL)₂CO₃(2.6g, 7.85mmol, 2 equiv.) and Pd (dppf) Cl₂ CH₂Cl₂(0.5g, 0.59mmol, 0.15 equiv.)). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 3 hours. Filtering the resulting mixture with CH₂Cl₂The filter cake was washed (1X 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM/PE (0-100%) after EA/DCM (0-10%) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1.1g, 85.58%). LCMS M/z (ESI), [ M + H]⁺＝328.0。¹H NMR(300MHz,DMSO-d₆)δ3.47(s,3H),3.91(s,3H),6.36(d,J＝9.4Hz,1H),7.35(dd,J＝9.3,2.6Hz,1H),7.43(d,J＝0.8Hz,1H),7.63(s,2H),7.85(d,J＝2.6Hz,1H),8.32(d,J＝0.8Hz,1H)

Step 2.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrile 2-oxazinecarboxylic acid

3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (7g, 21.39mmol, 1 eq) to a stirred mixture in THF (500mL) and methanol (100mL) was added portionwise a solution of LiOH (1024.4mg, 42.77mmol, 2 eq) in water (20 mL). The resulting mixture was stirred at 35 ℃ under an air atmosphere for 3 hours. The mixture was neutralized to pH 6 with HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (6.3g, 94.03%). LCMS M/z (ESI), [ M + H]⁺＝314.0。

Step 3.3 amino group-N- [ (6-methoxypyridin-2-yl) methyl]-6- (1-methyl-6-oxo-1, 6-dihydropyrazine Pyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 17)

To HATU (24.3mg, 0.06mmol, 2 equiv.) and 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (10mg, 0.03mmol, 1 eq) in DMF (5mL) was added DIEA (10.3mg, 0.08mmol, 2.5 eq) portionwise. The resulting mixture was stirred at room temperature for 5 min. 1- (6-methoxypyridin-2-yl) methylamine (6.6mg, 0.05mmol, 1.5 eq) was added portionwise. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and passed through preparative TLC (CH) ₂Cl₂MeOH 3:1) to give 3-amino-N- [ (6-methoxypyridin-2-yl) methyl as a yellow solid]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 17) (30mg, 27.10%). LCMS M/z (ESI), [ M + H]⁺＝434.0，¹H NMR(300MHz,DMSO-d₆)δ9.36(t,J＝6.1Hz,1H),8.29(d,J＝0.8Hz,1H),8.02(d,J＝2.6Hz,1H),7.79(s,2H),7.65(t,J＝7.8Hz,1H),7.48-7.32(m,2H),6.90(d,J＝7.3Hz,1H),6.68(d,J＝8.2Hz,1H),6.31(d,J＝9.4Hz,1H),4.53(d,J＝6.0Hz,2H),3.81(s,3H),3.45(s,3H)。

Example 18.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (6-methylpyridin-2-yl) methyl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 18)

Scheme 15

Step 1.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrile Oxazine-2-carboxylic acid methyl ester

3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1.1g, 4.32mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (2.0g, 8.64mmol, 2 equiv.) in 1, 4-bis

Pd (dppf) Cl was added to a mixture in an alkane (40mL)₂(0.3g, 0.43mmol, 0.1 equiv.) and Cs₂CO₃(2.8g, 8.64mmol, 2 equiv.). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 2 hours and concentrated in vacuo. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (4%) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1g, 70.72%). LCMS M/z (ESI), [ M + H]⁺＝328.0。¹H NMR:(400MHz,DMSO-d₆)δ3.46(s,3H),3.90(s,3H),6.35(d,1H),7.34(dd,1H),7.43(d,1H),7.64(s,2H),7.85(d,1H),8.32(d,1H)。

Step 2.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrile 2-oxazinecarboxylic acid

To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

To a solution of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1g, 3.06mmol, 1 eq) in MeOH (30mL) THF (10mL) was added LiOH (0.1g, 6.11mmol, 2.00 eq). The resulting mixture was stirred at 40 ℃ under an air atmosphere for 2 hours. The mixture was adjusted to pH 5 with HCl. The solvent was removed under reduced pressure to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (800mg, 83.58%). LCMS M/z (ESI), [ M + H]⁺＝314.0。¹H NMR:(400MHz,DMSO-d₆)δ3.46(s,3H),6.30(d,1H),7.28(dd,1H),7.39(d,1H),7.83(s,2H),7.97(d,1H),8.30(d,1H)。

Step 3.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (6-methylpyridin-2- Radical) methyl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 18)

3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.32mmol, 1 eq) and HATU (242.7mg, 0.64mmol, 2 eq) and DIEA (123.8mg, 0.96mmol, 3 eq) in DMF (5mL) was added 1- (6-methylpyridin-2-yl) methylamine (58.5mg, 0.48mmol, 1.5 eq) in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. Pouring the mixture into water, filtering, and filtering The solid was collected and washed with MeOH (10mL) and dried in vacuo to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (6-methylpyridin-2-yl) methyl as a yellow solid]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 18) (24mg, 18.01%). LCMS M/z (ESI), [ M + H]⁺＝418.3。¹H NMR(400MHz,DMSO-d₆)δ3.48(s,3H),4.58(d,J＝6.1Hz,2H),6.33(d,J＝9.4Hz,1H),7.15(d,J＝7.7Hz,2H),7.36～7.47(m,2H),7.65(t,J＝7.7Hz,1H),7.81(s,2H),8.06(d,J＝2.6Hz,1H),31(d,J＝0.8Hz,1H),8 2.47(s,3H),9.45(t,J＝6.1Hz,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 18.

Example 19.3-amino-N- [ [3- (difluoromethoxy) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 19)

Scheme 16

Step 1.1- [3- (difluoromethoxy) pyridin-2-yl]Methylamine

To a stirred mixture of 3- (difluoromethoxy) pyridine-2-carbonitrile (70mg, 0.41mmol, 1 eq) and Raney nickel (7.1mg, 0.1mmol, 0.2 eq) in MeOH (5mL) was added NH portionwise at room temperature₃.H₂O (1 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for a further 3 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. This gives 1- [3- (difluoromethoxy) pyridin-2-yl as a purple oil]Methylamine (50mg, 69.7%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H ]⁺＝175.2。

Step 2.3-amino-N- [ [3- (difluoromethoxy) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6- Dihydropyridin-3-yl) -5- (1, 3-)

Azol-2-yl) pyrazine-2-carboxamide (Compound 19)

Reaction of 1- [3- (difluoromethoxy) pyridin-2-yl at room temperature under an air atmosphere]Methylamine (41.7mg, 0.24mmol, 1.5 equiv.) and 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

To a stirred solution/mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (50mg, 0.16mmol, 1 eq) in DMF (4mL) was added HATU (242.7mg, 0.64mmol, 4 eq) and DIEA (82.5mg, 0.64mmol, 4 eq) dropwise. The resulting mixture was stirred at room temperature for a further 0.5 h. The resulting mixture was added dropwise to water (200mL), the resulting mixture was filtered, and the filter cake was washed with MeOH (3X 10 mL). This gives 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid [3- (difluoromethoxy) pyridin-2-yl]Methyl ester (compound 19) (18mg, 23.7%). LCMS M/z (ESI), [ M + H]⁺＝470.2。¹H NMR(DMSO,400MHz)δ3.5(3H,s),4.7(2H,d),6.3(1H,d),7.3-7.5(3H,m),7.7(1H,d),7.8(1H,s),8.0(1H,d),8.3(1H,s),8.4(1H,dd),9.3(1H,t)。

Example 21: preparation of N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl ] methyl ] -3- (difluoromethoxy) pyridine-2-carboxamide (Compound 21)

Scheme 17

Step 1.N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl]Methyl radical]-3- (difluoromethoxy) pyridine- 2-carboxamides

To a mixture of 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (40mg, 0.16mmol, 1 eq) and 3- (difluoromethoxy) pyridine-2-carboxylic acid (59.9mg, 0.32mmol, 2.0 eq) in DCM (2.5mL) were added HATU (120.4mg, 0.32mmol, 2 eq) and TEA (48.1mg, 0.5mmol, 3 eq) and stirred at room temperature under an air atmosphere for 6 hours. The resulting mixture was quenched with water (20mL) and CH₂Cl₂(3X 20mL) was extracted. By H₂The combined organic layers were washed with O (3X 310 mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] as a yellow solid]Methyl radical]-3- (difluoromethoxy) pyridine-2-carboxamide (30mg, 42.5%). LCMS M/z (ESI), [ M + H]⁺＝424.1。

Step 2.N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyri dine Oxazin-2-yl]Methyl radical]-3- (difluoromethoxy) pyridine-2-carboxamide (Compound 21)

To N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl group]Methyl radical]-3- (difluoromethoxy) pyridine-2-carboxamide (30mg, 0.07mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (33.3mg, 0.14mmol, 2.0 equiv.) in dioxane

alkane/H₂To the mixture in O (1mL) was added Pd (dppf) Cl₂(10.4mg, 0.01mmol, 0.2 eq.) and K₃PO₄(45.1mg, 0.21mmol, 3 equiv.) and stirred at 90 ℃ under nitrogen atmosphere for 10 h. The residue was purified by preparative TLC (PE/EtOAc 1:1) followed by preparative HPLC (column: Xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10MMOL/L NH)₄HCOO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 25% B to 27% B within 8 min; 254,220 nm; rt: 7.32min) to give N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl) as a white solid]Methyl radical]-3- (difluoromethoxy) pyridine-2-carboxamide (Compound 21) (2.7mg, 7.61%). LCMS M/z (ESI) [ M + H ]]⁺＝497.2。¹H NMR (400MHz, methanol-d)₄)δ3.52(s,2H),4.70(s,1H),7.08-7.23(m,1H),7.33(dd,J＝9.4,2.6Hz,1H),7.45-7.55(m,1H),7.65(dd,J＝8.4,4.6Hz,1H),7.74-7.84(m,1H),8.56(dd,J＝4.6,1.3Hz,1H)。

Example 23.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ [6- (methylamino) pyridin-2-yl]Methyl radical]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 23)

Scheme 18

Step 1.6- (methylamino) pyridine-2-carbonitrile

To a solution of 6-bromopyridine-2-carbonitrile (500mg, 2.7mmol, 1 eq) in THF (10mL) was added methylamine (424.3mg, 13.6mmol, 5.0 eq) at room temperature and stirred at 80 ℃ under an air atmosphere for 6 h. The residue was purified by preparative TLC (PE/EtOAc 5:1) to give 6- (methylamino) pyridine-2-carbonitrile as a white solid (80mg, 21.9%). LCMS M/z (ESI), [ M + H ]⁺＝134.3。

Step 2.6- (aminomethyl) -N-methylpyridin-2-amine

To a stirred mixture of 6- (methylamino) pyridine-2-carbonitrile (80mg, 0.6mmol, 1 eq) and Raney nickel (51.5mg, 0.6mmol, 1.0 eq) in MeOH (5mL) was added NH portionwise at room temperature₃.H₂O (21.1mg, 0.60mmol, 1 equiv.). The resulting mixture was stirred at 15 ℃ under a hydrogen atmosphere for 30min and concentrated under reduced pressure to give 6- (aminomethyl) -N-methylpyridin-2-amine (60mg, 72.8%) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝137.1。

Step 3.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ [6- (methylamino) pyridine- 2-radical]Methyl radical]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 23)

To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.22mmol, 1 eq) and 6- (aminomethyl) -N-methylpyridin-2-amine (46.0mg, 0.3mmol, 1.5 eq) were added to a stirred solution/mixture in DMF (3mL) dropwise/portionwise HATU (169.9mg, 0.5mmol, 2 eq) and DIEA (86.6mg, 0.6mmol, 3 eq) and stirred at 15 ℃ under an air atmosphere for 10 min. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 x 150mm 5 μm; mobile phase A: water (0.05% NH) ₃ H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 20% B to 28% B within 7 min; 254/220 nm; rt: 6.5min) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ [6- (methylamino) pyridin-2-yl ] -as a yellow solid]Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 23) (8mg, 8.3%). LCMS M/z (ESI), [ M + H]⁺＝433.2。¹H NMR (400MHz, methanol-d)₄)δ2.8(s,2H),3.6(s,2H),4.5(s,1H),6.4(d,J＝8.2Hz,1H),6.4-6.6(m,1H),7.3-7.4(m,1H),7.5(dd,J＝9.3,2.6Hz,1H),8.0(d,J＝2.5Hz,1H),8.0(d,J＝0.8Hz,1H)。

Example 24.3-amino-N- [ (6-aminopyridin-2-yl) methyl]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 24)

Scheme 19

Step 1.6- (aminomethyl) pyridin-2-amine

To a solution of 6-aminopyridinecarbonitrile (100mg, 0.84mmol, 1 eq) in 20mL MeOH in a 50mL round bottom flask under a nitrogen atmosphere was added Raney nickel (10mg, 0.12mmol, 0.14 eq). The mixture was hydrogenated using a hydrogen balloon under a hydrogen atmosphere at room temperature for 1.5 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give 6- (aminomethyl) pyridin-2-amine (100mg, 96.73%) as a brown oil. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝124.0。

Step 2.3-amino-N- [ (6-aminopyridin-2-yl) methyl ]-6- (1-methyl-6-oxo-1, 6-dihydropyrazine Pyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 24)

3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (381.5mg, 1.22mmol, 1.5 equiv.) and HATU (617.5mg, 1.62mmol, 2 equiv.) in DMF (15.0 mL)) DIEA (314.8mg, 2.44mmol, 3 equiv.) and 6- (aminomethyl) pyridin-2-amine (100mg, 0.81mmol, 1 equiv.) are added to the stirred mixture in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography on CH₂Cl₂MeOH (20:1) to give 3-amino-N- [ (6-aminopyridin-2-yl) methyl as a yellow solid]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 24) (57mg, 16.43%). LCMS M/z (ESI), [ M + H]⁺＝419.0。¹H NMR(400MHz,DMSO-d₆)δ3.48(s,3H),4.39(d,J＝6.2Hz,2H),5.92(s,2H),6.32(dd,J＝8.8,3.8Hz,2H),6.42(d,J＝7.3Hz,1H),7.28～7.40(m,2H),7.42(s,1H),7.83(s,2H),8.07(d,J＝2.6Hz,1H),8.31(s,1H),9.26(t,J＝6.2Hz,1H)。

Example 25.3-amino-N- ((4- (dimethylamino) pyrimidin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 25)

Scheme 20

Step 1.4- (dimethylamino) pyrimidine-2-carbonitrile

4-bromopyrimidine-2-carbonitrile (980mg, 5.3mmol, 1 equiv.) and NHMe were added at 80 deg.C in a 40mL sealed tube ₂A solution of (15mL, 30.00mmol, 5.6 equiv.) in THF (10mg) was maintained for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexanes/EtOAc (1:1) to give 4- (dimethylamino) pyrimidine-2-carbonitrile as a white solid (700mg, 88.7%). LCMS M/z (ESI), [ M + H]⁺＝149.2。

Step 2.2- (aminomethyl) -N, N-dimethylpyrimidin-4-amine

To a stirred mixture of 4- (dimethylamino) pyrimidine-2-carbonitrile (80mg, 0.5mmol, 1 eq) and raney nickel (9.3mg, 0.1mmol, 0.2 eq) in MeOH (5mL) was added NH dropwise at room temperature₄OH (1 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for another 1 hour. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure to give 70mg of a brown oil. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝153.2。

Step 3.3-amino-N- [ [4- (dimethylamino) pyrimidin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-di Hydropyrid-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 25)

3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (50mg, 0.16mmol, 1 eq) and 2- (aminomethyl) -N, N-dimethylpyrimidin-4-amine (36.4mg, 0.2mmol, 1.5 eq) were added in portions to a stirred mixture in DMF (5mL) with DIEA (82.5mg, 0.64mmol, 4 eq) and HATU (242.7mg, 0.6mmol, 4 eq). The resulting mixture was stirred at room temperature for a further 30 min. The resulting mixture was added to water and filtered, and the filter cake was washed with EtOAc (3X 5mL) and MeOH (2X 5 mL). Recrystallization of the crude product from water/DMF (5:1mL) gave 3-amino-N- [ [4- (dimethylamino) pyrimidin-2-yl ] as a yellow solid ]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 25) (14mg, 19.41%). LCMS M/z (ESI), [ M + H]⁺＝448.3。¹H NMR(DMSO,400MHz)δ3.0(6H,s),3.5(3H,s),4.5(2H,d),6.3(1H,d),6.6(1H,d),7.4-7.4(2H,m),7.8(1H,s),8.0(1H,d),8.1(1H,d),8.3(1H,d),9.2(1H,t)。

Example 26.3-amino-N- [ [6- (azetidin-1-yl) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 26)

Scheme 21

Step 1.6- (azetidin-1-yl) pyridine-2-carbonitrile

6-bromopyridine-2-carbonitrile (500mg, 2.732mmol, 1 equiv.), azetidine (202.79mg, 3.552mmol, 1.30 equiv.) and K were added at room temperature to a 40mL sealed tube₂CO₃(755.19mg, 5.464mmol, 2.00 equiv.) in DMF (20 mL). The mixture was stirred at 80 ℃ for 2 hours and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with PE/EtOAc (1:1) to give 6- (azetidin-1-yl) pyridine-2-carbonitrile as a white solid (400mg, 91.97%). LCMS M/z (ESI), [ M + H]⁺＝160.2。

Step 2.1- [6- (azetidin-1-yl) pyridin-2-yl]Methylamine

A50 mL round bottom flask was charged with Raney nickel (40mg, 0.47mmol, 0.32 equiv.) and 6- (azetidin-1-yl) pyridine-2-carbonitrile (230mg, 1.44mmol, 1 equiv.) in MeOH (20mL) at room temperature. Mixing the mixture in H ₂Stirred under atmosphere for 2 hours. Raney nickel is removed by filtration. The filtrate was concentrated under reduced pressure to give 1- [6- (azetidin-1-yl) pyridin-2-yl as a yellow oil]Methylamine (200mg, 84.81%), which was used in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝164.2。

Step 3.3-amino-N- [ [6- (azetidin-1-yl) pyridin-2-yl]Methyl radical]-6-(1-methyl-6-oxo Substituted-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 26)

To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.26mmol, 1 eq.) and 1- [6- (azetidin-1-yl) pyridin-2-yl]Methylamine (62.9mg, 0.39mmol, 1.5 equivalents) to a mixture in DMF (5mL) was added HATU (195.4mg, 0.51mmol, 2 equivalents) and DIEA (99.6mg, 0.77mmol, 3 equivalents). The resulting mixture was stirred for 60min and concentrated in vacuo. By preparative HPLC with the following conditions (column: Xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10MMOL/L NH)₄HCO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 25% B to 43% B within 7 min; 254,220 nm; rt: 6.68min) to give 3-amino-N- [ [6- (azetidin-1-yl) pyridin-2-yl ] as a yellow solid ]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 26) (11mg, 9.40%). LCMS M/z (ESI), [ M + H]⁺＝459.3。¹H NMR(300MHz,DMSO-d₆)δ2.28(2H,p),3.47(3H,s),3.89(4H,t),4.45(2H,d),6.22(1H,d),6.33(1H,d),6.58(1H,d),7.34-7.53(3H,m),7.83(2H,s),8.02(1H,d),8.31(1H,s),9.35(1H,t)。

Example 27.3-amino-N- (5- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 27)

Scheme 22

Step 1.5 preparation of (dimethylamino) -2-fluorocyclohexane-1, 3-diene-1-carbonitrile

To a solution of 5-amino-2-fluorobenzonitrile (2g, 14.69mmol, 1 eq) in DMF (40mL) at 0 deg.C was added NaH (1057.7mg, 44.08mmol, 3 eq). After stirring for 5min, MeI (8341.4mg, 58.77mmol, 4 equiv.) was added dropwise at 0 ℃. The resulting solution was stirred at 0 ℃ for 2 hours and treated with NH₄Saturated aqueous Cl (50 mL). The resulting solution was extracted with 3X 50mL of ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column together with dichloromethane/methanol (40: 1). This gave 1.2g (49.75%) of 5- (dimethylamino) -2-fluorocyclohexane-1, 3-diene-1-carbonitrile as a light yellow solid. LCMS M/z (ESI), [ M + H]⁺＝165.2。¹HNMR(400MHz,DMSO-d₆)δ2.89(6H,s),7.01-7.07(2H,m),7.25-7.32(1H,m)。

Step 2.3- (aminomethyl) -4-fluoro-N, N-dimethylaniline

To a mixture of Raney nickel (52.18mg, 0.609mmol, 0.20 equiv.) and 5- (dimethylamino) -2-fluorobenzonitrile (500mg, 3.045mmol, 1 equiv.) in MeOH (50mL) in a 250mL round bottom flask was added NH ₄OH (2mL, 51.361mmol, 16.87 equiv.). The resulting solution was stirred at room temperature under a hydrogen atmosphere for 2 hours. The raney nickel is filtered off. The filtrate was concentrated to give 400mg (78.08%) of 3- (aminomethyl) -4-fluoro-N, N-dimethylaniline as a solid. LCMS M/z (ESI), [ M-NH ]₂]⁺＝152.3。¹HNMR(400MHz,DMSO-d₆)δ2.83(6H,s),3.70(2H,d),6.52-6.57(1H,m),6.75-6.88(1H,m),7.06-7.13(1H,m)

Step 3.3-amino-N- (5- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyrazine Pyridin-3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 27)

To a 25mL round bottom flask 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

To a mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (50mg, 0.16mmol, 1 eq) and 3- (aminomethyl) -4-fluoro-N, N-dimethylaniline (32.2mg, 0.19mmol, 1.20 eq) in DMF (10mL) was added TEA (48.5mg, 0.48mmol, 3.0 eq) and HATU (66.8mg, 0.18mmol, 1.1 eq). The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched with 50mL of water. The resulting solid was collected by filtration and dried in vacuo to give 17.2mg (23.25%) of 3-amino-N- [ [5- (dimethylamino) -2-fluorophenyl ] group as a yellow solid]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 27). LCMS M/z (ESI), [ M + H ]⁺＝464.2。¹HNMR(300MHz,DMSO-d₆)δ2.80(6H,s),3.45(3H,s),4.52(2H,d),6.30-6.33(1H,m),6.59-6.62(1H,m),6.63-6.64(1H,m),6.73-6.76(1H,m),7.00-7.03(1H,m),7.36-7.39(2H,m),7.76-7.78(2H,m),8.02-8.03(1H,m),8.29(1H,s),9.20-9.24(1H,m)。

Example 28.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) -N- ((6- (pyrrolidin-1-yl) pyridin-2-yl) methyl) pyrazine-2-carboxamide (Compound 28)

Scheme 23

Step 1.1- [6- (pyrrolidin-1-yl) pyridin-2-yl]Methylamine

To 6- (pyrrole)Alkan-1-yl) pyridine-2-carbonitrile (200mg, 1.1mmol, 1 equiv.) and Raney nickel (98.9mg, 1.1mmol, 1.0 equiv.) to a mixture in MeOH (10mL) NH was added₃.H₂O (40.5mg, 1.1mmol, 1 equiv.) and stirred at 15 ℃ under a hydrogen atmosphere for 30 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 1- [6- (pyrrolidin-1-yl) pyridin-2-yl as a white solid]Methylamine (120mg, 58.6%). LCMS M/z (ESI), [ M + H]⁺＝178.3。

Step 2.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) - N- [ [6- (pyrrolidin-1-yl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamides (Compound 28)

To 1- [6- (pyrrolidin-1-yl) pyridin-2-yl at room temperature]Methylamine (100mg, 0.56mmol, 1 eq) and 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (176.7mg, 0.56mmol, 1.00 equiv.) to a mixture in DMF (3mL) was added HATU (429.0mg, 1.13mmol, 2 equiv.) and DIEA (218.7mg, 1.69mmol, 3 equiv.). The mixture was stirred at 15 ℃ for 60min under an air atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH) ₄HCOO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 39% B to 40% B within 9 min; 254,220 nm; rt: 8.3min) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) -N- [ [6- (pyrrolidin-1-yl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 28) (36.7mg, 13.17%). LCMS M/z (ESI), [ M + H]⁺＝473.3，¹H NMR (400MHz, methanol-d)₄)δ1.8-1.9(m,4H),3.3(d,J＝6.6Hz,4H),4.5(d,J＝5.5Hz,2H),6.3(dd,J＝13.3,8.9Hz,2H),6.5(d,J＝7.3Hz,1H),7.4-7.5(m,3H),7.8(s,1H),7.9(d,J＝2.6Hz,1H),8.3(d,J＝0.8Hz,1H),9.3(t,J＝5.6Hz,1H)。

Example 29: preparation of 3-amino-N- [ (2, 6-difluorophenyl) methyl ] -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 29)

Scheme 24

Step 1.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, preparation of 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 29)

To 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group at room temperature under a nitrogen atmosphere]-5- (4-fluorophenyl) pyrazine-2-carboxamide (100mg, 0.25mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (119.7mg, 0.5mmol, 2.0 equiv.) in dioxane

alkane/H₂To the mixture in O (2mL) was added Pd (dppf) Cl₂(37.3mg, 0.1mmol, 0.2 eq.) and K ₃PO₄(162.1mg, 0.8mmol, 3 equiv.). The mixture was stirred at 90 ℃ under a nitrogen atmosphere for 10 hours. The residue was purified by preparative TLC (PE/EtOAc 1:2) followed by preparative HPLC (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃ H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 39% B to 49% B within 7 min; 254/220 nm; rt: 6.18min) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 29) (7mg, 5.85%). LCMS m/z (E)SI)[M+H]⁺＝466.2。¹H NMR (400MHz, methanol-d)₄)δ3.55(s,2H),4.73(s,2H),6.38(d,J＝9.2Hz,1H),6.93-7.05(m,2H),7.10-7.19(m,2H),7.30(dd,J＝9.4,2.6Hz,1H),7.32-7.42(m,1H),7.50-7.61(m,2H),7.88(d,J＝2.5Hz,1H)。

Example 30.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) -N- [ [3- (trifluoromethoxy) pyridin-2-yl]Methyl radical]Preparation of pyrazine-2-carboxamide (Compound 30)

Scheme 25

Step 1.3- (trifluoromethoxy) pyridine-2-carbonitrile.

To 2-bromo-3- (trifluoromethoxy) pyridine (300mg, 1.24mmol, 1 eq) and Zn (CN) at room temperature under a nitrogen atmosphere₂(291.2mg, 2.48mmol, 2 equiv.) in THF (15mL) and H₂t-BuXantPhos-Pd-G3(197.0mg, 0.25mmol, 0.2 equiv.) and t-BuXantPhos (171.3mg, 0.25mmol, 0.2 equiv.) were in a stirred mixture in O (3 mL). The resulting mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure. By preparative TLC (CH) ₂Cl₂/MeOH 20:1) to give 3- (trifluoromethoxy) pyridine-2-carbonitrile as a white solid (200mg, 85.76%). LCMS M/z (ESI), [ M + H]⁺＝188.9。

Step 2.1- [3- (trifluoromethoxy) pyridin-2-yl]Methylamine.

To 3- (trifluoromethoxy) pyridine-2-carbonitrile (100mg, 0.53mmol, 1 eq) and NH under a nitrogen atmosphere₃.H₂To a solution of O (1.0mL, 28.54mmol, 48.31 equiv) in MeOH (10mL) was added Raney nickel (22.8mg, 0.27mmol, 0.5 equiv). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). Concentrating the filtrate under reduced pressure. This gives 1- [3- (trifluoromethoxy) pyridin-2-yl as a purple oil]Methylamine (80mg, 78.32%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝193.2。

Step 3.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) - N- [ [3- (trifluoromethoxy) pyridin-2-yl ] amino acids]Methyl radical]Pyrazine-2-carboxamide (Compound 30)

To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.26mmol, 1 eq.) and 1- [3- (trifluoromethoxy) pyridin-2-yl]Methylamine (98.1mg, 0.51mmol, 2 equiv.) in DMF (10mL) was added HATU (194.2mg, 0.51mmol, 2 equiv.) and DIEA (66.0mg, 0.51mmol, 2 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. The solvent was removed under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10MMOL/L NH) ₄HCOO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 25% B to 46% B within 7 min; 254/220 nm; rt: 6.83min) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) -N- [ [3- (trifluoromethoxy) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 30) (10mg, 8.03%). LCMS M/z (ESI), [ M + H]⁺＝488.2。¹H NMR:(400MHz,MeOD)δ3.65(s,3H),4.85(s,2H),6.53(d,1H),7.38(d,1H),7.51(m,2H),7.84(d,1H),8.07(dd,2H),8.54(d,1H)。

Example 31.3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydroPyridin-3-yl]-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 31)

Scheme 26

Step 1.3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-

Azole- 2-Yl) pyrazine-2-carboxylic acid methyl ester

To a stirred solution of 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (340.1mg, 1.34mmol, 2 equivalents) and 5-bromo-1- (difluoromethyl) -1, 2-dihydropyridin-2-one (150mg, 0.67mmol, 1 equivalent) in THF (20mL) was added KOAc (197.2mg, 2.01mmol, 3.00 equivalents) and Pd (dppf) Cl in portions at room temperature under a nitrogen atmosphere₂ CH₂Cl₂(82.0mg, 0.10mmol, 0.15 equiv.). The resulting mixture was stirred at 75 ℃ for 3 hours under a nitrogen atmosphere. To this resulting mixture of 1- (difluoromethyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one in THF (20mL) at room temperature under a nitrogen atmosphere was added 3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (84.5mg, 0.33mmol, 0.50 equiv.), Cs₂CO₃(432.7mg, 1.33mmol, 2 equiv.) and Pd (dppf) Cl₂ CH₂Cl₂(70.5mg, 0.09mmol, 0.13 equiv.). The resulting mixture was stirred at 75 ℃ for 4 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH₂Cl₂The filter cake was washed (2X 20 mL). The filtrate was concentrated under reduced pressure.By preparative TLC (CH)₂Cl₂MeOH30:1) to give 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl as a yellow solid]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (100mg, 18.65%). LCMS M/z (ESI), [ M + H]⁺＝364.1。¹H NMR(300MHz,DMSO-d₆)δ3.87(s,3H),6.51(d,J＝9.7Hz,1H),7.41(s,1H),7.59(dd,J＝9.6,2.5Hz,1H),7.69(s,1H),7.80(d,J＝2.5Hz,1H),7.90(d,J＝8.8Hz,1H),8.32(d,J＝0.8Hz,1H)。

Step 2.3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-

Azole- 2-yl) pyrazine-2-carboxylic acid

To 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl group at room temperature]-5-(1,3-

To a stirred solution of methyl oxazol-2-yl) pyrazine-2-carboxylate (90mg, 0.25mmol, 1 eq) in THF (15mL) was added dropwise a solution of LiOH (11.9mg, 0.50mmol, 2.01 eq) in water (1 mL). The resulting mixture was stirred at room temperature under an air atmosphere for 3 hours. The mixture was neutralized to pH 6 with 1N aqueous HCl and concentrated in vacuo to give crude 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl as a yellow solid ]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (85mg, 98.24%) which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝350.0。

Step 3.3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-N- [ (3-fluoropyridine-) 2-yl) methyl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 31)

To 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl under an air atmosphere at room temperature]-5-(1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (10mg, 0.03mmol, 1 equivalent), DIEA (11.1mg, 0.09mmol, 3.00 equivalents), and HATU (21.8mg, 0.06mmol, 2.00 equivalents) in DMF (8mL) was added 1- (3-fluoropyridin-2-yl) methylamine (5.4mg, 0.04mmol, 1.50 equivalents) dropwise. The resulting mixture was stirred at room temperature under an air atmosphere for 3 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and passed through preparative TLC (CH)₂Cl₂MeOH 20:1) to give 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl as a yellow solid]-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 31) (30mg, 28.64%). LCMS M/z (ESI), [ M + H]⁺＝458.2，¹H NMR(300MHz,DMSO-d₆)δ9.30(t,J＝5.9Hz,1H),8.35(dd,J＝4.0,2.3Hz,1H),8.30(d,J＝0.8Hz,1H),8.10(s,0H),7.97(d,J＝2.5Hz,1H),7.87(d,J＝13.8Hz,2H),7.75，7.64(m,2H),7.41(q,J＝4.3Hz,2H),6.50(d,J＝9.7Hz,1H),4.68(dd,J＝5.7,1.5Hz,2H)。

Example 32.3-amino-N- [ (2, 6-difluorophenyl) methyl]-6- [ imidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 32)

Scheme 27

Step 1.3-amino-6- (imidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxylic acid methyl ester

3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (300mg, 1.18mmol, 1 equiv.) and 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a]Pyridine (431.4mg, 1.77mmol, 1.5 equiv.) in bis

Alkane (18mL) and H₂To a stirred mixture in O (2mL) was added Cs portion by portion₂CO₃(767.7mg, 2.36mmol, 2 equiv.) and Pd (dppf) Cl₂(172.4mg, 0.24mmol, 0.2 equiv.). The resulting mixture was stirred at 90 ℃ overnight. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with DCM (3X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 20:1) to give 3-amino-6- [ imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (165mg, 41.6%). LCMS M/z (ESI), [ M + H]⁺＝337.2。¹H NMR(DMSO-d₆,400MHz)δ3.9(3H,s),7.1(1H,dd,J＝9.4,1.8Hz),7.4(1H,s),7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.2Hz),7.7(1H,d,J＝19.0Hz),8.0(1H,d,J＝1.1Hz),8.3(1H,s),8.7(1H,t,J＝1.4Hz)

Step 2.3-amino-6- (imidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxylic acid

To 3-amino-6- [ imidazo [1,2-a ] at room temperature]Pyridin-7-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (160mg, 0.48mmol, 1 equiv.) to a stirred solution in THF (20mL) and water (2mL) was added LiOH (13.7mg, 0.57mmol, 1.2 equiv.) portionwise. The resulting mixture was stirred at room temperature for 4 hours and adjusted to PH 5 with 1N aqueous HCl. The resulting mixture was concentrated in vacuo and used directly in the next step without further purification. LCMS M/z (ESI), [ M + H ]⁺＝323.2。

Step 3.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 32)

3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.25mmol, 1 eq) and 1- (2, 6-difluorophenyl) methylamine (71.1mg, 0.50mmol, 2 eq) in DMF (5mL) was added HATU (377.5mg, 1mmol, 4 eq) and DIEA (128.3mg, 1mmol, 4 eq) portionwise. The resulting mixture was stirred at room temperature for 0.5 hour. The resulting mixture was quenched with water, and the resulting solid was collected by filtration and slurried with MeOH (5 mL). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 32) (30mg, 25.8%). LCMS M/z (ESI), [ M + H]⁺＝448.2。¹H NMR(DMSO-d₆,400MHz)δ4.6(2H,d,J＝5.8Hz),7.1(2H,t,J＝7.9Hz),7.2(1H,dd,J＝9.4,1.8Hz),7.3-7.4(2H,m),7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.3Hz),7.9(3H,d,J＝23.3Hz),8.3(1H,s),8.7(1H,t,J＝1.3Hz),9.2(1H,t,J＝5.9Hz)。

Example 33.3-amino-N- (3- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 33)

Scheme 28

Step 1.3- (dimethylamino) -2-fluorobenzonitrile

To a stirred mixture of 3-amino-2-fluorobenzonitrile (300mg, 2.20mmol, 1 equiv.) and NaH (158.7mg, 6.61mmol, 3.00 equiv.) in DMF (10mL) was added iodomethane (938.4mg, 6.61mmol, 3.00 equiv.) portionwise at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was quenched with water (30mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with water (3X 10mL) and anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and purified by preparative TLC (PE/EtOAc 5:1) to give 3- (dimethylamino) -2-fluorobenzonitrile (160mg, 44.2%) as a light yellow crude solid. LCMS M/z (ESI), [ M + H]⁺＝165.2。¹H NMR (chloroform-d, 400MHz) δ 2.9(6H, d, J ═ 1.3Hz),7.1-7.1(3H, m).

Step 2.3- (aminomethyl) -2-fluoro-N, N-dimethylaniline

To a stirred mixture of 3- (dimethylamino) -2-fluorobenzonitrile (160mg, 0.97mmol, 1 eq) and raney nickel (16.7mg, 0.19mmol, 0.20 eq) in MeOH (20mL) was added NH portionwise at room temperature₄OH (2 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for another 1 hour. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝169.0。

Step 3.3-amino-N- (3- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyrazine Pyridin-3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 33)

3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.26mmol, 1 equiv.) and 3- (aminomethyl) -2-fluoro-N, N-dimethylaniline (85.9mg, 0.5mmol, 2.0 equiv.) were added to a stirred mixture in DMF (5mL) in portions HATU (194.2mg, 0.51mmol, 2.00 equiv.) and DIEA (132.0mL, 1.02mmol, 4.00 equiv.). The resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 20:1) to give the crude product 3-amino-N- (3- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (3-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxamide (100 mg). The crude product (100mg) was purified by preparative HPLC with the following conditions (column: Xselect CSH OBD column 30 x 150mm 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 16% B to 27% B over 7 min; 254; 220 nm; Rt: 4.40min) to give 3-amino-N- (3- (dimethylamino) -2-fluorobenzyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (100mg) as a tan solid

Oxazol-2-yl) pyrazine-2-carboxamide (compound 33) (44mg, 37.06%). LCMS M/z (ESI), [ M + H]⁺＝464.2。¹H NMR(DMSO-d₆,400MHz)δ2.8(5H,s),4.6(2H,d,J＝6.3Hz),6.3(1H,d,J＝9.4Hz),6.9-7.0(2H,m),7.1(1H,t,J＝7.8Hz),7.4-7.4(2H,m),7.8(1H,s),8.0(1H,d,J＝2.6Hz),8.3(1H,d,J＝0.8Hz),9.3(1H,t,J＝6.4Hz)。

EXAMPLE 35 preparation of 3-amino-N- (2, 6-difluorobenzyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 35)

Scheme 29

Step 1.3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid methyl ester

To a stirred solution of methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (2.5g, 11.26mmol, 1 eq) and 2H-1,2, 3-tris (1555.4mg, 22.52mmol, 2 eq) in DMSO (50mL) was added t-BuONa (1082.1mg, 11.26mmol, 1 eq) portionwise at room temperature. The resulting mixture was stirred in an oil bath for 3 hours at 60 ℃, cooled to room temperature and quenched with water (200 mL). The resulting solid was collected by filtration, dried in vacuo and purified by a silica gel column (DCM: EA 0-20%) to give 1.6g of crude product. The crude product was further purified by preparative TLC (DCM: EA6:1) to give methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (800mg, 29%). ¹H NMR (300MHz, chloroform-d) delta 4.06(s,3H),8.03(s, 2H).

Step 2.3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid

To a stirred mixture of methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (200mg, 0.79mmol, 1 eq) in THF (50mL) was added dropwise a solution of LiOH (38.0mg, 1.59mmol, 2.02 eq) in water (2mL) at room temperature. The resulting mixture was stirred at 40 ℃ for 3 hours. The resulting mixture was concentrated to 10mL in vacuo. The mixture was acidified to pH 6 with HCl (aq). The precipitated solid was collected by filtration and dried in vacuo to give 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (120mg, 52.91%) as a yellow solid, which was used in the next step without further purification. LCMS M/z (ESI), [ M +H]⁺＝240.9。

Step 3.3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group]-5- (2H-1,2, 3-triazol-2-yl) pyrazin- 2-carboxamides

To a stirred solution of 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (130mg, 0.54mmol, 1 equivalent), DIEA (209.5mg, 1.62mmol, 3.00 equivalents), and 1- (2, 6-difluorophenyl) methylamine (116.0mg, 0.81mmol, 1.50 equivalents) in DMF (10mL) was added dropwise 50% W T at room temperature₃P (687mg, 1.08mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and passed through preparative TLC (CH) ₂Cl₂Purification in MeOH 20:1) to give 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] p-toluenesulfonate as a yellow solid]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (110mg, 55.67%). LCMS M/z (ESI), [ M + H]⁺＝366.0。¹H NMR (300MHz, chloroform-d) δ 8.00(s,3H),7.38-7.30(m,1H),6.98(t, J ═ 7.8Hz,2H),4.77(d, J ═ 6.0Hz, 2H).

Step 4.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- (1-methyl-6-oxo-1, 6-dihydropyridine-3- Yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 35)

To 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group at room temperature under a nitrogen atmosphere]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (100mg, 0.27mmol, 1 eq), Cs₂CO₃(267.3mg, 0.82mmol, 3 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (128.6mg, 0.55mmol, 2.00 equiv.) in 1, 4-bis

To a stirred mixture in an alkane (20mL) was added Pd (dppf) Cl in portions₂CH₂Cl₂(44.7mg, 0.05mmol, 0.2 equiv.). The resulting mixture was stirred at 90 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂/MeOH 201) purifying the residue to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid ]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 35) (40mg, 33.04%). LCMS M/z (ESI), [ M + H]⁺＝439.2，¹H NMR(300MHz,DMSO-d₆)δ9.18(t,J＝5.9Hz,1H),8.13(s,2H),7.93(s,2H),7.76(d,J＝2.6Hz,1H),7.48-7.25(m,1H),7.08(t,J＝8.0Hz,2H),6.73(dd,J＝9.5,2.7Hz,1H),6.20(d,J＝9.5Hz,1H),4.61(d,J＝5.9Hz,2H),3.39(s,3H)。

Example 36.3-amino-N- ((3- (hydroxymethyl) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 36)

Scheme 30

Step 1.2- (((tert-butoxycarbonyl) amino) methyl) nicotinic acid methyl ester

To a mixture of methyl 2- (aminomethyl) pyridine-3-carboxylate (1g, 6.02mmol, 1 equiv.) and TEA (1826.8mg, 18.05mmol, 3.0 equiv.) in DCM (30mL) in a 250mL round bottom flask was added Boc portionwise at room temperature₂O (1379.0mg, 6.32mmol, 1.05 equiv.). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was diluted with 50mL of water. The resulting solution was extracted with 3X 50mL of dichloromethane, dried over anhydrous sodium sulfate and concentrated. This gives 1.5g (93.61%) of 2- ([ [ (tert-butoxy) carbonyl ] as a solid]Amino group]Methyl) pyridine-3-carboxylic acid methyl ester. LCMS M/z (ESI), [ M + H]⁺＝267.1。

Step 2.((3- (hydroxymethyl) pyridin-2-yl) methyl) carbamic acid tert-butyl ester

Place 2- ([ [ (tert-butoxy) carbonyl) in a 50-mL round-bottom flask]Amino group]Methyl) pyridine-3-carboxylic acid methyl ester (100mg, 0.38mmol, 1 eq) in THF (5 mL). At this point Then LiAlH was added portionwise at 0 deg.C₄(42.8mg, 1.13mmol, 3 equiv.). The resulting solution was stirred at 0 ℃ for 1 hour in a water/ice bath. The reaction was then quenched by the addition of 0.043mL of water and 0.172mL of NaOH (15% in water). The resulting solid was filtered off. The filtrate was concentrated and 85mg (94.9%) of N- [ [3- (hydroxymethyl) pyridin-2-yl ] as a solid were produced]Methyl radical](iii) carbamic acid tert-butyl ester. LCMS M/z (ESI), [ M + H]⁺＝239.2。¹H NMR(300MHz,DMSO-d₆)δ1.40(9H,s),4.28(2H,d),4.58(2H,d),5.31-5.33(1H,m)7.00(1H,s),7.29-7.32(1H,m),7.77-7.79(1H,m)。

Step 3.(2- (aminomethyl) pyridin-3-yl) methanol

Placing N- [ [3- (hydroxymethyl) pyridin-2-yl ] in a 10-mL round bottom flask]Methyl radical]A solution of tert-butyl carbamate (50mg, 0.21mmol, 1 eq), TFA (1mL) in DCM (3 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated and yielded 28mg (96.6%) of [2- (aminomethyl) pyridin-3-yl as a solid]Methanol TFA salt. LCMS M/z (ESI), [ M + H]⁺＝139.3。¹H NMR(300MHz,DMSO-d₆)δ4.25(2H,m)4.58-4.60(2H,m),7.44(1H,m),7.86-7.88(1H,m),8.25(3H,s),8.54-8.56(1H,m)。

Step 4.3-amino-N- ((3- (hydroxymethyl) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydro Pyridin-3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 36)

[2- (aminomethyl) pyridin-3-yl ] into a 50-mL round-bottomed flask at room temperature]Methanol (52.9mg, 0.38mmol, 2.0 equiv.), 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

To a mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (60mg, 0.19mmol, 1 eq) in DMF (15mL) was added HATU (87.4mg, 0.23mmol, 1.2 eq) and DIEA (74.3mg, 0.57mmol, 3.0 eq). The resulting solution was stirred at room temperature for 1 hour Then (c) is performed. The reaction was then quenched by the addition of 20mL of water. The resulting solution was extracted with 3X 25mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1X 10mL of saturated brine. The resulting mixture was concentrated. By preparative HPLC with the following conditions (column: Xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10MMOL/L NH)₄HCOO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 30% B to 30% B within 7 min; 254,220 nm; rt: 6.35min) to purify the crude product. This gives 20mg (24.09%) of 3-amino-N- [ [3- (hydroxymethyl) pyridin-2-yl ] as a yellow solid]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 36). LCMS M/z (ESI), [ M + H]⁺＝434.2。¹HNMR(300MHz,DMSO-d₆)δ3.47(3H,s),4.65(4H,d),5.42(1H,d),6.32-6.36(1H,m),7.29-7.34(2H,m),7.35-7.41(1H,m),7.75-7.81(3H,m),8.01(1H,s),8.30-8.43(1H,s),8.35-8.38(1H,m),9.36-9.38(1H,m)。

The compounds listed in the table below were prepared using the procedure described for compound 36.

Example 38.3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (2, 6-difluorophenyl) methyl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 38)

Scheme 31

Step 1.5-bromo-1-cyclopropyl-1, 2-dihydropyridin-2-one.

To 5-bromo-1, 2-dihydropyridin-2-one (2g, 11.49mmol, 1 eq.), cyclopropylboronic acid (2.0g, 23.28mmol, 2.03 eq.) and CU (AcO) at room temperature under a nitrogen atmosphere ₂(2.1g, 0.01mmol, 1 eq.) in CH₂ClCH₂To the mixture in Cl (50mL) was added Na₂CO₃(2.4g, 0.02mmol, 2 equiv.) and 44-di-tert-butyl-22-bipyridine (3.1g, 0.01mmol, 1 equiv.). The resulting mixture was stirred at 70 ℃ for 12 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (20:1) gave 5-bromo-1-cyclopropyl-1, 2-dihydropyridin-2-one (600mg, 24.39%) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝213.9,215.9。¹H NMR:(300MHz,CDCl₃)δ0.86(tdd,2H),1.13(m,2H),3.31(tt,1H),6.48(m,1H),7.34(m,2H)。

Step 2.3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid esters An amide.

To 3-amino-6-chloro-5- (1,3-

To a solution of oxazol-2-yl) pyrazine-2-carboxylic acid (50mg, 0.21mmol, 1 equiv.) and 1- (2, 6-difluorophenyl) methylamine (44.6mg, 0.31mmol, 1.5 equiv.) in DMF (5mL) was added T₃P (132.2mg, 0.42mmol, 2.00 equiv.) and DIEA (80.6mg, 0.62mmol, 3 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours and concentrated in vacuo. By preparative TLC (CH)₂Cl₂/MeOH20:1) to give 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (120mg, 39.47%). LCMS M/z (ESI), [ M + H ]⁺＝366.0。¹H NMR:(300MHz,DMSO-d₆)δ4.53(d,2H),7.06(d,2H),7.37(q,1H),7.55(s,1H),7.85(s,2H),8.39(s,1H),9.08(t,1H)。

Step 3.1-cyclopropyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-di Hydropyridin-2-ones.

To a solution of 5-bromo-1-cyclopropyl-1, 2-dihydropyridin-2-one (100mg, 0.47mmol, 1 equivalent) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (177.9mg, 0.70mmol, 1.50 equivalents) in THF (10mL) at room temperature under an atmosphere was added KOAc (137.5mg, 1.40mmol, 3.00 equivalents) and Pd (dppf) Cl₂ CH₂Cl₂(38.1mg, 0.05mmol, 0.1 equiv.). The mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. This resulting solution of 1-cyclopropyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one in THF (10mL) was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝262.1。

Step 4.3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (2, 6-difluorophenyl) Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 38).

