RU2809631C2 - Pyrazine compounds and their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to new pyrazine compounds of Formula I, where A, B, R₁, R₂, V, W, X, Y, m, n are defined in the claims and act specifically on adenosine receptors, in particular on A2a. The invention also relates to pharmaceutical compositions containing one or more compounds as an active ingredient, and the use of these compounds in the treatment of diseases associated with adenosine receptors (AR), for example cancer, such as non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), prostate cancer and breast cancer.

EFFECT: obtaining pyrazine compounds and their use.

47 cl, 4 tbl, 308 ex

Description

FIELD OF THE INVENTION

The present invention relates to new pyrazine compounds that specifically target adenosine receptors (especially A1 and A2, in particular A2a). The present invention also relates to pharmaceutical compositions containing one or more compounds as an active ingredient, and the use of these compounds in the treatment of diseases associated with adenosine receptors (AR), for example cancer, such as non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) ), prostate cancer and breast cancer.

BACKGROUND ART

Adenosine is a naturally occurring nucleoside that elicits a variety of physiological responses through interactions with the adenosine receptor family. In humans, there are four subtypes of adenosine receptors (A1, A2a, A2b, and A3) based on their biochemical and pharmacological properties, such as ligand binding characteristics, glycosylation, and functions.

The inflammatory response helps clear harmful agents from the body, but inflammation is also a nonspecific response that can harm healthy tissue. There is a wide range of pathogenic factors that can initiate the inflammatory response, including infection, allergens, autoimmune stimuli, immune response to transplanted tissue, noxious chemicals and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal trauma, and tumor growth.

There are reports that adenosine receptors play a non-redundant role in the negative regulation of inflammation in vivo, acting as a physiological “STOP” (termination mechanism) that can limit the immune response and thereby protect normal tissues from excessive damage by the immune system during pathogenesis of various diseases. Adenosine receptors such as A2a, A2b and A3 have been shown to suppress the immune response during inflammation and protect tissue from damage by the immune system. Inhibition of adenosine receptor signaling can be used to enhance and prolong the immune response. Adenosine suppresses long-term inflammation by acting through the adenosine A2a receptor (Ohta et al., Nature, 2001, 414: 916-920). The adenosine A2b receptor is involved in the regulation of cell growth (see Adenosine A2b Receptors as Therapeutic Targets, Drug Dev. Res., 45: 198; Feoktistov et al., Trends Pharmacol. Sci., 19: 148-153).

In view of this, compounds that target adenosine receptors are needed as pharmacological agents and are of significant interest as drugs for the treatment of diseases associated with adenosine receptors, such as cancer (for example, NSCLC, RCC, prostate cancer or breast cancer glands), Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, human immunodeficiency virus (HIV) infection, adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID), acute heart failure (AHF) and chronic heart failure, chronic obstructive pulmonary disease (COPD) or asthma.

BRIEF DESCRIPTION OF THE INVENTION

According to one aspect of the present invention there is provided a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein X, A ring, B ring, W, V, Y, Rb R ₂ type are as defined herein.

According to one aspect of the present invention there is provided a compound represented by formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, Z, Y, R ₁ , R ₂ , type are as defined herein.

According to one aspect of the present invention there is provided a compound represented by formula (Ia-i):

or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring Q, R ₁ , R ₂ , R ₃ , R ₇ , m, n and i are as defined herein.

According to one aspect of the present invention there is provided a compound represented by formula (Ia-ii):

or a pharmaceutically acceptable salt thereof, wherein ring A, Z, Y, R ₁ and m are as defined herein.

According to one aspect of the present invention there is provided a compound represented by formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring Q, R ₁ , R ₂ , R ₃ , R ₇ , m, n and i are as defined herein.

According to another aspect, the present invention also relates to pharmaceutical compositions containing one or more compounds or a pharmaceutically acceptable salt thereof as an active ingredient, and the use of such compounds or a pharmaceutically acceptable salt thereof in the treatment of adenosine receptor (AR) associated diseases, such as cancer , such as NSCLC, RCC, prostate cancer or breast cancer.