To a solution of 1-cyclopropyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (100mg, 0.38mmol, 1 eq) in THF (10mL) under a nitrogen atmosphere was added 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] methyl ]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (280.1mg, 0.77mmol, 2 equiv.), Cs₂CO₃(249.5mg, 0.77mmol, 2.00 equiv.) and Pd (dppf) Cl₂ CH₂Cl₂(31.3mg, 0.04mmol, 0.1 equiv.). The mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours and under vacuumAnd (5) concentrating. By preparative TLC (CH)₂Cl₂/MeOH20:1) to give 3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 38) (20mg, 11.25%).

LCMS:m/z(ESI),[M+H]⁺＝465.2。¹H NMR:(300MHz,MeOD)δ0.93(dd,2H),1.12(m,2H),2.00(s,1H),4.73(s,2H),6.52(d,1H),7.01(t,2H),7.36(m,1H),7.56(dd,1H),7.84(d,1H),8.08(d,1H)。

Example 39.3-amino-N- [ [ 2-fluoro-6- (morpholin-4-yl) phenyl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 39)

Scheme 32

Step 1.2-fluoro-6- (morpholin-4-yl) benzonitrile

To a stirred mixture of 2, 6-difluorobenzonitrile (1000mg, 7.19mmol, 1 equiv.) and morpholine (939.5mg, 10.78mmol, 1.5 equiv.) in DMSO (10mL) was added DIEA (1858.2mg, 14.38mmol, 2.00 equiv.) in portions at room temperature. The resulting mixture was stirred at 80 ℃ under an air atmosphere for 2.5 hours. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (2X 300 mL). The combined organic layers were washed with water (2X 100mL) and anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2-fluoro-6- (morpholin-4-yl) benzonitrile (637mg, 42.97%) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝207.0。¹H NMR (400MHz, chloroform-d) δ 3.21-3.28(m,4H),3.85-3.92(m,4H),6.78(dt, J ═ 8.4,4.2Hz,2H),7.47(td, J ═ 8.4,6.6Hz, 1H).

And 2. step 2. 1- [ 2-fluoro-6- (morpholin-4-yl) phenyl]Methylamine

To a solution of 2-fluoro-6- (morpholin-4-yl) benzonitrile (200mg, 0.97mmol, 1 eq) in MeOH at room temperature was added raney nickel (166.2mg, 1.94mmol, 2 eq). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (2X 10 mL). The filtrate was concentrated under reduced pressure to give 1- [ 2-fluoro-6- (morpholin-4-yl) phenyl ] as a white oil]Methylamine (150mg, 73.56%), which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝211.2。

Step 3.3-amino-N- [ [ 2-fluoro-6- (morpholin-4-yl) phenyl]Methyl radical]-6- (1-methyl-6-oxo-1, 6- Dihydropyridin-3-yl) -5- (1, 3-)

Azol-2-yl) pyrazine-2-carboxamide (Compound 39)

3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (200mg, 0.64mmol, 1 eq.) and 1- [ 2-fluoro-6- (morpholin-4-yl) phenyl ]Methylamine (134.2mg, 0.64mmol, 1 equiv.) in a stirred mixture of DMF (10mL) was added T in portions₃P (812.5mg, 2.55mmol, 4 equiv.) and DIEA (247.5mg, 1.92mmol, 3 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The resulting mixture was poured into water (30 mL). The resulting solid was collected by filtration and slurried with MeOH (10 mL). The resulting solid was collected by filtration and dried under reduced pressure to give 3-amino-N- [ [ 2-fluoro-6- (morpholin-4-yl) phenyl ] as a yellow solid]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 39) (120 m)g，37.18％)。LCMS:m/z(ESI),[M+H]⁺＝506.1。¹H NMR(400MHz,DMSO-d₆)δ2.88(t,J＝4.5Hz,4H),3.34(s,3H),3.64(t,J＝4.5Hz,4H),4.72(d,J＝5.8Hz,2H),6.32(d,J＝9.4Hz,1H),7.00(dd,J＝9.8,8.4Hz,1H),7.07(d,J＝8.1Hz,1H),7.29～7.43(m,3H),7.83(s,2H),7.97(d,J＝2.6Hz,1H),8.30(d,J＝0.8Hz,1H),9.14(t,J＝5.8Hz,1H)。

Example 40.3-amino-N- (1- (2, 6-difluorophenyl) ethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 40)

Scheme 33

Step 1.3-amino-N- [1- (2, 6-difluorophenyl) ethyl]-6- (1-methyl-6-oxo-1, 6-dihydropyridine- 3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide.

3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.32mmol, 1 equiv.), T₃To a stirred mixture of P (242.7mg, 0.76mmol, 2.39 equiv.) and DIEA (123.8mg, 0.96mmol, 3 equiv.) in DMF (10mL) was added 1- (2, 6-difluorophenyl) ethan-1-amine (75.3mg, 0.48mmol, 1.5 equiv.) in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was poured into water (30 mL). The resulting solid was collected by filtration and slurried with MeOH (10 mL). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-N- [1- (2, 6-difluorophenyl) ethyl ester as a yellow solid Base of]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (40mg, 27.42%). LCMS M/z (ESI), [ M + H]⁺＝453.0。

Step 2.3-amino-N- (1- (2, 6-difluorophenyl) ethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 40-1 and Compound 40-2)

The racemate product (60mg) was purified by preparative chiral HPLC on eluent. Column: CHIRALPAKIG, 20 × 250mm, 5 μm; mobile phase A: hex: DCM ═ 5:1(10mm NH)₃-MEOH) -HPLC, mobile phase B: EtOH- -HPLC; flow rate: 16 mL/min; gradient: 50B to 50B within 16 min; 220/254 nm; RT 1: 10.8 of the total weight of the mixture; RT 2: 12.8. this gave 3-amino-N- (1- (2, 6-difluorophenyl) ethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (2, 6-dihydropyridin-3-yl) as a yellow solid

Oxazol-2-yl) pyrazine-2-carboxamide (isomer 1) (compound 40-1) (15 mg). LCMS M/z (ESI), [ M + H]⁺＝453。¹H NMR (400MHz, MeOD). delta.1.62 (d,3H),3.64(s,3H),5.68(q,1H),6.53(m,1H),7.00(m,2H),7.32(m,2H),7.49(dd,1H),7.93(d,1H),8.03(d, 1H). Chirality: tR 1.967 min. And 3-amino-N- (1- (2, 6-difluorophenyl) ethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (b) as a yellow solid

Oxazol-2-yl) pyrazine-2-carboxamide (isomer 2) (compound 40-2) (15 mg). LCMS M/z (ESI), [ M + H]⁺＝453.2。¹H NMR (400MHz, MeOD). delta.1.62 (d,3H),3.64(s,3H),5.68(q,1H),6.53(dd,1H),6.99(m,2H),7.32(m,2H),7.50(dd,1H),7.93(d,1H),8.03(d, 1H). Chirality: tR 2.500min, mixed chirality：tR＝1.981min,2.480min。

Example 41.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 41)

Scheme 34

Step 1.5-bromo-1- (2-hydroxyethyl) pyridin-2 (1H) -one

To a mixture of 5-bromo-1, 2-dihydropyridin-2-one (2g, 11.49mmol, 1 eq.) and 2-iodoethan-1-ol (4.0g, 22.98mmol, 1.999 eq.) in DMSO (30mL) in a 50-mL round bottom at room temperature was added K₂CO₃(4.8g, 34.47mmol, 2.999 equiv.). The resulting mixture was stirred at room temperature for 16 hours. The reaction was then quenched by the addition of 50mL of water. The resulting solution was extracted with 3X 50mL of ethyl acetate and the organic layers were combined. The resulting organic layer was washed with 3X 50mL of saturated NaCl. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:2) to give 330mg (12%) of 5-bromo-1- (2-hydroxyethyl) -1, 2-dihydropyridin-2-one as a white solid. LCMS M/z (ESI), [ M + H ]⁺＝218.1。¹HNMR (400MHz, chloroform-d) delta 3.93(2H, s),4.08(2H, s),4.41-4.53(1H, m),6.49(1H, d),7.66-7.69(2H, m)

Step 2.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 41)

Placing 5-bromo-1- (2-hydroxyethyl) -1, 2-dihydropyridin-2-one (298.1mg, 1.37mmol, 5 equivalents) in a 50-mL round-bottomed flask,4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (416.6mg, 1.64mmol, 6 equivalents), Pd (dppf) Cl₂(120.0mg, 0.16mmol, 0.60 equiv.), KOAc (80.5mg, 0.82mmol, 3 equiv.), bis

Alkane (15 mL). The resulting solution was stirred in an oil bath for 2 hours at 80 ℃. The resulting mixture was used directly in the next step. To this mixture was added 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (100mg, 0.27mmol, 1 equiv.), Pd (dppf) Cl₂(100.0mg, 0.14mmol, 0.5 equiv.), K₃PO₄(348.2mg, 1.64mmol, 6.00 equiv.), bis

Alkane (15mL) and water (10 mL). The resulting solution was stirred under N₂The reaction was carried out under an atmosphere at 80 ℃ in an oil bath for a further 16 hours. The resulting mixture was concentrated. The resulting solution was extracted with 3X 30mL of ethyl acetate. The organic layer was concentrated. By preparative HPLC with the following conditions (column: Xbridge Prep C18 OBD column, 5 μm, 30X 150 mm; mobile phase A: water (10MMOL/L NH) ₄HCO₃) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 18% B to 42% B within 7 min; 254,220 nm; rt: 6.42min) to purify the crude product. This gave 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- [1- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 41) (20mg, 15.3%). LCMS M/z (ESI), [ M + H]⁺＝469.2。¹HNMR(300MHz,DMSO-d₆)δ3.61-3.63(2H,m),3.91-3.94(2H,m),4.60(2H,d),4.86-4.89(2H,m),6.32-6.35(1H,m),7.04-7.12(2H,m),7.34-7.39(3H,m),7.40-7.41(2H,m),7.45-7.48(1H,m),8.28(1H,s),9.09-9.11(1H,m)。

Example 42.3-amino-N- [ (2, 6-difluorophenyl) methyl]-5-(1,3-

Azol-2-yl) -6- [1- (oxetan-3-yl) -6-oxo-1, 6-dihydropyridin-3-yl]Preparation of pyrazine-2-carboxamide (Compound 42)

Scheme 35

Step 1.5-bromo-1- (oxetan-3-yl) -1, 2-dihydropyridin-2-one

To a stirred mixture of 5-bromo-1, 2-dihydropyridin-2-one (200mg, 1.15mmol, 1 equiv.) and 3-bromooxetane (629.8mg, 4.60mmol, 4 equiv.) in DMF (10mL) at room temperature under an air atmosphere was added K in portions₂CO₃(476.6mg, 3.45mmol, 3 equiv.). The resulting mixture was stirred at 100 ℃ for 3 hours under an air atmosphere. The resulting mixture was poured into water. By CH₂Cl₂The resulting mixture was extracted (2X 100 mL). The combined organic layers were washed with water (1X 30mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (10:1) to give 5-bromo-1- (oxetan-3-yl) -1, 2-dihydropyridin-2-one (120mg, 45.38%) as a white solid. LCMS M/z (ESI), [ M + H ]⁺＝230.0。¹H NMR (400MHz, chloroform-d) δ 4.66-4.74(m,2H),4.96(ddd, J ═ 7.3,6.2,1.0Hz,2H),5.55(tt, J ═ 6.3,5.3Hz,1H),6.71(dd, J ═ 8.8,0.7Hz,1H),7.67(dd, J ═ 8.7,2.5Hz,1H),8.11(dd, J ═ 2.6,0.7, 1H).

Step 2.1- (Oxetan-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan- 2-yl) pyridin-2 (1H) -ones

To 5-bromo-1- (oxetan-3-yl) -1, 2-dihydropyridin-2-one (230mg, 1.00mmol, 1 eq) and 4,4,5, 5-tetramethyl-2- (4,4,5,to a stirred mixture of 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (507.7mg, 2.00mmol, 2 equivalents) in THF (7mL) was added KOAc (294.3mg, 3.00mmol, 3 equivalents) and Pd (dppf) Cl in portions₂(146.3mg, 0.20mmol, 0.2 equiv.). The resulting mixture was stirred at 80 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝278.2。

Step 3.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-5-(1,3-

Azol-2-yl) -6- [1- (Oxetanyl) Alk-3-yl) -6-oxo-1, 6-dihydropyridin-3-yl]Pyrazine-2-carboxamide (Compound 42)

To 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group at room temperature under a nitrogen atmosphere ]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (200mg, 0.55mmol, 1 equiv.) and 1- (oxetan-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (151.6mg, 0.55mmol, 1 equiv.) to a stirred solution/mixture in THF (20mL) was added Pd (dppf) Cl in portions₂(80.0mg, 0.11mmol, 0.20 equiv.) and Cs₂CO₃(534.5mg, 1.64mmol, 3.00 equiv.). The resulting mixture was stirred at 80 ℃ for 3 hours under a nitrogen atmosphere. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30-150 mm 5 μm; mobile phase A: water (0.05% NH)₃ H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 25% B to 50% B within 7 min; 254/220 nm; rt: 5.20min) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-5-(1,3-

Azol-2-yl) -6- [1- (oxetan-3-yl) -6-oxo-1, 6-dihydropyridin-3-yl]Pyrazine-2-carboxamide (5mg, 1.90%) (compound 42). LCMS M/z (ESI), [ M + H]⁺＝481.2。¹H NMR(300MHz,DMSO-d₆)δ4.58(d,J＝5.8Hz,2H),4.66(t,J＝7.0Hz,2H),4.83(t,J＝7.4Hz,2H),5.56(p,J＝7.3Hz,1H),6.37(d,J＝9.4Hz,1H),7.07(t,J＝8.0Hz,2H),7.28～7.45(m,2H),7.60(dd,J＝9.4,2.5Hz,1H),7.75(s,2H),7.96(d,J＝2.5Hz,1H),8.29(d,J＝0.8Hz,1H),9.11(t,J＝5.9Hz,1H)。

Example 45.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) -N- [ (1, 3-thiazol-4-yl) methyl]Preparation of pyrazine-2-carboxamide (Compound 45)

Scheme 36

Step 1.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl ]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid methyl ester Esters

3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1200mg, 4.71mmol, 1 eq.) and 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a]Pyridine (1725.6mg, 7.07mmol, 1.50 equiv.) in bis

To a stirred mixture of alkane (20mL) and water (2mL) was added Pd (dppf) Cl in portions₂(689.7mg, 0.94mmol, 0.2 equiv.) and Cs₂CO₃(3071.0mg, 9.43mmol, 2 equiv.). The resulting mixture was stirred at 90 ℃ overnight. The mixture was allowed to cool to room temperature. Filtering the resulting mixtureThe filter cake was washed with DCM (3X 10 mL). The filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (50:1) elution gave 3-amino-6- [ imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1200mg, 75.71%). LCMS M/z (ESI), [ M + H]⁺＝337。¹H NMR(DMSO-d₆,400MHz)δ3.9(3H,s),7.1(1H,dd,J＝9.4,1.8Hz),7.4(1H,s),7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.2Hz),7.7(2H,s),8.0(1H,s),8.3(1H,s),8.7(1H,t,J＝1.4Hz)

Step 2.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid

Azol-2-yl) pyrazine-2-carboxylic acid methyl ester (2.5g, 7.4mmol, 1 equiv.) to a stirred solution in THF (30mL) was added LiOH (0.2g, 8.4mmol, 1.12 equiv.) and H in portions ₂O (5 mL). The resulting mixture was stirred at room temperature for an additional 4 hours and acidified with 1N aqueous HCl to PH 6, the resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (2g, 83.5%). LCMS M/z (ESI), [ M + H]⁺＝323.2。¹H NMR(DMSO-d₆,400MHz)δ3.9(3H,s),7.1(1H,dd,J＝9.4,1.8Hz),7.4(1H,s),7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.2Hz),7.7(2H,s),8.0(1H,s),8.3(1H,s),8.7(1H,t,J＝1.4Hz)。

Step 3.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (1, 3-thia-zole Oxazol-4-yl) methyl]Pyrazine-2-carboxamide (Compound 45)

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.31mmol, 1 equiv.) and 1- (1, 3-thiazol-4-yl) methylamine (70.9mg, 0.6mmol, 2.0 equiv.) in DMF (3mL) was added HATU (471.9mg, 1.2mmol, 4.0 equiv.) and DIEA (160.4mg, 1.2mmol, 4.0 equiv.) in portions. The resulting mixture was stirred at room temperature for a further 60 min. The resulting mixture was poured into water (30mL), the resulting solid was collected by filtration and slurried with MeOH (16mL), the resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) -N- [ (1, 3-thiazol-4-yl) methyl]Pyrazine-2-carboxamide (compound 45) (43mg, 32.8%). LCMS M/z (ESI), [ M + H ]⁺＝419.2。¹H NMR(DMSO-d₆,400MHz)δ2.6(3H,s),4.6(2H,d,J＝6.2Hz),7.2(1H,s),7.3-7.4(2H,m),7.6(1H,d,J＝9.3Hz),7.8(1H,s),8.0(1H,s),8.0(1H,s),8.3(1H,s),8.9(1H,s),9.3(1H,t,J＝6.1Hz)。

The compounds listed in the table below were prepared using the procedure described for compound 45.

Example 46.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- ((3- (methylamino) pyridin-2-yl) methyl) -5- (meth: (meth)

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 46)

Scheme 37

Step 1.2-cyano-3- (methylamino) pyridine (3- (methyiamino) picolinatotrile)

To a solution of 3-fluoropyridine-2-carbonitrile (500mg, 4.09mmol, 1 eq) in THF (20mL) was added methylamine (190.8mg, 6.14mmol, 1.50 eq) at room temperature. The resulting mixture was stirred at 50 ℃ for 3 hours. The reaction was quenched by the addition of water (10mL) at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to give 3- (methylamino) pyridine-2-carbonitrile (300mg, 55.02%) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝134.0。

Step 2.2- (aminomethyl) -N-methylpyridin-3-amine

To a stirred solution of 3- (methylamino) pyridine-2-carbonitrile (100mg, 0.75mmol, 1 eq) in THF (15mL) at room temperature under a nitrogen atmosphere was added raney nickel (128.7mg, 1.50mmol, 2.00 eq) in portions. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to give 2- (aminomethyl) -N-methylpyridin-3-amine (90mg, 87.35%) as a brown semi-solid. LCMS M/z (ESI), [ M + H ]⁺＝138.0。

Step 3.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- ((3- (methylamino) pyridine- 2-yl) methyl) -5- (C

Azol-2-yl) pyrazine-2-carboxamide (Compound 46)

At room temperature to 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.22mmol, 1 eq) and 2- (aminomethyl) -N-methylpyridin-3-amine (36.8mg, 0.27mmol, 1.20 eq) were added portionwise to a stirred mixture in DMF (10mL) DIEA (86.6mg, 0.67mmol, 3 eq) and T₃P (142.2mg, 0.45mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (40mL) at room temperature. The precipitated solid was collected by filtration and washed with water (10 mL). The product was poorly soluble and purified by wet milling with DMF (5 mL). The resulting yellow solid was collected by filtration, washed with methanol (10mL) and dried under infrared light to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ [3- (methylamino) pyridin-2-yl ] -as a yellow solid]Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 46) (20mg, 19.46%). LCMS M/z (ESI), [ M + H]⁺＝433.2，¹H NMR(300MHz,DMSO-d₆)δ2.74(d,J＝4.5Hz,3H),3.47(s,3H),4.46(d,J＝5.3Hz,2H),5.68(d,J＝5.0Hz,1H),6.33(d,J＝9.4Hz,1H),6.88(d,J＝7.9Hz,1H),7.13(dd,J＝8.0,4.8Hz,1H),7.30-7.47(m,2H),7.69-7.90(m,3H),8.01(d,J＝2.6Hz,1H),8.29(s,1H),9.40(d,J＝5.4Hz,1H)。

Example 47.3-amino-6- (1H-1, 3-benzodiazol-5-yl) -N- [ (3-fluoropyridin-2-yl) methyl ]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 47)

Scheme 38

Step 1.3-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid esters Amides of carboxylic acids

3-amino-6-chloro-5- (1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (2000mg, 8.31mmol, 1 eq) and 1- (3-fluoropyridin-2-yl) methylamine (1572.7mg, 12.47mmol, 1.5 eq) in DMF (20mL) was added DIEA (4297.4mg, 33.25mmol, 4 eq) and T₃P (10579.6mg, 33.25mmol, 4 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was poured into water. The resulting solid was collected by filtration and dried under an infrared lamp to give 3-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl as a yellowish green solid]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (2.2g, 75.89%). LCMS M/z (ESI), [ M + H]⁺＝349.1。¹H NMR(400MHz,DMSO-d₆)δ4.68(dd,J＝5.7,1.7Hz,2H),7.43(dt,J＝8.6,4.4Hz,1H),7.59(s,1H),7.73(ddd,J＝10.0,8.4,1.3Hz,1H),7.92(s,2H),8.38～8.46(m,2H),9.17(t,J＝5.7Hz,1H)。

Step 2.3-amino-6- (1H-1, 3-benzodiazol-5-yl) -N- [ (3-fluoropyridin-2-yl) methyl]-5-(1, 3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 47).

In N₂3-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (100mg, 0.29mmol, 1 equiv.) and 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-1, 3-benzene Oxadiazole (140.0mg, 0.57mmol, 2 equiv.) in 1, 4-bis

Alkane (10mL) and H₂Addition of Cs to O (1mL) solution₂CO₃(186.9mg, 0.57mmol, 2 equiv.) and Pd (dppf) Cl₂(21.0mg, 0.03mmol, 0.1 equiv.). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 24 hours and concentrated in vacuo. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 21% B to 31% B within 7 min; 254/220 nm; rt: 6.45min) to give 3-amino-6- (1H-1, 3-benzooxadiazol-5-yl) -N- [ (3-fluoropyridin-2-yl) methyl as a yellow solid]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 47) (12mg, 16.20%). LCMS M/z (ESI), [ M + H]⁺＝431.1。¹H NMR:(300MHz,DMSO-d₆)δ4.73(m,2H),7.23(dd,1H),7.34(s,1H),7.41(dt,1H),7.55(d,1H),7.72(m,4H),8.19(s,1H),8.30(s,1H),8.38(dt,1H),9.31(t,1H),13.12(s,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 47.

EXAMPLE 48 preparation of 5- (2, 6-Dimethylpyridin-4-yl) -6- (4-fluorophenyl) -N4- (2- ((3-fluoropyridin-2-yl) amino) ethyl) pyrimidine 2, 4-diamine (Compound 48)

Scheme 39

Step 1.6- (aminomethyl) pyridin-2-amine

To a mixture of 6-aminopyridine-2-carbonitrile (100mg, 0.8mmol, 1 eq) and Raney nickel (21.6mg, 0.3mmol, 0.3 eq) in THF (10mL) was added NH dropwise at room temperature ₄OH (1 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for a further 40 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 6- (aminomethyl) pyridin-2-amine (80mg, 77.4%) as a light brown oil, which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝124.3。

Step 2.3-amino-N- [ (6-aminopyridin-2-yl) methyl]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5- (1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 48)

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.3mmol, 1 equiv.) and a stirred solution/mixture of 6- (aminomethyl) pyridin-2-amine (76.4mg, 0.6mmol, 2.0 equiv.) in DMF (3mL) were added HATU (471.9mg, 1.2mmol, 4.0 equiv.) and DIEA (160.4mg, 1.2mmol, 4.0 equiv.) dropwise/portion-wise. The resulting mixture was stirred at room temperature for a further 30 min. The resulting mixture was added dropwise to water. The resulting mixture was filtered and the filter cake was washed with water (3X 10 mL). The crude product was recrystallized from DCM/MeOH (5: 16 mL) to give 3-amino-N- [ (6-aminopyridin-2-yl) methyl ] p-toluenesulfonate as a yellow solid]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 48) (89mg, 66.1%). LCMS M/z (ESI), [ M + H ]⁺＝428.1。¹H NMR(DMSO-d₆,400MHz)δ4.4(2H,d,J＝6.1Hz),5.9(2H,d,J＝6.0Hz),6.3(1H,d,J＝8.1Hz),6.4(1H,d,J＝7.2Hz),7.2(1H,dd,J＝9.4,1.8Hz),7.3(1H,t,J＝7.8Hz),7.4(1H,s),7.5(1H,d,J＝9.4Hz),7.6(1H,d,J＝1.3Hz),7.9(3H,s),8.3(1H,s),8.8(1H,t,J＝1.4Hz),9.3(1H,t,J＝6.2Hz)

Example 49.3-amino-N- ((6-amino-3-fluoropyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 49)

Scheme 40

Step 1. (6-amino-3-fluoropyridin-2-yl) methylcarbamic acid tert-butyl ester

To 6-bromo-5-fluoropyridin-2-amine (19mg, 0.10mmol, 1 eq) and Na at room temperature under a nitrogen atmosphere₂CO₃(42.2mg, 0.40mmol, 4 equiv.) and tert-butyl N- [ (trifluoromethylboryl) methyl]To a stirred mixture of potassium carbamate (70.7mg, 0.30mmol, 3 equiv.) in toluene (20mL) and water (3mL) were added 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (S-Phos) (12.3mg, 0.03mmol, 0.3 equiv.) and Pd (AcO)₂(6.7mg, 0.03mmol, 0.3 equiv.). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 30:1) to give N- [ (6-amino-3-fluoropyridin-2-yl) methyl as a brown solid]Tert-butyl carbamate (130mg, 41.17%). LCMS M/z (ESI), [ M + H]⁺＝242.1。

Step 2.6- (aminomethyl) -5-fluoropyridin-2-amine

To N- [ (6-amino-3-fluoropyridin-2-yl) methyl at room temperature]Tert-butyl carbamate (120mg, 0.50mmol, 1 eq) was added dropwise to a stirred solution in DCM (5mL) to 1, 4-bis

HCl (gas) in alkane (362.7mg, 9.95mmol, 20 equiv.). The resulting mixture was allowed to stand at room temperatureStirred under an air atmosphere for 3 hours. The resulting mixture was concentrated to give 6- (aminomethyl) -5-fluoropyridin-2-amine (100mg, 142.44%) as an off-white solid, which was used in the next step without purification.¹H NMR(300MHz,DMSO-d₆)δ3.98(d,J＝5.8Hz,2H),6.64(dd,J＝9.1,3.3Hz,1H),7.53(t,J＝9.1Hz,1H)。

Step 3.3-amino-N- ((6-amino-3-fluoropyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-di Hydropyridin-3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 49)

To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (90mg, 0.29mmol, 1 equiv.), 6- (aminomethyl) -5-fluoropyridin-2-amine (61.2mg, 0.43mmol, 1.51 equiv.), and DIEA (149.3mg, 1.15mmol, 4.02 equiv.) to a stirred mixture of DMF (10mL) was added T dropwise₃P (182.8mg, 0.57mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of water (40mL) at room temperature. The precipitated solid was collected by filtration and washed with methanol (20mL) to give 3-amino-N- [ (6-amino-3-fluoropyridin-2-yl) methyl ] as a yellow solid]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 49) (30mg, 15.95%). LCMS M/z (ESI), [ M + H ]⁺＝437.2。¹H NMR(300MHz,DMSO-d₆)δ3.48(s,3H),4.50(dd,J＝5.8,2.1Hz,2H),5.85(s,2H),6.20-6.47(m,2H),7.20-7.49(m,3H),7.81(s,2H),8.05(d,J＝2.6Hz,1H),8.31(d,J＝0.8Hz,1H),9.09(t,J＝5.8Hz,1H)。

Example 50.3-amino-N- [ [ 3-fluoro-6- (methylamino) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 50)

Scheme 41

Step 1.6-bromo-5-fluoro-N-methylpyridin-2-amine

To a mixture of (acetoxy) copper acetate (1.64g, 9.03mmol, 2.5 equiv.) and methylboronic acid (540.6mg, 9.03mmol, 2.5 equiv.) in bis (ethyl acetate) at room temperature under an air atmosphere

To a stirred mixture in an alkane (30mL) was added pyridine (1g, 12.64mmol, 3.5 equivalents) and 6-bromo-5-fluoropyridin-2-amine (690mg, 3.61mmol, 1 equivalent) in portions. The resulting mixture was stirred at 100 ℃ for 3 hours under an air atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM (2X 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 4:1) to give 6-bromo-5-fluoro-N-methylpyridin-2-amine (120mg, 16.20%) as a brown solid. LCMS M/z (ESI), [ M + H]⁺＝205.1,207.1。

Step 2. (3-fluoro-6- (methylamino) pyridin-2-yl) methylcarbamic acid tert-butyl ester

Tert-butyl N- [ (trifluoroboranyl) methyl group at room temperature under nitrogen atmosphere]To a stirred mixture of potassium carbamate (346.9mg, 1.46mmol, 3 equivalents) and 6-bromo-5-fluoro-N-methylpyridin-2-amine (100mg, 0.49mmol, 1 equivalent) in toluene (20mL) and water (3mL) was added S-Phos (60.1mg, 0.15mmol, 0.3 equivalents), Pd (AcO) ₂(32.9mg, 0.15mmol, 0.3 equiv.) and Na₂CO₃(206.8mg, 1.95mmol, 4.00 equiv.). The resulting mixture was stirred at 95 ℃ for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 30:1) to purify the residue to give a brown solidBulk N- [ [ 3-fluoro-6- (methylamino) pyridin-2-yl]Methyl radical]Tert-butyl carbamate (90mg, 72.28%). LCMS M/z (ESI), [ M + H]⁺＝256.3。

Step 3.6- (aminomethyl) -5-fluoro-N-methylpyridin-2-amine

To N- [ [ 3-fluoro-6- (methylamino) pyridin-2-yl group at room temperature]Methyl radical]To a stirred solution of tert-butyl carbamate (80mg, 0.31mmol, 1 eq) in DCM (5mL) was added HCl (6m) (228.9mg, 6.28mmol, 20.03 eq) dropwise. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure to give 6- (aminomethyl) -5-fluoro-N-methylpyridin-2-amine (45mg, 98.71%) as an off-white solid.¹H NMR(300MHz,DMSO-d₆)δ,2.82(d,J＝2.5Hz,3H),4.02(dd,J＝5.9,2.2Hz,2H),6.49(d,J＝9.6Hz,1H),7.40(t,J＝8.3Hz,1H)。

And 4. step 4. 3-amino-N- ((3-fluoro-6- (methylamino) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (b 1)

Azol-2-yl) pyrazine-2-carboxamide (Compound 50)

To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.22mmol, 1 eq) and 6- (aminomethyl) -5-fluoro-N-methylpyridin-2-amine (38.1mg, 0.25mmol, 1.10 eq) in DMF (10mL) was added DIEA (86.6mg, 0.67mmol, 3 eq) and (3H3) phosphine (17.9mg, 0.45mmol, 2.00 eq) 50% EA solution dropwise. The resulting mixture was stirred at room temperature under an air atmosphere for 3 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and washed with MeOH (20mL) to give 3-amino-N- [ [ 3-fluoro-6- (methylamino) pyridin-2-yl ] as a yellow solid ]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 50) (25mg, 24.59%). LCMS M/z (ESI), [ M + H]⁺＝451.2。¹H NMR(300MHz,DMSO-d₆)δ2.63(d,J＝4.7Hz,3H),3.43(s,3H),4.51(dd,J＝5.3,2.1Hz,2H),6.21-6.42(m,2H),6.49(p,J＝4.5,4.0Hz,1H),7.22-7.46(m,3H),7.82(s,2H),7.95(d,J＝2.6Hz,1H),8.28(d,J＝0.8Hz,1H),9.21(t,J＝5.2Hz,1H)。

EXAMPLE 52 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (4-fluoro-2-methoxybenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 52)

Scheme 42

Step 1.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (4-fluoro-2-methoxybenzyl) -5- (4-fluoro Preparation of phenyl) pyrazine-2-carboxamide (Compound 52)

To a mixture of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (0.05g, 0.15mmol), (4-fluoro-2-methoxyphenyl) methylamine (0.03g, 0.22mmol) in DMF (5mL) at 20 ℃ were added DIEA (0.06g, 0.44mmol) and HATU (0.06g, 0.15 mmol). The mixture was then stirred at this temperature for 1 hour. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then purified with rp-c18 and concentrated to give the product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (4-fluoro-2-methoxybenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 52) as a white solid (0.04g, yield: 56.9%). LCMS M/z (ESI), [ M + H ]⁺＝476.1。¹H NMR(500MHz,DMSO-d6)δppm 2.3(s,6H),3.9(s,3H),4.5(d,J＝6.3Hz,2H),6.7(td,J＝8.4,2.4Hz,1H),6.9(d,J＝11.2Hz,1H),7.0(s,2H),7.2-7.2(m,3H),7.4(dd,J＝8.8,5.7Hz,2H),9.1(t,J＝6.3Hz,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 52.

EXAMPLE 56 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide (Compound 56)

Scheme 43

Step 1.3 preparation of amino-5, 6-dichloropyrazine-2-carboxylic acid

To a stirred solution of methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (3.6g, 16.29mmol) in MeOH (20mL) at 25 deg.C was added NaOH (1.3g, 32.58 mmol). The mixture was then stirred at this temperature for 16 hours. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then concentrated to give the crude product 3-amino-5, 6-dichloropyrazine-2-carboxylic acid (2.6g, yield: 77.1%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝208.1。

Step 2.5- ((3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yl) oxy) -3-amino-6-chloro-N- (2-methyl) oxy Preparation of oxybenzyl) pyrazine-2-carboxamides

To a mixture of 3-amino-5, 6-dichloropyrazine-2-carboxylic acid (2.5g, 12.08mmol), (2-methoxyphenyl) methylamine (1.99g, 14.5mmol) in DMF (20mL) was added DIEA (4.67g, 36.24mmol) and HATU (4.59g, 12.08mmol) at 20 ℃. The mixture was then stirred at this temperature for 1 hour. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was subsequently purified by chromatography on silica gel The solution was concentrated to give the product 5- ((3H- [1,2, 3) as a white solid]Triazolo [4,5-b]Pyridin-3-yl) oxy) -3-amino-6-chloro-N- (2-methoxybenzyl) pyrazine-2-carboxamide (5g, yield: 97.1%). LCMS M/z (ESI), [ M + H]⁺＝427.2。

Step 3.3-amino-6-chloro-N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamidePreparation of

At 110 deg.C 5- ((3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yl) oxy) -3-amino-6-chloro-N- (2-methoxybenzyl) pyrazine-2-carboxamide (0.2g, 0.47mmol) to a stirred solution in DMF (5mL) was added 1H-pyrazole (0.05g, 0.7mmol) and K₂CO₃(0.33g, 2.35 mmol). The mixture was then stirred at 110 ℃ for 3 hours. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then purified by silica gel chromatography and concentrated to give the product 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide as a white solid (0.14g, yield: 83.3%). LCMS M/z (ESI), [ M + H]⁺＝359.1。

Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1H-pyrazole- Preparation of 1-yl) pyrazine-2-carboxamide (Compound 56)

To 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide (0.07g, 0.2mmol), (2-methoxyphenyl) methylamine (0.07g, 0.29mmol) in bis (hydroxymethyl) formamide at 120 deg.C

To a mixture of alkanes (10mL) was added K₃PO₄(0.12g, 0.59mmol) and Pd₂dba₃(0.02g, 0.02 mmol). The mixture was then stirred at this temperature for 0.5 h. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then concentrated and purified with rp-c18 to give the product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyri-dine as a white solidOxazine-2-carboxamide (compound 56) (0.017g, yield: 20.3%). LCMS M/z (ESI), [ M + H]⁺＝429.5。¹H NMR(500MHz,DMSO-d6)δppm 2.3(s,6H),2.7-2.8(m,2H),3.5(br d,J＝6.0Hz,2H),3.7(s,3H),5.6-5.7(m,1H),6.3(br s,2H),6.6(s,2H)6.7-6.9(m,3H),7.0(br t,J＝8.7Hz,2H),7.2(br t,J＝7.1Hz,3H)。

EXAMPLE 57.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide (Compound 57) preparation

Scheme 44

Step 1.2 preparation of cyano-3- (difluoromethoxy) pyridine

To a stirred solution of 2-cyano-3-hydroxypyridine (2.2g, 18.33mmol) in ACN (10mL) and water at-78 deg.C was added dimethyl (bromodifluoromethyl) phosphonate (8.72g, 36.66mmol) and KOH (3.08g, 54.99 mmol). The mixture was then stirred at-78 ℃ for 16 hours. LCMS showed reaction completion. Water was added and extracted with EA and concentrated to give 2-cyano-3- (difluoromethoxy) pyridine as a dark oil. LCMS M/z (ESI), [ M + H ]⁺＝171.4。

Step 2 preparation of (3- (difluoromethoxy) pyridin-2-yl) methylamine

To a stirred solution of 2-cyano-3- (difluoromethoxy) pyridine (1.5g, 8.82mmol) in THF (20mL) at 0 deg.C was added LiAlH₄(0.5g, 13.23 mmol). The mixture was then stirred at 0 ℃ for 1 hour. LCMS showed desired product. Water was added and extracted with EA. Concentration gave a yellow oil. LCMS M/z (ESI), [ M + H]⁺＝175.1。

Step 3.3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -6- (2, 6-dimethylpyridine-4- Preparation of yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 57)

To 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorobenzene at 20 deg.CYl) pyrazine-2-carboxylic acid (0.03g, 0.09mmol),(3- (difluoromethoxy) pyridin-2-yl) methylamine(0.02g, 0.13mmol) to a mixture in DMF (5mL) were added DIEA (0.03g, 0.27mmol) and HATU (0.03g, 0.09 mmol). The mixture was then stirred at this temperature for 1 hour. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then purified with rp-c18 and concentrated to give the product 3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 57) as a white solid (0.03g, yield: 68.4%). LCMS M/z (ESI), [ M + H ]⁺＝495.6。¹H NMR(500MHz,DMSO-d6)δppm 2.3(s,6H),4.7(d,J＝6.0Hz,2H),7.0(s,2H),7.2-7.3(m,3H),7.3-7.5(m,4H),7.7(d,J＝8.5Hz,1H),8.4(d,J＝3.5Hz,1H),9.2(t,J＝5.7Hz,1H)。

EXAMPLE 58 preparation of 3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 58)

Scheme 45

Step 1.3-amino-6-chloro-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) pyri-dine Preparation of oxazine-2-carboxamides

To a mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (0.12g, 0.45mmol), (3- (difluoromethoxy) pyridin-2-yl) methylamine (0.08g, 0.45mmol) in DMF (5mL) was added DIEA (0.17g, 1.35mmol) and HATU (0.17g, 0.45mmol) at 20 ℃. The mixture was then stirred at this temperature for 1 hour. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then purified with rp-c18 and concentrated to give the product 3-amino-6-chloro-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide as a white solid (0.07g, yield: 36.8%)。LCMS:m/z(ESI),[M+H]⁺＝424.2。

Step 2.3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) -6- (1-methyl) Preparation of 1, 6-dihydropyridin-3-yl-6-oxo-2-pyrazinecarboxamide (Compound 58)

To 3-amino-6-chloro-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (0.06g, 0.14mmol), 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.05g, 0.21mmol) in bis (I) at 120 deg.C

To the mixture in alkane (3mL) was added K₃PO₄(0.09g, 0.43mmol) and Pd₂dba₃(0.01g, 0.01 mmol). The mixture was then stirred at this temperature for 0.5 h. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then concentrated and purified with RP-C18 to give the product 3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 58) as a white solid (0.025g, yield: 35.5%). LCMS M/z (ESI), [ M + H]⁺＝497.2。¹H NMR(500MHz,DMSO-d6)δppm 3.4(s,3H),4.7(d,J＝5.7Hz,2H),6.2(d,J＝9.5Hz,1H),7.1(dd,J＝9.5,2.5Hz,1H),7.2-7.3(m,3H),7.4(s,1H),7.4(dd,J＝8.5,4.7Hz,1H),7.5-7.6(m,3H),7.7(d,J＝8.2Hz,1H),8.0(d,J＝2.5Hz,1H),8.4(d,J＝4.4Hz,1H),9.2(t,J＝6.0Hz,1H)。

EXAMPLE 59 preparation of 3-amino-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 59)

Scheme 46

Step 1.3-amino-6-chloro-N-(2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) pyri-dine Preparation of oxazine-2-carboxamides

To a mixture of 3-amino-6-chloro-5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxylic acid (0.1g, 0.4mmol), 2- (difluoromethoxy) aniline (0.1g, 0.59mmol) in DMF (5mL) was added DIEA (0.15g, 1.19mmol) and HATU (0.15g, 0.4mmol) at 20 ℃. The mixture was then stirred at this temperature for 1 hour. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then purified with rp-c18 and concentrated to give the product 3-amino-6-chloro-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide as a white solid (0.05g, yield: 30.7%). LCMS M/z (ESI), [ M + H]⁺＝413.4。

Step 2.3-amino-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) -6- (1-methyl) Preparation of 1, 6-dihydropyridin-3-yl-6-oxo-2-pyrazinecarboxamide (Compound 59)

To 3-amino-6-chloro-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (0.03g, 0.07mmol), 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.03g, 0.11mmol) in bis (N, N-dimethylformamide) at 120 deg.C

To the mixture in alkane (3mL) was added K ₃PO₄(0.05g, 0.22mmol) and Pd₂dba₃(0.01g, 0.01 mmol). The mixture was then stirred at this temperature for 0.5 h. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then concentrated and purified with rp-c18 to give the product 3-amino-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 59) as a white solid (0.02g, yield: 56.6%). LCMS M/z (ESI), [ M + H]⁺＝486.1。¹H NMR(500MHz,DMSO-d6)δppm 2.2(s,3H),3.5(s,3H),6.3(d,J＝9.5Hz,1H),6.4(d,J＝2.5Hz,1H),7.0(dd,J＝9.5,2.5Hz,1H),7.1-7.5(m,5H),7.8-7.9(m,2H),8.1(d,J＝2.2Hz,1H),8.3-8.3(m,1H),10.3(s,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 59.

EXAMPLE 61.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (5-methylfuran-3-yl) pyrazine-2-carboxamide (Compound 61) preparation

Scheme 47

Step 1.3 preparation of methyl 3-amino-6-chloro-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (0.5g, 2.26mmol), 4,5, 5-tetramethyl-2- (5-methylfuran-2-yl) -1,3, 2-dioxaborolane (0.71g, 3.39mmol) in bis (N-methyl-ethyl-L-methyl-2-oxolane at 100 deg.C

To the mixture in alkane (20mL) was added Na₂CO₃(0.94g, 4.53mmol) and Pd (dppf) Cl₂(0.83g, 1.13 mmol). The mixture was then stirred at this temperature for 2 hours. LCMS showed the reaction was complete and purified by silica gel chromatography to afford the desired product methyl 3-amino-6-chloro-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate. LCMS M/z (ESI), [ M + H ]⁺＝268.4。

Step 2.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid Preparation of methyl esters

To methyl 3-amino-6-chloro-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (0.26g, 1mmol), 2, 6-dimethyl-4- (4,4, 5) at 100 deg.C-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.23g, 1mmol) in bis

To the mixture in alkane (20mL) was added Na₂CO₃(0.94g, 4.53mmol) and Pd (dppf) Cl₂(0.073g, 0.1 mmol). The mixture was then stirred at this temperature for 2 hours. LCMS showed the reaction was complete and purified by silica gel chromatography to afford the desired product methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylate. LCMS M/z (ESI), [ M + H]⁺＝339.5。

Step 3.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid Preparation of

To a stirred solution of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylate (0.4g, 1.18mmol) in MeOH (20mL) at 25 ℃ was added NaOH (0.09g, 2.37 mmol). The mixture was then stirred at this temperature for 16 hours. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 10 mL). The organic solution was then concentrated to give the crude product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid as a yellow solid (0.3g, yield: 78.2%). LCMS M/z (ESI), [ M + H ]⁺＝325.2。

Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (5-methylfuran Preparation of pyran-2-yl) pyrazine-2-carboxamide (Compound 61)

To a mixture of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid (0.05g, 0.15mmol), (2-methoxyphenyl) methylamine (0.021g, 0.15mmol) in DMF (5mL) was added DIEA (0.058g, 0.45mmol) and HATU (0.057g, 0.15mmol) at 20 ℃. The mixture was then stirred at this temperature for 1 hour. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was subsequently purified using rp-c18The solution was concentrated to give the product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxamide (compound 61) as a white solid (0.021g, yield: 32%). LCMS M/z (ESI), [ M + H]⁺＝444.1。¹H NMR(500MHz,DMSO-d6)δppm 2.2(s,3H),2.4(s,6H),3.8(s,3H),4.5(d,J＝6.3Hz,2H),6.2(d,J＝3.2Hz,1H),6.5(d,J＝3.2Hz,1H),6.9(t,J＝7.4Hz,1H),7.0(d,J＝8.2Hz,1H),7.1-7.2(m,3H),7.2(t,J＝7.1Hz,1H),8.9(t,J＝6.3Hz,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 61.

EXAMPLE 63.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxamide (Compound 63) preparation

Scheme 48

Step 1.3 preparation of methyl 3-amino-6-chloro-5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (0.5g, 2.26mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid (0.43g, 3.39mmol) in bis (hydroxymethyl) phosphonium bromide at 100 deg.C

To the mixture in alkane (20mL) was added Na₂CO₃(0.57g, 4.53mmol) and Pd (dppf) Cl₂(0.83g, 1.13 mmol). The mixture was then stirred at this temperature for 2 hours. LCMS showed the reaction was complete and purified by silica gel chromatography to afford the desired product methyl 3-amino-6-chloro-5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate. LCMS M/z (ESI), [ M + H]⁺＝268.6。

Step 2.3-amino-6- (2, 6)-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazin-2-one Preparation of methyl formate

To methyl 3-amino-6-chloro-5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate (0.4g, 1.5mmol), (2, 6-dimethylpyridin-4-yl) boronic acid (0.34g, 2.25mmol) in dipyridyl-bis (hydroxymethyl) borate at 100 deg.C

To the mixture in alkane (20mL) was added Na₂CO₃(0.45g, 3mmol) and Pd (dppf) Cl₂(0.55g, 0.75 mmol). The mixture was then stirred at this temperature for 2 hours. LCMS showed the reaction was complete and purified by silica gel chromatography to afford the desired product methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate. LCMS M/z (ESI), [ M + H]⁺＝339.2。

Step 3.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazin-2- Preparation of formic acid

To a stirred solution of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate (0.4g, 1.18mmol) in MeOH (20mL) at 25 ℃ was added NaOH (0.09g, 2.37 mmol). The mixture was then stirred at this temperature for 16 hours. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 10 mL). The organic solution was then concentrated to give the crude product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylic acid as a yellow solid (0.3g, yield: 78.2%). LCMS M/z (ESI), [ M + H]⁺＝325.5。

Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1-methyl- Preparation of 1H-pyrazol-4-yl) pyrazine-2-carboxamide (Compound 63)

To 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylic acid (0.05g, 0.15mmol), (2-methoxyphenyl) methylamine (0.021g, 0.15mmol) in DMF (5mL) at 20 deg.CDIEA (0.058g, 0.45mmol) and HATU (0.057g, 0.15mmol) were added to the mixture. The mixture was then stirred at this temperature for 1 hour. LCMS showed reaction completion. The mixture was then concentrated and the residue poured into water and then extracted with EA (2 × 25 mL). The organic solution was then purified with rp-c18 and concentrated to give the product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxamide (compound 63) as a white solid (0.004g, yield: 6%). LCMS M/z (ESI), [ M + H ]⁺＝444.2。¹H NMR(500MHz,DMSO-d6)δppm 2.2(s,3H),2.4(s,6H),3.8(s,3H),4.5(d,J＝6.3Hz,2H),6.2(d,J＝3.2Hz,1H),6.5(d,J＝3.2Hz,1H),6.9(t,J＝7.4Hz,1H),7.0(d,J＝8.2Hz,1H),7.1-7.2(m,3H),7.2(t,J＝7.1Hz,1H),8.9(t,J＝6.3Hz,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 63.

EXAMPLE 72 preparation of 3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 72)

Scheme 49

Step 1.3 preparation of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (4.4g, 19.91mmol), 2- (4-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (3.07g, 21.9mmol) in bis (ethyl acetate)

To a mixture of alkane (50mL) and water (5mL) was added Na₂CO₃(4.22g, 39.82mmol) and dppfPdCl₂(2.84g, 3.98 mmol). Then mixingThe compound is at 100 ℃ under N₂Stirred under atmosphere for 1 hour. The mixture was then concentrated and the residue poured into water (100mL) and then extracted with EA (100mL × 3). The organic solution was then concentrated to give the crude product as a yellow solid (5.5g, 98% yield), which was used in the next step without further purification. MS M/z (ESI) [ M + H ]]⁺＝282.2。

Step 2.3 preparation of amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid

To a mixture of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (1.1g, 3.9mmol) in methanol (5mL) and water (3mL) was added LiOH (0.3g, 12 mmol). The mixture was then stirred at 20 ℃ for 3 hours. The mixture was then diluted by citric acid solution (2N, 50mL) and then filtered. The solid was dried to give 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid as a yellow solid (0.95g, 91% yield). MS M/z (ESI) [ M + H ] ]⁺＝268.2。

Step 3.3-amino-6-chloro-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide Preparation of

To a mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (100mg, 0.37mmol), (2- (difluoromethoxy) phenyl) methylamine (80mg, 0.46mmol), and DIEA (100mg, 0.78mmol) in DMF (3mL) was added HATU (200mg, 0.53mmol) at 20 ℃. The resulting mixture was stirred at 20 ℃ for 10 min. The mixture was purified by C18-40 g (MeCN/water ═ 5% to 80%) to give 3-amino-6-chloro-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide as a yellow solid (120mg, 76% yield). MS M/z (ESI) [ M + H ]]⁺＝423.3。

Step 4.3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo- Preparation of 1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 72)

To 3-amino-6-chloro-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (90mg, 0.21mmol), 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl-cyclopentane-yl) pyridin-2 (1H) -one (50mg, 0.21mmol), Pd₂(dba)₃(8mg, 0.0087mmol), tricyclohexylphosphine (11mg, 0.039mmol) and K₃PO₄(75mg, 0.35mmol) in bis

To the mixture in alkane (3mL) was added water (1 mL). The resulting mixture was sealed and heated in a microwave at 120 ℃ for 15 min. The mixture was filtered and the filtrate was purified by C18-40 g (MeCN/water ═ 5% -80%) to give 3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 72) as a yellow solid (82mg, 78% yield). LCMS M/z (ESI), [ M + H ]⁺＝496.3。¹H NMR(500MHz,DMSO-d6)δppm 3.42(s,3H),4.57(d,J＝6.31Hz,2H),6.20(d,J＝9.46Hz,1H),7.10(dd,J＝9.30,2.68Hz,1H),7.16-7.30(m,5H),7.30-7.36(m,2H),7.44-7.83(m,3H),7.64(br d,J＝16.08Hz,1H),7.99(d,J＝2.52Hz,1H),9.23(t,J＝6.31Hz,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 72.

EXAMPLE 75.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (Compound 75) preparation

Scheme 50

Step 1.3-amino-6-chloro-N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2- Preparation of carboxamides

To 5- ((3H- [1,2, 3)]Triazolo [4,5-b]Mixing pyridin-3-yl) oxy) -3-amino-6-chloro-N- (2-methoxybenzyl) pyrazine-2-carboxamide (500mg, 1.2mmol) in DMF (5mL)To the mixture were added 3-methyl-1H-pyrazole (120mg, 1.5mmol) and K₂CO₃(350mg, 2.5 mmol). The resulting mixture was heated at 120 ℃ for 1 hour. The mixture was purified by C18-40g (MeCN/water ═ 5% to 80%) to give 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (200mg, 46% yield) and 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (5-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (40mg, 7% yield) as yellow solids. LCMS M/z (ESI) [ M + H ]]⁺＝373.2。

Step 2.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (3-methyl- Preparation of 1H-pyrazol-1-yl) pyrazine-2-carboxamide (Compound 75)

To 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (45mg, 0.12mmol), (2, 6-dimethylpyridin-4-yl) boronic acid (20mg, 0.13mmol), Pd₂(dba)₃₍7mg, 0.0076mmol), tricyclohexylphosphine (13mg, 0.046mmol) and K₃PO₄(45mg, 0.21mmol) in bis

To the mixture in alkane (3mL) was added water (1 mL). The resulting mixture was sealed and heated in a microwave at 120 ℃ for 15 min. The mixture was filtered and the filtrate was purified by C18-40 g (MeCN/water 5% -80%) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (compound 75) as a white solid (36mg, 67% yield). LCMS M/z (ESI), [ M + H]⁺＝444.3。¹H NMR(500MHz,DMSO-d6)δppm2.10(s,3H),2.34(s,6H),3.84(s,3H),4.50(d,J＝6.31Hz,2H),6.34(d,J＝2.52Hz,1H),6.86(s,2H),6.89(t,J＝7.41Hz,1H),7.00(d,J＝8.20Hz,1H),7.15(d,J＝7.25Hz,1H),7.23(t,J＝7.90Hz,1H),7.98(d,J＝2.21Hz,3H),9.04(t,J＝6.42Hz,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 75.

EXAMPLE 77 preparation of 3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 77)

Scheme 51

Step 1.5 preparation of bromo-1- (oxetan-3-yl) pyridin-2 (1H) -one

To a mixture of 5-bromopyridin-2 (1H) -one (1.2g, 6.9mmol) in DMF (10mL) was added 3-iodooxetane (1.3g, 7.1mmol) and Cs ₂CO₃(2.7g, 8.3 mmol). The resulting mixture was heated at 100 ℃ for 4 hours. The mixture was filtered and the filtrate was purified by C18-40 g (MeCN/water 5% -40%) to give 5-bromo-1- (oxetan-3-yl) pyridin-2 (1H) -one (310mg, 20% yield) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝230.1。

Step 2.1- (Oxetan-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan- Preparation of 2-yl) pyridin-2 (1H) -ones

To 5-bromo-1- (oxetan-3-yl) pyridin-2 (1H) -one (260mg, 1.1mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (300mg, 1.2mmol) and PdCl₂(dppf) (30mg, 0.041mmol) in bis

KOAc (250mg, 2.6mmol) was added to the mixture in an alkane (5 mL). The mixture was then heated in a microwave at 90 ℃ for 30 min. The mixture was then diluted with water (50mL) and extracted with EA (50 mL). By means of brine and anhydrous Na₂SO₄To dry the organic layer, followed by concentration, the crude product was obtained as a brown solid (250mg, 80% yield). MS M/z (ESI)278.3[ M + H ]]⁺。

Step 3.3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo- Preparation of 1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 77)

To 1- (oxetan-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (20mg, 0.072mmol), 3-amino-6-chloro-N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (35mg, 0.89mmol), Pd₂(dba)₃(7mg, 0.0076mmol), tricyclohexylphosphine (13mg, 0.046mmol) and K₃PO₄(45mg, 0.21mmol) in bis

To the mixture in alkane (3mL) was added water (1 mL). The resulting mixture was sealed and heated in a microwave at 120 ℃ for 15 min. The mixture was filtered and the filtrate was purified by C18-40 g (MeCN/water ═ 5% -80%) to give 3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 77) as a yellow solid (21mg, 57% yield). LCMS M/z (ESI), [ M + H]⁺＝508.3。¹H NMR(500MHz,DMSO-d6)δppm 4.30(s,2H),4.64(t,J＝6.94Hz,2H),4.94(t,J＝7.41Hz,2H),5.62(quin,J＝7.01Hz,1H),6.40(d,J＝9.14Hz,1H),6.99(br t,J＝7.72Hz,2H),7.10(br t,J＝8.67Hz,2H),7.24(dd,J＝9.46,2.21Hz,1H),7.30-7.37(m,1H),7.54(br dd,J＝8.51,5.36Hz,2H),7.86(d,J＝2.21Hz,1H)。

EXAMPLE 78 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-fluorophenylmethyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 78)

Scheme 52

3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-fluorophenylmethyl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid Preparation of the amine (Compound 78)

To a stirred mixture of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (20mg, 0.059mmol), (2-fluorophenyl) methylamine (7.4mg, 0.059mmol) and DIPEA (15mg, 0.118mmol) was added HATU (25mg, 0.065mmol) in one portion at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solution was purified by C18-40 g (MeCN/water 0% -80%) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-fluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 78) (16.3mg, 61.94% yield) as an off white solid. LCMS M/z (ESI), [ M + H ]⁺＝446.4。¹H NMR(500MHz,CDCl₃)δppm 1.9(brs,2H),2.5(s,6H),4.7(d,J＝6.3Hz,2H),6.9(s,2H),7.0(t,J＝8.7Hz,2H),7.1-7.2(m,2H),7.25-7.30(m,1H),7.3-7.4(m,3H),8.3(brt,J＝6.1Hz,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 78.

EXAMPLE 82 preparation of 3-amino-6- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (Compound 82)

Scheme 53

3-amino-6-chloro-5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (30mg, 0.078mmol), 1, 3-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (23mg, 0.093mmol) and K₃PO₄(28mg, 0.132mmol) in bis

Suspension in alkane (1.50 mL)/water (0.375mL) with N₂Purged and degassed 3 times, then added Pcy₃(6.5mg, 0.023mmol) and Pd₂(dba)₃(7mg, 0.008 mmol). The resulting mixture was again treated with N₂Purge and degas 3 times. The reaction mixture was sealed and heated at 120 ℃ for 1 hour by means of a microwave reactor. The solution was filtered and evaporated under reduced pressure. The residue was purified by C18-40 g flash chromatography, eluting with a gradient of 0% to 60% MeCN/water (0.05% ammonia hydroxide) to give 3-amino-6- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (compound 82) as a yellow solid (25mg, 68.08% yield). LCMS M/z (ESI), [ M + H ]⁺＝474.4。¹H NMR(500MHz,CDCl₃)δppm 1.7(s,2H),2.1(s,3H),3.5(s,3H),3.9(s,3H),4.7(d,J＝6.3Hz,2H),6.9(d,J＝8.2Hz,1H),6.9(t,J＝7.4Hz,1H),7.1(t,J＝8.7Hz,2H),7.1(d,J＝2.2Hz,1H),7.2(s,1H),7.3-7.3(m,1H),7.3-7.4(m,1H)7.5(dd,J＝8.8,5.4Hz,2H),8.4(brt,J＝6.0Hz,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 82. .

EXAMPLE 83.3-amino-6- (2-amino-6-methylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (Compound 83)

Scheme 54

(2-amino-6-methylpyridin-4-yl) boronic acidPreparation of

4-bromo-6-methylpyridin-2-amine (80mg, 0.428mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (130mg, 0.513mmol) and KOAc (50mg, 0.51mmol) in bis

Suspension in alkane (4mL) with N₂Purged and degassed 3 times, followed by addition of PdCl₂(dppf) (16mg, 0.021 mmol). The resulting mixture was again treated with N₂Purge and degas 3 times. The reaction mixture was sealed and heated at 100 ℃ for 16 hours. The solution was filtered and evaporated under reduced pressure to give (2-amino-6-methylpyridin-4-yl) boronic acid (96mg, crude material), which was used in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝153.3

Step 2.3-amino-6- (2-amino-6-methylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) Yl) pyrazine-2-carboxamide (Compound 83)

3-amino-6-chloro-5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (30mg, 0.078mmol), (2-amino-6-methylpyridin-4-yl) boronic acid (48mg, 0.093mmol) and K ₃PO₄(48mg, 0.244mmol) in Ethans

Suspension in alkane (1.50 mL)/water (0.37mL) with N₂Purged and degassed 3 times, then added Pcy₃(6.5mg, 0.023mmol) and Pd₂(dba)₃(7mg, 0.008 mmol). The resulting mixture was again treated with N₂Purge and degas 3 times. The reaction mixture was sealed and heated at 120 ℃ for 1 hour by means of a microwave reactor. The solution was filtered and evaporated under reduced pressure. The residue was purified by C18-40 g flash chromatography, eluting with a gradient of 0% to 100% MeCN/water (0.05% ammonia hydroxide) to give 3-amino-6- (2-amino-6-methylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (compound 83) as an off-white solid (7.6mg, 21.3% yield). LCMS M/z (ESI), [ M + H]⁺＝495.3。¹H NMR(500MHz,CDCl₃)δppm 1.9(brs,2H),2.3(s,3H),3.9(s,3H),4.7(d,J＝6.3Hz,2H),4.7(brs,2H),6.3(s,1H),6.5(s,1H),6.9(d,J＝8.2Hz,1H),6.9-7.0(m,1H),7.0(t,J＝8.5Hz,2H),7.3-7.4(m,2H),7.4-7.5(m,2H),8.4(brt,J＝6.1Hz,1H)。

EXAMPLE 86. preparation of N- ((3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl) methyl) -2-methoxybenzamide (Compound 86)

Scheme 55

Step 1.3 preparation of amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile

To 3-amino-5, 6-dichloropyrazine-2-carbonitrile (300mg, 1.5mmol) and (4-fluorophenyl) boronic acid (233mg, 1.6mmol) in bis

2M Na was added to a solution in alkane (14mL)₂CO₃(1.6mL) in the reaction. The mixture obtained is treated with N₂Purged and degassed 3 times, followed by addition of PdCl ₂(dppf) (58mg, 0.079 mmol). The resulting mixture was again treated with N₂Purge and degas 3 times. The resulting mixture was heated at 80 ℃ for 6 hours under a nitrogen balloon atmosphere. The reaction was diluted with water (20mL) and extracted with EtOAc (3X 20 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and the filtrate evaporated under reduced pressure to give 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (395mg, crude material) as a brown solid. LCMS M/z (ESI), [ M + H]⁺＝249.2。

Step 2.3 preparation of amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carbonitrile

3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (395mg, 1.5mmol) and (2, 6-dimethylpyridin-4-yl) boronic acid (288mg, 1.9mmol) in Di

Solution in alkane (14 mL). Followed by addition of 2M Na₂CO₃(1.6mL) was added to the reaction. The mixture obtained is treated with N₂Purged and degassed 3 times, followed by addition of PdCl₂(dppf) (58mg, 0.079 mmol). The resulting mixture was again treated with N₂Purge and degas 3 times. Mixing the obtained mixture inHeated at 90 ℃ for 16 hours under a nitrogen balloon atmosphere. The reaction was diluted with water (20mL) and extracted with EtOAc (3X 20 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and the filtrate evaporated under reduced pressure and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 10/1-3/1(v/v)) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carbonitrile (311mg, 61% yield) as a brown solid. LCMS M/z (ESI), [ M + H ]⁺＝320.3。

Step 3.3 preparation of 3- (aminomethyl) -5- (2, 6-dimethylpyridin-4-yl) -6- (4-fluorophenyl) pyrazin-2-amine

A solution of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carbonitrile (60mg, 0.188mmol) in anhydrous THF (0.5mL) was added dropwise to LiAlH by ice/water bath at 0 deg.C₄(14mg, 0.376mmol) in dry THF (1.5mL) with stirring. The reaction was slowly warmed to room temperature and stirred at room temperature for 16 hours. The reaction was diluted with anhydrous THF (10mL) and cooled by an ice/water bath at 0 ℃ with stirring. Sodium sulphate decahydrate (500mg, three portions) was then added and the resulting mixture was stirred at this temperature for 30min, then filtered and the filtrate was concentrated in vacuo to give 3- (aminomethyl) -5- (2, 6-dimethylpyridin-4-yl) -6- (4-fluorophenyl) pyrazin-2-amine (50mg, 82% yield) as a brown oil. LCMS M/z (ESI), [ M + H]⁺＝324.4

Step 4.N- ((3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl) methyl) - Preparation of 2-methoxybenzamide (Compound 86)

A solution of 3- (aminomethyl) -5- (2, 6-dimethylpyridin-4-yl) -6- (4-fluorophenyl) pyrazin-2-amine (50mg, 0.15mmol) and TEA (47mg, 0.46mmol) in NMP (1mL) was cooled at 0 ℃ by an ice/water bath and a solution of 2-methoxybenzoyl chloride (26mg, 0.155mmol) in NMP (1.0mL) was subsequently added dropwise to the reaction. The resulting mixture was stirred and slowly warmed to room temperature for 2 hours. The solution was purified by C18-40 g flash chromatography, elution gradient 0% to 50% MeCN/water (0.05% ammonium hydroxide) to give N- ((3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorobenzene) as an off-white solid Yl) pyrazin-2-yl) methyl) -2-methoxybenzamide (compound 86) (15mg, 46% yield). LCMS M/z (ESI), [ M + H]⁺＝458.3。¹H NMR(500MHz,CDCl₃)δppm 2.5(s,6H),3.9(s,3H),4.8(d,J＝6.3Hz,2H),6.0(brs,2H),6.9(s,2H),7.0-7.0(m,3H),7.1-7.1(m,1H),7.3-7.4(m,2H),7.5-7.5(m,1H),8.3(dd,J＝7.9,1.6Hz,1H),8.7(brt,J＝6.0Hz,1H)

EXAMPLE 87 preparation of 3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 87)

Scheme 56

Step 1.3 preparation of amino-6-chloro-N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide

To a stirred mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (200mg, 0.74mmol), (2, 6-difluorophenyl) methylamine (107mg, 0.74mmol), and DIPEA (93mg, 1.49mmol) was added HATU (313mg, 0.82mmol) in one portion at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solution was purified by C18-40 g (MeCN/water 0% -60%) to give 3-amino-6-chloro-N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide as a yellow solid (290mg, 99% yield). LCMS M/z (ESI), [ M + H]⁺＝393.2。

Step 2.3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- (2, 6-difluorobenzyl) Preparation of yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 87)

3-amino-6-chloro-N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (50mg, 0.12mmol), 1-cyclopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (40mg, 0.15mmol) and K ₃PO₄(46mg, 0.21mmol) in bis

Suspension in alkane (2.0 mL)/water (0.4mL) with N₂Purged and degassed 3 times, then added Pcy₃(11mg, 0.039mmol) and Pd₂(dba)₃(12mg, 0.013 mmol). The resulting mixture was again treated with N₂Purge and degas 3 times. The reaction mixture was sealed and heated at 120 ℃ for 15min by means of a microwave reactor. The solution was filtered and evaporated under reduced pressure. The residue was purified by C18-40 g flash chromatography, eluting with a gradient of 0% to 70% MeCN/water (0.05% ammonia hydroxide) to give 3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 87) as a yellow solid (40mg, 64% yield). LCMS M/z (ESI), [ M + H]⁺＝492.3 ¹H NMR(500MHz,CDCl₃)δppm 0.5-0.7(m,2H),0.9-1.2(m,2H)1.6(brs,2H),3.2-3.4(m,1H),4.8(d,J＝6.3Hz,2H),6.5(d,J＝9.1Hz,1H),6.9(t,J＝7.9Hz,2H),7.1(t,J＝8.5Hz,2H),7.2-7.3(m,1H),7.3-7.3(m,2H),7.4-7.5(m,2H),8.2(brt,J＝6.3Hz,1H)。

EXAMPLE 88. preparation of N- ((3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl) methyl) -2, 6-difluorobenzamide (Compound 88)

Scheme 57

Step 1.3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2- Preparation of carbonitrile

To 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (395mg, 1.587mmol) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (448mg, 1.905mmol) in bis

2M Na was added to a solution in alkane (14mL)₂CO₃(336mg, 1.6mL) was in the reaction. The mixture obtained is treated with N₂Purging and degassing 3 times, followed byAddition of PdCl₂(dppf) (58mg, 0.079 mmol). The resulting mixture was again treated with N₂Purge and degas 3 times. The resulting mixture was heated at 90 ℃ under a nitrogen balloon atmosphere for 16 hours. The reaction was diluted with water (20mL) and extracted with EtOAc (3X 20 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and the filtrate evaporated under reduced pressure and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 10/1-3/1(v/v)) to give 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carbonitrile as a brown solid (235mg, 46% yield). LCMS M/z (ESI), [ M + H]⁺＝322.3。

Step 2.5- (5-amino-6- (aminomethyl) -3- (4-fluorophenyl) pyrazin-2-yl) -1-methylpyridine-2 (1H) - Preparation of ketones

A solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carbonitrile (51mg, 0.159mmol) in anhydrous THF (0.5mL) was added dropwise to LiAlH by ice/water bath at 0 deg.C₄(12mg, 0.317mmol) in dry THF (1.5mL) with stirring. The reaction was slowly warmed to room temperature and stirred at room temperature for 16 hours. The reaction was diluted with anhydrous THF (10mL) and cooled by an ice/water bath at 0 ℃ with stirring. Sodium sulfate decahydrate (500mg, triplicate) was then added and the resulting mixture was stirred at this temperature for 30min, then filtered and the filtrate was concentrated in vacuo to give 5- (5-amino-6- (aminomethyl) -3- (4-fluorophenyl) pyrazin-2-yl) -1-methylpyridin-2 (1H) -one as a brown oil (52mg, 100% yield). LCMS M/z (ESI), [ M + H ]⁺＝326.5

Step 3.N- ((3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyridine Preparation of oxazin-2-yl) methyl) -2, 6-difluorobenzamide (Compound 88)

A solution of 5- (5-amino-6- (aminomethyl) -3- (4-fluorophenyl) pyrazin-2-yl) -1-methylpyridin-2 (1H) -one (52mg, 0.16mmol) and TEA (49mg, 0.48mmol) in NMP (1mL) was cooled at 0 ℃ by an ice/water bath, and a solution of 2, 6-difluorobenzoyl chloride (34mg, 0.19mmol) in NMP (1.0mL) was subsequently added dropwise to the reaction. Stirring the obtained mixtureStir and warm slowly to room temperature for 2 hours. The solution was purified by C18-40 g flash chromatography, eluting with a gradient of 0% to 60% MeCN/water (0.05% ammonia hydroxide) to give N- ((3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl) methyl) -2, 6-difluorobenzamide (compound 88) as an off white solid (8mg, 11% yield). LCMS M/z (ESI), [ M + H]⁺＝466.3。¹H NMR(500MHz,CDCl₃)δppm3.5(s,3H),4.8(d,J＝6.3Hz,2H),5.5(brs,2H),6.4(d,J＝9.5Hz,1H),7.0-7.0(m,3H),7.1(t,J＝8.7Hz,2H),7.1(dd,J＝9.5,2.5Hz,1H),7.4-7.5(m,4H)。

EXAMPLE 89 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (Compound 89)

Scheme 58

To a mixture of alkane (50mL) and water (5mL) was added Na₂CO₃(4.22g, 39.82mmol) and DppfPdCl₂(2.84g, 3.98 mmol). The mixture is subsequently heated at 100 ℃ under N₂Stirred under atmosphere for 1 hour. The mixture was then concentrated and the residue poured into water (100mL) and then extracted with EA (100mL × 3). The organic solution was then concentrated to give the crude product as a yellow solid (5.5g, 98% yield), which was used in the next step without further purification. MS M/z (ESI) [ M + H ]]⁺＝282.2。

Step 2.3 preparation of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylate Prepare for

To methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (2.8g, 9.96mmol), 2, 6-dimethylpyridin-4-yl) boronic acid (1.51g, 9.96mmol) in bis

Mixture of alkane (50mL) and water (5mL) Na was added₂CO₃(3.01g, 19.93mmol) and Pd (PPh)₃)₄(1.42g, 1.99 mmol). The mixture was then heated at 80 ℃ under N₂Stirred under atmosphere for 8 hours. The mixture was then concentrated and the residue poured into water (100mL) and then extracted with EA (100mL × 3). The organic solution was then concentrated to give the crude product, which was further purified by flash column to give the desired methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylate as a yellow solid (2.5g, 71% yield). MS M/z (ESI) [ M + H ] ]⁺＝353.4。¹H NMR(500MHz,DMSO-d6)δppm 2.33(s,6H),3.89(s,3H),6.89(s,2H),7.22(t,J＝8.29Hz,2H),7.43(t,J＝6.58Hz,2H),7.61(br s,2H)。

Step 3.3 preparation of amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid

To a stirred solution of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylate (2.3g, 6.53mmol) in methanol (25mL) and water (5mL) was added sodium hydroxide (1.3g, 32.66 mmol). The mixture was then stirred at 45 ℃ for 2 hours. The solution was then concentrated and the residue was suspended in 25mL of water. The solution was washed twice with 15mL DCM. The inorganic layer was then acidified to pH 3 with 0.5N HCl. The solid formed was collected and dried to give the desired product as a white solid (1.70g, 77% yield). MS M/z (ESI) [ M + H ]]⁺＝339.4。¹H NMR(500MHz,DMSO-d6)δppm 2.31-2.38(m,6H),6.94(s,2H),7.22(t,J＝8.41Hz,2H),7.43(t,J＝6.73Hz,2H),7.64(br s,2H),12.56-13.99(m,1H)。

Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) Preparation of pyrazine-2-carboxamide (Compound 89)

To a stirred solution of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (25mg, 0.07mmol), (2-methoxyphenyl) methylamine (20mg, 0.15mmol), and DIEA (15mg, 0.118mmol) in DMF (2mL) was added HATU (40mg, 0.11mmol) at room temperature in one portion. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The solution was purified by C18-40 g (MeCN/water ═ 5% -60%) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (compound 89) as an off white solid (19.8mg, 59.2% yield). MS M/z (ESI) [ M + H ] ]⁺＝458.4。¹H NMR(500MHz,CDCl₃)δppm 2.33(s,6H),3.86(s,3H),4.46-4.57(m,2H),6.87-6.95(m,1H),7.02(s,3H),7.13-7.30(m,4H),7.38-7.48(m,2H),7.51-8.20(m,2H),9.02-9.13(m,1H)。

The compounds listed in the table below were prepared using the procedure described for compound 89.

Example 93.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5-phenylpyrazine- Preparation of 2-carboxamide (Compound 93)

Scheme 59

Step 1.3 preparation of methyl amino-6-chloro-5-phenylpyrazine-2-carboxylate

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (0.22g, 1.0mmol), phenylboronic acid (0.13g, 1.05mmol) in dioxane

A mixture of alkane (3mL) and water (0.3mL) was added Na₂CO₃(0.21g, 1.99mmol) and Pd (dppf) Cl₂(0.14g, 0.20 mmol). Then mixingThe compound is at 100 ℃ under N₂Stirred under atmosphere for 1 hour. The mixture was then concentrated and the residue poured into water (100mL) and then extracted with EA (10mL × 3). The organic solution was then concentrated to give the crude product as a yellow solid (0.24g, 91% yield), which was used in the next step without further purification. MS M/z (ESI) [ M + H ]]⁺＝263.3。

Step 2.3 preparation of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylate

To methyl 3-amino-6-chloro-5-phenylpyrazine-2-carboxylate (0.24g, 0.91mmol) and (2, 6-dimethylpyridin-4-yl) boronic acid (0.14g, 0.96mmol) in bis

Na was added to a mixture of an alkane (5mL) and water (0.5mL) ₂CO₃(0.19g, 1.82mmol) and Pd (PPh)₃)₄(0.14g, 0.20 mmol). The mixture was then heated at 80 ℃ under N₂Stirred under atmosphere for 8 hours. The mixture was then concentrated and the residue poured into water (10mL) and then extracted with EA (10mL × 3). The organic solution was then concentrated to give the crude product, which was further purified by flash column to give the desired methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylate as a yellow solid (0.30g, 98% yield). MS M/z (ESI) [ M + H ]]⁺＝335.4。

Step 3.3 preparation of amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylic acid

To a stirred solution of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylate (0.30g, 0.90mmol) in methanol (10mL) and water (2mL) was added sodium hydroxide (0.18g, 4.49 mmol). The mixture was then stirred at 45 ℃ for 2 hours. The solution was then concentrated and the residue was suspended in 5mL of water. The solution was washed with DCM (2X 5 mL). The inorganic layer was then acidified to pH 3 with 0.5N HCl. The solid formed was collected and dried to give the desired product as a white solid (0.14g, 49% yield). MS M/z (ESI) [ M + H ]]⁺＝321.4。

Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5-phenylpyrazine- Preparation of 2-carboxamide (Compound 93)

To a stirred solution of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylic acid (35mg, 0.11mmol), (2-methoxyphenyl) methylamine (22mg, 0.16mmol), and DIEA (28mg, 0.22mmol) in DMF (2mL) was added HATU (50mg, 0.13mmol) at room temperature in one portion. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The solution was purified by C18-40 g (MeCN/water ═ 5% to 60%) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5-phenylpyrazine-2-carboxamide (compound 93) as an off white solid (23.0mg, 48% yield). MS M/z (ESI) [ M + H ]]⁺＝440.4。¹H NMR(500MHz,CDCl₃)δppm 2.30(s,6H),3.86(s,3H),4.52(d,J＝6.31Hz,2H),6.91(t,J＝7.36Hz,1H),6.99-7.04(m,3H),7.18(d,J＝7.57Hz,1H),7.25(t,J＝7.87Hz,1H),7.35-7.45(m,5H),7.82(br s,2H),9.06(t,J＝6.31Hz,1H)。

Example 94.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-N- [ (5-methyl-1, 3-thiazol-4-yl) methyl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 94)

Scheme 60

And (1).N- [ (5-methyl-1, 3-thiazol-4-yl) methyl]Carbamic acid tert-butyl ester

To 4-bromo-5-methyl-1, 3-thiazole (400mg, 2.3mmol, 1 eq) and tert-butyl N- [ (trifluoro-lambda 4-boryl) methyl at room temperature under a nitrogen atmosphere]To a stirred mixture of potassium carbamate (639.11mg, 2.7mmol, 1.2 equiv.) in toluene (16mL) was added Na in portions₂CO₃(714.3mg, 6.7mmol, 3.0 equiv.), S-Phos (368.9mg, 0.9mmol, 0.4 equiv.), Water (2mL) and Pd (AcO) ₂(100.9mg, 0.45mmol, 0.2 equiv.). Will be describedThe mixture was stirred at 90 ℃ overnight. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 5:1) to give N- [ (5-methyl-1, 3-thiazol-4-yl) methyl ] as a yellow crude solid]Tert-butyl carbamate (280mg, 54.6%). LCMS M/z (ESI), [ M + H]⁺＝229.2。

Step 2.1- (5-methyl-1, 3-thiazol-4-yl) methylamine

To N- [ (5-methyl-1, 3-thiazol-4-yl) methyl group at room temperature under an air atmosphere]To a stirred solution of tert-butyl carbamate (270mg, 1.2mmol, 1 eq) in DCM (5mL) was added 4N HCl bis (N-HCl) dropwise

Alkane (5mL) solution. The resulting mixture was stirred at room temperature for another 3 hours. The resulting mixture was concentrated under reduced pressure. This gave 1- (5-methyl-1, 3-thiazol-4-yl) methylamine (150mg, 91.0%) as a brown crude solid which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝129.3。

Step 3.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-N- [ (5-methyl-1, 3-thiazol-4-yl) methyl Base of]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 94)

3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere ]Pyridin-6-yl]-5-(1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.3mmol, 1 eq) and 1- (5-methyl-1, 3-thiazol-4-yl) methylamine (79.6mg, 0.6mmol, 2.0 eq) in DMF (5mL) was added HATU (471.9mg, 1.24mmol, 4.0 eq) and DIEA (160.4mg, 1.2mmol, 4.0 eq) in portions. The resulting mixture was stirred at room temperature for a further 60 min. The resulting mixture was poured into water (20mL) and collected by filtrationThe resulting solid was washed with water (10 mL). The crude material was slurried with MeOH (5mL) to give 3-amino-6- [ imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ (5-methyl-1, 3-thiazol-4-yl) methyl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 94) (106mg, 77.9%). LCMS M/z (ESI), [ M + H]⁺＝433.2。¹H NMR (methanol-d)₄,400MHz)δ2.6(3H,s),4.7(2H,s),7.2(1H,dd,J＝9.3,1.8Hz),7.3(1H,s),7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.3Hz),7.9(1H,s),8.0(1H,s),8.7(1H,d,J＝1.5Hz),8.8(1H,s)。

Example 95.3-amino-N- [ (4-aminopyrimidin-2-yl) methyl]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 95)

Scheme 61

Step 1.2- (aminomethyl) pyrimidin-4-amine

To a stirred mixture of 4-aminopyrimidine-2-carbonitrile (200mg, 1.67mmol, 1 eq) in THF (10mL) was added Raney nickel (71.3mg, 0.83mmol, 0.5 eq) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The resulting mixture was filtered and the filter cake was washed with THF (2X 5 mL). The filtrate was concentrated under reduced pressure to give 2- (aminomethyl) pyrimidin-4-amine (200mg, 96.75%) as a pale yellow solid, which was used in the next step without further purification. LCMS M/z (ESI), [ M + H ]⁺＝125.1。

Step 2.3-amino-N- [ (4-aminopyrimidin-2-yl) methyl]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5- (1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 95)

A stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.31mmol, 1 eq) and 2- (aminomethyl) pyrimidin-4-amine (77.0mg, 0.62mmol, 2 eq) in DMF (10mL) was added T portionwise₃P (394.9mg, 1.24mmol, 4 equiv.) and DIEA (120.3mg, 0.93mmol, 3 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere overnight. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃ H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 25% B within 7 min; 254/220 nm; rt: 5.77min) to yield 3-amino-N- [ (4-aminopyrimidin-2-yl) methyl ] methyl as a yellow solid]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 95) (13mg, 9.78%). LCMS M/z (ESI), [ M + H]⁺＝429.2，¹H NMR(400MHz,DMSO-d₆)δ4.33～4.77(m,2H),6.29(d,J＝5.9Hz,1H),7.18(dd,J＝9.3,1.8Hz,2H),7.37(d,J＝0.8Hz,1H),7.52(d,J＝9.3Hz,1H),7.61(d,J＝1.2Hz,1H),7.96(d,J＝1.1Hz,1H),8.00(d,J＝5.9Hz,4H),8.28(d,J＝0.8Hz,1H),8.80(t,J＝1.4Hz,1H),9.18(t,J＝5.8Hz,1H)。

Example 96.3-amino-N- [ [2- (dimethylphosphoryl) -6-fluorophenyl ] group]Methyl radical]-6- [ imidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 96)

Scheme 62

Step 1.2- (dimethylphosphoryl) -6-fluorobenzonitrile

To 2-bromo-6-fluorobenzonitrile (1g, 5.00mmol, 1 equiv.) and (methylphosphoryl) methane (0.4g, 1.00 equiv.) in 1, 4-bis (methylene chloride) under a nitrogen atmosphere

To the mixture in alkane (15mL) was added Pd (AcO)₂(0.1g, 0.1 equiv.), XantPhos (0.6g, 0.2 equiv.), and K₃PO₄(2.1g, 0.01mmol, 2.00 equiv.). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂/MeOH 20:1) to give 2- (dimethylphosphoryl) -6-fluorobenzonitrile (620mg, 62.90%) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝198.0。¹H NMR:(300MHz,DMSO-d₆)δ1.83(s,3H),1.87(s,3H),7.80(m,2H),7.95(m,1H)。

Step 2.1- [2- (dimethylphosphoryl) -6-fluorophenyl]Methylamine.

To 2- (dimethylphosphoryl) -6-fluorobenzonitrile (600mg, 3.04mmol, 1 eq) and NH at room temperature under a nitrogen atmosphere₃.H₂To a solution of O (0.1mL, 3.82mmol, 1.13 equiv) in MeOH (10mL) was added Raney nickel (130.4mg, 1.52mmol, 0.5 equiv). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure to give 1- [2- (dimethylphosphoryl) -6-fluorophenyl ] as a purple oil ]Methylamine (550mg, 89.83%), which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝202.2，¹H NMR:(300MHz,DMSO-d₆)δ1.82(m,6H),3.17(s,3H),4.02(d,2H),7.45(s,3H)。

Step 3.3-amino-N- [ [2- (dimethylphosphoryl) -6-fluorophenyl ] group]Methyl radical]-6- [ imidazo [1,2-a ]]Pyridine- 6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 96).

To 1- [2- (dimethylphosphoryl) -6-fluorophenyl at room temperature]Methylamine (10mg, 0.05mmol, 1 eq) and 3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

To a solution of oxazol-2-yl) pyrazine-2-carboxylic acid (16.0mg, 0.05mmol, 1.00 equiv.) in DMF (5mL) was added T₃P (31.6mg, 0.10mmol, 2 equiv.) and DIEA (19.3mg, 0.15mmol, 3 equiv.). The resulting solution was stirred at room temperature under an air atmosphere for 60 min. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10MMOL/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 20 mL/min; gradient: 25% B to 35% B within 8 min; 254/220 nm; rt: 6.27min) to give 3-amino-N- [ [2- (dimethylphosphoryl) -6-fluorophenyl ] group as a yellow solid]Methyl radical]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 96) (95mg, 37.81%). LCMS M/z (ESI), [ M + H ]⁺＝506.2。¹H NMR:(300MHz,DMSO-d₆)δ1.85(d,6H),4.90(d,2H),7.12(dd,1H),7.37(d,1H),7.49(m,4H),7.62(m,1H),7.86(s,2H),7.91(s,1H),8.28(d,1H),8.88(d,1H),9.98(t,1H)。

Example 101.3-amino-N- ((3-fluoropyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 101)

Scheme 63

Step 1.3-Methylimidazo [1,2-a ]]Pyridin-6-ylboronic acids

A mixture of 2-bromo-1, 1-dimethoxypropane (500mg, 2.73mmol, 1 eq.) in 2.5mL of 1N aqueous HCl was stirred at 80 ℃ for 1 hour. The mixture was cooled to room temperature and NaHCO was used₃(solid) neutralized to pH 7. With CHCl₃The aqueous layer was extracted (3X 5 mL). To the obtained CHCl at room temperature₃To the solution was added 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (180.3mg, 0.82mmol, 0.30 equiv) in portions. The resulting mixture was stirred at 80 ℃ overnight. The resulting mixture was concentrated under reduced pressure to give the crude product as a crude oil, which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝177.0。

Step 2.3-amino-N- ((3-fluoropyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridine-6- Base) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 101)

To 3-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl at room temperature under a nitrogen atmosphere]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (100mg, 0.29mmol, 1 eq.) and [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]Boric acid (100.9mg, 0.57mmol, 2.00 equiv.) in 1, 4-bis

Cs was added in portions to a stirred mixture in an alkane (20mL)₂CO₃(467.2mg, 1.43mmol, 5 equiv.) and Pd (dppf) Cl₂ CH₂Cl₂(70.3mg, 0.09mmol, 0.3 equiv.). The resulting mixture was stirred at 105 ℃ overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂The residue was purified with MeOH 20:1) to give 3-amino-N- [ (3-fluoropyridin-2-yl) methyl ] p]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 101) (23mg, 18.05%). LCMS M/z (ESI), [ M + H]⁺＝445.2。¹H NMR(400MHz,DMSO-d₆)δ2.44(d,J＝0.9Hz,3H),4.72(dd,J＝5.8,1.7Hz,2H),7.25(dd,J＝9.4,1.8Hz,1H),7.31-7.47(m,3H),7.50(dd,J＝9.4,1.0Hz,1H),7.72(ddd,J＝10.0,8.3,1.3Hz,1H),7.90(s,2H),8.29(d,J＝0.8Hz,1H),8.33-8.42(m,2H),9.36(t,J＝5.9Hz,1H)。

Example 102.3-amino-N- [ (2, 6-difluorophenyl) methyl]-6- [1- (3-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (example 102)

Scheme 64

Step 1.5-bromo-1- (3-hydroxypropyl) -1, 2-dihydropyridin-2-one.

To a solution of 5-bromo-1, 2-dihydropyridin-2-one (1g, 5.75mmol, 1 eq.) and 3-iodopropan-1-ol (2.1g, 11.49mmol, 2 eq.) in DMF (15mL) at room temperature was added K₂CO₃(1.6g, 11.49mmol, 2 equiv.). The mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CHCl) ₃MeOH 20:1) to give 5-bromo-1- (3-hydroxypropyl) -1, 2-dihydropyridin-2-one (300mg, 22.49%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝232.1,234.1。¹H NMR:(300MHz,DMSO-d₆)δ1.12(q,2H),2.79(m,2H),3.27(t,2H),4.03(s,1H),5.69(d,1H),6.78(dd,1H),7.09(d,1H)。

Step 2.1- (3-hydroxypropyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one.

To a solution of 5-bromo-1- (3-hydroxypropyl) -1, 2-dihydropyridin-2-one (200mg, 0.86mmol, 1 eq.) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (437.7mg, 1.72mmol, 2 eq.) in THF (15mL) at room temperature under a nitrogen atmosphere was added KOAc (137.5mg, 1.40mmol, 3.00 eq.) and Pd (dppf) Cl₂(63.1mg, 0.09mmol, 0.1 equiv.). The mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The mixture was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝280.3。

Step 3.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- [1- (3-hydroxypropyl) -6-oxo-1, 6-dihydro Pyridin-3-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 102).

To a solution of 1- (3-hydroxypropyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (305.3mg, 1.09mmol, 2.00 equiv.) in THF (15mL) at room temperature under a nitrogen atmosphere was added 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] methyl ]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (200mg, 0.55mmol, 1 equiv.), Cs₂CO₃(356.4mg, 1.09mmol, 2.00 equiv.) and Pd (dppf) Cl₂(40.0mg, 0.05mmol, 0.10 equiv.). The mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours and passed through preparative TLC (CH)₂Cl₂The residue was purified with MeOH 20:1) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- [1- (3-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 102) (60mg, 22.74%). LCMS M/z (ESI), [ M + H]⁺＝483.3。¹H NMR:(300MHz,DMSO-d₆)δ1.76(p,2H),3.40(q,2H),3.91(t,2H),4.58(m,3H),6.36(d,1H),7.08(t,2H),7.38(m,2H),7.51(dd,1H),7.75(s,2H),7.85(d,1H),8.28(s,1H),9.10(t,1H)。

Example 103.3-amino-N- [ (2, 6-difluorophenyl) methyl]-6- [1- (2-methoxyethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 103)

Scheme 65

Step 1.5-bromo-1- (2-methoxyethyl) -1, 2-dihydropyridin-2-one

To a stirred mixture of 5-bromo-1, 2-dihydropyridin-2-one (500mg, 2.87mmol, 1 equiv.) and 1-bromo-2-methoxyethane (1597.6mg, 11.49mmol, 4 equiv.) in DMF (15mL) at 80 ℃ under an air atmosphere was added K in portions₂CO₃(1191.4mg, 8.62mmol, 3 equiv.). The resulting mixture was stirred at 80 ℃ for 5 hours under an air atmosphere. The resulting mixture was poured into water. The resulting mixture was extracted with EtOAc (2X 100 mL). The combined organic layers were washed with water (1X 40mL) and anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (5:1) to give 5-bromo-1- (2-methoxyethyl) -1, 2-dihydropyridin-2-one (200mg, 29.99%) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝231.9。¹H NMR(400MHz,DMSO-d₆)δ3.24(s,3H),3.56(t,J＝5.3Hz,2H),4.04(t,J＝5.3Hz,2H),6.38(d,J＝9.6Hz,1H),7.53(dd,J＝9.7,2.8Hz,1H),7.91(d,J＝2.8Hz,1H)。

Step 2.1- (2-methoxyethyl) -5- (4,4, 5)-tetramethyl-1, 3, 2-dioxaborolan-2- Yl) pyridin-2 (1H) -ones

To a stirred mixture of 5-bromo-1- (2-methoxyethyl) -1, 2-dihydropyridin-2-one (150mg, 0.65mmol, 1 equivalent) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (328.3mg, 1.29mmol, 2 equivalents) in THF (5mL) at 80 deg.C under a nitrogen atmosphere was added Pd (dppf) Cl in portions₂(94.6mg, 0.13mmol, 0.2 equiv.) and KOAc (190.3mg, 1.94mmol, 3 equiv.). The resulting mixture was stirred at 80 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝280.3。

Step 3.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- [1- (2-methoxyethyl) -6-oxo-1, 6- Dihydropyridin-3-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 103)

To 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group at 100 ℃ under a nitrogen atmosphere]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (100mg, 0.27mmol, 1 equiv.) and 1- (2-methoxyethyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (152.7mg, 0.55mmol, 2.00 equiv.) are added portionwise to a stirred mixture in THF (8mL) Pd (dppf) Cl₂(40.0mg, 0.05mmol, 0.2 equiv.) and Cs₂CO₃(356.4mg, 1.09mmol, 4 equiv.). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (20:1) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl as a yellowish green solid]-6- [1- (2-methoxyethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 103) (33mg, 24.77%). LCMS M/z (ESI), [ M + H]⁺＝483.2。¹H NMR(400MHz,DMSO-d₆)δ3.22(s,3H),3.57(t,J＝5.4Hz,2H),4.04(t,J＝5.5Hz,2H),4.61(d,J＝5.9Hz,2H),6.35(d,J＝9.4Hz,1H),7.10(t,J＝8.0Hz,2H),7.34～7.46(m,2H),7.47(dd,J＝9.4,2.6Hz,1H),7.75～7.80(m,2H),7.88(d,J＝2.6Hz,1H),8.30(d,J＝0.8Hz,1H),9.07(t,J＝5.9Hz,1H)。

EXAMPLE 104 preparation of 3-amino-N- [ (3-fluoropyridin-2-yl) methyl ] -6- [ imidazo [1,2-a ] pyridin-6-yl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 104)

Scheme 66

Step 1.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2- Formic acid

To methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (300mg, 1.178mmol, 1 eq) and 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] imidazole at room temperature under a nitrogen atmosphere ]Pyridine (431.39mg, 1.767mmol, 1.5 equiv.) in dioxane

To a stirred mixture in an alkane (20mL) was added Pd (dppf) Cl in portions₂₍172.41mg, 0.236mmol, 0.2 equiv.), water (2mL) and Cs₂CO₃(1151.62mg, 3.535mmol, 3 equiv.). The resulting mixture was stirred at 90 ℃ overnight. The resulting mixture was filtered and the filter cake was washed with DCM (3X 10 mL). The filtrate was acidified to PH 5 with 2N aqueous HCl. The resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ imidazo [1,2-a ] as a brown crude solid]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (290mg, 76.37%) without a further oneStep (5) purification is directly used in the next step. LCMS M/z (ESI), [ M + H]⁺＝323.2。

Step 2.3-amino-N- [ (3-fluoropyridin-2-yl) methyl]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(2H- 1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 104)

3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]To a stirred mixture of-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.31mmol, 1 eq) and 1- (3-fluoropyridin-2-yl) methylamine (67.1mg, 0.62mmol, 2 eq) in DMF (3mL) was added HATU (471.9mg, 1.24mmol, 4 eq) and DIEA (160.4mg, 1.24mmol, 4 eq) portionwise. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched by water (10mL), and the resulting solid was collected by filtration and washed with water (3 × 10 mL). The crude material was slurried with MeOH (6mL), and the resulting solid was collected by filtration and dried in vacuo to give 3-amino-N- [ (3-fluoropyridin-2-yl) methyl as a yellow solid ]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 104) (48mg, 35.5%). LCMS M/z (ESI), [ M + H]⁺＝431.2。¹H NMR(DMSO-d₆,400MHz)δ4.7(2H,d,J＝5.9Hz),6.7(1H,dd,J＝9.4,1.8Hz),7.4(2H,dd,J＝8.8,4.4Hz),7.6(1H,d,J＝1.2Hz),7.7(1H,ddd,J＝10.0,8.3,1.3Hz),7.9(1H,s),8.1(3H,s),8.4(1H,dt,J＝4.7,1.5Hz),8.6-8.7(1H,m),9.4(1H,t,J＝6.0Hz)。

Example 107.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamides

Example 108.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamides

Step 1.5-bromo-1- (2-hydroxypropyl) -1, 2-dihydropyridin-2-one.