DETAILED DESCRIPTION

According to one aspect of the present invention there are provided compounds of formula (I):

or a pharmaceutically acceptable salt thereof,

Where

X is selected from amino, halogen, hydroxyl, cyano, C _1-12 alkoxyl, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, C _1-12 alkanoylamino;

ring A is a 3-12 membered saturated or unsaturated mono- or polycyclic heterocyclyl;

ring B is selected from a 3-12 membered saturated or unsaturated carbocyclyl or a 3-12 membered saturated or unsaturated mono- or polycyclic heterocyclyl;

W represents -C _1-12 alkylene- or -C(O)-, which may be substituted singly or independently multiple times with hydroxyl, C _1-12 alkyl, C _1-12 alkoxy or a C _1-12 alkyl-OH group;

V represents -NH-, -CI-C _1-12 alkylene-, -NH-C(O)- or N-attached pyrrolidinyl, which may be substituted singly or independently multiple times with hydroxyl, C _1-12 alkyl, C _{1- 12} alkoxyl, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino or C _1-12 alkyl-OH groups;

Y represents hydrogen, halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbonyl, carbamate, sulfonyl, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 alkanoyl, C _1-12 alkyl-OH, C _1-12 alkyl-cyano, C _1-12 alogenalkyl, C _1-12 alogenalkoxy, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _{1- 12} alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkylsulfonyl, C _1-12 alkanoylamino, 3-12 membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl , which may optionally be substituted once or independently multiple times by the group R ₃ ;

each R ₁ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl groups -OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, 3-10 membered saturated or unsaturated carbocyclyl, or 3-10 membered saturated or unsaturated heterocyclyl, each R ₁ optionally being further substituted once or independently multiple times by an R ₄ group;

each R ₂ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _1-12 alkyl groups -OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl)2amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, 3-10 membered saturated or unsaturated carbocyclyl, or 3-10 membered saturated or unsaturated heterocyclyl, each R ₂ optionally being further substituted once or independently multiple times by an R ₅ group;

each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxyl, C _1-12 alkyl-OH groups, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-( C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl)phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclyl or 3- 10-membered saturated or unsaturated heterocyclyl, wherein each R ₃ may optionally be additionally substituted once or independently multiple times by an R ₆ group,

wherein each R ₄ , R ₅ or R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, phosphinyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _1-12 alkyl-OH groups, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl , N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, C _1-12 alkanoylamino, C _1-12 alkylsulfonyl and C _1-12 haloalkoxy;

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

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

In some embodiments, X is selected from amino, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, or C _1-12 alkanoylamino.

In some embodiments, X is amino.

In some embodiments, Ring A is a 3-12 membered saturated or unsaturated mono- or polycyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S.

In some embodiments, ring A is a 6-10 membered unsaturated mono- or polycyclic heterocyclyl.

In some embodiments, ring A is selected from

In some embodiments, ring A is selected from

In some embodiments, each R ₁ is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy , ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl, oxetanyl or 1,1-dioxothietanyl, which may optionally be further substituted singly or independently multiple times with an _R4 group, each _R4 being independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy or C _1-12 haloalkoxy.

In some embodiments, each R ₁ is independently selected from amino, chloro, methyl, difluoromethyl, trifluoromethyl, aminomethyl, ethyl, hydroxyethyl, isopropyl, hydroxypropyl, methoxyethyl, 2-hydroxyl-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 mono- or polycyclic heterocyclyl 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 ₂ is independently selected from halogen, hydroxyl, amino, C _1-12 alkyl, or C _1-12 haloalkyl, wherein each R ₂ may optionally be further substituted once or independently multiple times with an R ₅ group selected from halogen, hydroxyl , cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy or C _1-12 haloalkoxy.

In some embodiments, each R ₂ is independently selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, ethoxyl, methoxyl, difluoromethoxy, trifluoromethoxy, methylamino, dimethylamino , ethylamino, isopropanylamino, hydroxymethyl or hydroxyethyl.

In some embodiments, each R ₂ is independently 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 _1-12 alkylene- or N-attached pyrrolidinyl, which may be substituted singly or independently multiple times with hydroxyl, C _1-12 alkyl, C _1-12 alkoxyl or C _1-12 alkyl-OH group.

In some embodiments, Y is hydrogen, hydroxyl, amino, cyano, carbonyl, carbamoyl, _C1-12 alkyl, _C1-12 alkyl-OH, _C1-12 alkoxyl, sulfonyl, ( _C1-12 alkyl)sulfonyl, N -(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, 3 -12-membered saturated or unsaturated carbocyclyl or 3-12-membered saturated or unsaturated heterocyclyl, which may optionally be substituted singly or independently multiple times with R ₃ .