5-bromo-1, 2-dihydropyridin-2-one (1g, 5.75mmol, 1 equiv.) and 1-bromopropan-2-ol (1.6g, 0.01mmol, 2.00 equiv.), K at 80 deg.C under an air atmosphere₂CO₃A solution of (1.6g, 0.01mmol, 2.00 equiv.) in DMF (15mL) was stirred for 4 h. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH20:1) to give 5-bromo-1- (2-hydroxypropyl) -1, 2-dihydropyridin-2-one (0.9g, 67.48%) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝232.1,234.1。¹H NMR:(300MHz,DMSO-d₆)δ1.05(dd,3H),3.55(ddd,1H),3.85(dddd,1H),3.96(ddd,1H),4.89(dd,1H),6.35(dd,1H),7.50(m,1H),7.82(t,1H)。

Step 2.1- (2-hydroxypropyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one.

To a solution of 5-bromo-1- (2-hydroxypropyl) -1, 2-dihydropyridin-2-one (300mg, 1.29mmol, 1 eq.) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (656.5mg, 2.59mmol, 2 eq.) in THF (15mL) was added KOAc (137.5mg, 1.40mmol, 3.00 eq.) and Pd (dppf) Cl ₂(94.6mg, 0.13mmol, 0.10 equiv.). The mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝280.1。

Step 3.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

To 3-amino-6-bromo-5-(2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid methyl ester (200mg, 0.67mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (314.4mg, 1.34mmol, 2.00 equiv.) in THF (15mL) was added Cs₂CO₃(435.8mg, 1.34mmol, 2 equiv.) and Pd (dppf) Cl₂(48.9mg, 0.07mmol, 0.1 equiv.). After stirring at 80 ℃ for 2 hours under nitrogen atmosphere, by preparative TLC (CH)₂Cl₂/MeOH 20:1) to give 3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5- (2-ethyl-phenyl) -5- (d-tert-butyl-ethyl) -ethyl acetate as a yellow solid

Oxazol-2-yl) pyrazine-2-carboxamide (racemate, 10mg, 4.77%). LCMS M/z (ESI), [ M + H]⁺＝483.3。¹H NMR:(300MHz,DMSO-d₆)δ1.05(d,3H),3.62(m,1H),3.93(m,2H),4.60(s,2H),4.83(d,1H),6.35(d,1H),7.08(t,2H),7.38(m,2H),7.49(dd,1H),7.74(s,2H),7.80(d,1H),8.27(d,1H),9.05(t,1H)。

Step 4.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxamide (unknown absolute, Peak 1, Compound 107) and 3-amino-N- (2, 6-Difluoro) Benzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5- (2-hydroxy-propyl) -methyl-benzyl ester

Azol-2-yl) pyrazine-2-carboxamides (unknown absolute, peak 2, compound 108).

The racemate product (100mg) was purified by preparative chiral HPLC on eluent. Column: column: (R, R) Whelk-O1, 21.1 x 250mm, 5 μm; mobile phase A: hex (8mmol/L NH)₃MeOH) - — HPLC, mobile phase B: EtOH- -HPLC; flow rate: 20mL/min(ii) a Gradient: 50B to 50B within 26 min; 254/220 nm; RT 1: 16.649, respectively; RT 2: 19.223. this gave 3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5- (2-hydroxy-ethyl) -5-methyl (tert-butyl) acetate as a yellow solid

Azol-2-yl) pyrazine-2-carboxamide (isomer 1) (Compound 107) (30mg, 30%) LCMS M/z (ESI), [ M + H]⁺＝483.3。¹H NMR:(300MHz,DMSO-d₆) δ 1.05(d,3H),3.62(m,1H),3.93(m,2H),4.60(s,2H),4.83(d,1H),6.35(d,1H),7.08(t,2H),7.38(m,2H),7.49(dd,1H),7.74(s,2H),7.80(d,1H),8.27(d,1H),9.05(t, 1H). Chirality: tR 2.59 min. And 3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5- (2-hydroxy-phenyl) -5- (b-hydroxy-phenyl) as a yellow solid

Oxazol-2-yl) pyrazine-2-carboxamide (isomer 2) (compound 108) (30mg, 30%). LCMS M/z (ESI), [ M + H]⁺＝483.3。¹H NMR:(300MHz,DMSO-d₆) δ 1.05(d,3H),3.62(m,1H),3.93(m,2H),4.60(s,2H),4.83(d,1H),6.35(d,1H),7.08(t,2H),7.38(m,2H),7.49(dd,1H),7.74(s,2H),7.80(d,1H),8.27(d,1H),9.05(t, 1H). Chirality: tR ═ 3.03min, mixed chirality: tR 2.59min,3.03 min.

Example 111.3-amino-N- ((6- (3- (dimethylamino) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 111)

Scheme 67

Step 1.2-cyano-6- (3- (dimethylamino) azetidin-1-yl) pyridine

Placing 6-chloro in a 50-mL round-bottom flaskPyridine-2-carbonitrile (1.5g, 10.826mmol, 1 equiv.), N-Dimethylazetidin-3-amine-dihydrochloride (1.87g, 10.826mmol, 1 equiv.), DMF (10mL, 129.218mmol, 11.94 equiv.), K₂CO₃(4.49g, 32.479mmol, 3 equiv.). The resulting solution was stirred at 80 ℃ for 16 hours. The resulting solution was extracted with 3X 20mL of dichloromethane. The residue was applied to a silica gel column together with dichloromethane/methanol (50: 1). This gave 6- [3- (dimethylamino) azetidin-1-yl (475mg, 21.69%) as a light brown solid ]Pyridine-2-carbonitrile (Compound 111).¹H NMR (400MHz, chloroform-d) Δ 3.96(1H, s),6.20(6H, s),7.22-7.33(6H, m),7.83(2H, dd),8.05-8.14(2H, m),8.81(6H, s),10.62(1H, dd),11.02(1H, dd),11.57(1H, dd)

Step 2.1- (6- (aminomethyl) pyridin-2-yl) -N, N-Dimethylazetidin-3-amine

In a 25mL round bottom flask was placed 2-cyano-6- (3- (dimethylamino) azetidin-1-yl) pyridine. After this time MeOH (10mL, 246.989mmol, 111.01 equiv.), NH were added at room temperature₄OH (2mL, 51.361mmol, 23.09 eq.) and Raney nickel. The resulting mixture was stirred at room temperature for 1 hour. The solid was filtered off. The resulting mixture was concentrated. This gave 290mg (63.18%) of 1- [6- (aminomethyl) pyridin-2-yl as a solid]-N, N-dimethylazetidin-3-amine. LCMS M/z (ESI), [ M + H]⁺＝207.1 ¹H NMR (300MHz, methanol-d₄,)δ2.24(6H,s),3.27(1H,d),3.77(2H,s),3.79-3.89(2H,m),4.12(2H,t),6.32(1H,s),6.66(1H,d),7.51(1H,t)

Step 3.3-amino-N- ((6- (3- (dimethylamino) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 111)

Placing 3-amino-6- [ 3-methylimidazo [1,2-a ] in a 25-mL round-bottom flask]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (130mg), DMF (5mL), T₃P (750mg), DIEA (530mg), 1- [6- (aminomethyl) pyridin-2-yl ]-N, N-dimethylazetidin-3-amine (130 mg). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was extracted with 3 × 10mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was applied to a silica gel column together with dichloromethane/methanol (8: 1). By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 41% B within 7 min; 254/220 nm; rt: 5.10min) to purify the crude product and obtain the product. This gave (51.6mg) 3-amino-N- ([6- [3- (dimethylamino) azetidin-1-yl) as a yellow solid]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 111). LCMS M/z (ESI), [ M + H]⁺＝525.3 ¹H-NMR (300MHz, methanol-d)₄)δ2.03(6H,s),2.49(3H,d),3.03(1H,t),3.66(2H,dd),3.88-3.99(2H,m),4.55(2H,s),6.29(1H,d),6.67(1H,d),7.25-7.35(2H,m),7.39(1H,s),7.43-7.54(2H,m),7.99(1H,d),8.37(1H,s)_

Example 112.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -N- ((6- (4-methylpiperazin-1-yl) pyridin-2-yl) methyl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 112)

Scheme 68

Step 1.2-cyano-6- (4-methylpiperazin-1-yl) pyridine.

Mixing 6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 equiv.), 1-methylpiperonateOxazine (615.25mg, 6.142mmol, 1.5 equiv.), K ₂CO₃(1131.89mg, 8.190mmol, 2 equiv.) was dissolved in 3mL of DMF. The mixture was stirred at 50 ℃ for 8 hours. LCMS showed no problem for the reaction. Passing through silica gel column with DCM: CH₃The crude product was purified by OH (15:1) and further purified by preparative HPLC to give 2-cyano-6- (4-methylpiperazin-1-yl) pyridine (158mg, 19.08%) as a brown oil. LCMS M/z (ESI), [ M + H]⁺＝203.3。

(6- (4-methylpiperazin-1-yl) pyridin-2-yl) methylamine.

6- (4-Methylpiperazin-1-yl) pyridine-2-carbonitrile (140mg, 0.692mmol, 1 equiv.), Raney's nickel (118.60mg, 1.384mmol, 2.00 equiv.) were dissolved in 3mL NH₄OH and MeOH. The mixture is left at room temperature in H₂Stirred for 3 hours. LCMS showed no problem for the reaction. The crude product was purified by column on silica gel with DCM: CH₃OH (15:1) was eluted and the product was further purified by preparative HPLC to give (6- (4-methylpiperazin-1-yl) pyridin-2-yl) methylamine as a grey oil (40mg, 28.01%). LCMS M/z (ESI), [ M + H]⁺＝207.3。

Step 3.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -N- ((6- (4-methylpiperazin-1-) Yl) pyridin-2-yl) methyl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 112)

1- [6- (4-methylpiperazin-1-yl) pyridin-2-yl]Methylamine (29.44mg, 0.143mmol, 1.20 equivalents), 3-amino-6- [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (40mg, 0.119mmol, 1 eq), EDCI (45.60mg, 0.238mmol, 2.00 eq), HOBT (32.14mg, 0.238mmol, 2.00 eq), DIEA (92.23mg, 0.714mmol, 6.00 eq) were dissolved in 3mL DMF. The mixture was stirred at room temperature for 2 hours. LCMS shows no problem for reaction. Passing through silica gel column with DCM: CH₃OH (15:1) and further purification by preparative HPLC to give 3-amino-6- (3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl) -N- ((6- (4-methylpiperazin-1-yl) pyridin-2-yl) methyl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxamide (26.5mg, 42.47%). LCMS M/z (ESI), [ M + H]⁺＝525.3。¹H-NMR (300MHz, methanol-d)₄)δ:1.29(s,6H),2.29(1H,d),2.49(3H,d),3.31-3.48(4H,m),4.58(2H,s),6.67(2H,dd),7.24-7.33(2H,m),7.42(1H,d),7.46-7.58(2H,m),7.99(1H,d),8.39(1H,t)。

EXAMPLE 113 preparation of 3-amino-5- (4-fluorophenyl) -N- [ [3- (2-hydroxyethoxy) pyridin-2-yl ] methyl ] -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 113)

Scheme 69

Step 1.3- (2-Hydroxyethoxy) pyridine-2-carbonitrile

To 3-fluoropyridine-2-carbonitrile (1.5g, 12.3mmol, 1 equiv.) and ethane-1, 2-diol (1.5g, 24.5mmol, 2 equiv.) in 1, 4-bis

Addition of Cs to a mixture in an alkane (25mL)₂CO₃(8.0g, 24.5mmol, 2 equiv.). The mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (5:1) to give 3- (2-hydroxyethoxy) pyridine-2-carbonitrile as a yellow oil (1g, 49.6%). LCMS M/z (ESI), [ M + H ]⁺＝166.1。¹H-NMR(300MHz,DMSO-d₆)δ3.75(2H,q),4.23(2H,m),4.97(1H,t),7.68(1H,dd),7.81(1H,dd),8.28(1H,dd)。

Step 2.2- [ [2- (aminomethyl) pyridin-3-yl]Oxy radical]Ethan-1-ol

To 3- (2-hydroxyethoxy) pyridine-2-carbonitrile (200mg, 1.2mmol, 1 eq) in MeOH (5mL) and NH₃H₂To a solution in O (1mL) was added Raney nickel (469.7mg, 5.5mmol, 3 equiv.). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. This gives 2- [ [2- (aminomethyl) pyridin-3-yl ] as a violet oil]Oxy radical]Ethan-1-ol (200 mg). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝169.3。

Step 3.3-amino-5- (4-fluorophenyl) -N- [ [3- (2-hydroxyethoxy) pyridin-2-yl]Methyl radical]-6-(1- methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 113)

To 2- [ [2- (aminomethyl) pyridin-3-yl group]Oxy radical]Ethyl-1-ol (200mg, 1.2mmol, 1 equiv.) and a solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxylic acid (302.4mg, 0.8mmol, 0.7 equiv.) in DMF (15mL) were added T in portions₃P (756.7mg, 2.4mmol, 2 equiv.), DIEA (307.4mg, 2.4mmol, 2 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product (60mg) was purified by preparative HPLC with the following conditions (column: XSelect CSH OBD column 30 x 150mm 5um N; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 45% B over 7 min; 254; 220 nm; Rt: 7.02min) to give 3-amino-5- (4-fluorophenyl) -N- [ [3- (2-hydroxyethoxy) pyridin-2-yl as a yellow solid ]Methyl radical]-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (compound 113) (20mg, 6.55%). LCMS M/z (ESI), [ M + H]⁺＝514.3。¹H NMR(300MHz,DMSO-d₆)δ3.76(2H,t),3.98(3H,s),4.12(2H,t),4.69(2H,d),7.15(2H,q),7.37(4H,m),7.51(1H,d),7.67(1H,d),7.76(2H,s),8.04(1H,d),8.10(1H,dd),9.22(2H,d)。¹⁹F NMR(282MHz,DMSO-d₆)δ-74.48,-112.25。

The compounds listed in the table below were prepared using the procedure described for compound 113.

EXAMPLE 114.preparation of 3-amino-5- (4-fluorophenyl) -N- [ [3- (2-methoxyethoxy) pyridin-2-yl ] methyl ] -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxamide (Compound 114)

Scheme 70

Step 1.N- [2- [ (2-cyanopyridin-3-yl) oxy group]Ethyl radical]-N-methylcarbamate

To 3-fluoropyridine-2-carbonitrile (1.5g, 12.2mmol, 1 equiv.) and tert-butyl N- (2-hydroxyethyl) -N-methylcarbamate (4.3g, 24.5mmol, 2 equiv.) in 1, 4-bis-formamide at room temperature

Addition of Cs to a mixture in an alkane (25mL)₂CO₃(8.01g, 24.6mmol, 2.0 equiv.). The mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (10:1) to give N- [2- [ (2-cyanopyridin-3-yl) oxy) as a yellow solid]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester (1.8g, 52.8%). LCMS M/z (ESI), [ M + H]⁺＝179.0。¹H-NMR(300MHz,DMSO-d₆)δ1.36(9H,s),2.90(3H,d),3.57(2H,t),4.33(2H,q),7.69(1H,dd),7.82(1H,d),8.29(1H,dd)。

Step 2.1- [3- (2-methoxyethoxy) pyridin-2-yl]Methylamine

To 3- (2-methoxyethoxy) pyridine-2-carbonitrile (300mg, 1.7mmol, 1 eq) in MeOH (5mL) and NH at room temperature ₃H₂Raney nickel (288.4mg, 3.3mmol, 2 equiv.) was added in portions to a solution in O (1 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphereFor 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. This gives 1- [3- (2-methoxyethoxy) pyridin-2-yl as a purple oil]Methylamine (200mg, 65.2%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝183.1。

Step 3.3-amino-5- (4-fluorophenyl) -N- [ [3- (2-methoxyethoxy) pyridin-2-yl ] amino]Methyl radical]-6- (1-methyl-1H-1, 3-benzoxadiazol-6-yl) pyrazine-2-carboxamide (Compound 114)

To 1- [3- (2-methoxyethoxy) pyridin-2-yl group at room temperature]Methylamine (180mg, 1mmol, 1 equiv.) and a solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzoxadiazol-6-yl) pyrazine-2-carboxylic acid (251.2mg, 0.7mmol, 0.7 equiv.) in DMF (15mL) were added T in portions₃P (628.6mg, 2mmol, 2 equiv.) and DIEA (255.3mg, 2mmol, 2 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH) ₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 45% B within 7 min; 254/220 nm; rt: 6.83min) to give 3-amino-5- (4-fluorophenyl) -N- [ [3- (2-methoxyethoxy) pyridin-2-yl ] as a yellow solid]Methyl radical]-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (compound 114) (48.1mg, 9.2%). LCMS M/z (ESI), [ M + H]⁺＝528.3。¹H NMR(300MHz,DMSO-d₆)δ3.29(3H,s),3.69(2H,dd),3.78(3H,s),4.20(2H,dd),4.62(2H,d),7.10(1H,d),7.15(2H,t),7.28(1H,dd),7.44(4H,m),7.69(2H,m),8.08(1H,dd),8.19(1H,s),9.18(1H,t)。

EXAMPLE 115.3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -N- ([3- [2- (methylamino) ethoxy ] pyridin-2-yl ] methyl) pyrazine-2-carboxamide (Compound 115) preparation

Scheme 71

Step 1.N- [2- [ (2-cyanopyridin-3-yl) oxy group]Ethyl radical]-N-methylcarbamic acid tert-butyl ester

Cs was added in portions to a mixture in an alkane (25mL)₂CO₃(8.01g, 24.5mmol, 2 equiv.). The resulting mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (10:1) to give N- [2- [ (2-cyanopyridin-3-yl) oxy) as a yellow solid ]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester (1.8g, 52.8%). LCMS M/z (ESI), [ M + H]⁺＝278.0。¹H-NMR(300MHz,DMSO-d₆)δ1.36(9H,s),2.90(3H,d),3.57(2H,t),4.33(2H,q),7.69(1H,dd),7.82(1H,d),8.29(1H,dd)。

Step 2.N- (2- [ [2- (aminomethyl) pyridin-3-yl)]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester

To N- [2- [ (2-cyanopyridin-3-yl) oxy group at room temperature]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester (300mg, 1.08mmol, 1 equiv.) in MeOH (5mL) and NH₃H₂To a solution in O (1mL) was added Raney nickel (185.3mg, 2.1mmol, 2 equiv.). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. This gave N- (2- [ [2- (aminomethyl) pyridin-3-yl) as a violet oil]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester (200mg, 65.7%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝282.3。

Step 3.N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) Pyrazin-2-yl radicals]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Ethyl) -N-methylcarbamate

To N- (2- [ [2- (aminomethyl) pyridin-3-yl) at room temperature]Oxy radical]Tert-butyl ethyl) -N-methylcarbamate (200mg, 0.7mmol, 1 equiv.) and a solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxylic acid (180.8mg, 0.5mmol, 0.7 equiv.) in DMF (15mL) were added T in portions ₃P (452.3mg, 1.4mmol, 2 equiv.) and DIEA (183.7mg, 1.4mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂/MeOH 20:1) to give N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazin-2-yl) as a yellow solid]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Tert-butyl ethyl) -N-methylcarbamate (150mg, 33.6%). LCMS M/z (ESI), [ M + H]⁺＝627.4。

Step 4.3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -N- ([3- [2- (methylamino) ethoxy]Pyridin-2-yl]Methyl) pyrazine-2-carboxamide (Compound 115)

At room temperature to 4N.HCl (gas) in 1, 4-bis

To the solution in an alkane (10mL) was added N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazin-2-yl) in portions]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Tert-butyl ethyl) -N-methylcarbamate (150mg, 0.2mmol, 1 eq). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH) ₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 43% B within 7 min; 254/220 nm; rt: 5.8min) to give 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) -N- ([3- [2- (methylamino) ethoxy ] ethoxy) -6- (1-methyl-1H) -1, 3-benzoxadiazol-6-yl) as a yellow solid]Pyridin-2-yl]Methyl) pyrazine-2-AAmide (compound 115) (51mg, 40.5%). LCMS M/z (ESI), [ M + H]⁺＝527.3。¹H NMR(300MHz,DMSO-d₆)δ2.31(3H,s),2.85(2H,t),3.79(3H,s),4.11(2H,t),4.66(2H,d),7.09(3H,m),7.28(1H,dd),7.44(5H,m),7.69(2H,d),8.08(1H,dd),8.20(1H,s),9.18(1H,t)。

EXAMPLE 116 preparation of 3-amino-N- ([3- [2- (dimethylamino) ethoxy ] pyridin-2-yl ] methyl) -5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxamide (Compound 116)

Scheme 72

Step 1.3- [2- (dimethylamino) ethoxy group]Pyridine-2-carbonitriles

To 3-fluoropyridine-2-carbonitrile (1g, 8.1mmol, 1 equiv.) and 2- (dimethylamino) ethan-1-ol (1.4g, 0.02mmol, 2.0 equiv.) in 1, 4-bis (methanol) at room temperature

Addition of Cs to a mixture in an alkane (25mL)₂CO₃(5.3g, 0.02mmol, 2 equiv.). The resulting mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (2:3) to give 3- [2- (dimethylamino) ethoxy ] ethanol as a yellow oil]Pyridine-2-carbonitrile (1.2g, 76.6%). LCMS M/z (ESI), [ M + H ]⁺＝192.1。¹H-NMR(300MHz,DMSO-d₆)δ2.21(6H,s),2.66(2H,t),4.26(2H,t),7.68(1H,ddd),7.79(1H,dt),8.27(1H,dt)。

Step 2.1- [3- [2- (dimethylamino) ethoxy]Pyridin-2-yl]Methylamine

To 3- [2- (dimethylamino) ethoxy group at room temperature]Pyridine-2-carbonitrile (300mg, 1.5mmol, 1 eq) in MeOH (5mL) and NH₃H₂To a solution in O (1mL) was added Raney nickel (403.2mg, 4.7mmol, 3 equiv.). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. Filtering to obtainThe mixture was washed the filter cake with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. This gives 1- [3- [2- (dimethylamino) ethoxy ] as a purple oil]Pyridin-2-yl]Methylamine (200mg, 65.3%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝196.1。

Step 3.3-amino-N- ([3- [2- (dimethylamino) ethoxy)]Pyridin-2-yl]Methyl) -5- (4-fluorophenyl) 6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 116)

To 1- [3- [2- (dimethylamino) ethoxy group at room temperature]Pyridin-2-yl]Methylamine (200mg, 1.02mmol, 1 equiv.) and 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxylic acid (260.5mg, 0.7mmol, 0.7 equiv.) in DMF (15mL) were added T in portions₃P (651.8mg, 2.04mmol, 2 equiv.) and DIEA (264.7mg, 2.04mmol, 2 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH) ₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 43% B within 7 min; 254/220 nm; rt: 7.08min) to give 3-amino-N- ([3- [2- (dimethylamino) ethoxy) ethanol) as a yellow solid]Pyridin-2-yl]Methyl) -5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxamide (compound 116) (46.5mg, 8.40%). LCMS M/z (ESI), [ M + H]⁺＝541.4。¹H NMR(300MHz,DMSO-d₆)δ2.20(6H,s),2.66(2H,t),3.79(3H,s),4.15(2H,t),4.63(2H,d),7.10(3H,m),7.29(1H,dd),7.46(4H,m),7.58(2H,s),7.69(1H,d),8.08(1H,dd),8.20(1H,s),9.18(1H,t)。

EXAMPLE 117.3-amino-5- (4-fluorophenyl) -N- ([3- [ (2-hydroxyethyl) amino ] pyridin-2-yl ] methyl) -6- (1-methyl-1H-1, 3-benzoxadiazol-6-yl) pyrazine-2-carboxamide preparation (Compound 117)

Scheme 73

Step 1.3- [ (2-hydroxyethyl) amino group]Pyridine-2-carbonitriles

To a mixture of 3-fluoropyridine-2-carbonitrile (1.5g, 12.3mmol, 1 equiv.) and 2-aminoethan-1-ol (1.5g, 24.5mmol, 2 equiv.) in DMSO (25mL) was added Cs portion by portion at room temperature₂CO₃(8.01g, 24.5mmol, 2 equiv.). The resulting mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (1:1) to give 3- [ (2-hydroxyethyl) amino group as a yellow oil]Pyridine-2-carbonitrile (1g, 49.8%). LCMS M/z (ESI), [ M + H]⁺＝164.2。¹H-NMR(300MHz,DMSO-d₆)δ3.25(2H,q),3.54(2H,t),4.83(1H,s),6.18(1H,t),7.29(1H,dd),7.39(1H,ddd),7.86(1H,dd)。

Step 2.2- [ [2- (aminomethyl) pyridin-3-yl ]Amino group]Ethan-1-ol

To 3- [ (2-hydroxyethyl) amino group at room temperature]Pyridine-2-carbonitrile (300mg, 1.8mmol, 1 eq) in MeOH (5mL) and NH₃H₂To a solution in O (1mL) was added Raney nickel (472.5mg, 5.5mmol, 3 equiv). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. This gives 2- [ [2- (aminomethyl) pyridin-3-yl ] as a violet oil]Amino group]Ethan-1-ol (230mg, 74.8%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝168.1。

Step 3.3-amino-5- (4-fluorophenyl) -N- ([3- [ (2-hydroxyethyl) amino group]Pyridin-2-yl]Methyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 117)

To 2- [ [2- (aminomethyl) pyridin-3-yl group]Amino group]Ethyl-1-ol (200mg, 1.2mmol, 1 equiv.) and a solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxylic acid (304.2mg, 0.8mmol, 0.7 equiv.) in DMF (15mL) were added T in portions₃P(761.1mg，2.3mmol, 2 equiv.) and DIEA (309.1mg, 2.4mmol, 2 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH) ₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 36% B within 7 min; 254/220 nm; rt: 5.57min) to give 3-amino-5- (4-fluorophenyl) -N- ([3- [ (2-hydroxyethyl) amino) as a yellow solid]Pyridin-2-yl]Methyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (compound 117) (33.3mg, 5.4%). LCMS M/z (ESI), [ M + H]⁺＝513.4。¹H NMR(300MHz,DMSO-d₆)δ3.17(2H,d),3.60(2H,q),3.78(3H,s),4.50(2H,d),4.78(1H,t),5.47(1H,t),6.98(1H,d),7.09(4H,m),7.44(3H,m),7.74(4H,m),8.19(1H,s),9.40(1H,t)。

Example 118.3-amino-N- ((4- (dimethylamino) pyridin-3-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 118)

Scheme 74

Step 1.4- (dimethylamino) nicotinonitrile

In a 20mL vial at room temperature was added dimethylamine (295.63mg, 6.557mmol, 2.00 equiv.), 4-bromopyridine-3-carbonitrile (600mg, 3.279mmol, 1 equiv.), and K₂CO₃(1.36g, 9.836mmol, 3.00 equiv.). The resulting mixture was stirred at 40 ℃ for 2 hours. The resulting mixture was filtered and the filter cake was washed with DCM (2X 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative tlc (etoac) to give 4- (dimethylamino) pyridine-3-carbonitrile (470mg, 97.40%) as an off-white solid (crude material).¹H-NMR(400MHz,CDCl₃)δ3.26(6H,s),6.55(1H,d),8.23(1H,d),8.47(1H,s)

Step 2.3- (aminomethyl) -N, N-dimethylpyridin-4-amine

4- (dimethylamino) pyridine-3-carbonitrile (470mg, 3.193mmol, 1 eq) and Raney nickel (957.56mg, 11.177mmol, 3.50 eq), NH were reacted at room temperature under a hydrogen atmosphere₃H₂A solution of O (1.12g, 31.958mmol, 10.01 eq) in MeOH was stirred for 7 hours. The resulting mixture was filtered and the filter cake was washed with DCM (2X 10 mL). The filtrate was concentrated under reduced pressure. This gave 3- (aminomethyl) -N, N-dimethylpyridin-4-amine (467mg, 96.71%) as a green oil. LCMS M/z (ESI), [ M + H]⁺＝152.3。¹H-NMR(300MHz,MeOD-d₄)δ2.75-3.05(6H,m),3.93(2H,s),6.95(1H,s),7.90-8.51(2H,m)。

Step 3.3-amino-N- ((4- (dimethylamino) pyridin-3-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 118)

To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.208mmol, 1 eq.) and DIEA (80.70mg, 0.624mmol, 3.00 eq.), T₃To a stirred solution of P (132.45mg, 0.416mmol, 2.00 equiv) in DMF was added 3- (aminomethyl) -N, N-dimethylpyridin-4-amine (62.95mg, 0.416mmol, 2.00 equiv) dropwise. The resulting mixture was stirred at room temperature for 1 hour. By preparative TLC (CH)₂Cl₂The residue was purified with MeOH 20:1) to give a yellow solid. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (10MMOL/L NH) ₄HCO₃) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 50% B within 7 min; 254/220 nm; rt: 5.82min) to obtain the crude product (90mg)To 3-amino-N- [ [4- (dimethylamino) pyridin-3-yl ] as yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 118) (45mg, 46.05%). LCMS M/z (ESI), [ M + H]⁺＝470.3。¹H-NMR(400MHz,DMSO-d₆)δ2.42(3H,d),2.80(6H,s),4.57(2H,d),6.89(1H,d),7.26(1H,dd),7.38(2H,dd),7.48(1H,dd),7.89(2H,s),8.19-8.30(3H,m),8.34(1H,dd),9.39(1H,t)。

Example 119.preparation of 3-amino-N- [ [3- (carbamoylmethoxy) pyridin-2-yl ] methyl ] -5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 119)

Scheme 75

Step 1.2- [ (2-cyanopyridin-3-yl) oxy]Acetamide

Reacting K at 80 ℃ in an air atmosphere₂CO₃A mixture of (448.75mg, 3.247mmol, 3 equivalents), 2-chloroacetamide (121.45mg, 1.299mmol, 1.2 equivalents), and 3-hydroxypyridine-2-carbonitrile (130mg, 1.082mmol, 1 equivalent) in DMF (6mL) was stirred for 16 h. The resulting mixture was diluted with water (30mL) and extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (3X 30mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 12:1) to give 2- [ (2-cyanopyridin-3-yl) oxy) as a white solid ]Acetamide (100mg, 52.15%). LCMS M/z (ESI), [ M + H]⁺＝178.0。¹H-NMR(300MHz,CDCl₃)δ:4.78(2H,s),7.47(1H,d),7.61(2H,d),7.70(1H,d),8.32(1H,d)

Step 2.2- [ [2- (aminomethyl) pyridin-3-yl]Oxy radical]Acetamide

Under hydrogen atmosphere at room temperatureRaney nickel (26.98mg, 0.315mmol, 0.62 equiv.) and 2- [ (2-cyanopyridin-3-yl) oxy]A mixture of acetamide (90mg, 0.508mmol, 1 eq) in MeOH (5mL) was stirred for 1 h. The precipitated solid was collected by filtration and washed with MeOH (3X 10 mL). Concentrating the obtained mixture under reduced pressure to obtain 2- [ [2- (aminomethyl) pyridin-3-yl ] as a purple solid]Oxy radical]Acetamide (60mg, 65.18%). LCMS M/z (ESI), [ M + H]⁺＝182.1

Step 3.3-amino-N- [ [3- (carbamoylmethoxy) pyridin-2-yl]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 119)

Reacting T at room temperature in an air atmosphere₃P (100mg, 1.344mmol, 4 equiv.), DIEA (470.5mg, 1.344mmol, 4.00 equiv.), 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxylic acid (120mg, 0.336mmol, 1.00 equiv.), and 2- [ [2- (aminomethyl) pyridin-3-yl ] pyrazine-2-carboxylic acid]Oxy radical]A mixture of acetamide (59.8mg, 0.336mmol, 1 eq.) in DMF (0.2mL) was stirred for 4 hours. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH) ₃H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 31% B to 45% B within 8 min; 254/220 nm; rt: 7.30min) to give 3-amino-N- [ [3- (carbamoylmethoxy) pyridin-2-yl ] as a yellow solid]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxamide (compound 119) (20mg, 12.14%). LCMS M/z (ESI), [ M + H]⁺＝527.3。¹H-NMR(300MHz,DMSO-d₆)δ3.80(3H,s),4.61(2H,s),4.75(2H,d),7.08(1H,d),7.15(2H,t),7.27-7.38(2H,m),7.43(2H,d),7.50(2H,d),7.64(2H,s),7.72(1H,s),8.13(1H,d),8.21(1H,s),9.23(1H,d)。¹⁹F NMR(282MHz,DMSO-d₆)δ:-112.591

Example 120/121 (R/S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 120/121)

Scheme 76

Step 1.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -N- ((1-methylpyrrolidin-2-yl) Methyl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

Oxazol-2-yl) pyrazine-2-carboxylic acid (300mg, 0.892mmol, 1 eq), Et₃N (270.79mg, 2.676mmol, 3.00 equiv.) and T₃To a stirred solution of P (851.48mg, 2.676mmol, 3.00 equivalents) in DMF was added 1- (1-methylpyrrolidin-2-yl) methylamine (203.73mg, 1.784mmol, 2.00 equivalents) dropwise. The resulting mixture was stirred at room temperature overnight. By preparative TLC (CH) ₂Cl₂The residue was purified with MeOH 20:1) to give a yellow solid. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 23% B to 38% B within 7 min; 254/220 nm; rt: 6.33min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ (1-methylpyrrolidin-2-yl) methyl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (120mg, 31.10%). LCMS M/z (ESI), [ M + H]⁺＝433.3。¹H-NMR(400MHz,DMSO-d₆)δ1.55-1.67(3H,m),1.78-1.88(1H,m),2.14(1H,q),2.31(3H,s),2.42(4H,d),2.94(1H,dd),3.20-3.29(1H,m),3.48(1H,ddd),7.19(1H,dd),7.36(1H,d),7.40(1H,d),7.49(1H,dd),7.90(2H,s),8.27(1H,d),8.31-8.36(1H,m),8.66(1H,t)。

Step 2.(R/S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -N- ((1-methylpyrrolidine- 2-yl) methyl) -5- (C

Azol-2-yl) pyrazine-2-carboxamide (Compound 120/121)

By preparative HPLC with the following conditions (column: CHIRALPAK IG,20 × 250mM, 5 μm; mobile phase a: Hex: DCM ═ 3:1(10mM NH)₃-MEOH) -HPLC, mobile phase B: EtOH-HPLC; flow rate: 18 mL/min; gradient: 50B to 50B within 25 min; 220/254 nm; RT 1: 13.303, respectively; RT 2: 19.802) to obtain 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (isomer 1) (Compound 120) (42mg, 42.00%), LCMS M/z (ESI), [ M + H ]⁺＝433.2。¹H-NMR(400MHz,DMSO-d₆)δ1.60(3H,dp),1.76-1.89(1H,m),2.15(1H,q),2.30(3H,s),2.42(4H,d),2.93(1H,dd),3.24(1H,dd),3.48(1H,dd),7.19(1H,dd),7.35(1H,d),7.40(1H,d),7.48(1H,dd),8.24(1H,d),8.35(1H,dd)。

3-amino-6- [ 3-methylimidazo [1,2-a ] as yellow solid]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (isomer 2) (compound 121) (40mg, 40%). LCMS M/z (ESI), [ M + H]⁺＝433.2。¹H-NMR(400MHz,DMSO-d₆)δ1.59(3H,ddt),1.77-1.90(1H,m),2.14(1H,q),2.29(3H,s),2.42(4H,d),2.89-2.96(1H,m),3.24(1H,dd),3.48(1H,dd),7.19(1H,dd),7.34(1H,d),7.40(1H,d),7.48(1H,dd),8.24(1H,d),8.35(1H,dd)

EXAMPLE 122 (R) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) -N- (pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (Compound 122)

Scheme 77

Step 1.(R) -2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrile Oxazine-2-carboxamido) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Oxazol-2-yl) pyrazine-2-carboxylic acid (140mg, 0.416mmol, 1 equiv.) and a stirred solution of tert-butyl (2R) -2- (aminomethyl) pyrrolidine-1-carboxylate (125.06mg, 0.624mmol, 1.50 equiv.), DIEA (161.40mg, 1.249mmol, 3.00 equiv.) in DMF was added T dropwise₃P (264.91mg, 0.833mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (100 mL). By CH₂Cl₂The resulting mixture was extracted (4X 100 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH) ₂Cl₂MeOH 20:1) to give (2R) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (156mg, 72.26%).LCMS:m/z(ESI),[M+H]⁺＝519.2。

Step 2.(R) -3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Azol-2-yl) -N- (pyri-dine Pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (Compound 122)

(2R) -2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] was added to a 50mL round bottom flask at room temperature]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (140mg, 0.270mmol, 1 equiv.) and TFA (2.00mL, 17.541mmol, 99.74 equiv.). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 mL). Saturated NaHCO at room temperature₃The reaction was quenched. By CH₂Cl₂The resulting mixture was extracted (3X 100 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃+0.1％NH₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 10% B to 30% B within 7 min; 254/220 nm; rt: 6.82min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ [ (2R) -pyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 122) (60mg, 53.11%). LCMS M/z (ESI), [ M + H]⁺＝419.2。¹H-NMR(400MHz,DMSO-d₆)δ1.32-1.44(1H,m),1.54-1.82(3H,m),2.43(3H,d),2.71-2.86(2H,m),3.23(3H,ddt),7.21(1H,dd),7.38(2H,dd),7.49(1H,dd),7.91(2H,s),8.27(1H,d),8.34(1H,t),8.75(1H,t)

Example 123 (S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) -N- (pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (Compound 123)

Scheme 78

Step 1.(S) -2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

3-amino-6- [ 3-methylimidazo [1,2-a ] was added at room temperature in an 8mL vial]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (140mg, 0.416mmol, 1 equiv.) and tert-butyl (2S) -2- (aminomethyl) pyrrolidine-1-carboxylate (125.06mg, 0.624mmol, 1.50 equiv.) and DIEA (161.40mg, 1.249mmol, 3.00 equiv.), T₃P (264.91mg, 0.833mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (100 mL). By CH₂Cl₂The resulting mixture was extracted (4X 100 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 20:1) to give (2S) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (170mg, 78.75%). LCMS:m/z(ESI),[M+H]⁺＝519.4。

Step 2.(S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) -N- (pyri-dine Pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (Compound 123)

(2S) -2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] was added to a 50mL round bottom flask at room temperature]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (170mg, 0.328mmol, 1 equiv.) and TFA (3mL, 40.389mmol, 123.21 equiv.). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 mL). Saturated NaHCO at room temperature₃Quench the reaction and use CH₂Cl₂(3X 100 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 37% B within 7 min; 254/220 nm; rt: 5.73min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ [ (2S) -pyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 123) (60mg, Y ═ 43.74%). LCMS M/z (ESI), [ M + H]⁺＝419.2。¹H-NMR(400MHz,DMSO-d₆)δ1.38(1H,ddt),1.51-1.81(3H,m),2.43(3H,d),2.71-2.84(2H,m),3.22(3H,ddt),7.20(1H,dd),7.38(2H,dd),7.49(1H,dd),7.91(2H,s),8.27(1H,d),8.34(1H,dd),8.74(1H,t)。

Example 128 (R) -3-amino-6- (3-ethyl)Pyrazolo [1,5-a]Pyridin-5-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 128)

Scheme 79

Step 1.1- [ 5-Bromopyrazolo [1,5-a ]]Pyridin-3-yl]Ethan-1-ol

To 5-bromopyrazolo [1,5-a ] at-50 ℃ under a nitrogen atmosphere]Pyridine-3-carbaldehyde (1g, 4.444mmol, 1 eq.) and CH₃MgBr (2.12g, 17.8mmol, 4.00 equiv.) in a stirred solution of THF (20 mL). At 0 ℃ by addition of saturated NH₄The reaction was quenched with Cl (aq) (5 mL). By CH₂Cl₂The aqueous layer was extracted (3X 30 mL). The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give 1- [ 5-bromopyrazolo [1,5-a ] as a white solid]Pyridin-3-yl]Ethan-1-ol (600mg, 56.01%). LCMS M/z (ESI), [ M + H]⁺＝241.2。

Step 2.5-bromo-3-ethylpyrazolo [1,5-a ]]Pyridine compound

1- [ 5-Bromopyrazolo [1,5-a ] at room temperature in an air atmosphere]Pyridin-3-yl]Ethan-1-ol (640mg, 2.65mmol, 1 equiv.) and triethylsilane (1852.03mg, 15.93mmol, 6.0 equiv.) in a stirred solution in TFA (10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 5:1) to give 5-bromo-3-ethylpyrazolo [1,5-a ] as a white solid ]Pyridine (490mg, 82.0%). LCMS M/z (ESI), [ M + H]⁺＝225.1。

Step 3.3-Ethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1, 5-a]pyridine compound

To 5-bromo-3-ethylpyrazolo [1,5-a ]]Pyridine (430mg, 1.9mmol, 1 equiv.) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (970.2mg, 3.81mmol, 2.0 equivalents) to bis

To a solution in alkane (10mL) was added K₃PO₄(1216.5mg, 5.73mmol, 3.0 equiv.) and Pd (dppf) Cl₂(279.6mg, 0.38mmol, 0.2 equiv.). After stirring at 90 ℃ for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 12:1) to give 3-ethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] as a white solid]Pyridine (420mg, 80.78%). LCMS M/z (ESI), [ M + H]⁺＝273.2。

Step 4.3-amino-6- [ 3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl]-5-(1,3-

Azol-2-yl) pyrazine- 2-Carboxylic acid methyl ester

To 3-amino-6-chloro-5- (1, 3-)

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (400mg, 1.571mmol, 1 equiv.) and 3-ethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] ]Pyridine (641.31mg, 2.356mmol, 1.50 equiv.) in bis

K was added to a solution of alkane (10mL) and water (1mL)₃PO₄(1000.35mg, 4.713mmol, 3 equiv.) and Pd (dppf) Cl₂(229.89mg, 0.314mmol, 0.2 equiv.). After stirring at 85 ℃ for 2 hours under nitrogen atmosphere, by preparative TLC (CH)₂Cl₂MeOH 15:1) to give 3-amino-6- [ 3-ethylpyrazolo [1,5-a ] as a brown-yellow solid]Pyridin-5-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (300mg, 52.4%). LCMS M/z (ESI), [ M + H]⁺＝365.3。

Step 5.3-amino-6- (3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxylic acid esters Acid(s)

3-amino-6- [ 3-ethylpyrazolo [1,5-a ] at room temperature in an air atmosphere]Pyridin-5-yl]-5-(1,3-

A solution of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (280mg, 0.77mmol, 1 equiv.) and LiOH (36.8mg, 1.54mmol, 2.0 equiv.) in THF (20mL) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified to pH 5 with HCl (1 aq). The precipitated solid was collected by filtration and concentrated in vacuo to give 3-amino-6- [ 3-ethylpyrazolo [1,5-a ] as a tan solid]Pyridin-5-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (240mg, 89.15%). LCMS M/z (ESI), [ M + H]⁺＝351.3。

Step 6.3-amino-6- [ 3-ethylpyrazolo [1,5-a ] ]Pyridin-5-yl]-N- [ [ (2R) -1-methylpyrrolidine- 2-radical]Methyl radical]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 128)

Oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.2mmol, 1 equiv.), 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (34.22mg,a solution of 0.3mmol, 1.5 equiv), HATU (151.95mg, 0.4mmol, 2 equiv), DIEA (77.5mg, 0.6mmol, 3 equiv) in DMF (2mL) was stirred for 30 min. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 40% B to 50% B within 8 min; 254/220 nm; rt: 7.25min) to give 3-amino-6- [ 3-ethylpyrazolo [1,5-a ] as a yellow solid]Pyridin-5-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 128) (20.1mg, 22.42%). LCMS M/z (ESI), [ M + H]⁺＝447.3。¹H NMR(400MHz,DMSO-d₆)δ1.2(3H,t),1.6(3H,dt),1.8(1H,q),2.2(1H,q),2.3(3H,s),2.4(1H,s),2.7(2H,q),2.9-3.0(1H,m),3.2-3.3(m,1H),3.4-3.5(m,1H),6.8(1H,dd),7.4(1H,d),7.6(1H,dd),7.9(1H,s),7.9(1H,s),8.3(1H,d),8.6(1H,dd),8.6(1H,t)。

Example 129 (S) -3-amino-6- (3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 129)

Scheme 80

Step 1.3-amino-6- [ 3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl]-N- [ [ (2R) -1-methylpyrrolidine- 2-radical]Methyl radical]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 129)

3-amino-6- [ 3-ethylpyrazine at room temperature in air atmosphereAzolo [1,5-a ]]Pyridin-5-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.200mmol, 1 equiv.), 1- [ (2S) -1-methylpyrrolidin-2-yl]A solution of methylamine (34.22mg, 0.300mmol, 1.5 equiv.), HATU (151.95mg, 0.400mmol, 2.00 equiv.), DIEA (77.47mg, 0.599mmol, 3 equiv.) in DMF (2mL) was stirred for 30 min. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 39% B to 51% B within 8 min; 254/220 nm; rt: 7.67min) to give 3-amino-6- [ 3-ethylpyrazolo [1,5-a ] as a yellow solid]Pyridin-5-yl]-N- [ [ (2S) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 129) (29.8mg, 22.42%). LCMS M/z (ESI), [ M + H]⁺＝447.3。¹H NMR(400MHz,DMSO-d₆)δ1.2(3H,t),1.5-1.7(3H,m),1.8-1.9(1H,m),2.2(1H,q),2.3(3H,s),2.4(1H,s),2.7(2H,q),2.9-3.0(1H,m),3.2-3.3(1H,m),3.5(1H,ddd),6.8(1H,dd),7.4(1H,s),7.5-7.6(1H,m),7.9(1H,s),7.9(1H,s),8.3(1H,s),8.6(1H,d),8.6(1H,t)。

Example 130.preparation of 3-amino-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -N- [ [ (2S) -1-methylpyrrolidin-2-yl ] methyl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 130)

Scheme 81

Step 1.3-amino-6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) -5- (1, 3-)

Oxazol-2-yl) -N- [ (1, 3-thiazole-4-yl) methyl]Pyrazine-2-carboxamide (Compound 130)

To 3-amino-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (300mg, 0.892mmol, 1 eq.) and 1- [ (2S) -1-methylpyrrolidin-2-yl) was added under an air atmosphere at room temperature]Methylamine (101.86mg, 0.892mmol, 1 equivalent) in a stirred solution in DMF T was added dropwise/portion by portion₃P (851.47mg, 2.676mmol, 3 equiv.) and DIEA (576.44mg, 4.460mmol, 5 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 4 hours. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (3X 10mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 18% B to 35% B within 7 min; 254/220 nm; rt: 7.08min) to give 3-amino-6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) -N- [ [ (2S) -1-methylpyrrolidin-2-yl ] as a yellow solid ]Methyl radical]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 130) (20mg, 5.18%). LCMS M/z (ESI) [ M + H ]]⁺＝433.2；¹H-NMR(400MHz,MeOD-d₄)δ1.68-1.81(2H,m),1.81(1H,s),1.96-2.08(1H,m),2.33(1H,q),2.47(3H,d),2.61(1H,s),3.06-3.13(1H,m),3.42-3.47(1H,m),3.66-3.70(1H,m),3.85(3H,s),7.03-7.06(1H,m),7.40(1H,s),7.53(1H,d),7.91(2H,s),8.14(1H,s)。

EXAMPLE 131 preparation of (R) -3-amino-6- (1-methyl-1H-benzo [ D ] imidazol-6-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 131)

Scheme 82

Step 1.3-amino-6- (1-methyl-1H-benzo [ D ]]Imidazol-6-yl) -5- (2H-1,2, 3-triazol-2-yl) pyri dine 2-oxazinecarboxylic acid

3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid methyl ester (500mg, 1.964mmol, 1 eq), 1-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-1, 3-benzodiazole (608.25mg, 2.356mmol, 1.20 eq), Pd (dppf) Cl at 100 ℃ under a nitrogen atmosphere₂(287.36mg, 0.393mmol, 0.2 equiv.) and Cs₂CO₃(2559.16mg, 7.855mmol, 4.0 equiv.) in bis

A solution in alkane (40mL) and water (5mL) was stirred for 16 hours. The resulting mixture was extracted with EtOAc (3X 40 mL). The aqueous solution was acidified to pH 6 with HCl (1M). The precipitated solid was collected by filtration and washed with water (2X 10 mL). This provided 3-amino-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid as a light yellow solid (240mg, 36.34%). LCMS M/z (ESI), [ M + H ]⁺＝337.1。¹H-NMR(300MHz,MeOD-d₄)δ3.93(3H,s),7.33-7.35(2H,m),7.43-7.46(1H,m),7.82-7.84(2H,m),8.12(1H,s)

Step 2.(R) -3-amino-6- (1-methyl-1H-benzo [ D)]Imidazol-6-yl) -N- ((1-methylpyrrolidine-2-) Yl) methyl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 131)

3-amino-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq), 1- [ (2R) -1-methylpyrrolidin-2-yl were reacted at room temperature]A mixture of methylamine (67.91mg, 0.595mmol, 2.0 equiv.), T3P (473.04mg, 1.487mmol, 5 equiv.), and DIEA (384.29mg, 2.973mmol, 10 equiv.) in DMF (5mL) was stirred for 2 hours. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (20mL) and over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 20% B to 35% B within 7 min; 254/220 nm; rt:5.73min) to give 3-amino-6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) -N- [ [ (2R) -1-methylpyrrolidin-2-yl ] as a yellow solid]Methyl radical]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 131) (20mg, 15.55%). LCMS M/z (ESI), [ M + H ]⁺＝433.3。¹H-NMR(300MHz,DMSO-d₆)δ1.67-1.69(3H,m),1.86-1.89(1H,m),2.15-2.17(1H,m),2.33(3H,s),2.45-2.47(1H,m),2.96-2.97(1H,m),3.31-3.34(1H,m),3.74(3H,m),6.84-6.87(1H,m),7.25(1H,s),7.48(1H,s),8.01-8.03(2H,m),8.07-8.09(2H,m),8.20(1H,s),8.66-8.68(1H,m)。

The compounds listed in the table below were prepared using the procedure described for compound 131.

Example 134/135.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ [ (2R/2S) -oxetan-2-yl]Methyl radical]Preparation of pyrazine-2-carboxamide (Compound 134/135)

Scheme 83

Step 1.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) -N- [ (Oxetan-2-yl) methyl]Pyrazine-2-carboxamides

At 25 ℃ under nitrogen atmosphere towards T₃To a stirred mixture of P (946.09mg, 2.973mmol, 5.00 equiv.) and 1- (oxetan-2-yl) methylamine (77.72mg, 0.892mmol, 1.50 equiv.) in DMF (5mL) was added 3-amino-6- [ 3-methylimidazo [1,2-a ] dropwise]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (200mg, 0.595mmol, 1 eq) and DIEA (307.44mg, 2.379mmol, 4.00 eq). The resulting mixture was stirred at 25 ℃ under a nitrogen atmosphere for 6 hours. The reaction was quenched by the addition of water (50mL) at 25 ℃. The aqueous layer was extracted with EtOAc (3X 50 mL). The aqueous layer was evaporated. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 19% B to 29% B within 7 min; 254/220 nm; rt: 6.45min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (oxetan-2-yl) methyl]Pyrazine-2-carboxamide (90mg, 37.33%). LCMS M/z (ESI), [ M + H]⁺＝406.2。

Step 2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) -N- [ [ (2R/2S) -oxetan-2-yl]Methyl radical]Preparation of pyrazine-2-carboxamide (Compound 134/135)

The crude product (150mg) was purified by preparative HPLC accompanied by the following conditions (column: CHIRALPAK IE, 2X 25cm, 5 μm; mobile phase A: MTBE (10mM NH3-MEOH) - - -HPLC- -, mobile phase B: EtOH- - -HPLC; flow rate: 20 mL/min; gradient: 20B to 20B over 18 min; 220/254 nm; RT 1: 12.678; RT 2: 14.094) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ [ (2R) -oxetan-2-yl]Methyl radical]Pyrazine-2-carboxamide (isomer 1) (compound 134) (60mg, 40%).LCMS:m/z(ESI),[M+H]⁺＝406.1。¹H NMR(300MHz,MeOD-d₄) δ 2.50(3H, d),2.52-2.61(1H, m),2.72(1H, t),3.60-3.79(2H, m),4.56(1H, dt),4.63-4.74(1H, m),4.95-5.07(1H, m),7.26(1H, dd),7.32(1H, d),7.38(1H, d),7.48(1H, dd),8.00(1H, d),8.37(1H, d). And 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ [ (2R) -oxetan-2-yl]Methyl radical]Pyrazine-2-carboxamide (isomer 2) (compound 135) (60mg, 40%). LCMS M/z (ESI), [ M + H ]⁺＝406.1。¹H NMR(300MHz,MeOD-d₄)δ2.50(3H,d),2.55(1H,d),2.71(1H,d),3.64(1H,dd),3.74(2H,dd),4.56(1H,dt),4.63-4.74(1H,m),4.95-5.07(1H,m),7.26(1H,dd),7.32(1H,d),7.38(1H,d),7.48(1H,dd),8.00(1H,d),8.37(1H,s)。

EXAMPLE 136 (R) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 136)

Scheme 84

(R) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 136)

Placing 3-amino-6- [ 3-methylimidazo [1,2-a ] in a 25mL round-bottomed flask]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (100)mg, 0.297mmol, 1 eq), DIEA (384.30mg, 2.973mmol, 10 eq) and (R) - (tetrahydrofuran-3-yl) methylamine (90.23mg, 0.892mmol, 3 eq) in DMF (4 mL). At 0 ℃ C₃P (378.44mg, 1.189mmol, 4 equiv.) was added to the above solution. The resulting solution was stirred at room temperature for 1 hour. By preparative HPLC with the following conditions: (column: Xbridge Prep OBD C18 column 30X 150mm5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 37% B within 7 min; 254/220 nm; rt: 5.85min) to purify the reaction mixture. This gave 67mg (53.72%) of (R) -3-amino-6- (3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl) -5-, (

Oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (compound 136). LCMS M/z (ESI), [ M + H]⁺＝420.2。¹H-NMR(400MHz,MeOD-d₄)δ1.75(1H,dt),2.02-2.15(1H,m),2.53(3H,d),2.65(1H,t),3.45(2H,d),3.65(1H,dd),3.76(1H,q),3.83(1H,dd),3.92(1H,td),7.28(1H,dd),7.34(1H,d),7.41(1H,s),7.46-7.53(1H,m),8.02(1H,d),8.40(1H,s)

Example 137 (S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 137)

Scheme 85

Step 1.(S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl)) Pyrazine-2-carboxamide (Compound 137)

3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 equiv.) and (S) - (tetrahydrofuran-3-yl) methylamine (130mg, 1.285mmol, 4.32 equiv.) in DMF were added DIEA (1.04mL, 5.946mmol, 20 equiv.) and T₃P (473.05mg, 1.487mmol, 5 equivalents). The reaction mixture was diluted with water (25 mL). The aqueous layer was extracted with EtOAc (2X 25 mL). The combined organic layers were concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃+0.1％NH₃.H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 35% B within 7 min; 254/220 nm; rt: 6.48min) to give (S) -3-amino-6- (3-methylimidazo [1, 2-a) as a yellow solid ]Pyridin-6-yl) -5-, (

Oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (compound 137) (70mg, 56.00%). LCMS M/z (ESI), [ M + H]⁺＝420.3；¹H-NMR(400MHz,MeOD-d₄)δ1.75(1H,dt),2.02-2.15(1H,m),2.53(3H,d),2.65(1H,t),3.45(2H,d),3.65(1H,dd),3.76(1H,q),3.83(1H,dd),3.92(1H,td),7.28(1H,dd),7.34(1H,d),7.41(1H,s),7.46-7.53(1H,m),8.02(1H,d),8.40(1H,s)。

The compounds listed in the table below were prepared using the procedure described for compound 137.

EXAMPLE 138 preparation of 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -N- [ [ (2R) -1-methylpyrrolidin-2-yl ] methyl ] pyrazine-2-carboxamide (Compound 138)

Scheme 86

Step 1.3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]pyrazine-2-A Acid(s)

In a 100mL round bottom flask purged and maintained with an inert nitrogen atmosphere was placed 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (1g, 3.736mmol, 1 eq), [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (1.12g, 6.364mmol, 1.70 equiv.), Cs₂CO₃(3.04g, 9.330mmol, 2.50 equiv.), bis

Alkane (25mL), Pd (dppf) Cl₂(273.39mg, 0.374mmol, 0.10 equiv.). The resulting solution was stirred at 100 ℃ for 16 hours. Using 20mL of H₂The resulting solution was diluted with O. The resulting solution was extracted with 3X 20mL of ethyl acetate and the aqueous layers were combined. The pH of the solution was adjusted to 4 with HCl (1 mol/L). The solid was collected by filtration. This gave 500mg (36.83%) of 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a brown solid ]Pyridin-6-yl]Pyrazine-2-carboxylic acid. LCMS M/z (ESI), [ M + H]⁺＝364。¹H NMR(400MHz,DMSO-d₆)δ2.37(3H,s),6.97(1H,d),7.21(2H,t),7.38(2H,t),7.51(2H,d),7.62(2H,s),8.26(1H,s)

Step 2.3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N-[[(2R)- 1-Methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamides (Compound 138)

Place 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] in a 20-mL vial]Pyridin-6-yl]Pyrazine-2-carboxylic acid (130mg, 0.358mmol, 1 equiv.), 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (81.71mg, 0.716mmol, 2.00 equiv.), DMF (6mL), DIEA (0.31mL, 2.396mmol, 3.42 equiv.), T₃P (569.19mg, 1.789mmol, 5.00 equiv.). The resulting solution was stirred at 20 ℃ for 16 hours. The resulting mixture was concentrated in vacuo. By preparative HPLC (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 34% B to 49% B within 7 min; 254/220 nm; rt: 6.52min) to purify the crude product. This gave 54.29mg (33.02%) of 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (Compound 138). LCMS M/z (ESI), [ M + H]⁺＝460。¹H-NMR(400MHz,DMSO-d₆)δ1.61(3H,d),1.73-1.95(1H,m),2.12(1H,dd),2.32(3H,s),2.37(3H,d),2.42(1H,s),2.89-3.03(1H,m),3.17-3.29(1H,m),3.50(1H,d),6.99(1H,d),7.21(2H,t),7.31-7.43(2H,m),7.45-7.56(2H,m),7.74(2H,s),8.24(1H,d),8.63(1H,t)。19F NMR(400MHz,DMSO-d6,)-112.225(1F)

Example 147.3-amino-N- (2-methoxyethyl) -6- (3-methylimidazo [1,2-a ] ]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 147)

Scheme 87

Step 1.3-amino-N- (2-methoxyethyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides(Compound 147)

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (90mg, 0.268mmol, 1 eq) and 2-methoxyethyl-1-amine (60.30mg, 0.803mmol, 3 eq) in DMF was added DIEA (164.08mg, 1.270mmol, 5 eq) and T dropwise₃P (323.16mg, 1.016mmol, 4 equiv.). The resulting solution was stirred at room temperature for 1 hour. Water (25mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (3X 25 mL). The combined organic layers were washed with brine (1X 15mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 18% B to 32% B within 7 min; 254 nm; rt: 6.83min) to yield 3-amino-N- (2-methoxyethyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 147) (50mg, 49.78%). LCMS M/z (ESI), [ M + H]⁺＝394.2。¹H-NMR(400MHz,MeOD-d₄)δ2.52(3H,d),3.39(3H,s),3.55-3.65(4H,m),7.26-7.29(1H,m),7.33(1H,d),7.40(1H,d),7.48-7.51(1H,m),8.00(1H,d),8.36-8.38(1H,m)。

The compounds listed in the table below were prepared using the procedure described for compound 147.

Example 149: 3-amino-N- (3-methoxypropyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 149)

Scheme 88

Step 1.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine- 2-Carboxylic acid methyl ester

3-amino-6-chloro-5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (3000mg, 11.8mmol, 1 eq.) and [ 3-methylimidazo [1,2-a]Pyridin-6-yl]Boric acid (4146.7mg, 23.6mmol, 2 equiv.) in bis

Cs was added in portions to a stirred mixture in an alkane (300mL)₂CO₃(11516.2mg, 35.3mmol, 3 equiv.) and Pd (dppf) Cl₂(1724.1mg, 2.4mmol, 0.2 equiv.). The resulting mixture was stirred at 95 ℃ for 1.5 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH₂Cl₂EtOAc (1:4) elution affording 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1500mg, 36.3%). LCMS M/z (ESI), [ M + H ]⁺＝351.3。¹H-NMR(400MHz,DMSO-d₆)δ2.12(3H,s),2.38(3H,d),7.04(1H,dd),7.36-7.38(2H,m),7.46-7.55(1H,m),7.71(2H,s),8.27(1H,d),8.80(1H,t)。

Step 2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine- 2-carboxylic acid

At 45 ℃ will3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

A mixture of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1500mg, 4.3mmol, 1 eq) and LiOH (205.1mg, 8.6mmol, 2 eq) in THF (100mL) and MeOH (20mL) was stirred for 1.5 h. The resulting mixture was stirred at 45 ℃ under an air atmosphere for 2.5 hours. The mixture was acidified to pH 5 with HCl (aq). The resulting mixture was concentrated in vacuo to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (1200mg, 83.3%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝337.3。

Step 3.3-amino-N- (3-methoxypropyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1, 3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 149)

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.3mmol, 1 eq) and 3-methoxypropan-1-amine (53mg, 0.6mmol, 2 eq) in DMF (8mL) was added HATU (226.1mg, 0.6mmol, 2 eq) and DIEA (115.3mg, 0.9mmol, 3 eq) portionwise. The resulting mixture was stirred at room temperature under an air atmosphere for 2.5 hours. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH) ₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 21% B to 34% B within 7 min; 254/220 nm; rt: 6.67min) to purifyThe crude product (80mg) was obtained as 3-amino-N- (3-methoxypropyl) -6- [ 3-methylimidazo [1,2-a ] yellow-green solid]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 149) (10mg, 8.3%). LCMS M/z (ESI), [ M + H]⁺＝408.3。¹H-NMR(400MHz,DMSO-d₆)δ1.78(2H,p),2.43(3H,s),3.22(3H,s),3.39(4H,q),7.23(1H,dd),7.38(2H,d),7.48(1H,d),7.91(2H,s),8.23-8.35(2H,m),8.89(1H,t)

EXAMPLE 154 preparation of 3-amino-N- [ [1- (dimethylamino) cyclopropyl ] methyl ] -5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] pyrazine-2-carboxamide (Compound 154)

Scheme 89

Step 1.[ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid

5- (3,3,4, 4-tetramethylborane-1-yl) pyridin-2-amine (20.0g, 92.5mmol, 1.0 eq.) was added to HCl (1.0mol/L) and stirred at 80 ℃ for 1 hour under an air atmosphere. With NaHCO₃The mixture was basified to pH 7. With CHCl₃The resulting mixture was extracted (5X 40 mL). And passing through anhydrous Na₂SO₄And (5) drying. After filtration, 2-bromo-1, 1-dimethoxypropane (49.9g, 272.9mmol, 2.9 equiv.) was added to the above mixture. The resulting mixture was stirred at 100 ℃ for 10 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. Recrystallization of the crude product from EtOAc/MeOH (20: 150 mL) afforded [ 3-methylimidazo [1,2-a ] as a white solid ]Pyridin-6-yl]Boric acid (14.6g, 87.8%). LCMS M/z (ESI), [ M + H]⁺＝177.2。

Step 2.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid methyl ester

Methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (20g, 90.1mmol, 1.0 eq.) and (C: (R) (R)) at 90 ℃ under a nitrogen atmosphere4-fluorophenyl) boronic acid (13.9g, 99.1mmol, 1.1 equiv.) and Pd (dppf) Cl₂(6.6g, 9.0mmol, 0.1 equiv.) and Na₂CO₃(19.1g, 180.2mmol, 2.0 equiv.) in 1, 4-bis

alkane/H₂The mixture in O (300mL) was stirred for 2 hours. The resulting mixture was extracted with EtOAc (3X 200 mL). By H₂The combined organic layers were washed with O (3X 80mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was recrystallized from MeOH (100mL) to give methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (19.2g, 74.2%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝282.2。

Step 3.3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]pyrazine-2-A Acid methyl ester

3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid methyl ester (9.2g, 32.6mmol, 1.0 equiv.) and [ 3-methylimidazo [1,2-a ] at 90 ℃ under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (11.5g, 65.3mmol, 2.0 equiv.) and Pd (dppf) Cl₂(2.4g, 3.3mmol, 0.1 eq.) and K ₃PO₄(13.9g, 65.3mmol, 2.0 equiv.) in 1, 4-bis

alkane/H₂The mixture in O (200mL) was stirred for 2 hours. The resulting mixture was extracted with EtOAc (4X 80 mL). By H₂The combined organic layers were washed with O (3X 30mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH₂Cl₂EtOAc (2:1) elution gave 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a tan solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (9.5g, 76.1%). LCMS M/z (ESI), [ M + H]⁺＝378.3。

And 4. step 4. 3-amino-5- (4-fluorophenyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) pyrazin-2-yl Acid(s)

To the 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (3.0g, 7.9mmol, 1.0 equiv.) and lithium alcohol (380.8mg, 15.9mmol, 2.0 equiv.) in THF/H₂O ═ 20:1(82mL) in a stirred solution. The resulting mixture was stirred at room temperature under an air atmosphere for 4.0 hours. The desired product can be detected by LCMS. With HCl (in II)

In an alkane) the mixture was acidified to pH 3. The precipitated solid was collected by filtration and washed with water (2X 10mL) to give 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a pale yellow solid ]Pyridin-6-yl]Pyrazine-2-carboxylic acid (2.1g, 72.7%). LCMS M/z (ESI), [ M + H]⁺＝364.2。¹H-NMR(400MHz,DMSO-d₆)δ2.35-2.42(3H,m),6.97(1H,dd),7.14-7.28(2H,m),7.34-7.43(2H,m),7.45-7.57(2H,m),7.65(2H,s),8.28(1H,t)。

Step 5.3-amino-N- [ [1- (dimethylamino) cyclopropyl [ ]]Methyl radical]-5- (4-fluorophenyl) -6- [ 3-methylimidazole And [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 154)

3-amino-5- (4-fluorophenyl) -6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]A mixture of pyrazine-2-carboxylic acid (100.0mg, 0.3mmol, 1.0 equiv.) and 1- (aminomethyl) -N, N-dimethylcycloprop-1-amine (49.0mg, 0.4mmol, 1.5 equiv.) and HATU (217.6mg, 0.6mmol, 2.0 equiv.) and DIEA (111.0mg, 0.9mmol, 3.0 equiv.) in DMF (2.5mL) was stirred for 1 h. The reaction was quenched with water at room temperature. The solid was isolated and the crude product was subsequently recrystallized from EtOH (4mL) to give 3-amino-N- [ [1- (dimethylamino) cyclopropyl ] as a yellow solid]Methyl radical]-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (compound 154) (25mg, 18.6%). LCMS M/z (ESI), [ M + H]⁺＝460.3。¹H NMR(400MHz,DMSO-d₆)δ0.43-0.52(2H,m),0.61-0.70(2H,m),2.39(9H,d),3.49(2H,d),6.97(1H,dd),7.21(2H,t),7.33-7.44(2H,m),7.46-7.54(2H,m),7.72(2H,s),8.32(1H,s),8.67(1H,t)。

The compounds listed in the table below were prepared using the procedure described for compound 154.

EXAMPLE 156 preparation of (2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] pyrazin-2-yl ] methyl ] -1-methylpyrrolidine-2-carboxamide (Compound 156)

Scheme 90

Step 1.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide

3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid methyl ester (2.0g, 7.10mmol, 1 eq) and NH were added at room temperature in a 50mL sealed tube₃(g) In MeOH (30mL, 7.0mmol/L), heated at 50 deg.C for 5 hours, and concentrated to give 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide as a pale yellow solid (1.5g, 79%). LCMS M/z (ESI), [ M + H]⁺＝267.1。

Step 2.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile

3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide (1.5g, 5.63mmol, 1 equiv.) and POCl were added at room temperature to a 25mL round bottom flask₃(10mL, 107.28mmol, 19.07 equiv.) and heated at 90 ℃ for 3 hours. Cooling to room temperature, pouring NaHCO₃(aqueous solution, 200ml), filtered and dried to give a yellow colour3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (1.2g, 86%) as a solid. LCMS M/z (ESI), [ M + H]⁺＝249.2。

Step 3.3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine

A500 mL round bottom flask was charged with a solution of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (1.4g, 5.63mmol, 1 eq) and Raney nickel (0.3g, 3.50mmol, 0.62 eq) in methanol (150mL) at room temperature in H ₂Stirring under conditions (about 1.5atm) for 15 h, filtration and concentration gave 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (1.1g, crude material) as a light brown solid. LCMS M/z (ESI), [ M-NH ]₂]⁺＝236.2。

Step 4.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]-1-methylpyrrolidine-2-carboxamide

DIEA (306.89mg, 2.38mmol, 2.0 equiv.) is added dropwise to a stirred mixture of (2S) -1-methylpyrrolidine-2-carboxylic acid (168.68mg, 1.31mmol, 1.10 equiv.), 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (300mg, 1.19mmol, 1 equiv.) and HATU (496.58mg, 1.31mmol, 1.1 equiv.) in DMF (3.0mL) at 0 deg.C under a nitrogen atmosphere, stirred at room temperature for 3 hours, water (15mL) is added, filtered and dried to give (2S) -N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl as a light yellow solid]Methyl radical]-1-methylpyrrolidine-2-carboxamide (250mg, 57.88%). LCMS M/z (ESI), [ M + H]⁺＝364.2。

Step 5.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 156)

Reacting (2S) -N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] at 90 ℃ under a nitrogen atmosphere ]Methyl radical]-1-methylpyrrolidine-2-carboxamide (180.0mg, 0.5mmol, 1.0 equiv.) and [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (174.1mg, 0.9mmol, 2.0 equiv.) and Pd (dppf) Cl₂(36.2mg, 0.1mmol, 0.1 equiv.) and K₃PO₄(315.1mg, 1.5mmol, 3.0 equiv.) in 1, 4-bis

alkane/H₂The mixture in O (4.0mL) was stirred for 10 hours. By preparative TLC (CH)₂Cl₂The residue was purified by preparative HPLC with the following conditions (column: xbridge Prep OBD C¹⁸Columns 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 43% B within 7 min; 254/220 nm; rt: 6.70min) to give (2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a pale yellow solid]Pyridin-6-yl]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (compound 157) (20.0mg, 8.6%). LCMS M/z (ESI), [ M + H]⁺＝460.3。¹H-NMR(400MHz,DMSO-d₆)δ1.73(3H,td),2.10(1H,dd),2.19-2.38(7H,m),2.80(1H,dd),3.04(1H,dd),4.30-4.49(2H,m),6.68(2H,s),6.99(1H,dd),7.17(2H,t),7.34(1H,s),7.37-7.49(3H,m),8.01(1H,s),8.44(1H,t)。

EXAMPLE 157 preparation of (2R) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] pyrazin-2-yl ] methyl ] -1-methylpyrrolidine-2-carboxamide (Compound 157)

Scheme 91

Step 1.(2R) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 157)

Reacting (2R) -N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] at 90 ℃ under a nitrogen atmosphere]Methyl radical]-1-methylpyrrolidine-2-carboxamide (180.0mg, 0.5mmol, 1.0 equiv.) and [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (174.1mg, 0.9mmol, 2.0 equiv.) and Pd (dppf) Cl₂(36.2mg, 0.1mmol, 0.2 equiv.) andK₃PO₄(315.1mg, 1.5mmol, 3.0 equiv.) in 1, 4-bis

alkane/H₂The mixture in O (4.0mL) was stirred for 10 hours. By preparative TLC (CH)₂Cl₂The residue was purified by preparative HPLC with the following conditions (column: xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 43% B within 7 min; 254/220 nm; rt: 6.70min) to give (2R) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a pale yellow solid]Pyridin-6-yl]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (compound 157) (20.0mg, 8.6%). LCMS M/z (ESI), [ M + H]⁺＝460.3。¹H-NMR(400MHz,DMSO-d₆)δ1.73(3H,td),2.10(1H,dd),2.19-2.38(7H,m),2.80(1H,dd),3.04(1H,dd),4.30-4.49(2H,m),6.68(2H,s),6.99(1H,dd),7.17(2H,t),7.34-7.49(4H,m),8.01(1H,s),8.44(1H,t)。

The compounds listed in the table below were prepared using the procedure described for compound 157.

Example 161 (S) -3-amino-N- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 161)

Scheme 92

Step 1.(S) -2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrile Oxazine-2-carboxamido) methyl) -4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

3-amino-6- [ 3-methylimidazo [1,2-a ] at 0 ℃ in an air atmosphere]Pyridin-6-yl]-5-(1,3-

To a stirred solution of (150mg, 0.446mmol, 1 equivalent) oxazol-2-yl) pyrazine-2-carboxylic acid and (2S) -tert-butyl 2- (aminomethyl) -4, 4-difluoropyrrolidine-1-carboxylate (210.75mg, 0.892mmol, 2.00 equivalents), DIEA (172.93mg, 1.338mmol, 3.00 equivalents) in DMF was added T-butyl dropwise₃P (283.83mg, 0.892mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was diluted with EtOAc (40 mL). The resulting mixture was washed with 2X 40mL of water. Through anhydrous Na₂SO₄The organic layer was dried and the solid was filtered off and concentrated in vacuo. By preparative TLC (CH)₂Cl₂MeOH 200:15) to give (2S) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides ]Methyl radical]-4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (220mg, 88.95%). LCMS M/z (ESI), [ M + H]⁺＝555.2。

Step 2.(S) -3-amino-N- ((4, 4-difluoropyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Tert-butyl-4, 4-difluoropyrrolidine-1-carboxylate (220mg, 0.397mmol, 1 equiv.) and TFA ((2mL, 26.926mmol, 67.87 equiv.) the resulting mixture was stirred at room temperature under an air atmosphere for 1 hour, the solvent and TFA were evaporated off to give 3-amino-N- [ (4, 4-difluoropyrrolidin-2-yl) methyl as a yellow solid]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (180mg, 99.84%) (crude material). LCMS M/z (ESI), [ M + H]⁺＝455.2。

Step 3.(S) -3-amino-N- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo) [1,2-a]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 161)

3-amino-N- [ [ (2S) -4, 4-difluoropyrrolidin-2-yl ester at room temperature in an air atmosphere]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl ]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (180mg, 0.396mmol, 1 equiv.) and HCHO (118.93mg, 3.961mmol, 10.00 equiv.), DIEA (510.9mg, 3.961mmol, 10.00 equiv.) in CH₂Cl₂To a stirred mixture in MeOH (6mL) and NaBH (3mL) was added portionwise₃CN (149.35mg, 2.377mmol, 6.00 equiv.). The reaction mixture was stirred at room temperature for 2 hours. Quenched by water (50mL) and extracted by DCM (2X 50mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dry, filter off the solid and evaporate the solvent. The residue was purified by preparative TLC (DCM: MeOH ═ 20:1) to give a yellow solid. By preparative HPLC with the following conditions (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 27% B to 40% B within 7 min; 254/220 nm; rt: 6.05min) to give 3-amino-N- [ [ (2S) -4, 4-difluoro-1-methylpyrrolidin-2-yl ] as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 161) (60mg, 32.34%). LCMS M/z (ESI), [ M + H]⁺＝469.2。¹H NMR(400MHz,DMSO-d₆)δ2.19(1H,dt),2.33(3H,s),2.43(4H,s),2.61(1H,ddd),2.78(1H,s),3.38(1H,d),3.53(1H,s),7.20(1H,dd),7.38(2H,d),7.49(1H,d),7.89(2H,s),8.29(2H,d),8.77(1H,t)

EXAMPLE 162 (R) -3-amino-N- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a) ]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 162)

Scheme 93

Step 1.(R) -2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.446mmol, 1 eq) and tert-butyl (2R) -2- (aminomethyl) -4, 4-difluoropyrrolidine-1-carboxylate (210.75mg,0.892mmol, 2.00 equiv.), DIEA (172.93mg, 1.338mmol, 3.00 equiv.) in DMF was added T dropwise₃P (283.83mg, 0.892mmol, 2.00 equiv.). The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with 2X 50mL of water and 2X 50mL of saturated NaCl, over anhydrous Na₂SO₄The organic layer was dried, and the resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 20:1) to give (2R) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (220mg, 88.95%). LCMS M/z (ESI), [ M + H]⁺＝555.2；¹H-NMR(400MHz,DMSO-d₆)δ1.28(9H,s),2.43(4H,s),2.63(1H,s),3.48(1H,s),3.64(1H,s),3.80(1H,s),4.02(1H,q),4.29(1H,s),7.20(1H,s),7.42(3H,dd),7.89(2H,s),8.31(2H,d),9.03(1H,d)

Step 2.(R) -3-amino-N- ((4, 4-difluoropyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a) ] Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

To (2R) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) at room temperature under an air atmosphere]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]To a stirred solution of tert-butyl (4, 4-difluoropyrrolidine-1-carboxylate (220mg, 0.397mmol, 1 eq) in DCM was added TFA (2mL, 26.926mmol, 67.87 eq). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. Evaporation of DCM and TFA gave 3-amino-N- [ [ (2R) -4, 4-difluoropyrrolidin-2-yl as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (99.84%) (crude material). LCMS M/z (ESI), [ M + H]⁺＝455.2H-NMR(400MHz,DMSO-d₆)δ2.40(1H,t),2.56(3H,s),2.73(1H,dq),3.75(3H,d),3.85(1H,q),4.08(1H,dd),7.34(1H,s),7.92-8.17(5H,m),8.34(1H,s),8.96(1H,s),9.20(1H,t)

Step 3.(R) -3-amino-N- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo) [1,2-a]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 162)

To 3-amino-N- [ [ (2R) -4, 4-difluoropyrrolidin-2-yl at room temperature under an air atmosphere]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (180mg, 0.396mmol, 1 equiv.) and HCHO (118.93mg, 3.961mmol, 10.00 equiv.), DIEA (307.15mg, 2.377mmol, 6.00 equiv.) in CH₂Cl₂To a stirred mixture in (6mL)/MeOH (3mL) was added NaBH dropwise ₃CN (149.35mg, 2.377mmol, 6.00 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The reaction was quenched by the addition of water (50mL) at room temperature. By CH₂Cl₂The aqueous layer was extracted (2X 50 mL). The organic layers were combined and passed over anhydrous Na₂SO₄Drying and evaporation of the solvent gave a yellow solid. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 20 mL/min; gradient: 32% B to 45% B within 8 min; 254; 220 nm; rt: 7.67min) to give 3-amino-N- [ [ (2R) -4, 4-difluoro-1-methylpyrrolidin-2-yl ] as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 162) (40mg, 21.56%). LCMS M/z (ESI), [ M + H]⁺＝469.2 1H NMR(400MHz,DMSO-d₆)δ2.19(1H,dt),2.33(3H,s),2.42(4H,s),2.54-2.71(1H,m),2.79(1H,s),3.55(1H,d),7.20(1H,dd),7.38(2H,d),7.49(1H,d),7.90(2H,s),8.29(2H,d),8.77(1H,t)。

Example 171.3-amino-N- [ (6- [ 1-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl radical]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 171)

Scheme 94

Step 1.6- (6-cyanopyridin-2-yl) -1, 6-diazaspiro [3.3]Heptane-1-carboxylic acid tert-butyl ester

6-Fluoropyridine-2-carbonitrile (1.5g, 12.29mmol, 1 eq.) and 1, 6-diazaspiro [3.3 ] were reacted at 50 ℃ under an air atmosphere ]Heptane-1-carboxylic acid tert-butyl ester (2.92g, 14.73mmol, 1.20 equiv.) and K₂CO₃A mixture of (5.09g, 36.829mmol, 3.00 equiv.) in DMF (20mL) was stirred for 10 h. The resulting mixture was extracted with EtOAc (4X 20 mL). By H₂The combined organic layers were washed with O (2X 10mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (6:1) to give 6- (6-cyanopyridin-2-yl) -1, 6-diazaspiro [3.3 ] as a white solid]Heptane-1-carboxylic acid tert-butyl ester (2.69g, 72.17%). LCMS M/z (ESI), [ M + H]⁺＝301.3。

Step 2.1- (6- [ 1-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl radical]Pyridin-2-yl) methylamines

6- (6-cyanopyridine-2) is reacted at 50 ℃ under an air atmosphere-yl) -1, 6-diazaspiro [3.3]Heptane-1-carboxylic acid tert-butyl ester (0.5g, 1.665mmol, 1 eq.) and LiAlH₄A mixture of (0.13g, 3.425mmol, 2.06 equiv.) in THF (10mL) was stirred for 6 hours. The reaction was quenched by addition of EtOAc (20mL) at room temperature. And then extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with water (3X 10mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gave 1- (6- [ 1-methyl-1, 6-diazaspiro [3.3 ] as a white solid ]Heptane-6-yl radical]Pyridin-2-yl) methylamine (200mg, 53.93%). LCMS M/z (ESI), [ M + H]⁺＝219.2。

Step 3.3-amino-N- [ (6- [ 1-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl radical]Pyridin-2-yl) methyl Base of]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamides 171)

Azol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.31mmol, 1 eq.) and 1- (6- [ 1-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl radical]Pyridin-2-yl) methylamine (101.6mg, 0.465mmol, 1.50 equivalents) to a stirred solution/mixture in DMF (3mL) was added dropwise HATU (235.96mg, 0.621mmol, 2.00 equivalents) and DIEA (120.31mg, 0.931mmol, 3.0 equivalents). The crude product (100mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 40% B within 7 min; 254; 220 nm; Rt: 6.37min) to give 3-amino-N- [ (6- [ 1-methyl-1, 6-diazaspiro [3.3 ] as a yellow solid]Heptane-6-yl radical]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 171) (20mg, 12.01%). LCMS M/z (ESI), [ M + H ]⁺＝537.3。¹H NMR(400MHz,DMSO-d₆)δ2.1(5H,d),2.4(3H,s),2.9(2H,t),3.8(2H,d),4.0(2H,d),4.5(2H,d),6.3(1H,d),6.6(1H,d),7.3(1H,d),7.4(2H,d),7.4-7.5(2H,m),7.9(1H,s),8.3(1H,s),8.3(1H,s),9.4(1H,t)。

Example 172.3-amino-N- ((6- ((8-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 172)

Scheme 95

Step 1.2-cyano-6- ((1R,5S) -3-methyl-3, 8-diazabicyclo [3.2.1]Octane-3-yl) pyridines

6-Fluoropyridine-2-carbonitrile (594mg, 4.865mmol, 1 eq.) and 3-methyl-3, 8-diazabicyclo [3.2.1 ] at room temperature under an air atmosphere]To a stirred solution of octane (675.35mg, 5.351mmol, 1.10 equiv.) in DMF (10.5mL) was added K in portions₂CO₃(2756.59mg, 19.946mmol, 4.10 equiv.). The resulting mixture was stirred at 50 ℃ under an air atmosphere for 6.0 hours. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (Hexane/EtOAc 1:1) to give 6- [ 3-methyl-3, 8-diazabicyclo [3.2.1 ] as a pale yellow oil]Octane-8-yl]Pyridine-2-carbonitrile (613mg, 55.19%). LCMS M/z (ESI), [ M + H]⁺＝229.3

Step 2.(6- ((1R,5S) -3-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) pyridin-2-yl) methyl Amines as pesticides

Reaction of 6- [ 8-methyl-3, 8-diazabicyclo [3.2.1 ] in a hydrogen atmosphere at room temperature]Octane-3-yl]Pyridine-2-carbonitrile (613mg, 2.685mmol, 1 eq.) and NH ₃.H₂To a stirred solution of O (1.2mL, 190.218mmol, 65.14 equiv) in MeOH (15mL) was added raney nickel (345.07mg, 4.028mmol, 1.50 equiv) dropwise. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1.0 hour. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give 1- (6- [ 8-methyl-3, 8-diazabicyclo [3.2.1 ] as a yellow oil]Octane-3-yl]Pyridin-2-yl) methylamine (580mg, 94.99%). LCMS M/z (ESI), [ M + H]⁺＝233.3。

Step 3.3-amino-N- ((6- ((1R,5S) -3-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl) pyridine Pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

Oxazol-2-yl) pyrazine-2-carboxamide (200mg, 0.596mmol, 1 eq) and 1- (6- [ 3-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl]Pyridin-2-yl) methylamine (207.85mg, 0.895mmol, 1.50 equiv.) to a stirred solution in DMF (4.00mL, 205.218mmol, 324.98 equiv.) was added HATU (453.56mg, 1.193mmol, 2.00 equiv.) and DIEA (308.34mg, 2.386mmol, 4.00 equiv.) in portions. The desired product can be detected by LCMS. By preparative TLC (CH) ₂Cl₂MeOH 20:1) to give 3-amino-N- [ (6- [ 3-methyl-3, 8-diazabicyclo [3.2.1 ] as a yellow solid]Octane-8-yl]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (100mg, 30.45%). By preparative HPLC with the following conditions (column: X Bridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 43% B within 7 min; 254; 220 nm; rt: 6.77min) to give 3-amino-N- [ (6- [ 3-methyl-3, 8-diazabicyclo [3.2.1 ] as a yellow solid]Octane-8-yl]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 172) (39mg, 23.9%). LCMS M/z (ESI), [ M + H]⁺＝551.3。¹H NMR(400MHz,DMSO-d₆)δ1.57(4H,s),1.92(3H,s),2.04(2H,d),2.17(2H,d),2.43(3H,d),4.36(2H,s),4.48(2H,d),6.57(2H,t),7.23(1H,dd),7.35(1H,d),7.38-7.55(3H,m),7.94(2H,s),8.27(1H,d),8.38(1H,s),9.34(1H,t)

Example 175.3-amino-N- ((6- (6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 175)

Scheme 96

Step 1.2-cyano-6- (6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl) pyridines

6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 eq) oxalic acid was added to a 40mL sealed tube at room temperature; 2, 6-diazaspiro [3.4 ] ]Octane-6-carboxylic acid tert-butyl ester (1609.41mg, 5.323mmol, 1.3 equiv.), K₂CO₃(1697.83mg, 12.285mmol, 3 equiv.) and DMF (10 mL). The resulting mixture was stirred at 50 ℃ for 3 hours. The reaction was quenched by addition of saturated NaCl (aq) (250mL) at room temperature. The resulting mixture was extracted with EtOAc (2X 125 mL). The combined organic layers were washed with saturated NaCl (aq) (250mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 30:1) to give 6- [ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1 ] as a white solid]Heptane-2-yl radical]Pyridine-2-carbonitrile (700mg, 79.78%). LCMS M/z (ESI), [ M + H]⁺＝259.2

Step 2.(6- (6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl) pyridin-2-yl) methylamine

2- (6-cyanopyridin-2-yl) -2, 6-diazaspiro [3.4 ] was added to a 40mL sealed tube]Octane-6-carboxylic acid tert-butyl ester (500mg, 1.590mmol, 1 equiv.) in THF (10mL) followed by addition of LiAlH at 0 deg.C₄(301.81mg, 7.952mmol, 5 equiv.). This solution was stirred at 70 ℃ for 2 hours. The desired product can be detected by LCMS. The reaction was quenched by the addition of water (0.5mL) at 0 ℃. The solid was filtered off. The filtrate was concentrated in vacuo to give 1- (6- [ 6-methyl-2, 6-diazaspiro [3.4 ] as a yellow oil ]Octane-2-yl]Pyridin-2-yl) methylamine (250mg, 67.66%). LCMS M/z (ESI), [ M + H]⁺＝233.3。

Step 3.3-amino-N- ((6- (6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl) pyridin-2-yl) methyl 6- (3-methylimidazo [1, 2-a) methyl ester]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

1- (6- [ 6-methyl-2, 6-diazaspiro [3.4 ] is added to a 10mL sealed tube at room temperature]Octane-2-yl]Pyridin-2-yl) methylamine (150mg, 0.646mmol, 1 eq), 3-amino-6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (65.14mg, 0.194mmol, 1.50 equiv.), HATU (490.98mg, 1.291mmol, 2.00 equiv.), and DIEA (333.77mg, 2.583mmol, 4 equiv.) in DMF (10mL) for 2 hours. The desired product can be detected by LCMS. Preparative HPLC was performed with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm,5 μm; mobile phase A:, mobile phase B: MeOH- -HPLC; flow rate: 20 mL/min;gradient: 66% B to 70% B within 7 min; 254; 220 nm; rt: 6.32min) to give 3-amino-N- [ (6- [ 6-methyl-2, 6-diazaspiro [3.4 ] as a yellow solid]Octane-2-yl]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl ]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 175) (15mg, 14.3%). LCMS M/z (ESI), [ M + H]⁺＝551.3。¹H NMR(400mHz,DMSO-d₆)δ1.87(2H,t),2.22(3H,s),2.36-2.45(5H,m),2.48(2H,s),3.66-3.80(4H,m),4.47(2H,d),6.23(1H,d),6.61(1H,d),7.28(1H,dd),7.36(1H,d),7.38-7.57(3H,m),7.93(2H,s),8.25-8.37(2H,m),9.38(1H,d)

Example 198.3-amino-6- (3- (aminomethyl) imidazo [1, 2-a)]Pyridin-6-yl) -N- ((3-Fluoropyridin-2-yl) methyl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 198)

Scheme 97

(S) -2-methyl-N- ((6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidamide Azole [1,2-a ]]Pyridin-3-yl) methyl) propane-2-sulfinamide

N- ([ 6-bromoimidazo [1,2-a ] is reacted at 90 ℃ under a nitrogen atmosphere]Pyridin-3-yl]Methyl) carbamic acid tert-butyl ester (700mg, 2.146mmol, 1 eq) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (817.42mg, 3.219mmol, 1.50 eq) and Pd (dppf) Cl₂(157.02mg, 0.215mmol, 0.1 equiv.) and AcOK (421.22mg, 4.292mmol, 2 equiv.) in 1, 4-bis

Mixture in alkane (10mL)Stirred for 2 hours. By preparative TLC (H)₂Cl₂/MeOH 30:1) to give N- [ [6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] as a brown-yellow solid]Pyridin-3-yl]Methyl radical]Carbamic acid tert-butyl ester (500mg, 49.94%). LCMS m/z (ES)⁺),[M+H]⁺＝432.3

Step 2.(S) -3-amino-6- (3- (((tert-butylsulfinyl) amino) methyl) imidazo [1,2-a ]Pyridine-6- -N- ((3-fluoropyridin-2-yl) methyl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

To (S) -2-methyl-N- [ [6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] in a hydrogen atmosphere at room temperature]Pyridin-3-yl]Methyl radical]Propane-2-sulfinamide (649.19mg, 1.721mmol, 2.00 equivalents) and 3-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (300mg, 0.860mmol, 1 equivalent) in bis

alkane/H₂K was added dropwise/portion by portion to a stirred solution in 7:1(16mL)₃PO₄(547.83mg, 2.581mmol, 3.0 equiv.) and Pd (dppf) Cl₂.CH₂Cl₂(147.53mg, 0.181mmol, 0.21 equiv.). The resulting mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2.0 hours. The desired product can be detected by LCMS: m/z (ES)⁺),[M+H]⁺＝564.3

Step 3.3-amino-6- (3- (aminomethyl) imidazo [1, 2-a)]Pyridin-6-yl) -N- ((3-fluoropyridin-2-yl) Methyl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

3-amino-N- [ (3-fluoropyridin-2-yl) methyl group was added to a 10.0mL sealed tube at room temperature]-6- [3- ([ [ (S) -2-methylpropane-2-sulfinyl group]Amino group]Methyl) imidazole [1,2-a]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (150mg) and Diphenyl Ether-N-methyl

alkane/HCl (6.0 mL). The resulting mixture was stirred at room temperature under an air atmosphere for 60 min. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DMF (4 mL). And subjected to preparative HPLC. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH) ₃H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 21% B to 31% B within 8 min; 254/220 nm; rt: 7.53min) to give 3-amino-6- [3- (aminomethyl) imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 198) (20mg, 6.12%). LCMS m/z (ES)⁺),[M+H]⁺＝460.2。¹H-NMR(DMSO-d₆,40MHz)δ4.01(2H,s),4.67-4.76(2H,m),7.29(1H,dd),7.33-7.56(4H,m),7.72(1H,ddd),7.90(2H,s),8.28(1H,d),8.38(1H,dt),8.57(1H,t),9.34(1H,t)

EXAMPLE 199.3-amino-5- (4-fluorophenyl) -N- ([3- [2- (methylamino) ethoxy ] pyridin-2-yl ] methyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] pyrazine-2-carboxamide (Compound 199)

Scheme 98

Step 1.N- [2- [ (2-cyanopyridin-3-yl) oxyBase of]Ethyl radical]-N-methylcarbamic acid tert-butyl ester

In a 20-mL vial was placed 3-fluoropyridine-2-carbonitrile (800mg, 6.552mmol, 1 eq.), tert-butyl N- (2-hydroxyethyl) -N-methylcarbamate (1.38g, 7.875mmol, 1.20 eq.), DMF (4mL), K₂CO₃(2.26g, 16.352mmol, 2.50 equiv.). The resulting mixture was stirred at 80 ℃ for 16 hours. Using 20mL of H₂The resulting mixture was diluted with O. The resulting solution was extracted with 3X 8mL of ethyl acetate and the organic layers were combined. The resulting solution was washed with 3 × 10mL of brine, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc: petroleum ether ═ 1: 1). This gave 738mg (40.62%) of N- [2- [ (2-cyanopyridin-3-yl) oxy as a purple solid ]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester. LCMS M/z (ESI), [ M + H-tBu]⁺＝222.1 ¹H-NMR(300MHz,DMSO-d₆)δ1.34(9H,d),2.91(3H,d),3.58(2H,t),4.34(2H,s),7.71(1H,d),7.84(1H,d),8.31(1H,d)

Placing N- [2- [ (2-cyanopyridin-3-yl) oxy in a 25-mL round bottom flask purged and maintained with an inert hydrogen atmosphere]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester (738mg, 2.661mmol, 1 equiv.), MeOH (10mL), NH₃.H₂O (1mL, 25.681mmol, 9.65 equiv.), Raney nickel (227.99mg, 2.661mmol, 1.00 equiv.). The resulting solution was stirred at 16 ℃ for 2 hours. The solid was filtered off. The resulting mixture was concentrated in vacuo. This gave 700mg (93.49%) of N- (2- [ [2- (aminomethyl) pyridin-3-yl) as a violet solid]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester. LCMS M/z (ESI), [ M + H]⁺＝282.2

Step 3.N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a) ]]Pyridine-6- Base of]Pyrazin-2-yl radicals]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester

Place N- (2- [ [2- (aminomethyl) pyridin-3-yl) in a 6-mL vial]Oxy radical]Ethyl) -N-methylamino radicalTert-butyl formate (154.87mg, 0.550mmol, 2.00 equiv.), 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl ]Pyrazine-2-carboxylic acid (100mg, 0.275mmol, 1 equiv.), DIEA (0.34mL, 2.061mmol, 7.49 equiv.), DMF (2.5mL), T₃P (262.70mg, 0.826mmol, 3.00 equiv.). The resulting solution was stirred at 16 ℃ for 16 hours. Using 20mL of H₂The resulting solution was diluted with O. The resulting solution was extracted with 3X 10mL of ethyl acetate and the organic layers were combined. The resulting solution was extracted with 3X 10mL of brine, and the organic layers were combined and dried over anhydrous sodium sulfate. The residue was purified by preparative TLC (DCM: MeOH ═ 7: 1). This gave 93mg (53.92%) of N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a) ] as a yellow solid]Pyridin-6-yl]Pyrazin-2-yl radicals]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester. LCMS M/z (ESI), [ M/2+ H]⁺＝314.3

Step 4.3-amino-5- (4-fluorophenyl) -N- ((3- (2- (methylamino) ethoxy) pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) pyrazine-2-carboxamide 2,2, 2-trifluoroacetate (Compound 199)

Place N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a) ] in a 6-mL vial]Pyridin-6-yl]Pyrazin-2-yl radicals]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester (80mg, 0.128mmol, 1 eq), DCM (3.00mL), TFA (1.00mL, 13.46mmol, 105.2 eq). The resulting solution was stirred at 20 ℃ for 2 hours. The resulting mixture was concentrated in vacuo. The pH of the solution was adjusted to 9 with saturated sodium bicarbonate solution. The resulting solution was extracted with 3X 10mL of ethyl acetate and the organic layers were combined. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (DCM: MeOH ═ 3: 1). The crude product was purified by preparative HPLC (column: Sunfire Prep C18 OBD column, 10 μm, 19 x 250 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 10% B to 25% B over 10 min; 254,220 nm; Rt: 8.7 min). This gave 20.22mg of 3-amino-5- (4-fluorophenyl) -N- ((3- (2- (methylamino) ethoxy) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a) as a yellow solid ]Pyridin-6-yl) pyridineOxazine-2-carboxamide 2,2, 2-trifluoroacetate (compound 199). LCMS M/z (ESI), [ M + H]⁺＝527.3 ¹H-NMR(300MHz,DMSO-d₆)δ2.52-2.54(3H,m),2.71(3H,t),3.43(2H,s),4.34(2H,t),4.75(2H,d),7.23(2H,t),7.34(1H,d),7.44-7.58(3H,m),7.69(1H,d),7.79-7.90(2H,m),8.03(1H,d),8.13(1H,d),8.76(3H,d),9.34(1H,t)。¹⁹F NMR(300MHz,DMSO-d₆)δ-111.615(1F),-74.101(7.27F)

Example 202/206.3-amino-N- [ [ 1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 202)

3-amino-N- [ 1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 206)

Scheme 99

Step 1.6-bromo-3- (trifluoromethyl) imidazole [1,2-a ]]Pyridine compound

Reacting 6-bromo-3-iodoimidazo [1,2-a ] at 50 DEG C]Pyridine (1.5g, 4.645mmol, 1 equiv.), 15- (trifluoromethyl) -1 λ 4,12 λ 4-diaza-15-copper tetracyclo [10.2.1.0^ 5,14].0^[8,13]]A mixture of pentadeca-1, 3,5(14),6,8,10, 12-heptan-15-ylium (1.74g, 5.574mmol, 1.2 eq.) in DMF (15mL) was stirred overnight. By CH₂Cl₂The resulting mixture was diluted (100 mL). The resulting mixture was filtered and the filter cake was washed with DCM (2X 50 mL). The resulting mixture was washed with 2X 150mL of water. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (detection by mAU 220 nm) using CH₂Cl₂Elution with PE (40:60) gave 6-bromo-3- (trifluoromethyl) imidazo [1,2-a as a white solid]Pyridine (780mg, 63.36%).LCMS:m/z(ESI),[M+H]⁺＝267.1。¹H NMR(300MHz,DMSO-d₆)δ7.7(1H,dd),7.7-7.8(1H,m),8.2-8.2(1H,m),8.6-8.8(1H,m)。

Step 2.[3- (trifluoromethyl) imidazole [1,2-a ] ]Pyridin-6-yl]Boric acid

To 6-bromo-3- (trifluoromethyl) imidazole [1,2-a ]]Pyridine (500mg, 1.887mmol, 1 equiv.) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (958.14mg, 3.773mmol, 2.00 equiv.) in dioxane

AcOK (555.45mg, 5.660mmol, 3 equiv.) and Pd (dppf) Cl were added to a solution in alkane (20mL)₂(276.08mg, 0.377mmol, 0.2 equiv.). After stirring at 90 ℃ for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH/water, 10% to 50% gradient over 10 min; detector, UV 254nm, [3- (trifluoromethyl) imidazo [1,2-a ] is obtained as a white solid]Pyridin-6-yl]Boric acid (370mg, 85.29%). LCMS M/z (ESI), [ M + H]⁺＝231.1

Step 3.3-amino-N- [ [ (2S) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Oxazol-2-yl) -6- [3- (trifluoromethyl) imidazole [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxamides

To [3- (trifluoromethyl) imidazole [1,2-a ]]Pyridin-6-yl]Boronic acid (350mg, 1.522mmol, 1 equiv.) and 3-amino-6-chloro-N- [ (1-methylpyrrolidin-2-yl) methyl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (512.60mg, 1.522mmol, 1.00 equiv.) in Diphenyl Ether

Alkane (20mL) and H₂To a solution in O (2mL) was added K₃PO₄(969.25mg, 4.566mmol, 3 equiv.) and Pd (dppf) Cl₂(222.74mg, 0.304mmol, 0.2 equiv.). After stirring at 90 ℃ for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography on CH₂Cl₂MeOH (15:1) elution gave 3-amino-N- [ [ 1-methylpyrrolidin-2-yl ] as a pale yellow solid]Methyl radical]-5-(1,3-

Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (200mg, 27.01%). LCMS M/z (ESI), [ M + H]⁺＝487.3

Step 4.3-amino-N- [ [ 1-methylpyrrolidin-2-yl group]Methyl radical]-5-(1,3-

Azol-2-yl) -6- [3- (tris) Fluoromethyl) imidazole [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 202)/(Compound 206)

The crude product (100mg) was purified by preparative chiral HPLC accompanied by the following conditions (column: CHIRALPAK IG, 2.0cm I.D. 25cm L (5 μm); mobile phase A: CO2:75, mobile phase B: ETOH: ACN ═ 1: 25; flow rate: 40 mL/min; 220 nm; RT 1: 10; RT 2: 12.65) to give 3-amino-N- [ 1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 202) (50mg, 27.78%) and 3-amino-N- [ 1-methylpyrrolidin-2-yl) as a yellow solid ]Methyl radical]-5-(1,3-

Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (compound 206). 3-amino-N- [ 1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamides.

(Compound 202) LCMS M/z (ESI), [ M + H]⁺＝487.3。1H NMR(400MHz,DMSO-d₆)δ1.6(3H,ddd),1.8(1H,dd),2.1(1H,q),2.3(3H,s),2.4(1H,s),2.9(1H,dd),3.2(1H,ddd),3.5(1H,ddd),7.3(1H,s),7.7(1H,dd),7.8(1H,d),7.9-8.1(1H,m),8.2(1H,s),8.3(1H,s),8.6(2H,d)。

(Compound 206) LCMS M/z (ESI), [ M + H]⁺＝487.3。1H NMR(400MHz,DMSO-d₆)δ1.6(3H,ddd),1.8(1H,dd),2.1(1H,q),2.3(3H,s),2.4(1H,s),2.9(1H,dd),3.2(1H,ddd),3.5(1H,ddd),7.3(1H,s),7.7(1H,dd),7.8(1H,d),7.9-8.1(1H,m),8.2(1H,s),8.3(1H,s),8.6(2H,d)。

Example 214/209.3-amino-6- (3-chloroimidazo [1, 2-a)]Pyridin-6-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 214/209)

Scheme 100

Step 1. (3-Chloroimidazo [1, 2-a)]Pyridin-6-yl) boronic acid.

Mixing [ imidazole [1,2-a ]]Pyridin-6-yl]Boric acid (600mg, 3.705mmol, 1 equiv.) and NCS (1.24g, 9.262mmol, 2.50 equiv.) were dissolved in 3ml dmmf. The mixture was stirred at room temperature for 3 hours. LCMS showed no problem for the reaction. The crude product was purified by reverse phase HPLC to give [ 3-chloroimidazo [1,2-a ] as a white solid]Pyridin-6-yl]Boric acid (235mg, 32.3%). LCMS M/z (ESI), [ M + H]⁺＝197.2。

Step 2.3-amino-6- (3-chloroimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxylic acid esters And (4) acid.

[ 3-Chloroimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (169.69mg, 0.864mmol, 1.00 equiv.), 3-amino-6-chloro-5- (1, 3-)

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (220mg, 0.864mmol, 1 eq), Pd (dppf) Cl₂(126.44mg, 0.173mmol, 0.2 equiv.) and Cs₂CO₃(1126.03mg, 3.456mmol, 4 equiv.) was dissolved in 2.4mL of two

alkane/H₂O (5: 1). The mixture was stirred at 70 ℃ for 2 hours. LCMS showed no problem for the reaction. The mixture was concentrated, acidified with acetic acid and purified by reverse phase HPLC to give 3-amino-6- [ 3-chloroimidazo [1,2-a ] as a white solid]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (100mg, 31.22%). LCMS M/z (ESI), [ M + H]⁺＝371.2。

Step 3.3-amino-6- [ 3-chloroimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidine-2- Base of]Methyl radical]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 214)

Reacting 3-amino-6- [ 3-chloroimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.280mmol, 1 equiv.), 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (48.02mg, 0.420mmol, 1.5 equiv.), DIEA (253.61mg, 1.962mmol, 7 equiv.), and T₃P (267.58mg, 0.841mmol, 3 equiv.) was added to DMF (3 mL). Mixing the obtained suspensionStirred at room temperature for 3 hours. With saturated NH₄The reaction mixture was quenched with Cl (15mL) and extracted with EtOAc (3X 50mL) over Na₂SO₄The organic layer was dried, filtered and evaporated to give a yellow gum. The residue was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 29% B to 37% B within 8 min; 254; 220 nm; Rt: 6.57/7.42min) to give 3-amino-6- [ 3-chloroimidazo [1,2-a ] as a pale yellow solid ]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 214) (23.9mg, 18.8%). LCMS M/z (ESI), [ M + H]⁺＝453.2。¹H-NMR (400MHz, methanol-d)₄)δ1.66-1.84(3H,m),2.02(1H,dq),2.32(1H,q),2.46(3H,s),2.59(1H,s),3.09(1H,dd),3.42(1H,dd),3.66(1H,dd),7.33(1H,d),7.43(1H,dd),7.59(1H,dd),7.66(1H,s),8.03(1H,d),8.50(1H,dd)。

Step 4.3-amino-6- [ 3-chloroimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2S) -1-methylpyrrolidine-2- Base of]Methyl radical]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 209)

Reacting 3-amino-6- [ 3-chloroimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.280mmol, 1 equiv.), 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (48.02mg, 0.420mmol, 1.5 equiv.), DIEA (253.61mg, 1.962mmol, 7 equiv.), T₃P (267.58mg, 0.841mmol, 3 equiv.) was added to DMF (3 mL). The resulting suspension was stirred at room temperature for 3 hours. With saturated NH₄The reaction mixture was quenched with Cl (15mL), extracted with EtOAc (3X 50mL), and extracted with Na₂SO₄Drying the organic layerFiltration and evaporation gave a yellow gum. The residue was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 29% B to 37% B within 8 min; 254; 220 nm; Rt: 6.57/7.42min) to give 3-amino-6- [ 3-chloroimidazo [1,2-a ] as a pale yellow solid ]Pyridin-6-yl]-N- [ [ (2S) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (18.9mg, 14.8%). LCMS M/z (ESI), [ M + H]⁺＝453.2。¹H-NMR (400MHz, methanol-d)₄)δ1.72-1.84(3H,m),2.02(1H,dq),2.32(1H,q),2.46(3H,s),2.59(1H,s),3.09(1H,dt),3.42(1H,dd),3.66(1H,dd),7.33(1H,d),7.42(1H,dd),7.59(1H,dd),7.66(1H,s),8.03(1H,d),8.50(1H,dd)。

Example 219.3-amino-N- [ [ (3R) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 219)

Scheme 101

Step 1.N- [ [ (3R) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical](iii) carbamic acid tert-butyl ester.

TEA (757.86mg, 7.489mmol, 3 equiv.), cyclopropanecarbonyl chloride (391.44mg, 3.745mmol, 1.5 equiv.) and N- [ [ (3S) -pyrrolidin-3-yl ] were added under an air atmosphere at room temperature]Methyl radical]A mixture of tert-butyl carbamate (500mg, 2.496mmol, 1 eq) in DCM (15mL) was stirred for 16 h. The reaction was diluted with DCM (90mL), and the organic layer was washed with water (2X 100mL) and over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give N- [ [ (3R) -1-cyclopropanecarbonyl pyrrolidine-3-yl]Methyl radical]Tert-butyl carbamate (750mg, 111.95%).¹H-NMR (300MHz, chloroform-d) delta 0.77(2H, d),1.01(2H, d),1.46(9H, d),1.61(1H, d),1.68-1.85(1H, m),2.07(1H, d),2.33-2.58(1H, m),3.03-3.28(2H, m),3.28-3.49(1H, m),3.58-3.72(1H, m),3.72-3.87(1H, m)

Step 2.1- [ (3R) -1-Cyclopropanecarbonylpyrrolidin-3-yl]Methylamine.

TFA (1mL) and N- [ [ (3R) -1-cyclopropanecarbonyl pyrrolidin-3-yl were reacted at room temperature under an air atmosphere]Methyl radical]A mixture of tert-butyl carbamate (300mg, 1.118mmol, 1 eq) in DCM (3mL) was stirred for 1 h. The resulting mixture was concentrated under reduced pressure. With saturated NaHCO₃The residue was basified to pH 7 (aqueous solution). By CH₂Cl₂The resulting mixture was extracted (2X 50 mL). The combined organic layers were washed with water (2X 50mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 1- [ (3R) -1-cyclopropanecarbonyl-pyrrolidin-3-yl group as a brown oil]Methylamine (180mg, 95.71%). LCMS M/z (ESI), [ M + H]⁺＝169.1。¹H NMR(300MHz,DMSO-d₆,)δ0.64-0.79(4H,m),1.09-1.25(1H,m),1.59-1.81(2H,m),1.91-2.17(1H,m),2.90(2H,q),2.98-3.16(1H,m),3.23-3.50(1H,m),3.52-3.67(1H,m),3.69-3.90(1H,m),7.85(2H,s)

Step 3.3-amino-N- [ [ (3R) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 219).

DIEA (215.21mg, 1.665mmol, 7 equiv.), T was added under air atmosphere at room temperature₃P (378.44mg, 1.189mmol, 5 equiv.), 1- [ (3R) -1-cyclopropanecarbonyl-pyrrolidin-3-yl]Methylamine (160.08mg, 0.952mmol, 4 equivalents) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazinesA mixture of-2-carboxylic acid (80mg, 0.238mmol, 1 eq) in DMF (3mL) was stirred overnight. The desired product can be detected by LCMS. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (10MMOL/L NH) ₄HCO₃) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 28% B within 7 min; 254/220 nm; rt: 5.37min) to give 3-amino-N- [ [ (3R) -1-cyclopropanecarbonyl-pyrrolidin-3-yl as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 219) (60mg, 50.81%). LCMS M/z (ESI), [ M + H]⁺＝487.3。¹H-NMR(300MHz,DMSO-d₆)δ0.68(4H,d),1.59-1.83(2H,m),1.85-2.17(1H,m),2.44(3H,s),2.61(1H,s),3.05-3.32(1H,m),3.36-3.53(3H,m),3.60(1H,t),3.68-3.84(1H,m),7.24(1H,d),7.33-7.43(2H,m),7.49(1H,d),7.91(2H,s),8.28(1H,s),8.35(1H,d),8.96-9.10(1H,m)

Example 221.3-amino-N- [ [ (3S) -1-cyclopropanecarbonyl ] pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 221)

Scheme 102

Step 1.N- [ [ (3S) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical]Carbamic acid tert-butyl ester

To a stirred mixture of TEA (1515.71mg, 14.979mmol, 6.00 equiv.) and cyclopropanecarbonyl chloride (521.91mg, 4.993mmol, 2.00 equiv.) in DCM (10mL) was added N- [ [ (3R) -pyrrolidin-3-yl in portions at 25 ℃ under a nitrogen atmosphere]Methyl radical]Carbamic acid tert-butyl ester (500mg, 2.496mmol, 1 eq). Subjecting the resulting mixture to 25 deg.CThe mixture was stirred for 2 hours under an air atmosphere. By CH₂Cl₂The resulting mixture was extracted (3X 20 mL). And then passed over anhydrous Na₂SO₄The organic phase was dried. After filtration, the filtrate was concentrated under reduced pressure to give N- [ [ (3S) -1-cyclopropanecarbonyl pyrrolidin-3-yl ] as a yellow solid ]Methyl radical]Tert-butyl carbamate (670mg, 100.01%).¹H-NMR(300MHz,MeOD-d₄)δ0.85(4H,dt),1.44(9H,s),1.58-1.85(2H,m),2.05(1H,ddq),2.42(1H,dp),3.09(3H,dd),3.37(1H,q),3.48-3.73(2H,m),3.80(1H,dt)。

Step 2.1- [ (3S) -1-Cyclopropanecarbonylpyrrolidin-3-yl]Methylamine

To N- [ [ (3S) -1-cyclopropanecarbonyl pyrrolidin-3-yl ester at 25 ℃ under a nitrogen atmosphere]Methyl radical]To a stirred mixture of tert-butyl carbamate (300mg, 1.118mmol, 1 eq) in DCM (3mL) was added TFA (1 mL). The resulting mixture was stirred at 25 ℃ for 20min under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 1- [ (3S) -1-cyclopropanecarbonyl-pyrrolidin-3-yl group as a yellow oil]Methylamine (170mg, 90.39%). LCMS M/z (ESI), [2M + H]⁺＝337.2。

Step 3.3-amino-N- [ [ (3S) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 221)

3-amino-6- [ 3-methylimidazo [1,2-a ] at 25 ℃ in a nitrogen atmosphere]Pyridin-6-yl]-5-(1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (99.95mg, 0.297mmol, 0.50 equiv.) and DIEA (153.64mg, 1.189mmol, 2 equiv.) in DMF (5mL) was added T in portions₃P (472.81mg, 1.486mmol, 2.50 equiv.) and 1- [ (3S) -1-cyclopropanecarbonyl-pyrrolidin-3-yl]Methylamine (100mg, 0.594mmol, 1 eq). The resulting mixture was stirred at 25 ℃ for 4 hours under a nitrogen atmosphere. By passing Preparative HPLC was accompanied by the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 28% B within 7 min; 254/220 nm; rt: 5.37min) to give 3-amino-N- [ [ (3S) -1-cyclopropanecarbonyl-pyrrolidin-3-yl as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (60mg, 20.75%). LCMS M/z (ESI), [ M + H]⁺＝487.2。¹H-NMR(300MHz,DMSO-d₆)δ0.69(4H,d),1.70-2.10(3H,m),2.44(3H,s),2.50(1H,t),3.10(1H,dd),3.52(4H,d),3.68-3.80(1H,m),7.24(1H,dd),7.33-7.43(2H,m),7.49(1H,d),7.90(2H,s),8.28(1H,s),8.36(1H,d),9.02(1H,d)

EXAMPLE 223.3 preparation of amino-N- [ (3-fluoropyridin-2-yl) methyl ] -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -5- (morpholin-4-yl) pyrazine-2-carboxamide (Compound 223)

Scheme 103

Step 1.3-amino-6-chloro-5- (morpholin-4-yl) pyrazine-2-carboxylic acid methyl ester

To a stirred mixture of methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (50mg, 0.225mmol, 1 equiv.) and DIEA (87.31mg, 0.676mmol, 3 equiv.) in DMSO was added morpholine (39.24mg, 0.450mmol, 2 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and washed with water (1 × 100mL) and dried in vacuo to give methyl 3-amino-6-chloro-5- (morpholin-4-yl) pyrazine-2-carboxylate (1.8g, 97.71%) as a yellow solid. ¹H-NMR (400MHz, chloroform-d) delta 3.61-3.72(4H, m),3.75-3.88(4H, m),3.94(3H, s).

Step 2.3-amino-6- [ 3-methylimidazo [1,2-a]pyridin-6-yl]-5- (morpholin-4-yl) pyrazine-2-carboxylic acid methyl ester Acid methyl ester

To methyl 3-amino-6-chloro-5- (morpholin-4-yl) pyrazine-2-carboxylate (600mg, 2.200mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at 95 ℃ under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (580.81mg, 3.300mmol, 1.5 equiv.) in bis

Cs was added in portions to a stirred mixture in an alkane (50mL)₂CO₃(2150.70mg, 6.601mmol, 3 equiv.) and Pd (dppf) Cl₂(321.99mg, 0.440mmol, 0.2 equiv.). The resulting mixture was stirred at 95 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By silica gel column chromatography with CH₂Cl₂The residue was purified by elution with MeOH (20:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellowish green solid]Pyridin-6-yl]-methyl 5- (morpholin-4-yl) pyrazine-2-carboxylate (400mg, 49.35%). LCMS M/z (ESI), [ M + H]⁺＝369.3。¹H-NMR(400MHz,DMSO-d₆)δ3.26(4H,d),3.58(4H,d),3.79(3H,s),3.93(3H,s),7.30(2H,s),7.40(1H,s),7.52(1H,d),7.60(1H,d),8.45(1H,s)

Step 3.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (morpholin-4-yl) pyrazine-2-carboxylic acid methyl ester Acid(s)

To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a solution of methyl (400mg, 1.086mmol, 1 eq) 5- (morpholin-4-yl) pyrazine-2-carboxylate in THF (50mL) and methanol (10mL) was added LiOH (156.01mg, 6.515mmol, 6 eq) portionwise. The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The mixture was acidified to pH 6 with HCl (aq). The resulting mixture was concentrated in vacuo to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5- (morpholin-4-yl) pyrazine-2-carboxylic acid (350mg, 90.96%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝355.1。

Step 4.3-amino-N- [ (3-fluoropyridin-2-yl) methyl]-6-[3-methylimidazo [1,2-a ]]Pyridine-6- Base of]-5- (morpholin-4-yl) pyrazine-2-carboxamide (Compound 223)

3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]To a stirred mixture of-5- (morpholin-4-yl) pyrazine-2-carboxylic acid (100mg, 0.282mmol, 1 eq) and 1- (3-fluoropyridin-2-yl) methylamine (71.19mg, 0.564mmol, 2 eq) in DMF (10mL) was added HATU (214.59mg, 0.564mmol, 2 eq) and DIEA (109.41mg, 0.847mmol, 3 eq) in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 2.5 hours. The resulting mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: 5% ammonia, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 33% B to 48% B over 8 min; 254; 220 nm; Rt: 7.47min) to give 3-amino-N- [ (3-fluoropyridin-2-yl) methyl ] as a white solid]-6- [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]-5- (morpholin-4-yl) pyrazine-2-carboxamide (9mg, 6.83%) (compound 223). LCMS M/z (ESI), [ M + H]⁺＝463.3。¹H NMR(400MHz,DMSO-d₆)δ2.54(3H,d),3.63(4H,t),4.61-4.74(4H,m),7.36-7.45(2H,m),7.57-7.64(1H,m),7.66-7.79(2H,m),8.36(1H,dt),8.63(1H,s),8.93(1H,t)

Example 227/224 Trans/cis-3-amino-N- ((6- ((3- (dimethylamino) cyclobutyl) amino) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 227/224)

Scenario 104

Step 1.2-cyano-6- ((3- (dimethylamino) cyclobutyl) amino) pyridine

6-Fluoropyridine-2-carbonitrile (136mg, 1.114mmol, 1 equiv.), N1, N1-dimethyl RingA mixture of butane-1, 3-diamine dihydrochloride (250mg, 1.336mmol, 1.20 equivalents) and dipotassium carbonate (462mg, 3.343mmol, 3.00 equivalents) in 3mL DMF was stirred at 50 deg.C for 18 hours. After cooling to room temperature, water was added and extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was purified by column (DCM/MeOH 3/1) to give 6- [ [3- (dimethylamino) cyclobutyl ] as a white solid]Amino group]Pyridine-2-carbonitrile (155mg, 64.3%). LCMS M/z (ESI), [ M + H]⁺＝217.3。

Step 2, N1- (6- (aminomethyl) pyridin-2-yl) -N3, N3-dimethylcyclobutane-1, 3-diamine

Reacting 6- [ [3- (dimethylamino) cyclobutyl group]Amino group]Pyridine-2-carbonitrile (155mg, 0.717mmol, 1 equiv.), 1mL of Ammonia solution, and a mixture of Raney Nickel (100mg) in methanol (10mL) at 1atm H ₂Hydrogenation was carried out at room temperature for 3 hours. After filtration through celite, the filtrate was concentrated to dryness in vacuo and the residue was used directly in the next step. LCMS M/z (ESI), [ M + H]⁺＝221.2。

Step 3 cis/trans 3-amino-N- ((6- ((3- (dimethylamino) cyclobutyl) amino) pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 224/227)

To 3-amino-6- (1-methyl-1H-1, 3-benzoxadiazol-6-yl) -5- (1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.446mmol, 1 eq.) and N3- [6- (aminomethyl) pyridin-2-yl]To a mixture of N1, N1-dimethylcyclobutane-1, 3-diamine (145mg, 0.66mmol, 1.48 equivalents) in N, N-dimethylformamide (5mL) were added DIEA (0.39mL, 2.239mmol, 5.02 equivalents) and 50 wt% T₃A solution of P in ethyl acetate (860mg, 1.351mmol, 3.03 equiv.). The mixture was stirred at room temperature for 18 hours. ConcentrationAfter condensation to dryness, the residue was purified by preparative HPLC with the following conditions: (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 29% B to 37% B within 8 min; 254; 220 nm; Rt: 6.57/7.42min) to give trans-3-amino-6- [ 3-methyl-imidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (6- [ [3- (dimethylamino) cyclo-butyl ] methyl ] ethyl]Amino group]Pyridin-2-yl) methyl]Pyrazine-2-carboxamide (Compound 227) (6.6mg, 2.7%) (Compound 227) LCMS: M/z (ESI), [ M + H [ (])]⁺＝539.4。¹H-NMR(300MHz,MeOH-d₄) δ 1.87-1.95(2H, m),2.02-2.14(8H, m),2.43(3H, s),2.71-2.81(1H, m),3.97-4.02(1H, m),4.48(2H, s),6.26-6.28(1H, d),6.55-6.57(1H, d),7.22-7.48(5H, m),7.99(1H, s),8.38(1H, s), and cis-3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (6- [ [3- (di-methylamino) cyclobutyl ] -N]Amino group]Pyridin-2-yl) methyl]Pyrazine-2-carboxamide (Compound 224) (6.1mg, 2.5%) (Compound 224) LCMS: M/z (ESI), [ M + H [ (+ ])]⁺＝539.3。¹H-NMR(300MHz,MeOH-d₄)δ1.39-1.48(2H,m),1.56-1.66(1H,m),1.89(6H,s),2.16-2.24(2H,m),2.44(3H,s),3.76-3.87(1H,m),4.49(2H,s),6.29-6.32(1H,d),6.50-6.52(1H,d),7.25-7.37(4H,m),7.48-7.52(1H,d),7.97(1H,s),8.43(1H,s)。

EXAMPLE 229.3-amino-6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -N- [ [ (2R) -oxolane-2-yl ] methyl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 229) preparation

Scheme 105

Step 1.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) Pyrazine-2-carboxylic acid methyl ester

To methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (1g, 3.927mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (1.38g, 7.855mmol, 2 equiv.) in 1, 4-bis

Alkane (15mL) and H₂Cs was added portionwise to a stirred mixture in O (1.5mL)₂CO₃(2.56g, 7.855mmol, 2.00 equiv.) and Pd (dppf) Cl₂.CH₂Cl₂(0.64g, 0.785mmol, 0.2 equiv.). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 20:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-methyl 5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (1g, 72.68%). LCMS M/z (ESI), [ M + H]⁺＝351.1。¹H-NMR:(300MHz,DMSO-d₆)δ2.31(3H,s),3.91(3H,s),6.91(1H,m),7.42(2H,m),7.73(1H,m),7.91(2H,s),8.12(2H,s)。

Step 2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) Pyrazine-2-carboxylic acid

To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a stirred solution of methyl (950mg, 2.712mmol, 1 eq) 5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate in MeOH (15mL) and THF (3mL) was added LiOH (97.42mg, 4.067mmol, 1.5 eq) portionwise. The resulting mixture was stirred at room temperature for 4 hours. The residue was acidified to pH 5 with HCl (aq). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (400mg, 43.86%). LCMS M/z (ESI), [ M + H ]⁺＝337.1。

Step 3.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -oxolane-2- Base of]Methyl radical]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 229)

To 1- [ (2R) -Oxetan-2-yl radical at room temperature]Methylamine (60.15mg, 0.595mmol, 2 equivalents) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]To a stirred mixture of (E) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq) in DMF (10mL) was added DIEA (76.86mg, 0.595mmol, 2 eq) and T₃P (23.80mg, 0.595mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water at room temperature. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B:, flow rate: 20 mL/min; gradient: 30% B to 41% B within 8 min; 254; 220 nm; Rt: 7.17min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ (2R) -oxolane-2-yl]Methyl radical]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 229) (43mg, 34.48%). LCMS M/z (ESI), [ M + H ]⁺＝420.3。¹H NMR:(300MHz,DMSO-d₆)δ1.78(4H,m),2.36(3H,d),3.40(2H,d),3.62(1H,m),3.78(1H,m),4.04(1H,p),6.87(1H,dd),7.39(2H,m),7.92(1H,m),8.12(4H,s),8.85(1H,t)。

Example 230-1/230-2.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) -N- ((1,4, 4-trimethylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide (Compound 230-1/230-2)

Scenario 106

Step 1.2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine- 2-carboxamido) methyl) -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

3-amino-6- [ 3-methylimidazo [1,2-a ] at 0 ℃ in a nitrogen atmosphere]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (200mg, 0.595mmol, 1 equiv.), DIEA (230.58mg, 1.784mmol, 3 equiv.), and tert-butyl 2- (aminomethyl) -4, 4-dimethylpyrrolidine-1-carboxylate (271.58mg, 1.189mmol, 2 equiv.) to a stirred mixture in DMF (12mL) was added T dropwise₃P (378.44mg, 1.189mmol, 2 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was quenched by the addition of water (20mL) at room temperature. By CH₂Cl₂The resulting mixture was extracted (3X 20 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 20:1) to give 2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (180mg, 55.37%). LCMS M/z (ESI), [ M + H]⁺＝547.4。

Step 2.3-amino-N- ((4, 4-dimethylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-Base) a carboxamide group]Methyl radical]-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (160mg, 0.293mmol, 1 equiv.) to a stirred solution in DCM (8mL) was added TFA (3mL, 40.389mmol, 137.99 equiv.) dropwise. The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure to give 3-amino-N- [ (4, 4-dimethylpyrrolidin-2-yl) methyl group as a yellow oil]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (135mg, 98.12%). LCMS M/z (ESI), [ M + H]⁺＝447.4。

Step 3.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Oxazol-2-yl) -N- ((1,4, 4-trimethylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide

To 3-amino-N- [ (4, 4-dimethylpyrrolidin-2-yl) methyl group at room temperature under a nitrogen atmosphere ]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (155mg, 0.347mmol, 1 equiv.), DIEA (89.73mg, 0.694mmol, 2 equiv.), and paraformaldehyde (312.69mg, 3.471mmol, 10 equiv.) to a stirred mixture of DCM (12mL) and MeOH (4mL) was added NaBH in portions₃CN (65.44mg, 1.041mmol, 3 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction was quenched by the addition of water (20mL) at room temperature. By CH₂Cl₂The resulting mixture was extracted (3X 15 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 10:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (1,4, 4-trimethylpyrrolidin-2-yl) methyl]Pyrazine-2-carboxamide (130mg, 81.32%). LCMS M/z (ESI), [ M + H]⁺＝461.4。

Step 4.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Oxazol-2-yl) -N- ((1,4, 4-Trimethylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide (230-1/230-2)

Chiral preparative HPLC was performed with the following conditions (column: CHIRALPAK ID-03, 2.0cm i.d. 25cm L (5 μm); mobile phase a: Hex: DCM ═ 5:1(10mM NH) ₃-MEOH) -HPLC, mobile phase B: IPA-HPLC; flow rate: 20 mL/min; gradient: 25B to 25B within 22 min; 220/254 nm; RT 1: 15.342, respectively; RT 2: 17.566) to give 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (1,4, 4-trimethylpyrrolidin-2-yl) methyl]Pyrazine-2-carboxamide (Compound 230-1) (45mg, 43.41%) LCMS M/z (ESI), [ M + H]⁺＝461.3。¹H-NMR(400MHz,DMSO-d₆) δ 1.01(6H, d),1.46(1H, s),1.68(1H, s),2.05(1H, s),2.28(3H, s),2.42(3H, s),2.68(1H, s),3.48(1H, s),7.19(1H, dd),7.40(2H, d),7.49(1H, d),7.90(2H, s),8.31(2H, d),8.65(1H, s). And 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (1,4, 4-trimethylpyrrolidin-2-yl) methyl]Pyrazine-2-carboxamide (Compound 230-2) (45mg, 45%), LCMS: M/z (ESI), [ M + H ]]⁺＝461.3。¹H NMR(400MHz,DMSO-d₆)δ1.01(6H,d),1.46(1H,s),1.68(1H,s),2.05-2.28(4H,m),2.42(3H,s),2.68(1H,s),3.30(1H,s),3.48(1H,s),7.19(1H,dd),7.36(1H,s),7.40(1H,s),7.49(1H,d),7.90(2H,s),8.27(1H,s),8.31(1H,s),8.65(1H,s)。

EXAMPLE 231 preparation of (R) -3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1,2-a ] pyridin-6-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide (Compound 231)

Scheme 107

Step 1.3 preparation of methyl 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylate

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (1.5g, 6.756mmol, 1 equiv.) and (3-fluorophenyl) boronic acid (0.95g, 6.790mmol, 1.00 equiv.) in 1, 4-bis (phenyl) at room temperature under a nitrogen atmosphere

Alkane (100mL) and H₂To a stirred mixture in O (5mL) was added Cs portion by portion₂CO₃(6.60g, 0.020mmol, 3 equiv.) and Pd (dppf) Cl₂(0.74g, 0.001mmol, 0.15 equiv.). The resulting mixture was stirred at 70 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH₂Cl₂The filter cake was washed (1X 30 mL). The filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH₂Cl₂EtOAc (4:1) elution afforded methyl 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylate (900mg, 47.30%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝282.0。¹H-NMR (300MHz, chloroform-d) delta 4.03(3H, s),7.22(1H, m),7.41-7.59(2H, m),7.65(1H, ddd).

Step 2.3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) pyrazin-2-yl Acid methyl ester

To methyl 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylate (400mg, 1.420mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (324.88mg, 1.846mmol, 1.30 equiv.) in 1, 4-bis

Alkane (20mL) and H₂To a stirred mixture in O (2mL) was added Cs portion by portion₂CO₃(1388.09mg, 4.260mmol, 3 equiv.) and Pd (dppf) Cl₂(155.86mg, 0.213mmol, 0.15 equiv.). The resulting mixture was stirred at 90 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH ₂Cl₂The filter cake was washed (1X 20 mL). The filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 20:1) to give 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (300mg, 55.98%). LCMS M/z (ESI), [ M + H]⁺＝378.1。

¹H-NMR (300MHz, chloroform-d) delta 2.22-2.65(3H, m),4.04(3H, s),6.91-7.05(1H, m),7.05-7.23(2H, m),7.30(2H, d),7.44(2H, d),8.11(1H, t).

Step 3.3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) pyrazin-2-yl Acid(s)

To 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (300mg, 0.795mmol, 1 equiv.) in THF (20mL) and H₂To a stirred solution in O (4mL) was added LiOH (38.08mg, 1.590mmol, 2.00 equiv) portionwise. The resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified to pH 5 with HCl (aq). The resulting mixture was concentrated under reduced pressure to give 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid (280mg, 96.94%) was used in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝364.2。

Step 4.(R) -3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1, 2-a) ]Pyridin-6-yl) -N- ((1- Methylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide (Compound 231)

To 1- [ (2R) -1-methylpyrrolidin-2-yl group at room temperature]Methylamine (62.85mg, 0.550mmol, 2.00 equiv.) and 3-amino-5- (3-fluorophenyl) -6- [ 3-methylImidazo [1,2-a ]]Pyridin-6-yl]To a stirred mixture of pyrazine-2-carboxylic acid (100mg, 0.275mmol, 1 equiv.) in DMF (10mL) was added DIEA (106.71mg, 0.826mmol, 3.00 equiv.) and T in portions₃P (175.14mg, 0.550mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A (5% NH)₄HCO₃In water): and the mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 37% B to 51% B within 8 min; 254; 220 nm; rt: 7.27min) to give 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 231) (20mg, 15.81%). LCMS M/z (ESI), [ M + H]⁺＝460.3。¹H-NMR(400MHz,DMSO-d₆)δ1.65(3H,s),1.86(1H,s),2.18(1H,s),2.34(3H,s),2.37(3H,d),2.45(1H,s),2.97(1H,s),3.31(1H,s),3.51(1H,s),7.03(1H,dd),7.26(2H,ddd),7.30-7.35(1H,m),7.36-7.43(3H,m),7.77(2H,s),8.13-8.32(1H,m),8.67(1H,s)。

Example 235/232.3-amino-N- ((6- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a) ]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 235/232)

Scheme 109

Step 1.16- [3- (dimethylamino) pyrrolidin-1-yl]Pyridine-2-carbonitrile.

To a mixture of 6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 equiv.) and N, N-dimethylpyrrolidin-3-amine (701.41mg, 6.142mmol, 1.5 equiv.) in 2mL DMF was added potassium carbonate (1.14g, 8.190mmol, 2.00 equiv.). The mixture was stirred at 50 ℃ for 8 hours. Concentrating to dry, and removingThe residue was purified by column chromatography on silica gel using DCM/CH₃OH 10/1 gave 6- [3- (dimethylamino) pyrrolidin-1-yl as a yellow solid]Pyridine-2-carbonitrile (810mg, 80.0%). LCMS M/z (ESI), [ M + H]⁺＝217.1。

Step 2.1- [6- (aminomethyl) pyridin-2-yl]-N, N-dimethylpyrrolidin-3-amine.

At 1atm H₂At room temperature, 6- [3- (dimethylamino) pyrrolidin-1-yl]Pyridine-2-carbonitrile (200mg, 0.925mmol, 1 eq), Raney nickel (158.45mg, 1.849mmol, 2 eq) and NH₄A mixture of OH (50mg) in methanol (16mL) was hydrogenated for 3 hours. After filtration through celite, the filtrate was concentrated to dryness in vacuo and the residue was used directly in the next step. LCMS M/z (ESI), [ M + H]⁺＝221.1。

Step 3.3-amino-N- ([6- [3- (dimethylamino) pyrrolidin-1-yl) ]Pyridin-2-yl]Methyl) -6- [ 3-methyl Alkylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 235/232)

To 1- [6- (aminomethyl) pyridin-2-yl group]-N, N-dimethylpyrrolidin-3-amine (185mg, 0.840mmol, 1 equiv.), 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

To a mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (423mg, 1.260mmol, 1.50 equivalents) in N, N-di-methylformamide (5mL) was added DIEA (651.14mg, 5.038mmol, 6 equivalents), HOBt (226.92mg, 1.679mmol, 2 equivalents) and EDCI (321.94mg, 1.679mmol, 2 equivalents). The mixture was stirred at room temperature for 3 hours. After concentration to dryness, by chiral preparative HPLC with the following conditions (column: CHIRAL ART Cellulose-SB S-5um, 2X 25cm,5 μm; mobile phase A: Hex (8mmol/L NH)₃MeOH) -HPLC, mobile phase B: MeOH to EtOH 1: 1-HPLC; flow rate: 20 mL/min; gradient: 50B to 50B within 13 min; 220/254 nm; r_T1：8.028min；R_T2: 10.436min) to give 3-amino-N- ([6- [3- (dimethylamino) pyrrolidin-1-yl)]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 235) (77mg, 17.0%), LCMS: M/z (ESI), [ M + H]⁺＝539.4。¹H-NMR (300MHz, methanol-d) ₄) Δ 1.28(1H, m),1.48(1H, m),2.16(6H, s),2.48(3H, d),2.55-2.66(1H, m),3.09(2H, dt),3.52(2H, dt),4.54(2H, s),6.31(1H, d),6.57(1H, d),7.22-7.33(2H, m),7.38-7.56(3H, m),7.98(1H, d),8.37(1H, s) and 3-amino-N- ([6- [3- (dimethylamino) pyrrolidin-1-yl)]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 232) (30mg, 6.63%) LCMS M/z (ESI), [ M + H]⁺＝539.3。¹H-NMR (300MHz, methanol-d)₄)δ1.39-1.59(2H,m),2.16(6H,s),2.48(3H,d),2.55-2.66(1H,m),3.09(2H,dt),3.52(2H,dt),4.54(2H,s),6.31(1H,d),6.57(1H,d),7.22-7.33(2H,m),7.38-7.56(3H,m),7.98(1H,d),8.37(1H,s)。

Example 233 rac-3-amino-N- (2- (methyl (tetrahydrofuran-3-yl) amino) ethyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 233)

Scenario 110

Step 1. (tert-butyl 2- (methyl (tetrahydrofuran-3-yl) amino) ethyl) carbamate

The reaction mixture was washed with tert-butyl N- (2-bromoethyl) carbamate (400mg, 1.785mmol, 1 eq.), N-methoxyoxolane-3Amine (180.54mg, 1.785mmol, 1 eq.) and K₂CO₃A mixture of (740.06mg, 5.355mmol, 3.0 equiv.) in DMF (30mL) was stirred at 65 ℃ for 16 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with saturated brine (20mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gave N- [2- [ methyl (oxolan-3-yl) amino ] as a pale yellow oil ]Ethyl radical]Tert-butyl carbamate (410mg, 94.0%). LCMS M/z (ESI), [ M + H]⁺＝245.1。¹H-NMR(300mHz,DMSO-d₆)δ0.62(9H,s),1.02-1.05(1H,m),1.35-1.18(1H,m),1.45(2H,s),1.80-1.56(2H,m,2H),2.37-2.39(3H,m),2.50-2.53(1H,m),2.87-2.69(1H,m),2.91-2.94(1H,m),3.01-3.05(1H,m),3.12-3.15(1H,m)

Step 2. N1-methyl-N1- (tetrahydrofuran-3-yl) ethane-1, 2-diamine

Reacting N- [2- [ methyl (oxolane-3-yl) amino group]Ethyl radical]A solution of tert-butyl carbamate (200mg, 0.819mmol, 1 eq.) and TFA (3mL) in DCM (6mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. With saturated NaHCO₃The residue was neutralized to pH 7 (aqueous solution). The aqueous layer was extracted with EtOAc (3X 20 mL). The resulting mixture was concentrated under reduced pressure. This gave N- (2-aminoethyl) -N-methyloxacyclopentane-3-amine (105mg, 88.95%) as a pale yellow oil. LCMS M/z (ESI), [ M + H]⁺＝145.1。¹H-NMR(300mHz,DMSO-d₆)δ1.41-1.44(1H,m),1.60-1.64(1H,m),2.05-2.08(1H,d),2.16-2.19(1H,s),2.50-2.53(1H,m),2.65-2.67(4H,m),2.89-2.90(1H,m),2.97-2.99(1H,m),3.30-3.32(1H,m),3.37-3.39(2H,m)

Step 3 rac-3-amino-N- (2- (methyl (tetrahydrofuran-3-yl) amino) ethyl) -6- (3-methylimidazole And [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

Reacting 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.), N- (2-aminoethyl) -N-methyloxolan-3-amine (41.17mg, 0.285mmol, 1.2 equiv.), T₃A solution of P (227.06mg, 0.714mmol, 3.0 equiv.) and DIEA (92.23mg, 0.714mmol, 3.0 equiv.) in DMF (2mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with water (30mL) and extracted with EtOAc (3X 30 mL). The combined organic layers were washed with saturated brine (10mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Xbridge Prep C18OBD column 19X 150mm 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 20% B to 37% B within 7 min; 254/220 nm; Rt: 6.58min) to give 3-amino-N- [2- [ methyl (oxacyclopent-3-yl) amino ] in the form of a yellow solid]Ethyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 233) (12.2mg, 11.09%). LCMS M/z (ESI), [ M + H]⁺＝463.4 ¹H-NMR(300mHz,MeOD-d₄)δ1.81-1.85(1H,m),2.04-2.05(1H,m),2.32(3H,s),2.49(3H,s),2.59-2.63(2H,m),3.22-3.24(1H,m),3.29-3.34(2H,m),3.51-3.55(2H,m),3.60-3.65(2H,m),7.25-7.30(2H,m),7.31-7.38(1H,s),7.47-7.50(1H,m),8.02(1H,s),8.68(1H,s)。

Example 234.(3S) -3- [ (3-amino-6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]-5-(1,3-

Azole- 2-yl) pyrazin-2-yl) carboxamido]-N, N-dimethylbutanamidePreparation of (Compound 234)

Scheme 111

Step 1.(S) -4- (dimethylamino) -4-oxobutan-2-ylcarbamic acid tert-butyl ester

To (3S) -3- [ [ (tert-butoxy) carbonyl ] at room temperature under an air atmosphere]Amino group]To a stirred mixture of butyric acid (500mg, 2.460mmol, 1 equiv) and dimethylamine (221.83mg, 4.920mmol, 2 equiv) in DCM was added HATU (1870.86mg, 4.920mmol, 2 equiv) portionwise and DIEA (1.59g, 12.301mmol, 5 equiv) added dropwise. The resulting mixture was stirred at room temperature under an air atmosphere overnight. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient 5% to 20% within 10 min; detector, UV220 nm. This gives N- [ (2S) -1- (dimethylcarbamoyl) propan-2-yl as a pink solid ]Tert-butyl carbamate (550mg, 64.07%). LCMS (ESI) M/z [ M + H ]]⁺＝231.1；¹H-NMR(400MHz,CDCl₃-d)δ1.27(3H,d),1.44(9H,s),2.44-2.49(1H,m),2.60-2.65(1H,m),2.95(3H,s),3.04(3H,s),4.00-4.05(1H,m)。

(S) -3-amino-N, N-dimethylbutanamide

N- [ (2S) -1- (dimethylcarbamoyl) propan-2-yl was added to a 50mL round bottom flask at room temperature]Tert-butyl carbamate (200mg, 0.868mmol, 1 equiv.) and TFA (0.99g, 8.684mmol, 10 equiv.). The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) M/z [ M + H ]]⁺＝131.1；¹H-NMR(300MHz,CDCl₃-d)δ1.40(3H,d),2.70(2H,d),2.95(3H,s),3.01(3H,s),3.74(1H,s),7.78(3H,s),11.00(2H,s)。

Step 3.(S) -3-amino-N- (4- (dimethylamino) -4-oxobutan-2-yl) -6- (3-methylimidazo [1, 2-a]pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 234)

To (3S) -3-amino-N, N-dimethylbutanamide (77.42mg, 0.59) at room temperature under an air atmosphere5mmol, 2 equivalents) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

To a stirred solution/mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 equivalent) in DMF was added DIEA (768.59mg, 5.947mmol, 20.00 equivalents) and T dropwise₃P (946.09mg, 2.973mmol, 10.00 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere overnight. The crude product (100mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B: MeOH- -HPLC; flow rate: 20 mL/min; gradient: 49% B to 59% B over 8 min; 254; 220 nm; Rt: 6.97min) to give (3S) -3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]-N, N-dimethylbutanamide (15mg, 11.15%). LCMS (ESI) [ M + H ]]⁺＝449.3；¹H-NMR(400MHz,DMSO-d₆)δ1.23(3H,d),2.48(3H,d),2.52-2.60(1H,m),2.74-2.79(1H,m),2.83(3H,s),3.00(3H,s),4.38(1H,s),7.14-7.17(1H,m),7.37-7.41(2H,m),7.47-7.49(1H,m),8.28(1H,d),8.37(1H,s),9.01(1H,d)。

EXAMPLE 236 (3R) -3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Preparation of (E) -N, N-dimethylbutanamide (Compound 236)

Schema 112

Step 1.N- [ (2R) -1- (dimethylcarbamoyl) propan-2-yl](iii) carbamic acid tert-butyl ester.

DIEA (15) was treated at room temperature under an air atmosphere89.80mg, 12.301mmol, 5 equiv.), HATU (1870.86mg, 4.920mmol, 2 equiv.), dimethylamine hydrochloride (401.20mg, 4.920mmol, 2 equiv.), and (3R) -3- [ [ (tert-butoxy) carbonyl]Amino group]A mixture of butyric acid (500mg, 2.460mmol, 1 eq) in DCM (15mL, 1 eq) was stirred overnight. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (0-20% H)₂O/ACN) to obtain N- [ (2R) -1- (dimethylcarbamoyl) propan-2-yl group as a colorless oil]Tert-butyl carbamate (550mg, 1.35%). LCMS M/z (ESI), [ M + H]⁺＝231.0。¹H NMR (300MHz, chloroform-d) Δ 1.27(3H, d),1.44(9H, s),2.47(1H, d),2.64(1H, d),2.95(3H, s),3.04(3H, s),4.02(1H, d)

Step 2.(3R) -3-amino-N, N-dimethylbutanamide.

TFA (1.00mL, 13.463mmol, 15.50 equiv.) and N- [ (2R) -1- (dimethylcarbamoyl) propan-2-yl]A mixture of tert-butyl carbamate (200mg, 0.868mmol, 1 eq.) in DCM (3mL) was stirred at room temperature under an air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure to give (3R) -3-amino-N, N-dimethylbutanamide (100mg, 88.45%) as a pink oil.¹H NMR (300MHz, chloroform-d) delta 1.47(3H, d),2.76(2H, d),3.00(3H, s),3.06(3H, s),3.79(1H, s),7.81(2H, s)

Step 3.(3R) -3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazole-2- Radical) pyrazin-2-yl) carboxamido radical]-N, N-dimethylbutanamide (Compound 236)

DIEA (245.95mg, 1.903mmol, 8 equiv.), T were mixed under an air atmosphere at room temperature₃P (454.12mg, 1.427mmol, 6 equiv), (3R) -3-amino-N, N-dimethylbutanamide (123.88mg, 0.952mmol, 4 equiv) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (80mg,0.238mmol, 1 eq) in DMF (3mL) was stirred overnight. The desired product can be detected by LCMS. The crude product (100mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B: MeOH- -HPLC; flow rate: 20 mL/min; gradient: 47% B to 59% B over 8 min; 254; 220 nm; Rt: 7.40min) to give (3R) -3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]-N, N-dimethylbutanamide (compound 236) (60mg, 55.12%). LCMS M/z (ESI), [ M + H]⁺＝449.3。¹H-NMR(300MHz,DMSO-d₆)δ1.23(3H,d),2.46-2.49(3H,m),2.58(1H,d),2.76-2.83(4H,m),3.00(3H,s),4.39(1H,s),7.15(1H,d),7.39(2H,d),7.49(1H,d),7.93(2H,s),8.28(1H,d),8.38(1H,d),9.02(1H,d)。

Example 247-1/247-2.3-amino-N- ((1, 2-dimethylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 247-1/247-2)

Scheme 113

And (1). 2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azole-2-yl) Pyrazin-2-yl) carboxamido radicals]Methyl radical]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (200mg, 0.595mmol, 1 eq) and tert-butyl 2- (aminomethyl) -2-methylpyrrolidine-1-carboxylate (254.89mg, 1.189mmol, 2 eq) in DMF was added T-dropwise₃P (946.09mg, 2.973mmol, 5 equiv.) and DIEA (307.44mg, 2.379mmol, 4 equiv.). The resulting mixture was stirred at 25 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (50mL) and CH₂Cl₂(3X 50 mL). The combined organic layers were washed with brine (3X 50mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH) ₂Cl₂MeOH 20:1) to give 2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-tert-butyl 2-methylpyrrolidine-1-carboxylate (280mg, 88.40%). LCMS M/z (ESI), [ M + H]⁺＝533.3。¹H-NMR(300MHz,MeOD-d₄)δ1.18(5H,s),1.40(7H,d),1.81(2H,d),2.49(3H,d),3.49(1H,s),3.63(1H,t),3.80(1H,d),7.23-7.41(3H,m),7.49(1H,d),8.00(1H,s),8.30(1H,s)。

Step 2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ (2-methylpyrrolidin-2-yl) Methyl radical]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamides

To 2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] at 25 ℃ under a nitrogen atmosphere]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]To a stirred solution of tert-butyl-2-methylpyrrolidine-1-carboxylate (280mg) in DCM was added TFA (1.5 mL). The resulting mixture was heated at 25 ℃ toStirring for 30min under nitrogen atmosphere. Concentrating the resulting mixture under reduced pressure to obtain 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ (2-methylpyrrolidin-2-yl) methyl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (200mg, 87.96%). LCMS M/z (ESI), [ M + H]⁺＝433.2。

Step 3.2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]-5-(1,3-

3-amino-6- [ 3-methylimidazo [1,2-a ] at 25 ℃ in a nitrogen atmosphere ]Pyridin-6-yl]-N- [ (2-methylpyrrolidin-2-yl) methyl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (200mg, 0.462mmol, 1 equiv.) and PFA (138.73mg, 4.624mmol, 10 equiv.) to a stirred mixture of MeOH (8mL) was added NaBH dropwise₃CN (145.30mg, 2.312mmol, 5 equiv.) and DIEA (239.07mg, 1.850mmol, 4 equiv.). The resulting mixture was stirred at 25 ℃ under a nitrogen atmosphere for 2 hours. The mixture was purified by preparative HPLC with the following conditions (column: Atlantis Prep T3OBD column 19: 150mm 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 10% B to 20% B within 7 min; 254/220 nm; Rt: 6.08min) to give 3-amino-N- [ (1, 2-dimethylpyrrolidin-2-yl) methyl as a yellow solid]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (100mg, 58.12%).

Step 4.2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]-5-(1,3-

Azole-2-yl) Pyrazin-2-yl) carboxamido radicals]Methyl radical]-2-Methylpyrrolidine-1-carboxylic acid tert-butyl ester (Compound 247-1/247-2)

By chiral preparative HPLC with the following conditions (column: CHIRALPAK IG, 5 × 25cm, 5 μm; mobile phase a: Hex: DCM ═ 3:1(10mM NH)₃-MEOH) -HPLC, mobile phase B: EtOH- -HPLC; flow rate: 20 mL/min; gradient: 40B to 40B within 10 min; 220/254 nm; RT 1: 6.193, RT 2: 7.693) to give 3-amino-N- [ (1, 2-dimethylpyrrolidin-2-yl) as a yellow solid ]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (Compound 247-1) (30mg, 30.0%) and 3-amino-N- [ (1, 2-dimethylpyrrolidin-2-yl)]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 247-2) (30mg, 30.0%).

(Compound 247-1) LCMS M/z (ESI), [ M + H]⁺＝447.2。¹H-NMR(300MHz,MeOD-d₄)δ1.05(3H,s),1.56-1.68(1H,m),1.77(2H,p),1.85-1.97(1H,m),2.33(3H,s),2.49(3H,d),2.58-2.69(1H,m),2.97(1H,s),3.25(1H,s),3.53(1H,d),7.26(1H,dd),7.32(1H,d),7.39(1H,s),7.49(1H,d),8.00(1H,d),8.35(1H,s)

(Compound 247-2) LCMS M/z (ESI), [ M + H]⁺＝447.4。¹H-NMR(300MHz,MeOD-d₄)δ1.05(3H,s),1.56-1.68(1H,m),1.77(2H,p),1.85-1.97(1H,m),2.33(3H,s),2.49(3H,d),2.58-2.69(1H,m),2.97(1H,s),3.25(1H,s),3.53(1H,d),7.26-7.39(3H,m),7.49(1H,d),8.00(1H,d),8.35(1H,s)

EXAMPLE 257 preparation of (2R) -N- [ [ 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] pyrazin-2-yl ] methyl ] -1-methylpyrrolidine-2-carboxamide (Compound 257)

Scenario 114

Step 1.3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxamide

To NH at room temperature₃(g) To a solution in MeOH (15mL) was added methyl 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxylate (1000mg, 3.337mmol, 1 eq) portionwise. The mixture was stirred at 50 ℃ for 5 hours under an air atmosphere. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxamide as a yellow solid (930mg, 97.90%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝285.2。¹H-NMR(400MHz,DMSO-d₆)δ7.55-7.67(3H,m),7.74-7.85(3H,m),8.04(1H,s)

Step 2.3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carbonitrile

To a solution of phosphoryl chloride (5mL) was added 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxamide (900mg, 3.162mmol, 1 equiv) portionwise at room temperature. The resulting mixture was stirred at 90 ℃ for 2 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. By CH₂Cl₂The residue was dissolved (100mL) and basified with saturated NaHCO3 (aq) to pH 8. By CH₂Cl₂The resulting mixture was extracted (2X 100 mL). The combined organic layers were washed with water (2X 30mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (6:1) to give 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carbonitrile as a yellow solid (550mg, 65.24%). LCMS M/z (ESI), [ M + H]⁺＝267.0。¹H NMR(400MHz,DMSO-d₆)δ7.56-7.68(2H,m),7.73(2H,s),7.75-7.85(1H,m)

Step 3.3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine esters- 2-carbonitriles

To 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carbonitrile (400mg, 1.500mmol, 1 equiv.) and [ 3-methylimidazo [1,2-a ] at 90 ℃ under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (395.99mg, 2.250mmol, 1.5 equiv.) in bis

Cs was added in portions to a stirred mixture in an alkane (50mL)₂CO₃(977.56mg, 3.000mmol, 2 equiv.) and Pd (dppf) cl₂(219.53mg, 0.300mmol, 0.2 equiv.). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH) ₂Cl₂MeOH 20:1) to give 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carbonitrile (400mg, 55.19%). LCMS M/z (ESI), [ M + H]⁺＝363.3。

Step 4.3- (aminomethyl) -6- (3, 4-difluorophenyl) -5- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-amines

To 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]Pyrazine-2-carbonitrile (400mg, 1.104mmol, 1 equiv) to a solution in MeOH (50mL) was added Raney nickel (189.16mg, 2.208mmol, 2.00 equiv) in portions. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (2X 50 mL). The filtrate was concentrated in vacuo to give 3- (aminomethyl) -6- (3, 4-difluorophenyl) -5- [ 3-methylimidazo [1,2-a as a beige solid]Pyridin-6-yl]Pyrazin-2-amine (300mg, 74.17%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝367.3。

Step 5.(2R) -N- [ [ 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridine-6- Base of]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 257)

At room temperature in an air atmosphere to 3 To a stirred mixture of (aminomethyl) -5-chloro-6- (3, 4-difluorophenyl) pyrazin-2-amine (100mg, 0.369mmol, 1 equiv.) and (2R) -1-methylpyrrolidine-2-carboxylic acid (95.44mg, 0.739mmol, 2 equiv.) in DMF (10mL) was added HATU (210.72mg, 0.554mmol, 1.5 equiv.) and DIEA (191.00mg, 1.478mmol, 4 equiv.) portionwise. The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A: 5% ammonia in water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 50% B in 7 min; 254; 220 nm; Rt: 5.95min) to give (2R) -N- [ [ 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a white solid]Pyridin-6-yl]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (41mg, 23.17%) (Compound 257). LCMS M/z (ESI), [ M + H]⁺＝478.3。¹H-NMR(400MHz,DMSO-d₆)δ1.64-1.83(3H,m),2.03-2.19(1H,m),2.21-2.39(7H,m),2.81(1H,dd),3.04(1H,dt),4.32-4.49(2H,m),6.75(2H,s),6.98(1H,dd),7.15-7.24(1H,m),7.33-7.44(3H,m),7.49(1H,ddd),8.07-8.13(1H,m),8.45(1H,t)

Example 259.preparation of 3-amino-6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -N- [ [ (2R) -1-methylpyrrolidin-2-yl ] methyl ] -5-phenylpyrazine-2-carboxamide (Compound 259)

Scheme 115

Step 1.3-amino-6-chloro-5-phenylpyrazine-2-carboxylic acid methyl ester

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (600mg, 2.702mmol, 1 equiv.) and phenylboronic acid (336.09mg, 2.756mmol, 1.02 equiv.) in dioxane at room temperature under a nitrogen atmosphere

To a stirred mixture in an alkane (20mL) was added K in portions₃PO₄(1147.23mg, 5.405mmol, 2 equiv.) and Pd (d)ppf)Cl₂(395.46mg, 0.540mmol, 0.2 equiv.). The resulting mixture was stirred at 70 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give methyl 3-amino-6-chloro-5-phenylpyrazine-2-carboxylate (400mg, 56.14%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝264.3。¹H NMR(400MHz,DMSO-d₆)δ3.89(3H,s),7.53(3H,dd),7.61(2H,s),7.71-7.78(2H,m)

Step 2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-phenylpyrazine-2-carboxylic acid ester

To methyl 3-amino-6-chloro-5-phenylpyrazine-2-carboxylate (150mg, 0.569mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (200.22mg, 1.138mmol, 2 equiv.) in bis

To a stirred mixture in an alkane (10mL) CS was added portionwise₂CO₃(556.05mg, 1.707mmol, 3 equiv.) and Pd (dppf) Cl₂(83.25mg, 0.114mmol, 0.2 equiv.). The resulting mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH) ₂Cl₂MeOH 20:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-phenylpyrazine-2-carboxylic acid methyl ester (130mg, 63.59%). LCMS M/z (ESI), [ M + H]⁺＝360.3。¹H-NMR(400MHz,DMSO-d₆)δ2.27(3H,d),3.91(3H,s),7.09(1H,dd),7.34-7.48(7H,m),7.55(2H,d),8.00(1H,dd)

Step 3.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-phenylpyrazine-2-carboxylic acid

To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a solution of methyl (130mg, 0.417mmol, 1 eq.) 5-phenylpyrazine-2-carboxylate in THF (15mL) and methanol (5mL) was added LiOH (19.99mg, 0.835mmol, 2.00 eq). The mixture was stirred at 50 ℃ under an air atmosphere for 2.5 hours. Mixing with HCl (aq)The material was acidified to pH 6. The resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-phenylpyrazine-2-carboxylic acid (100mg, 80.05%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝346.2。

Step 4.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidine- 2-radical]Methyl radical]-5-phenylpyrazine-2-carboxamide (Compound 259)

3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere ]Pyridin-6-yl]-5-phenylpyrazine-2-carboxylic acid (100mg, 0.290mmol, 1 equiv.) and 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (66.13mg, 0.579mmol, 2 equiv.) in a stirred mixture of DMF (5mL) was added DIEA (112.27mg, 0.869mmol, 3 equiv.) and T in portions₃P (368.52mg, 1.158mmol, 4 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 2.5 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 38% B to 50% B within 8 min; 254; 220 nm; Rt: 7.65min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-phenylpyrazine-2-carboxamide (compound 259) (33mg, 25.81%). LCMS M/z (ESI), [ M + H]⁺＝442.3。¹H NMR(400MHz,DMSO-d₆)δ1.54-1.71(3H,m),1.79-1.90(1H,m),2.16(1H,q),2.33(6H,d),2.41-2.48(1H,m),2.96(1H,dd),3.26(1H,dt),3.51(1H,ddd),7.05(1H,dd),7.33-7.46(5H,m),7.43-7.51(2H,m),7.73(2H,s),8.14-8.20(1H,m),8.64(1H,t)

Example 261.3-amino-N- ((6- (3- ((dimethylamino) methyl) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 261)

Scheme 116

Step 1.2-cyano 6- (3- ((dimethylamino) methyl) azetidin-1-yl) pyridine

In a 50-mL round bottom flask was placed 6-bromopyridine-2-carbonitrile (423.10mg, 2.312mmol, 1.10 equiv.), DMF (4mL, 51.687mmol, 24.59 equiv.), K₂CO₃(871.41mg, 6.305mmol, 3 equiv.) and [ (azetidin-3-yl) methyl]Dimethylamine (240mg, 2.102mmol, 1 eq). The resulting solution was stirred at 50 ℃ for 16 hours. The resulting solution was extracted with 3 × 10mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was applied to a silica gel column together with dichloromethane/methanol (8: 1). This gave 190mg (41.80%) of 6- [3- [ (dimethylamino) methyl group as a pale yellow solid]Azetidin-1-yl]Pyridine-2-carbonitrile. LCMS M/z (ESI), [ M + H]⁺＝217.1。¹H-NMR(400MHz,DMSO-d₆)δ2.13(6H,s),2.47-2.49(2H,m),2.84-2.91(1H,m),3.62(2H,t),4.06(2H,t),6.65(1H,d),7.16(1H,d),7.64(1H,t)。

Step 2.1- (1- (6- (aminomethyl) pyridin-2-yl) azetidin-3-yl) -N, N-dimethylmethylamine

A50-mL round bottom flask was charged with MeOH (5mL, 0.094mmol, 2.03 equiv.), Raney nickel (0.75mg, 0.009mmol, 0.01 equiv.), 6- [3- [ (dimethylamino) methyl group]Azetidin-1-yl]Pyridine-2-carbonitrile (190mg, 0.878mmol, 1 eq.), NH₄OH (1mL, 25.681mmol, 29.23 equiv.). The resulting solution was stirred at room temperature for 1 hour. This gave 40mg (20.67%) of 1- (6- [3- [ (dimethylamino) methyl ] methyl as a tan oil]Azetidin-1-yl]Pyridin-2-yl) methylamine. LCMS M/z (ESI), [ M + H ]⁺＝220.95。¹H-NMR(400MHz,DMSO-d₆)δ2.13(6H,s),2.46(2H,d),2.83(1H,dt),3.53(2H,dd),3.59(2H,s),3.98(2H,t),6.17(1H,d),6.64(1H,d),7.43(1H,t)

Step 3.3-amino-N- ((6- (3- ((dimethylamino) methyl) azetidine-1-yl) pyridin-2-yl) methyl 6- (3-methylimidazo [1, 2-a) methyl ester]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 261)

Oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.), DMF (0.041mmol, 0.17 equiv.), DIEA (307.44mg, 2.379mmol, 10 equiv.), T₃P (454.12mg, 1.427mmol, 6 equivalents), 1- (6- [3- [ (dimethylamino) methyl group]Azetidin-1-yl]Pyridin-2-yl) methylamine (104.82mg, 0.476mmol, 2 equivalents). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was diluted with water (15mL), extracted with 3X 10mL of dichloromethane, and the organic layers were combined and concentrated. By preparative HPLC with the following conditions: (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 40% B over 7 min; 254; 220 nm; Rt: 5.82min) to purify the crude product and obtain the product. This gave 23.6mg (18.42%) of 3-amino-N- [ (6- [3- [ (dimethylamino) methyl ] amide as a yellow solid]Azetidin-1-yl]Pyridin-2-yl) methyl ]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 261). LCMS M/z (ESI), [ M + H]⁺＝539.5。¹H-NMR (400MHz, methanol-d)₄)δ2.23(6H,s),2.42(2H,d),2.53(3H,d),2.71-2.80(1H,m),3.53(2H,dd),4.00(2H,t),4.56(2H,s),6.27(1H,d),6.67(1H,d),7.27-7.36(2H,m),7.43(1H,d),7.46-7.56(2H,m),8.02(1H,d),8.41(1H,s)

EXAMPLE 268 preparation of (2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methyl-imidazole- [1,2-a ] pyridin-6-yl ] pyrazin-2-yl ] methyl ] oxolane-2-carboxamide (Compound 268)

Scheme 117

Step 1.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide

A solution of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (2.0g, 7.10mmol, 1 eq) and NH3(g) in MeOH (30mL, 7.0mmol/L) was added at room temperature in a 50mL sealed tube, heated at 50 ℃ for 5 hours, and concentrated to give 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide as a light yellow solid (1.5g, 79%). LCMS M/z (ESI), [ M + H]⁺＝267.0。

Step 2.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile

At 0 ℃ to POCl₃To a stirred solution (20mL) was added 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide (5.0g, 18.750mmol, 1 eq) in portions, stirred at 90 ℃ for 3 hours, and concentrated. The residue was dissolved in DCM (300mL) and NaHCO was added₃(aqueous solution) to PH 8.0. Extraction with DCM (3 × 50mL), drying of the combined organic layers and concentration gave 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile as a light brown solid (3.5g, 75%). LCMS M/z (ESI), [ M + H ]⁺＝249.2。

Step 3.3-amino-5- (4-fluorophenyl) -6- [ 3-methyl-imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carbonitriles

To 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (500mg, 2.01mmol, 1 eq.) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (530.81mg, 3.02mmol, 1.5 equiv.) and Pd (dppf) Cl₂(147mg, 0.20mmol, 0.1 equiv.) in II

To a stirred mixture in an alkane (15mL) was added K in portions₃PO₄(854mg, 4.02mmol, 2.0 equiv.) of H₂O (2.5mL) solution, and mixing the obtained solutionsThe material was stirred at 90 ℃ for 2 h, concentrated and purified by preparative TLC (DCM/MeOH ═ 40/1) to give 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a light yellow solid]Pyridin-6-yl]Pyrazine-2-carbonitrile (300mg, 43%). LCMS M/z (ESI), [ M + H]⁺＝345.2。

3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature under a hydrogen atmosphere]Pyridin-6-yl]To a stirred mixture of pyrazine-2-carbonitrile (500mg, 1.45mmol, 1 equiv.) and Raney nickel (62mg, 0.73mmol, 0.5 equiv.) in ethanol (10mL) was added NH ₃.H₂O (1.0mL) was stirred at room temperature for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 30 mL). The filtrate was concentrated under reduced pressure to give 3- (aminomethyl) -6- (4-fluorophenyl) -5- [ 3-methyl-imidazo [1,2-a ] as a pale brown solid]Pyridin-6-yl]Pyrazin-2-amine (450mg, 89%).¹H-NMR(300MHz,DMSO-d₆)δ2.28(3H,d),4.65(2H,d),5.47(1H,t),6.77(1H,dd),6.96(2H,s),7.34(2H,m),7.63(1H,dd)。

Step 5.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]Oxetane-2-carboxamide (Compound 268)

A solution of (2S) -oxolane-2-carboxylic acid (66.66mg, 0.57mmol, 2.0 equiv.) in DMF (2.0mL) was treated with HATU (218mg, 0.57mmol, 2.0 equiv.) at room temperature for 20min, followed by dropwise addition of 3- (aminomethyl) -6- (4-fluorophenyl) -5- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]Pyrazin-2-amine (100mg, 0.29mmol, 1 equiv.), DIEA (111mg, 0.86mmol, 3.0 equiv.), stirred for 2 hours, quenched by water (20mL), extracted with DCM (3X 20mL), dried and concentrated, followed by purification by preparative TLC to give (2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a white solid]Pyridin-6-yl]Pyrazin-2-yl radicals]Methyl radical]Oxirane-2-carboxamide (Compound 268) (45.2mg, 35%). LCMS m/z (ESI) ,[M+H]⁺＝447.3。¹H-NMR(300MHz,DMSO-d₆)δ1.80(2H,q),1.91(1H,m),2.14(1H,dq),2.32(3H,d),3.78(1H,q),3.94(1H,q),4.37(3H,m),6.69(2H,s),6.96(1H,dd),7.17(2H,t),7.35(2H,dd),7.42(2H,m),8.06(1H,d),8.40(1H,t)。

EXAMPLE 272.preparation of 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -N- [ [ (2R) -1-methylpyrrolidin-2-yl ] methyl ] pyrazine-2-carboxamide (Compound 272)

Scenario 118

Step 1.3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxylic acid methyl ester

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (2000mg, 9.008mmol, 1 equiv.) and (3, 4-difluorophenyl) boronic acid (1450.87mg, 9.188mmol, 1.02 equiv.) in a nitrogen atmosphere at room temperature

To a stirred mixture in an alkane (100mL) was added K in portions₃PO₄(3824.10mg, 18.016mmol, 2 eq.) and Pd (dppf) Cl₂(1318.20mg, 1.802mmol, 0.2 equiv.). The resulting mixture was stirred at 70 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give methyl 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxylate (1500mg, 55.57%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝300.2。¹H-NMR(400MHz,DMSO-d₆)δ3.89(3H,s),7.54-7.72(4H,m),7.78-7.89(1H,m)

Step 2.3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine- 2-formic acid ester

To methyl 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxylate (400mg, 1.335mmol, 1 equiv.) and [3- Methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (469.81mg, 2.670mmol, 2 equiv.) in dioxane

To a stirred mixture in an alkane (40mL) CS was added portionwise₂CO₃(869.84mg, 2.670mmol, 2 equiv.) and Pd (dppf) Cl2(195.34mg, 0.267mmol, 0.2 equiv.). The resulting mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 20:1) to give 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (300mg, 56.84%). LCMS M/z (ESI), [ M + H]+＝396.3。

Step 3.3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine- 2-carboxylic acid

To 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a solution of pyrazine-2-carboxylic acid methyl ester (200mg, 0.506mmol, 1 eq) in THF (20mL) and methanol (5mL) was added LiOH (48.46mg, 2.023mmol, 4 eq). The mixture was stirred at room temperature under an air atmosphere for 3 hours and acidified to pH 6 with HCl (aqueous solution). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]Pyrazine-2-carboxylic acid (150mg, 77.76%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝382.2。

Step 4.3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamides (Compound 272)

3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature under an air atmosphere]Pyridin-6-yl]Pyrazine-2-carboxylic acid (150mg, 0.393mmol, 1 eq.) and 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (89.83mg, 0.787mmol, 2 equivalents) in DMF (15mL) was mixed with stirringDIEA (152.51mg, 1.180mmol, 3 equivalents) and T were added in portions to the mixture₃P (500.62mg, 1.573mmol, 4 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: 5% ammonia, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 36% B to 49% B over 7 min; 254; 220 nm; Rt: 6.83min) to give 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 272) (23mg, 12.25%). LCMS M/z (ESI), [ M + H]+＝478.3。¹H-NMR(400MHz,DMSO-d₆)δ1.53-1.70(3H,m),1.78-1.89(1H,m),2.15(1H,q),2.32(3H,s),2.41(3H,s),2.41-2.49(1H,m),2.95(1H,dd),3.25(1H,dt),3.50(1H,ddd,),6.99(1H,dd),7.26(1H,t),7.38-7.49(3H,m),7.57(1H,ddd),7.77(2H,s),8.29(1H,d),8.66(1H,t)

Example 273.3-amino-N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 273)

Scheme 119

Step 1.N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl]Methyl radical](iii) carbamic acid tert-butyl ester.

TEA (854.86mg, 8.448mmol, 5 equiv.), dimethylamine hydrochloride (206.66mg, 2.534mmol, 1.50 equiv.), 4-nitrophenyl chloroformate (408.67mg, 2.028mmol, 1.20 equiv.) and N- [ [ (3R) -pyrrolidin-3-yl ] were reacted at 70 ℃ under an air atmosphere]Methyl radical]A mixture of tert-butyl carbamate hydrochloride (400mg, 1.690mmol, 1 eq) in ACN (20mL) was stirred overnight. The resulting mixture was diluted with water (50mL) and extracted with EtOAc (3 a/v)50mL) was extracted. The combined organic layers were washed with brine (3X 50mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl ] as a yellow oil]Methyl radical]Tert-butyl carbamate (370mg, 80.70%). LCMS M/z (ESI), [ M + H ]⁺＝272.1。¹H-NMR (300MHz, chloroform-d) delta 1.47(9H, s),1.56-1.70(1H, m),1.91-2.04(1H, m),2.27-2.43(1H, m),2.86(6H, s),3.16(3H, d),3.46(3H, q).

Step 2.(3S) -3- (aminomethyl) -N, N-dimethylpyrrolidine-1-carboxamide.

TFA (2mL, 26.926mmol, 42.98 equiv.) and N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl ] were added under an air atmosphere at room temperature]Methyl radical]A mixture of tert-butyl carbamate (170mg, 0.626mmol, 1 eq) in DCM (5mL) was stirred for 1 h. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give (3S) -3- (aminomethyl) -N, N-dimethylpyrrolidine-1-carboxamide (100mg, 93.21%) as a colorless oil. LCMS m/z¹H-NMR (300MHz, chloroform-d) delta 1.71(1H, s),2.14(1H, s),2.59(1H, s),2.90(6H, s),3.00(1H, s),3.18(1H, s),3.36(1H, s),3.50(3H, q)

Step 3.3-amino-N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl]Methyl radical]-6- [ 3-methyl Imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 273)

DIEA (184.46mg, 1.427mmol, 6 equiv.) and T were combined at room temperature under an air atmosphere₃P (227.06mg, 0.714mmol, 3 equiv.), (3S) -3- (aminomethyl) -N, N-dimethylpyrrolidine-1-carboxamide (81.47mg, 0.476mmol, 2 equiv.) and 3-amino-6- [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.2)38mmol, 1 eq) in DMF (3mL) was stirred overnight. With water (30mL) and saturated NaHCO₃The resulting mixture was diluted (30mL) with CH₂Cl₂(3X 40 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂The residue was purified with MeOH 12:1) to give the crude product. The crude product (100mg) was purified by preparative HPLC with the following conditions (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A: mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 35% B within 7 min; 254; 220 nm; Rt: 6.93min) to give 3-amino-N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 273) (20mg, 17.00%). LCMS M/z (ESI), [ M + H]⁺＝490.4。¹H NMR(300MHz,DMSO-d₆)δ1.60(1H,d),1.82-1.92(1H,m),2.44(4H,d),2.70(6H,s),3.11(1H,d),3.23-3.35(4H,m),3.37(1H,s),7.24(1H,d),7.38(2H,d),7.49(1H,d),7.90(1H,s),8.28(1H,d),8.32-8.39(1H,m),8.98(1H,t)

Example 276.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [6- (morpholin-4-yl) pyridin-2-yl]Methyl radical]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 276)

Scheme 120

Step 1.6- (Morpholin-4-yl) pyridine-2-carbonitrile

6-Fluoropyridine-2-carbonitrile (1g, 8.190mmol, 1 equiv.), morpholine (1.43g, 0.016mmol, 2 equiv.) and K were added to a 40mL round bottom flask at room temperature ₂CO₃(2.26g, 0.016mmol, 2 eq.) in DMF (15 mL). The resulting mixture was stirred at 80 ℃ for 6 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and washed with water (1 × 100mL) and dried in vacuo to give 6- (morpholin-4-yl) pyridine-2-carbonitrile as a white solid (1.5g, 96.79%). LCMS M/z (ESI), [ M + H]⁺＝190.3。¹H-NMR(300MHz,DMSO-d₆)δ3.46(4H,dd),3.66(4H,dd),7.18(2H,m),7.70(1H,dd)。

Step 2.1- [6- (morpholin-4-yl) pyridin-2-yl]Methylamine

To 6- (morpholin-4-yl) pyridine-2-carbonitrile (200mg, 1.057mmol, 1 eq) in MeOH (15mL) and NH at room temperature₃.H₂Raney nickel (271.67mg, 3.171mmol, 3 equiv.) was added portionwise to a solution in O (1 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure to give 1- [6- (morpholin-4-yl) pyridin-2-yl as a purple oil]Methylamine (150mg, 73.44%), which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝194.3。

Step 3.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [6- (morpholin-4-yl) pyridine- 2-radical]Methyl radical]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 276)

To 1- [6- (morpholin-4-yl) pyridin-2-yl at room temperature]Methylamine (172.39mg, 0.892mmol, 2 equiv.) and 3-amino-6- [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.446mmol, 1 equiv.) in DMF (15mL) T was added dropwise₃P (283.83mg, 0.892mmol, 2 equiv.) and DIEA (115.29mg, 0.892mmol, 2 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. Mixing the obtained mixtureConcentrating under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10mMOL/L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 31% B to 50% B within 8 min; 220/254 nm; Rt: 8.15min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [6- (morpholin-4-yl) pyridin-2-yl]Methyl radical]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 276) (60mg, 26.30%). LCMS M/z (ESI), [ M + H]⁺＝512.4。¹H NMR:(300MHz,DMSO-d₆)δ2.40(3H,d),3.35(4H,s),3.47(4H,dd),4.47(2H,d),6.65(2H,t),7.31(3H,m),7.49(2H,m),7.90(2H,s),8.26(1H,d),8.33(1H,m),9.33(1H,t)。

EXAMPLE 278 preparation of (R) -N- ((3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1,2-a ] pyridin-6-yl) pyrazin-2-yl) methyl) -1-methylpyrrolidine-2-carboxamide (Compound 278)

Scheme 121

Step 1.3 preparation of amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxamide

At room temperature to 30% NH₃(g) To a stirred solution in MeOH (20mL) was added 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylic acid methyl ester (900mg) portionwise. The resulting mixture was stirred at 50 ℃ for 4 hours. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxamide as a yellow solid (600 mg). LCMS M/z (ESI), [ M + H ]⁺＝267.0。¹H NMR (400MHz, chloroform-d) delta 7.21(1H, m),7.42-7.58(2H, m),7.62(1H, m).

Step 2.3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carbonitrile

To a stirred solution of phosphoryl chloride (2mL) was added 3-amino-6-chloro-5- (3-fluoro) in portions at room temperaturePhenyl) pyrazine-2-carboxamide (30 mg). The resulting mixture was stirred at 90 ℃ for 3 hours. The resulting mixture was concentrated under reduced pressure and diluted with DCM (20 mL). Saturated NaHCO at room temperature₃The reaction was quenched (aqueous solution). By CH₂Cl₂The resulting mixture was extracted (2X 30 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂EtOAc 5:1) to purify the residue to give 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carbonitrile as a yellow solid (400 mg). LCMS M/z (ESI), [ M + H]⁺＝249.0。¹H-NMR (300MHz, chloroform-d) delta 5.32(2H, d),7.21(1H, m),7.42-7.56(2H, m),7.61(1H, m).

Step 3.3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) pyrazin-2-yl Nitrile

To 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carbonitrile (350mg, 1.408mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (371.56mg, 2.111mmol, 1.50 equiv.) in bis

Alkane (20mL) and H ₂To a stirred mixture in O (2mL) was added Cs portion by portion₂CO₃(1375.87mg, 4.223mmol, 3 equiv.) and Pd (dppf) Cl₂(205.99mg, 0.282mmol, 0.2 equiv.). The resulting mixture was stirred at 90 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH₂Cl₂The filter cake was washed (1X 10 mL). The filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 40:1) to give 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carbonitrile (300mg, 61.89%). LCMS M/z (ESI), [ M + H]⁺＝345.2。

Step 4.3- (aminomethyl) -6- (3-fluorophenyl) -5- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) pyrazine- 2-amines

To the 3-amino group at room temperature under a nitrogen atmosphere-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carbonitrile (20mg, 0.058mmol, 1 eq.) and NH₃.H₂To a stirred solution of O (4.07mg, 0.116mmol, 2.00 equiv.) in EtOH (2mL) was added Raney nickel (9.95mg, 0.116mmol, 2.00 equiv.) in portions. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with EtOH (1X 10 mL). The filtrate was concentrated under reduced pressure to give 3- (aminomethyl) -6- (3-fluorophenyl) -5- [ 3-methylimidazo [1,2-a ] as a brown yellow solid ]Pyridin-6-yl]Pyrazin-2-amine (180mg, 71.17%). LCMS M/z (ESI), [ M + H]⁺＝349.3。

Step 5.(R) -N- ((3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) pyridine Oxazin-2-yl) methyl) -1-methylpyrrolidine-2-carboxamide (Compound 278)

To a stirred mixture of (2R) -1-methylpyrrolidine-2-carboxylic acid (36.70mg, 0.284mmol, 1.10 equiv.) in DMF (10mL) was added HATU (196.45mg, 0.517mmol, 2 equiv.) and DIEA (133.55mg, 1.033mmol, 4 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 10 min. To this stirred solution was added 3- (aminomethyl) -6- (3-fluorophenyl) -5- [ 3-methylimidazo [1,2-a ] portionwise at room temperature]Pyridin-6-yl]Pyrazin-2-amine (90mg, 0.258mmol, 1 eq). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A (5% NH)₃Water: and the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 43% B within 7 min; 254; 220 nm; rt: 6.48min) to give (R) -N- ((3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1, 2-a) as a white solid ]Pyridin-6-yl) pyrazin-2-yl) methyl) -1-methylpyrrolidine-2-carboxamide (compound 278) (26mg, 21.90%). LCMS M/z (ESI), [ M + H]⁺＝460.3。¹H NMR(400MHz,DMSO-d₆)δ1.40-1.92(3H,m),1.94-2.19(1H,m),2.22-2.39(7H,m),2.81(1H,dd),3.05(1H,dd),4.26-4.53(2H,m),6.73(2H,s),7.02(1H,dd),7.09-7.51(6H,m),7.91-8.18(1H,m),8.46(1H,t)。

Example 279/280.3-amino-N- ((3-methoxytetrahydrofuran-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 279/280)

Scenario 122

Step 1.3-Methoxyfuran-2-carbaldehyde oxime

A mixture of 3-methoxyfuran-2-carbaldehyde (252mg, 1.998mmol, 1 eq.) and hydroxylamine hydrochloride (210mg, 3.022mmol, 1.51 eq.) in pyridine (4mL) was stirred at room temperature for 18 h. After concentration to dryness, the residue was purified by column (PE/EA-2/1) to give N- [ (3-methoxyfuran-2-yl) methylene as a white solid]Hydroxylamine (200mg, 70.9%). LCMS M/z (ESI), [ M + H]⁺＝142.2。

Step 2. (3-methoxytetrahydrofuran-2-yl) methylamine

Reacting N- [ (3-methylfuran-2-yl) methylene]A mixture of hydroxylamine (460mg, 3.26mmol, 1 equiv.) and Raney nickel (300mg, 3.502mmol, 1.07 equiv.) in ethanol (70mL) was at 1atm H₂Hydrogenation was carried out at room temperature for 1 hour. After filtration through celite, the filtrate was concentrated to dryness in vacuo and the residue was used directly in the next step. LCMS M/z (ESI), [ M + H ]⁺＝132.2。

Step 3.3-amino-N- ((3-methoxytetrahydrofuran-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

To 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

To a mixture of oxazol-2-yl) -pyrazine-2-carboxylic acid (313mg, 0.931mmol, 1 equiv.) and 1- (3-methoxyfuran-2-yl) methylamine (366mg, 2.790mmol, 3.00 equiv.) in 5mL DMF was added DIEA (1.62mL, 9.300mmol, 9.99 equiv.) and 50 wt% T₃A solution of P in ethyl acetate (1.77g, 2.793mmol, 2.99 equivalents). The mixture was stirred at room temperature for 3 hours. By preparative HPLC (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 23% B to 33% B within 7 min; 254; 220 nm; rt: 6.45min) and chiral separation (column: CHIRALPAK IG, 20X 250mm, 5 μm; mobile phase A: hex: DCM ═ 3:1(10mM NH)₃MeOH) -HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL/min; gradient: 30B to 30B within 50 min; 254/220 nm; RT 1: 15.377, respectively; RT 2: 24.388) to give 3-amino-N- ((3-methoxytetrahydrofuran-2-yl) methyl) -6- (3-methylimidazo [1, 2-a) as a yellow solid ]Pyridin-6-yl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxamide (Compound 279) (15mg, 3.5%) and 3-amino-N- ((3-methoxytetrahydrofuran-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxamide (compound 280) (15mg, 3.5%). (Compound 279) LCMS M/z (ESI), [ M + H]⁺＝450.2。¹H-NMR(300MHz,DMSO-d₆)δ1.93-2.00(2H,m),2.40(3H,s),3.25(3H,s),3.41-3.48(1H,m),3.54-3.67(2H,m),3.75-3.83(1H,m),3.91-3.99(2H,m),7.20-7.23(1H,d),7.34(1H,s),7.38(1H,s),7.47-7.50(1H,d),7.89(2H,brs),8.25(1H,s),8.32(1H,s),8.66-8.70(1H,t)。

(Compound 280) LCMS M/z (ESI), [ M + H]⁺＝450.1。¹H-NMR(300MHz,DMSO-d₆)δ1.93-1.99(2H,m),2.40(3H,s),3.24(3H,s),3.41-3.48(1H,m),3.54-3.66(2H,m),3.75-3.83(1H,m),3.91-3.98(2H,m),7.20-7.23(1H,d),7.34(1H,s),7.38(1H,s),7.47-7.50(1H,d),7.89(2H,brs),8.25(1H,s),8.32(1H,s),8.66-8.70(1H,t)。

Example 281.3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Preparation of (E) -N, N,2, 2-tetramethylpropionamide (Compound 281)

Scheme 123

Step 1.2- (5-bromo-2-oxo-1, 2-dihydropyridin-1-yl) propionitrile

To the 3- [ [ (tert-butoxy) carbonyl group at 0 deg.C]Amino group]To a stirred mixture of-2, 2-dimethylpropionic acid (250mg, 1.151mmol, 1 eq), HATU (525.02mg, 1.381mmol, 1.2 eq) and DIEA (743.58mg, 5.753mmol, 5 eq) in DMF (5mL) was added dropwise a solution of dimethylamine (1.15mL, 2.301mmol, 2 eq) followed by stirring at 0 ℃ for 2 hours. The resulting mixture was diluted with EtOAc (30 mL). The combined organic layers were washed with water (3X 10mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give N- [2- (dimethylcarbamoyl) -2, 2-dimethylethyl as a yellow solid ]Tert-butyl carbamate (200mg, 71.1%). LCMS M/z (ESI), [ M + H]⁺＝245.4。

Step 2.3-amino-N, N,2, 2-tetramethylpropionamide

N- [2- (dimethylcarbamoyl) -2, 2-dimethylethyl group was added to a 6mL vial at room temperature]Tert-butyl carbamate (190mg, 0.778mmol, 1 eq.), and hydrochloric acid in bis

Alkane (4M, 5mL) and bis

Solution in alkane (3 mL). Then is onThe mixture was stirred at room temperature for 1.5 hours. And the reaction mixture was concentrated to give 3-amino-N, 2, 2-tetramethylpropionamide (110mg, 98.0%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝145.4。

Step 3.3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azole-2-yl) Pyrazin-2-yl) carboxamido radicals]-N, N,2, 2-tetramethylpropionamide

3-amino-N, N,2, 2-tetramethylpropionamide (110mg, 0.72mmol, 2 equiv.) and 3-amino-6- [ 3-methylimidazo [1,2-a ] are added at room temperature in a 6mL vial]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (120mg, 0.36mmol, 1 eq), HATU (164mg, 0.432mmol, 1.2 eq), DIEA (140mg, 1.08mmol, 3 eq), and DMF (1.5 mL). The mixture was then stirred at room temperature for 2 hours. The resulting mixture was diluted with EtOAc (20 mL). The residue was washed with brine (3X 10mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: X Bridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH) ₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 25% B to 40% B within 7 min; 254/220 nm; t is t_R: 5.77min) to give 3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]-N, 2, 2-tetramethylpropionamide (10mg, 6.0%). LCMS M/z (ESI), [ M + H]⁺＝463.3。¹H-NMR(400MHz,DMSO-d₆)δ1.26(6H,s),2.47(3H,d),2.95(6H,s),3.44(2H,d),7.11(1H,dd),7.38(1H,d),7.41(1H,d),7.49(1H,dd),7.91(2H,s),8.28(1H,d),8.35(1H,dd),8.79(1H,t)。

Example 284.3-amino-N- [ (6- [ 6-methyl-2, 6-diazaspiro [3.3 ]]Heptane-2-yl radical]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 284)

Scenario 124

Step 1.6- (6-cyanopyridin-2-yl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester

To 6-fluoropyridine-2-carbonitrile (1g, 8.190mmol, 1 equiv.) and 2, 6-diazaspiro [3.3 ] at room temperature]To a mixture of tert-butyl heptane-2-carboxylate (3.25g, 16.380mmol, 2 equiv.) in DMF (25mL) was added K2CO3(2.26g, 16.380mmol, 2 equiv.) in portions. The resulting mixture was stirred at 50 ℃ for 3 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (2:1) to give 6- (6-cyanopyridin-2-yl) -2, 6-diazaspiro [3.3 ] as a white solid ]Tert-butyl heptane-2-carboxylate (1.2g, 48.78%). LCMS M/z (ESI), [ M + H]⁺＝301.2。¹H-NMR:(300MHz,DMSO-d₆)δ1.38(9H,s),4.03(4H,s),4.12(4H,s),6.68(1H,dd),7.20(1H,dd),7.67(1H,dd)。

Step 2.1- (6- [ 6-methyl-2, 6-diazaspiro [3.3 ]]Heptane-2-yl radical]Pyridin-2-yl) methylamines

To 6- (6-cyanopyridin-2-yl) -2, 6-diazaspiro [3.3 ] at 0 ℃ under an air atmosphere]To a solution of tert-butyl heptane-2-carboxylate (300mg, 0.999mmol, 1 eq) in THF (15mL) was added LiAlH in portions₄(189.54mg, 4.994mmol, 5 equiv.). The mixture was stirred at room temperature for 1 hour. The resulting mixture was stirred at 70 ℃ for 3 hours under an air atmosphere. The reaction was quenched with water/ice at room temperature and extracted with EtOAc (3X 50 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. In the filtrationThereafter, the filtrate was concentrated under reduced pressure to give 1- (6- [ 6-methyl-2, 6-diazaspiro [3.3 ] as a yellow oil]Heptane-2-yl radical]Pyridin-2-yl) methylamine (100mg, 45.86%).¹H-NMR:(300MHz,DMSO-d₆)δ1.30(2H,d),2.18(3H,s),3.10(4H,d),3.60(2H,s),3.94(4H,s),6.19(1H,d),6.67(1H,d),7.45(1H,t)。

Step 3.3-amino-N- [ (6- [ 6-methyl-2, 6-diazaspiro [3.3 ]]Heptane-2-yl radical]Pyridin-2-yl) methyl Base of]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamides(Compound 284)

Oxazol-2-yl) pyrazine-2-carboxylic acid (90mg, 0.268mmol, 1 eq) and 1- (6- [ 6-methyl-2, 6-diazaspiro [3.3 ] ]Heptane-2-yl radical]Pyridin-2-yl) methylamine (116.84mg, 0.535mmol, 2 equiv.) to a solution in DMF (10mL) was added T3P (170.30mg, 0.535mmol, 2 equiv.) and DIEA (69.17mg, 0.535mmol, 2 equiv.) dropwise. The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 29% B to 38% B within 8 min; 254; 220 nm; rt: 6.95min) to give 3-amino-N- [ (6- [ 6-methyl-2, 6-diazaspiro [3.3 ] as a yellow solid]Heptane-2-yl radical]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 284) (30mg, 20.89%). LCMS M/z (ESI), [ M + H]+＝537.4。¹H NMR:(300MHz,DMSO-d₆)δ2.14(3H,s),2.40(3H,d),3.09(4H,s),3.84(4H,s),4.43(2H,d),6.21(1H,d),6.58(1H,d),7.26(1H,dd),7.34(1H,d),7.39(1H,s),7.45(1H,m),7.52(1H,dd),7.89(2H,s),8.25(1H,d),8.32(1H,s),9.34(1H,s)。

Example 285.3-amino-N- ([6- [ (3R) -3, 4-dimethylpiperazin-1-yl)]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 285)

Scheme 125

step 1

step 2

step 3

Raney Ni Raney nickel

50℃ 50℃

Step 1.6- [ (3R) -3, 4-dimethylpiperazin-1-yl ]Pyridine-2-carbonitriles

(2R) -1, 2-dimethylpiperazine (607.9mg, 5.32mmol, 1.3 equiv.), 6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 equiv.), K were added to a 40mL sealed tube at room temperature₂CO₃(1131.89mg, 8.190mmol, 2 equiv.) and DMF (10 mL). The resulting mixture was stirred at 50 ℃ for 3 hours. The reaction was quenched by addition of saturated NaCl (aq) (250mL) at room temperature. The resulting mixture was extracted with EtOAc (2X 125 mL). The combined organic layers were washed with saturated NaCl (aq) (250mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 30:1) to give 6- [ (3R) -3, 4-dimethylpiperazin-1-yl as a colorless oil]Pyridine-2-carbonitrile (540mg, 60.97%). LCMS M/z (ESI), [ M + H]⁺＝217.3

Step 2.1- [6- [ (3R) -3, 4-dimethylpiperazin-1-yl ] -E]Pyridin-2-yl]Methylamine

6- [ (iii) in a hydrogen atmosphere at room temperature3R) -3, 4-dimethylpiperazin-1-yl]Pyridine-2-carbonitrile (200mg, 0.925mmol, 1 eq) in MeOH (5mL) and NH₃.H₂Raney nickel (15.84mg, 0.185mmol, 0.20 equiv.) is added dropwise/portion-wise to a stirred mixture in O (0.5 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product/the resulting mixture gave 1- [6- [ (3R) -3, 4-dimethylpiperazin-1-yl ] as a colorless oil ]Pyridin-2-yl]Methylamine (162mg, 79.52%) and was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝221.4。

Step 3.3-amino-N- ([6- [ (3R) -3, 4-dimethylpiperazin-1-yl)]Pyridin-2-yl]Methyl) -6- [ 3-methyl Alkylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamides

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq.) and 1- [6- [ (3R) -3, 4-dimethylpiperazin-1-yl]Pyridin-2-yl]Methylamine (98.27mg, 0.446mmol, 1.5 equiv.) in a stirred solution/mixture of DMF (5mL) was added HATU (226.12mg, 0.595mmol, 2 equiv.) and DIEA (115.29mg, 0.892mmol, 3 equiv.) dropwise/portion. By CH₂Cl₂The resulting mixture was extracted (3X 20 mL). The combined organic layers were washed with water (3X 10mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 15:1) to purify the residue. The crude product (80mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 34% B to 45% B within 8 min; 254; 220 nm; Rt: 7.53min) to give 3-amino-N- ([6- [ (3R) -3, 4-dimethylpiperazin-1-yl) as a yellow solid ]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 285) (20mg, 12.49%). LCMS M/z (ESI), [ M + H]⁺＝539.4。¹H-NMR(DMSO-d₆,40MHz)δ1.7(3H,d),2.7(2H,s),2.9(3H,s),3.2(5H,s),3.6(1H,s),4.7-4.9(2H,m),5.3(1H,d),7.5(2H,dd),8.0(1H,d),8.2(2H,d),8.2-8.4(2H,m),8.7(1H,s),9.1(1H,d),10.1(1H,t)

Example 287-2 (S) -3-amino-N- ((6- (2, 4-dimethylpiperazin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 287-2)

Scheme 126

Step 1.6- [ (3S) -3, 4-dimethylpiperazin-1-yl]Pyridine-2-carbonitriles

(3S) -1, 3-dimethylpiperazine (607.89mg, 5.323mmol, 1.3 equivalents), 6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 equivalent), K were added to a 40mL sealed tube at room temperature₂CO₃(1131.89mg, 8.190mmol, 2 equiv.) and DMF (10 mL). The resulting mixture was stirred at 50 ℃ for 3 hours. The reaction was quenched by addition of saturated NaCl (aq) (250mL) at room temperature. The resulting mixture was extracted with EtOAc (2X 125 mL). The combined organic layers were washed with saturated NaCl (aq) (250mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 30:1) to give 6- [ (2S) -2, 4-dimethylpiperazin-1-yl) as a colorless oil]Pyridine-2-carbonitrile (280mg, 31.61%). LCMS M/z (ESI), [ M + H]⁺＝217.3

Step 2.1- [6- [ (2S) -2, 4-dimethylpiperazin-1-yl ] -2 ]Pyridin-2-yl]Methylamine

To 6- [ (2S) -2, 4-dimethylpiperazin-1-yl under a hydrogen atmosphere at room temperature]Pyridine-2-carbonitrile (280mg, 1.295mmol, 1 eq) in MeOH (5mL) and NH₂NH₂.H₂Raney nickel (22.18mg, 0.259mmol, 0.2 equiv.) is added dropwise/portion-wise to a stirred solution/mixture in O (0.5 mL). The resulting mixture was filtered and concentrated under reduced pressure to give 1- [6- [ (2S) -2, 4-dimethylpiperazin-1-yl ] as a colorless solid]Pyridin-2-yl]Methylamine (200mg, 70.12%). LCMS M/z (ESI), [ M + H]⁺＝221.4。

Step 3.3-amino-N- ([6- [ (2S) -2, 4-dimethylpiperazin-1-yl)]Pyridin-2-yl]Methyl) -6- [ 3-methyl Alkylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 287-2)

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 equivalent) and 1- [6- [ (2S) -2, 4-dimethylpiperazin-1-yl]Pyridin-2-yl]Methylamine (98.27mg, 0.446mmol, 1.50 equivalents) in a stirred solution/mixture of DMF (10mL) was added HATU (226.12mg, 0.595mmol, 2 equivalents) and DIEA (115.29mg, 0.892mmol, 3 equivalents) dropwise/portion wise. By CH₂Cl₂The resulting mixture was extracted (3X 20 mL). The combined organic layers were washed with water (3X 20mL) and anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 15:1) to purify the residue. The crude product (80mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 36% B to 47% B within 8 min; 254; 220 nm; Rt: 7.65min) to give 3-amino-N- ([6- [ (2S) -2, 4-dimethylpiperazin-1-yl) as a yellow solid]Pyridin-2-yl]Methyl radical) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 287-2) (20mg, 12.49%). LCMS M/z (ESI), [ M + H]⁺＝539.4。¹H NMR(400MHz,DMSO-d₆)δ0.9(3H,d),1.7(1H,t),1.8(1H,dd),2.0(3H,s),2.3(1H,d),2.4(4H,s),2.8-2.9(1H,m),3.9(1H,d),4.3(1H,s),4.5(2H,dd),6.6(2H,dd),7.2(1H,dd),7.3(1H,s),7.4(1H,s),7.4-7.5(2H,m),7.9(1H,s),8.3(1H,s),8.4(1H,s),9.3(1H,t)。

The compounds listed in the table below were prepared using the method described for compound 287-2.

EXAMPLE 290 preparation of (2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methyl-imidazole- [1,2-a ] pyridin-6-yl ] pyrazin-2-yl ] methyl ] oxolane-2-carboxamide (Compound 290)

Scheme 127

Step 1, methyl 3-methyl-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazole-2-) Radical) pyrazines

Under nitrogen atmosphere at room temperature with [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (4.15g, 23.6mmol, 2.00 equiv.), Pd (dppf) Cl₂(0.86g, 1.19mmol, 0.1 equiv.) and K ₃PO₄(7.50g, 35.3mmol, 3.0 equiv.) of H₂O (5.0mL) treatment of methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (3.0g, 11.8mmol, 1 eq) to bis

A solution in an alkane (50mL) was heated at 90 ℃ for 2 hours, cooled to room temperature, and concentrated. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (20/1) to give 3-methyl-6- [ 3-methylimidazo [1,2-a ] as a pale yellow solid]Pyridin-6-yl]-methyl 5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (1.8g, 44%). LCMS M/z (ESI), [ M + H]+＝351.3。

Step 2.3-methyl-6- [ 3-methyl-imidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) Pyrazine-2-carbaldehyde

A solution of methyl 3-amino-6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (1.0g, 2.85mmol, 1 equivalent) in THF (20mL) was treated with LiAlH4(162.5mg, 4.28mmol, 1.5 equivalents) at-70 ℃, stirred for 2 hours, quenched with EA (2.5mL), purified by preparative TLC to provide 3-methyl-6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carbaldehyde as a light yellow solid (280mg, 31%). LCMS M/z (esi), [ M + H ] + ═ 321.1.

Step 3.N- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]-5- (2H-1,2, 3-triazole-2-) Radical) pyrazin-2-yl) methyl]-2-methylpropane-2-sulfinamide

At room temperature with Ti (Oi-Pr)₄(2.5mL) treatment of 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]A mixture of-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carbaldehyde (260mg, 0.81mmol, 1 equiv.) and 2-methylpropane-2-sulfinamide (195mg, 1.62mmol, 2.0 equiv.) in THF (2.5mL) was heated at 70 deg.C for 2 hours, cooled to room temperature, and NaBH was added₄(123mg, 3.25mmol, 4.0 equiv.), stirred for 2 hours, quenched with 2.0ml of water, and filtered. The solid was washed with DCM/MeOH ═ 5/1(20mL), the organic layers combined, concentrated and purified by preparative TLC (DCM/MeOH ═ 50/1) to give N- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a light yellow solid]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazin-2-yl) methyl]-2-methylPropane-2-sulfinamide (230mg, 67%). LCMS M/z (ESI), [ M + H]⁺＝426.3。

For 1, 4-bis at room temperature

Treatment of N- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] with HCl (gas) in an alkane (2.0mL, 4.0mol/L) ]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazin-2-yl) methyl]A solution of (2-methylpropane-2-sulfinamide (160mg, 0.36mmol, 1 equiv.) in DCM (2.0mL) was stirred for 2 hours and concentrated to give 3- (aminomethyl) -5- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-6- (2H-1,2, 3-triazol-2-yl) pyrazin-2-amine (160mg, crude material). LCMS M/z (ESI), [ M + H]⁺＝322.3。

Step 5.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]Oxetane-2-carboxamide (Compound 290)

A solution of (2R) -1-methylpyrrolidine-2-carboxylic acid (112.5mg, 0.87mmol, 2.0 equiv.) in DMF (3.0mL) was treated with HATU (331mg, 0.87mmol, 2.00 equiv.) at room temperature for 20min, followed by dropwise addition of 3- (aminomethyl) -5- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]-6- (2H-1,2, 3-triazol-2-yl) pyrazin-2-amine (140mg, 0.44mmol, 1 eq), DIEA (167mg, 1.31mmol, 3.0 eq), stirred for 2H, and the residue was purified by preparative TLC (DCM/MeOH ═ 30/1) to give (2R) -N- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a white solid]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazin-2-yl) methyl]-1-methylpyrrolidine-2-carboxamide (65mg, 35%). LCMS (liquid Crystal display Module) [ M + H ] ]＝433.3。¹H NMR(400MHz,DMSO-d₆)δ1.74(3H,m),2.11(1H,m),2.32(7H,d),2.82(1H,dd),3.07(1H,dd),4.46(2H,t),6.87(1H,dd),7.15(2H,s),7.35(1H,s),7.42(1H,d),7.55(1H,d),8.09(2H,s),8.49(1H,t)。

EXAMPLE 291 preparation of (2R) -N- [ [ 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] pyrazin-2-yl ] methyl ] -1-methylpyrrolidine-2-carboxamide (Compound 291)

Scheme 128

Step 1.3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxylic acid methyl ester

To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (4g, 18.016mmol, 1 eq.) and (3, 5-difluorophenyl) boronic acid (2.90g, 18.376mmol, 1.02 eq.) in 1, 4-bis (phenyl) at room temperature under a nitrogen atmosphere

Alkane (100mL) and H₂To a stirred mixture in O (5mL) was added K in portions₃PO₄(7.65g, 36.031mmol, 2 equiv.) and Pd (dppf) Cl₂(2.64g, 3.603mmol, 0.2 equiv.). The resulting mixture was stirred at 70 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH₂Cl₂The filter cake was washed (1X 30 mL). The filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH₂Cl₂EtOAc (4:1) elution afforded methyl 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxylate (4g, 74.09%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝300.2。¹H-NMR:(300MHz,DMSO-d₆)δ3.89(3H,s),7.47(3H,dd),7.66(2H,s)。

Step 2.3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxamide

At room temperature to 30% NH₃To a stirred solution in MeOH (100mL) was added methyl 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxylate (4g, 13.348mmol, 1 eq) portionwise. The resulting mixture was stirred at 50 ℃ for 4 hours. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxamide as a yellow solid (3.5g, 92.11%). LCMS M/z (ESI), [ M + H ]⁺＝285.2。¹H-NMR:(300MHz,DMSO-d₆)δ7.43(3H,m),7.75(3H,s),8.04(1H,s).

Step 3.3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carbonitrile

To a stirred solution of phosphoryl chloride (40mL) was added 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxamide (2g, 7.026mmol, 1 eq) portionwise at room temperature. The resulting mixture was stirred at 90 ℃ for 12 hours. The resulting mixture was concentrated under reduced pressure and diluted with DCM (20 mL). Saturated NaHCO at room temperature₃The reaction was quenched (aqueous solution). By CH₂Cl₂The resulting mixture was extracted (2X 30 mL). Through anhydrous Na₂SO₄The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carbonitrile as a yellow solid (700mg, 37.36%).¹H-NMR:(300MHz,DMSO-d₆)δ7.43(3H,m),7.73(2H,s)。

Step 4.3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine- 2-carbonitriles

To 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carbonitrile (600mg, 2.250mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (791.99mg, 4.500mmol, 2.00 equiv.) in 1, 4-bis

To a stirred mixture of alkane (30mL) and H2O (4mL) was added Cs2CO3(1466.34mg, 4.500mmol, 2 equiv.) and Pd (dppf) Cl2(329.30mg, 0.450mmol, 0.2 equiv.) in portions. The resulting mixture was stirred at 90 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH ₂Cl₂The filter cake was washed (1X 10 mL). The filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 30:1) to give 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carbonitrile (300mg, 36.79%). LCMS M/z (ESI), [ M + H]⁺＝363.3。¹H-NMR:(300MHz,DMSO-d₆)δ2.37(3H,m),6.94(1H,dd),7.13(2H,m),7.37(3H,m),7.67(2H,s),8.18(1H,m)。

Step 5.3- (aminomethyl) -6- (3, 5-difluorophenyl) -5- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-amines

To the reaction mixture at room temperature under a nitrogen atmosphere, 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carbonitrile (100mg, 0.276mmol, 1 eq.) and NH₃.H₂To a stirred solution of O (1mL) in MeOH (15mL) was added Raney nickel (47.29mg, 0.552mmol, 2 equiv) in portions. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (1X 10 mL). The filtrate was concentrated under reduced pressure to give 3- (aminomethyl) -6- (3, 5-difluorophenyl) -5- [ 3-methylimidazo [1,2-a as a yellow solid]Pyridin-6-yl]Pyrazin-2-amine (90mg, 89.01%). LCMS M/z (ESI), [ M + H]⁺＝367.3。

Step 6.(2R) -N- [ [ 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridine-6- Base of]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 291)

To a stirred mixture of (2R) -1-methylpyrrolidine-2-carboxylic acid (56.41mg, 0.437mmol, 2.00 equiv.) in DMF (10mL) was added HATU (166.05mg, 0.437mmol, 2 equiv.) and DIEA (56.44mg, 0.437mmol, 2 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 10 min. To this stirred solution was then added 3- (aminomethyl) -6- (3, 5-difluorophenyl) -5- [ 3-methylimidazo [1,2-a ] portionwise at room temperature]Pyridin-6-yl]Pyrazin-2-amine (80mg, 0.218mmol, 1 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 35% B to 48% B over 7 min; 254/220 nm; Rt: 6.77min) to give (2R) -N- [ [ 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridine compound-6-yl]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (compound 291) (7mg, 6.71%). LCMS M/z (ESI), [ M + H]⁺＝478.4。¹H NMR:(300MHz,DMSO-d₆)δ1.72(3H,s),2.11(1H,dd),2.34(7H,m),2.81(1H,dd),3.04(1H,m),4.40(2H,m),6.77(2H,s),7.00(1H,dd),7.09(2H,m),7.25(1H,tt),7.40(2H,m),8.09(1H,t),8.45(1H,t)。

Example 296-1.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (2S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl ]Preparation of pyrazine-2-carboxamide (Compound 296-1)

Scheme 129

Step 1. methanesulfonic acid (S) -2- ((tert-butoxycarbonyl) amino) propyl ester

To N- [ (2S) -1-hydroxypropan-2-yl group at 0 ℃ under a nitrogen atmosphere]To a stirred solution of tert-butyl carbamate (5.0g, 28.534mmol, 1 eq) and TEA (3753.60mg, 37.095mmol, 1.3 eq) in DCM was added MsCl (4.90g, 42.801mmol, 1.5 eq) dropwise. By CH₂Cl₂The resulting mixture was extracted (2X 20 mL). The combined organic layers were washed with water (2X 20mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives methanesulfonic acid (S) -2- (S) as a white solidTertiary amineButoxycarbonyl) amino) propyl ester (6.5g, 89.9%). LCMS M/z (ESI), [ M + H]⁺No MS signal.

Step 2.(S) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamic acid tert-butyl ester

To N- [ (2S) -1- (methanesulfonyloxy) propan-2-yl]To a stirred solution of tert-butyl carbamate (3g, 11.843mmol, 1 eq) and 1H-1,2, 3-triazole (1.23g, 17.765mmol, 1.50 eq) in DMF (50mL) was added K in portions₂CO₃(3.27g，23.686mmol，200 equivalents). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere. The resulting mixture was diluted with EA (10mL) and washed with water (2X 10 mL). The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC to give tert-butyl (S) - (1- (2H-1,2, 3-triazol-2-yl) propan-2-yl) carbamate (1.2g, 44.7%) and tert-butyl (S) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamate (0.62g, 23.1%) as white solids.

(S) - (1- (2H-1,2, 3-triazol-2-yl) propan-2-yl) carbamic acid tert-butyl ester¹H-NMR (300MHz, chloroform-d) delta 1.09(3H, d),1.43(9H, s),4.21(1H, s),4.51(2H, d),7.63(2H, s).

(S) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamic acid tert-butyl ester¹H-NMR(300MHz,DMSO-d₆)δ1.02(4H,d),1.33(9H,s),3.91(1H,p),4.34(2H,qd),6.92(1H,d),7.70(1H,s),8.01(1H,d)。

Step 3.(S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine dihydrochloride

To tert-butyl (S) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamate (280mg, 1 eq) in 1, 4-bis at 25 deg.C

To a stirred solution in an alkane (5mL) was added dropwise a 1, 4-bis solution of 4M HCl

Alkane (5mL) solution. The mixture was stirred at room temperature for 1 hour. Concentration to dryness gave (S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine dihydrochloride (266mg, 90.5%) as a white solid. The crude product was used directly in the next step without further purification. .¹H-NMR(300MHz,DMSO-d₆)δ1.13(3H,d),3.68(1H,dt),4.63(2H,qd),7.78(1H,s),8.24(1H,s),8.44(2H,s)。

Step 4.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) -N- [(2S)-1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamides

To (2S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine (45mg, 0.357mmol, 1.50 equivalents), 3-amino-6- [ 3-methylimidazo [1,2-a ] at 0 deg.C]Pyridin-6-yl]-5-(1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.) and DIEA (184.46mg, 1.427mmol, 6.00 equiv.) in DMF was added T dropwise ₃P (454.12mg, 0.714mmol, 3.00 eq, 50%). The reaction mixture was purified by preparative HPLC with the following conditions (column: Shiseido CAPCELLCORE C18, 2.1 × 50mm, 2.7 μm; mobile phase A: water/0.05% TFA; mobile phase B: ACN/0.05% TFA; flow rate: 1.0 mL/min; gradient: 5% B to 95% B over 2.0min, hold for 0.7 min; 254nm) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (2S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamide (compound 296-1) (75mg, 70.9%). LCMS M/z (ESI), [ M + H]⁺＝445.3。¹H-NMR(300MHz,DMSO-d6)δ1.19(3H,d),2.45(3H,d),4.49-4.71(3H,m),7.19(1H,dd),7.37(2H,dd),7.48(1H,dd),7.69(1H,d),7.80(2H,s),8.10(1H,d),8.25(1H,d),8.28-8.35(1H,m),8.75(1H,d)。

Example 296-2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Preparation of pyrazine-2-carboxamide (Compound 296-2)

Scenario 130

Step 1 methanesulfonic acid (R) -2- ((tert-butoxy)Alkylcarbonyl) amino) propyl ester

To N- [ (2R) -1-hydroxypropan-2-yl group at 0 DEG C]To a stirred solution of tert-butyl carbamate (3g, 17.121mmol, 1 eq) and MsCl (2.55g, 22.257mmol, 1.3 eq) in DCM (50mL) was added TEA (3.46g, 34.241mmol, 2 eq) portionwise for 2 hours. By H₂O and NaHCO₃The reaction mixture was quenched (10mL), extracted with DCM (3X 20mL), and washed with Na ₂SO₄The organic layer was dried, which yielded (R) -2- ((tert-butoxycarbonyl) amino) propyl methanesulfonate (6.5g, 89.9%) as a white solid. LCMS M/z (ESI), [ M + H-tBu + MeCN]⁺＝239.1。

Step 2.N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Carbamic acid tert-butyl ester

Add N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl to a 10mL vial at 0 deg.C]Tert-butyl carbamate (5g, 19.739mmol, 1 equiv.), 1H-1,2, 3-triazole (2.04g, 29.608mmol, 1.50 equiv.), K₂CO₃(5.46g, 39.477mmol, 2.00 equiv.) and DMF (50 mL). The mixture was then stirred at 90 ℃ for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 mL). The organic layer was washed with brine (3X 10mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC with the following conditions: column, C₁₈Silica gel; mobile phase, MeOH/water, 10% to 50% gradient over 10 min; detector, UV 254nm, yielding:

n- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Carbamic acid tert-butyl ester (1g, 22.3%)¹H-NMR(300MHz,DMSO-d₆)δ0.99(3H,d),1.31(9H,s),3.72-4.00(1H,m),4.32(2H,qd),6.90(1H,d),7.68(1H,d),7.99(1H,d)；

N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl as white solid]Tert-butyl carbamate (2.9g, 64.9%).¹H-NMR(300MHz,DMSO-d₆)δ0.94(3H,d),1.31(9H,s),3.94(1H,p),4.24-4.43(2H,m),6.84(1H,d),7.74(2H,s)。

(R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine dihydrochloride

To (R) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamic acid tert-butyl ester (280mg, 1.24mmol, 1 eq) in 1, 4-bis (hydroxymethyl) amine at 25 deg.C

Alkane (5mL) solution. The mixture was stirred at room temperature for 1 hour. Concentration to dryness gave (R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine dihydrochloride (266mg, quantitative) as a white solid. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝127.1。

Step 4.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) -N- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamides

3-amino-6- [ 3-methylimidazo [1,2-a ] was added at 0 ℃ in a 10mL vial]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq), (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine (56.27mg, 0.446mmol, 1.5 eq), T₃P (283.83mg, 0.892mmol, 3 equivalents), DIEA (192.15mg, 1.487mmol, 5 equivalents), and DMF (10 mL). The mixture was then stirred at room temperature under a nitrogen atmosphere for 3 hours. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (10MMOL/L NH) ₄HCO₃) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 10% B to 50% B within 7 min; 254/220 nm; rt: 5.48min) to obtain 3-amino-6- [ 3-methylimidazo [1,2-a ] as a white solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamide (compound 296-2) (20mg, 15.1%). LCMS M/z (ESI), [ M + H]⁺＝445.2。¹H-NMR(300MHz,DMSO-d₆)δ1.19(3H,d),2.45(3H,d),4.49-4.71(3H,m),7.20(1H,dd),7.37(2H,dd),7.48(1H,dd),7.69(1H,d),7.79(2H,s),8.10(1H,d),8.25(1H,d),8.31(1H,d),8.75(1H,d)。

Example 297.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Preparation of pyrazine-2-carboxamides

Scheme 131

Step 1.(2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride

To N- [ (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl at room temperature]Tert-butyl carbamate (260mg, 1.15mmol, 1 eq) in 5mL 1, 4-bis

Adding HCl dropwise to a stirred mixture in an alkane

Solution in alkane (5 mL). After stirring for 1 hour, the mixture was concentrated to give (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride (230mg, 90.0%) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝127.2。

And 2. step 2. 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) -N- [ (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl ]Pyrazine-2-carboxamides.

To (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride (71mg, 0.357mmol, 1.50 equivalents) and 3-amino-6- [ 3-methylimidazo [1,2-a ] at 0 ℃ under an air atmosphere]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.), DIEA (184mg, 1.427mmol, 6.00 equiv.) to a stirred solution in DMF was added T dropwise₃P (454mg, 0.714mmol, 3.00 equiv., 50 wt%). The reaction mixture was purified by preparative HPLC (column: Shiseido CAPCELLCORE C18, 2.1 × 50mm, 2.7 μm; mobile phase A: water/0.05% TFA, mobile phase B: ACN/0.05% TFA; flow rate: 1.0 mL/min; gradient: 5% B to 95% B over 2.0min, hold for 0.7 min; 254nm) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Pyrazine-2-carboxamide (compound 297) (37mg, 35.0%). LCMS M/z (ESI), [ M + H]⁺＝445.3。¹H-NMR(300MHz,DMSO-d₆)δ1.13(3H,d),2.43(3H,d),4.48-4.74(3H,m),7.24(1H,dd),7.37(2H,dd),7.52(1H,dd),7.77(2H,s),7.82(2H,s),8.25(1H,d),8.30(1H,d),8.78(1H,d)。

Example 298.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Preparation of pyrazine-2-carboxamide (Compound 298)

Scheme 132

Step 1.(2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride.

To N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl at room temperature under an air atmosphere]To a stirred solution of tert-butyl carbamate (200mg, 0.88mmol, 1 eq) was added dropwise to 1, 4-bis

4M HCl (gas) in alkane (4mL) for 1 hour. The solvent was evaporated. This gave (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride (180mg, quantitative) as a white solid. LCMS M/z (ESI), [ M + H]⁺＝127.2。

And 2. step 2. 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazole-2-Radical) -N- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamides.

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq), (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine (56.27mg, 0.446mmol, 1.5 eq), T₃P (283.83mg, 0.892mmol, 3 equivalents), DIEA (192.15mg, 1.487mmol, 5 equivalents), and DMF (10 mL). The mixture was then stirred at room temperature under a nitrogen atmosphere for 4 hours. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (10MMOL/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 10% B to 50% B within 7 min; 254/220 nm; rt: 5.48min) to obtain 3-amino-6- [ 3-methylimidazo [1,2-a ] as a white solid ]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) -N- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamide (compound 298) (20mg, 15.1%). LCMS M/z (ESI), [ M + H]⁺＝445.3。¹H-NMR(300MHz,DMSO-d₆)δ1.13(3H,d),2.38-2.44(3H m,),4.61(1H,m),4.62-4.64(2H,m),7.19-7.27(1H,m),7.33-7.42(2H,m),7.52(1H,d),7.77(4H,s),8.18-8.34(2H,m),8.78(1H,d)。

Example 301.3-amino-N- ([3- [2- (methylamino) ethoxy)]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamide (Compound 301)

Protocol 133

And (1).N- [2- [ (2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-3-yl) oxy]Ethyl radical]-N-methylcarbamic acid tert-butyl ester

Place N- (2- [ [2- (aminomethyl) pyridin-3-yl) in a 6-mL vial]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester (209.15mg, 0.743mmol, 2.50 equivalents), 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq), DIEA (0.36mL, 2.805mmol, 9 eq), DMF (2.5mL), T₃P (283.83mg, 0.892mmol, 3.00 equiv.). The resulting solution was stirred at 0 ℃ for 16 hours. With 20mLH₂The resulting solution was diluted with O. The resulting solution was extracted with 3X 15mL of dichloromethane, and the organic layers were combined. The residue was purified by preparative TLC (DCM: MeOH ═ 5: 1). This gave 60mg (33.65%) of yellow colour Solid N- [2- [ (2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-3-yl) oxy]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester. LCMS M/z (ESI), [ M + H]⁺＝600.3。

Step 2.3-amino-N- ([3- [2- (methylamino) ethoxy ] ethyl]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxamides

In a 25mL round bottom flask was placed N- [2- [ (2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ])]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-3-yl) oxy]Ethyl radical]Tert-butyl N-methylcarbamate (60mg, 0.100mmol, 1 equiv.), DCM (3mL), TF (1mL, 13.463mmol, 134.55 equiv.). The resulting solution was stirred at 20 ℃ for 1 hour. The resulting mixture was concentrated in vacuo. The pH of the solution was adjusted to 8 with saturated sodium bicarbonate (aqueous solution). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (DCM: MeOH ═ 5:1) to give a yellow solid. The crude product was purified by preparative HPLC (column: Xbridge Prep C18 OBD column 19X 150mm 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 20% B to 38% B within 8 min; 254/220 nm; Rt: 7.19 min). This gave 10.53mg (19.59%) of 3-amino-N- ([3- [2- (methylamino) ethoxy ] as a yellow solid ]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide. LCMS M/z (ESI), [ M + H]⁺＝500.4。¹H-NMR(300MHz,DMSO-d₆)δ2.30(3H,s),2.44(3H,s),2.85(2H,d),4.10(2H,d),4.65(2H,d),7.20-7.31(2H,m),7.37(1H,d),7.38-7.46(2H,m),7.47-7.54(1H,m),8.06-8.08(2H,s)8.06(1H,d),8.28(1H,d),8.37(1H,s),9.26(1H,t)

Example 302.3-amino-N- ((6- (4- (dimethylamino) piperidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 302)

Scheme 134

Step 1.2-cyano-6- (4- (dimethylamino) piperidin-1-yl) pyridine

6-chloropyridine-2-carbonitrile (500mg, 3.609mmol, 1 eq.) and N, N-dimethylpiperidin-4-amine (508.99mg, 3.970mmol, 1.10 eq.), K were added at room temperature to a 20mL vial₂CO₃(1496.27mg, 10.826mmol, 3.00 equiv.) in DMF (10 mL). The resulting mixture was stirred at 60 ℃ for 15 hours under an air atmosphere. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with 2X 100mL of water and 2X 100mL of saturated brine. Through anhydrous Na₂SO₄The organic layer was dried and the solid was filtered off and the solvent was evaporated to give a yellow oil. The crude product was purified by TLC (EA: PE ═ 1:2) to give 6- [4- (dimethylamino) piperidin-1-yl group as a yellow oil]Pyridine-2-carbonitrile (438mg, 52.7%). LCMS M/z (ESI), [ M + H]⁺＝231.3。¹H-NMR(400MHz,MeOD-d₄)δ1.45(2H,qd),1.99(2H,dt),2.33(6H,s),2.49(1H,tt),2.89(2H,td),4.46(2H,dp),7.02(1H,d),7.08(1H,d),7.61(1H,dd)

Step 2.1- (6- (aminomethyl) pyridin-2-yl) -N, N-dimethylpiperidin-4-amine

6- [4- (dimethylamino) piperidin-1-yl ] -n-butyl in a 50mL round bottom flask at room temperature]Pyridine-2-carbonitrile (438mg, 1.902mmol, 1 eq) and Raney nickel (162.93mg, 1).902mmol, 1.00 eq), NH₃.H₂O (66.65mg, 1.902mmol, 1.00 equiv.). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The solid is filtered off and the solvent is evaporated, giving 1- [6- (aminomethyl) pyridin-2-yl ] as a yellow oil]-N, N-dimethylpiperidin-4-amine (406mg, 91.1%). LCMS M/z (ESI), [ M + H]⁺＝235.1。¹H-NMR(400MHz,MeOD-d₄)δ1.39-1.55(2H,m),1.97(2H,d),2.32(6H,s),2.43(1H,tt),2.80(2H,t),3.74(2H,s),4.46(2H,d),6.50-6.72(2H,m),7.48(1H,t)

Step 3.3-amino-N- ((6- (4- (dimethylamino) piperidin-1-yl) pyridin-2-yl) methyl) -6- (3-methyl) Imidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamide (Compound 302)

1- [6- (aminomethyl) pyridin-2-yl ] at 0 ℃ in an air atmosphere]-N, N-dimethylpiperidin-4-amine (55.75mg, 0.238mmol, 1.00 eq.) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.), DIEA (92.23mg, 0.714mmol, 3.00 equiv.) in DMF was added T dropwise₃P (151.37mg, 0.476mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 12 hours. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with 1X 50mL of water and 3X 50mL of brine. Through anhydrous Na ₂SO₄The organic layer was dried, filtered and evaporated to give a crude solid. By preparative TLC (CH)₂Cl₂The residue was purified with MeOH 12:1) to give a yellow solid. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30X 150mm 5 μm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 37% B to 50% B within 7 min; 254; 220 nm; rt: 5.52min) to purify the crude product (50mg) to obtain3-amino-N- ([6- [4- (dimethylamino) piperidin-1-yl) as yellow solid]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 302) (20mg, 15.21%). LCMS M/z (ESI), [ M + H]⁺＝553.4。¹H-NMR(400MHz,MeOD-d₄)δ1.21(2H,tt),1.52(2H,d),2.09-2.15(7H,m),2.49(3H,s),2.56(2H,dd),4.33(2H,d),4.57(2H,s),6.65(2H,dd),7.30(2H,d),7.42(1H,s),7.47-7.54(2H,m),8.00(1H,s),8.40(1H,s)

Example 303.3-amino-N- ((6- (3- (methylamino) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 303)

Scheme 135

Step 1 preparation of tert-butyl (1- (6-cyanopyridin-2-yl) azetidin-3-yl) (methyl) carbamate

6-bromopyridine-2-carbonitrile (500mg, 2.732mmol, 1 equiv.), N- (azetidin-3-yl) -N-methylcarbamic acid tert-butyl ester (559.76mg, 3.005mmol, 1.1 equiv.) and K were reacted at 60 deg.C ₂CO₃A mixture of (1132.78mg, 8.196mmol, 3.0 equiv.) in DMF (20mL) was stirred for 3 h. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (20mL) and over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (9:1) to give N- [1- (6-cyanopyridin-2-yl) azetidin-3-yl as a pale yellow solid]-N-methylcarbamic acid tert-butyl ester (600mg, 76.16%). LCMS M/z (ESI), [ M + H]⁺＝289.2。¹H-NMR(300mHz,DMSO-d₆)δ1.38(9H,s)2.86-2.88(3H,m),4.02-4.05(2H,m),4.16-4.19(2H,m),4.85(1H,s),6.70-6.73(1H,m),7.19-7.23(1H,m),7.67-7.69(1H,m)

Step 2 tert-butyl (1- (6- (aminomethyl) pyridin-2-yl) azetidin-3-yl) (methyl) carbamate

At room temperature in H₂The reaction is carried out by reacting N- [1- (6-cyanopyridin-2-yl) azetidin-3-yl]A mixture of tert-butyl-N-methylcarbamate (500mg, 1.734mmol, 1 equiv.), ammonium hydroxide (20.00mL), and Raney's nickel (99.54mg) in MeOH (20mL) was stirred for 1 hour. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. This gave N- [1- [6- (aminomethyl) pyridin-2-yl ] as a pale yellow oil]Azetidin-3-yl]-N-methyl-carbamic acid tert-butyl ester (502mg, 99.02%). LCMS M/z (ESI), [ M + H]⁺＝293.1。¹H-NMR(300mHz,DMSO-d₆)δ1.38(9H,s),2.85-2.87(3H,m),3.76(2H,s),3.92(2H,s),4.11(2H,s),6.28(1H,s),6.69(1H,s),7.51(1H,s)，

Step 3 (1- (6- ((3-amino-6- (3-methylimidazo [1, 2-a)) ]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrile Oxazine-2-carboxamido) methyl) pyridin-2-yl) azetidin-3-yl) (methyl) carbamic acid tert-butyl ester

Reacting 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq.), N- [1- [6- (aminomethyl) pyridin-2-yl]Azetidin-3-yl]-tert-butyl N-methylcarbamate (173.88mg, 0.595mmol, 2.0 equiv.), DIEA (192.15mg, 1.487mmol, 5.0 equiv.), and T₃A solution of P (189.22mg, 0.595mmol, 2.0 eq) in DMF (10mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic fraction was washed with brine (20mL)Organic layer, anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (10:1) to give N- [1- (6- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) ] as a pale yellow oil]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-2-yl) azetidin-3-yl]-N-methyl-carbamic acid tert-butyl ester (80mg, 44.06%). LCMS M/z (ESI), [ M + H]⁺＝611.3

Step 4.3-amino-N- ((6- (3- (methylamino) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3- Methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (

Azol-2-yl) pyrazine-2-carboxamides

N- [1- (6- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) ] is reacted at room temperature]Pyridin-6-yl]-5-(1,3-

Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-2-yl) azetidin-3-yl]A solution of tert-butyl-N-methylcarbamate (80mg, 0.131mmol, 1 eq) and TFA (2mL) in DCM (5mL) was stirred for 2 h. With saturated NaHCO₃The residue was neutralized to pH 7 (aqueous solution). The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with water (2X 30mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 32% B to 52% B within 8 min; 254/220 nm; rt: 7.88min) to give 3-amino-N- ([6- [3- (methylamino) azetidin-1-yl) as a yellow solid]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridine-6-Base of]-5-(1,3-

Oxazol-2-yl) pyrazine-2-carboxamide (compound 303) (30mg, 44.85%). LCMS M/z (ESI), [ M + H]⁺＝511.3 ¹H-NMR(300mHz,DMSO-d₆)δ2.20(3H,s),2.49(3H,s),3.57-3.59(1H,m),3.60-3.63(2H,m),4.03-4.07(2H,m),4.53(2H,s),6.26-6.28(1H,m),6.64-6.66(1H,m),7.28-7.30(2H,m),7.31-7.33(1H,m),7.45-7.49(2H,m),8.01(1H,s),8.37(1H,s)。

Example 304/305.preparation of 3-amino-6- (3-methylimidazo [1,2-a ] pyridin-6-yl) -5- (pyridin-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 304/305)

Scheme 136

Step 1.3-amino-6-chloro-5- (pyridin-2-yl) pyrazine-2-carboxylic acid ester

2- (tributylstannyl) pyridine (1658.12mg, 5.05mmol, 2.00 equiv.), methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (500mg, 2.525mmol, 1 equiv.), Pd (PPh)₃)₂Cl₂(158.06mg, 0.226mmol, 0.1 equiv.) and LiCl (190.94mg, 5.05mmol, 2 equiv.) in 1, 4-bis

The solution in alkane (20mL) was stirred at 90 ℃ under a nitrogen atmosphere for 16 hours. This reaction was purified with another batch of E02189-006. Subjecting the mixture to flash silica gel column chromatography using CH₂Cl₂MeOH (1:1) elution afforded the crude product. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 30:1) to give methyl 3-amino-6-chloro-5- (pyridin-2-yl) pyrazine-2-carboxylate (180mg, 30.20%) as a yellow solid. LCMS M/z (ESI), [ M + H]⁺＝265.2。¹H NMR(300MHz,DMSO-d₆)δ3.9(3H,s),7.5(1H,ddd),7.6-7.7(2H,m),7.8(1H,dt),8.0(1H,td),8.7(1H,ddd)

Step 2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (pyridin-2-yl) pyrazin-2-ylmethane Acid esters

3-amino-6-chloro-5- (pyridin-2-yl) pyrazine-2-carboxylic acid methyl ester (120mg, 0.453mmol, 1 eq), [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (159.58mg, 0.907mmol, 2 equiv.), Pd (dppf) Cl₂CH₂Cl₂(37.03mg, 0.045mmol, 0.1 equiv.) and Cs₂CO₃(295.45mg, 0.907mmol, 2 equiv.) in 1, 4-bis

Alkane (12.5mL) and H₂Solution in O (1.5mL) in N₂Stirred for 4 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 25:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-methyl 5- (pyridin-2-yl) pyrazine-2-carboxylate (50mg, 30.60%). LCMS M/z (ESI), [ M + H]⁺＝361.3

Step 3.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (pyridin-2-yl) pyrazin-2-ylmethane Acid(s)

To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]-methyl 5- (pyridin-2-yl) pyrazine-2-carboxylate (1 eq) in 1, 4-bis

Alkane (10mL) and H₂To a stirred solution in O (1mL) was added LiOH (3 equiv) in portions. The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 3 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The crude product (50mg) was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]⁺＝347.3

Step 4.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ (Oxetan-3-yl) methyl Base of]-5- (pyridin-2-yl) pyrazine-2-carboxamides

To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a stirred solution of-5- (pyridin-2-yl) pyrazine-2-carboxylic acid (50mg, 0.144mmol, 1 equiv.), DMF (5mL) and 1- (oxacyclopent-3-yl) methylamine (73.01mg, 0.722mmol, 5 equiv.) in DMF (5mL) was added DIPEA (93.29mg, 0.722mmol, 5 equiv.) in portions. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (20mL) at room temperature. By CH ₂Cl₂The resulting mixture was extracted (2X 25 mL). The combined organic layers were washed with water (2X 20mL) and anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)₂Cl₂MeOH 15:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ (Oxetan-3-yl) methyl]-5- (pyridin-2-yl) pyrazine-2-carboxamide (30mg, 48.39%). LCMS M/z (ESI), [ M + H]⁺＝430.3

Step 5, relative-3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (3R) -oxolane Alk-3-yl]Methyl radical]-5- (pyridin-2-yl) pyrazine-2-carboxamides

By preparative chiral HPLC with the following conditions (column: Chiralpak ID-2, 2X 25cm, 5 μm; mobile phase A: MTBE (10mM NH)₃-MEOH) -HPLC, mobile phase B: MeOH — HPLC; flow rate: 20 mL/min; gradient: 15B to 15B within 20 min; 220/254 nm; RT 1: 12.919, respectively; RT 2: 16.74) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ oxolane-3-yl ] radical]Methyl radical]-5- (pyridin-2-yl) pyrazine-2-carboxamide (Compound 304) (8mg, 26.67%) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ oxolane-3-yl ] radical ]Methyl radical]-5- (pyridin-2-yl) pyrazine-2-carboxamide (compound 305).

(Compound 304) LCMS M/z (ESI), [ M + H]⁺＝430.3。¹H NMR(400MHz,DMSO-d₆)δ1.7(1H,dq),1.9-2.1(1H,m),2.3(3H,s),2.6(1H,dt),3.29-3.37(2H,m),3.5(1H,dd),3.6-3.7(2H,m),3.8(1H,td),7.1(1H,dd),7.3(2H,t),7.4(1H,dd),7.8(2H,d),7.9(1H,td),8.1(1H,s),8.4(1H,d),9.0(1H,t)。

(Compound 305) LCMS M/z (ESI), [ M + H]⁺＝430.2。¹H NMR(400MHz,DMSO-d₆)δ1.7(1H,dq),1.9-2.1(1H,m),2.3(3H,s),2.6(1H,dt),3.37(2H,s),3.5-3.8(4H,td),7.1(1H,dd),7.3(2H,t),7.4(1H,dd),7.8(2H,d),7.9(1H,td),8.1(1H,s),8.4(1H,d),9.0(1H,t)。

Example 307: binding affinities to different adenosine receptors

The binding affinity and specificity of the compounds for the different subtypes of human adenosine receptors (hA1, hA2A, hA2B and hA3) were characterized by cell membrane chromatographic binding analysis.

Using hA1 membrane (from PerkinElmer) and [ 2 ]³H]-8-cyclopentyl-1, 3-Dipropylxanthine (DPCPX) incubation of compounds at different concentrations for 50min, while 100 μ Ι _ of 0.5% PEI solution was added to the UNFILTER-96GF/B filter plates for 60min at 4 ℃, followed by washing the UNIFILTER-96GF/B filter plates twice with 50ml washing buffer, transferring the membrane mixture to the UNIFILTER-96GF/B filter plates and washing the filter plates 4 times, followed by incubation for 10min at 55 ℃. Finally, 40 μ L ULTIMAGOLD was added to each well and CPMs were read by TopCount.

At 25 ℃ with a hA2a membrane (from Perkin Elmer) and³H]-CGS21680 incubation of compounds at different concentrations was continued for 90min while 100 μ Ι _ of 0.5% PEI solution was added to the UNFILTER-96GF/B filter plates for 60min at 4 ℃, followed by washing the UNFILTER-96GF/B filter plates twice with 50ml wash buffer, transferring the membrane mixture to the UNFILTER-96GF/B filter plates and washing the filter plates 4 times, followed by incubation for 10min at 55 ℃. Finally, 40 μ L ULTIMAGOLD was added to each well and CPMs were read by TopCount.

At 27 ℃ with a hA2b membrane (from Perkin Elmer) and³H]DPCPX were incubated with compounds at different concentrations for 60min and binding reactions were stopped by rapid filtration through UNIFILTER-96GF/C plates coated with 0.5% BSA using a cell collector. The filter plates were subsequently washed three times with ice-cold wash buffer and dried at 37 ℃ for 120 min. Finally, 50 μ L scintillation cocktail was added to each well and CPMs were read by TopCount.

At 27 ℃ with a hA3 membrane (from Perkin Elmer) and [ [ alpha ] ], a¹²⁵I]AB-MECA incubation of compounds at different concentrations for 60min, binding reactions were stopped by rapid filtration using a cell harvester via UNIFILTER-96GF/C plates coated with 0.5% BSA. The filter plates were subsequently washed three times with ice-cold wash buffer and dried at 37 ℃ for 120 min. Finally, 50 μ L scintillation cocktail was added to each well and CPMs were read by TopCount.

The binding affinities and specificities of exemplary compounds for human a1, A2a, A2b and A3 receptors are shown in table 3 below. The empty boxes in the table below indicate that no data has been collected.

Table 3: binding affinities of exemplary Compounds

Example 308: FLIPR^TMAnd cAMP inhibition assay

hADORA1/CHO (expression hA1) cells (Kingsry (Genscript)) were plated at 1X 10 on the day before the start of the experiment ⁴Individual cells/well were plated in 384-well polystyrene culture plates. On the day of the experiment, the supernatant was discarded and replaced with 40 μ L of dye per well (FLIPR calcium 5Assay Kit), and 5% CO was added at 37 ℃₂Lower incubation plate for 60 min. Subsequently to FLIPR^TMInhibition assay test compounds were added at different concentrations. Following 400s incubation with compound, 10 μ M adenosine was added to the cells and the signal captured by FLIPR.

On the day of the experiment, hA2a/CHO, hA2b/CHO, hA3/CHO and mA2a/CHO (Kinsley) were mixed at 5X 10³Individual cells/well were plated in 384-well polystyrene culture plates. At 37 ℃ 5% CO₂Next, the compound was preincubated with the cells for 30 min. Subsequently 10. mu.M adenosine was added to the cells and 5% CO at 37 ℃₂And then the cultivation is carried out for 30 min. The detection reagent (CISBIO) was added and the plates were incubated at room temperature for 60 min. The signal is captured by Envision.

Representation in different cell lines overexpressing adenosine receptorsFLIPR of plastic compound^TMAnd cAMP inhibitory activity are shown in table 4 below.

Table 4: FLIPR and cAMP inhibitory Activity of exemplary Compounds

Claims

1. A compound of formula (Ia-ii):

or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

ring a is azaindolizinyl; m is 1, R ₁Is C_1-3An alkyl group; z is a bond; y is cyclobutyl, which may optionally be substituted by R₃Mono-or independently poly-substituted therewith, wherein each R₃Independently selected from C_1-12An alkoxy group.

2. The compound of claim 1, wherein R₁Is methyl.

3. The compound of claim 1, wherein Y is cyclobutyl monosubstituted with methoxy.

4. The compound of claim 1, wherein the compound is selected from the group consisting of:

3-amino-N- ((1r,3r) -3-methoxycyclobutyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxamide;

3-amino-N- ((1s,3s) -3-methoxycyclobutyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxamide;

3-amino-N- (3-methoxycyclobutyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (

Oxazol-2-yl) pyrazine-2-carboxamide.

5. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

6. Use of one or more compounds according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of an adenosine receptor-related disease.

7. The use of claim 6, wherein the adenosine receptor-related disease is cancer, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive disorders, HIV, adenosine deaminase-severe combined immunodeficiency, acute and chronic heart failure, chronic obstructive pulmonary disease, or asthma.

8. The use of claim 7, wherein the cancer is non-small cell lung cancer, renal cell carcinoma, prostate cancer, or breast cancer.

9. The use of claim 6, wherein the medicament is used in combination with radiation therapy, chemotherapy, or immunotherapy.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4 in combination with an immunotherapeutic or chemotherapeutic agent.

11. The combination of claim 10, wherein the immunotherapeutic agent is selected from the group consisting of: an anti-PD-1/PD-L1 antibody, an anti-CTLA-4 antibody, an anti-CD 73 antibody, an anti-CD 39 antibody, an anti-CCR 2 antibody, or any combination thereof.

12. The combination according to claim 10, wherein the chemotherapeutic agent is selected from the group consisting of: platinum-based chemotherapeutic agents, docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, or any combination thereof.

13. The combination of claim 12, wherein the platinum-based chemotherapeutic agent is cisplatin or oxaliplatin.