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

which may optionally be substituted once or independently multiple times by the group R ₃ .

In some embodiments, Y is selected from:

which may optionally be substituted once or independently multiple times by the group R ₃ .

In some embodiments, Y is hydrogen, halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, sulfonyl, C _1-12 alkyl, C _1-12 alkoxyl, C _1-12 alkanoyl, C _1-12 alkyl-OH, C _1-12 alkyl-cyano, C _1-12 haloalkyl, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _{1 -12} alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkylsulfonyl, which may optionally be substituted singly or independently multiple times with an R ₃ group.

In some embodiments, each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, groups C _1-12 alkyl-OH, M-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl)phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, H-(C _1-12 alkyl-OH) amino, C _1-12 haloalkoxyl, 3-10 -membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl, each R ₃ optionally being further substituted once or independently multiple times by an R6 group. In some embodiments, each R ₃ is independently selected from

which may optionally be further substituted once or independently multiple times by the group R ₆ .

In some embodiments, each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, groups C _1-12 alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl)2amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _{1 -12} alkyl)carbamoyl, C _1-12 alkanoylamino, C _1-12 alkylsulfonyl, C _1-12 haloalkoxy or C _1-12 alkyl-substituted cycloalkyl.

In some embodiments, each R ₃ is independently selected from: hydroxyl, amino, cyano, carbamoyl, sulfonyl, phosphoryl, phosphinyl, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxyl, ethoxyl, ethylamino, hydroxyethyl, hydroxymethyl, hydroxyethoxyl, sulfonylmethyl, aminomethyl, cyclopropyl, cyclopropylcarbonyl, cyclobutylamino, cyclopropyl, cyclobutanyl, cyclohexyl, pyranyl, furanyl, phenyl, pyridinyl, pyrazinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 1,4-oxanyl, bicyclo [1 .1.1 ]pentanyl, 1,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo [2.2.1]heptanyl and 3,8-diazabicyclo[3.2.1]octanyl, which may optionally be further substituted once or independently multiple times with fluorine, hydroxyl, methoxyl, ethoxyl, amino, methylamino, dimethylamino, sulfonyl, methylsulfonyl, carbamoyl, N -methylcarbamoyl, N,N-dimethylcarbamoyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclopropanecarbonyl.

In some embodiments, each R ₃ is independently selected from: hydroxyl, cyano, fluorine, chlorine, bromine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxyl, difluoromethoxyl, trifluoromethoxyl, amino, methylamino, dimethylamino, hydroxyethoxy, methylaminoethoxyl, dimethylaminoethoxyl, hydroxyethylamino, aminocarbonylmethoxyl, 2-hydroxymethyl, methoxymethyl, methylsulfonyl, methyl sulfonyl methyl a, N-methylcarbamoyl, N,N-dimethylcarbamoyl, dimethylaminomethyl, hydroxymethyl, dimethylphosphoryl, methylaminocarbonyl, methylaminocarbonylmethyl, dimethylaminocarbonyl, dimethylaminocarbonylmethyl, 2-methoxyethyl, hydroxylethoxyl, methylami noethoxyl, cyclopropyl , cyclopropylcarbonyl, 3-(dimethylamino)cyclobutylamino, phenyl, pyridin-2-yl, azetidin-1-yl, pyrrolidin-1-yl, N-morpholinyl, 3-(dimethylamino)azetidin-1-yl, 4-methyl piperazin- 1-yl, 1,6-diazaspiro[3.3]heptan-6-yl, 3-methyl-1,6-diazaspiro[3.3]heptan-6-yl, 3,8-diazabicyclo[3.2.1]octane-8- yl, 8-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 8-methyl-3,8-diazabicyclo[3.2. 1]octan-3-yl, 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 2,6-diazaspiro[ 3.4]octan-2-yl, 6-methyl-2,6-diazaspiro[3.4]octan-2-yl, piperidinyl, piperazin-1-yl, 1-methylpiperidin-4-yl, 3-(dimethylamino)pyrrolidine, 3 -(dimethylaminomethyl)azetidin-1-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,6- diazaspiro[3.3]heptan-2-yl or 3,4-dimethylpiperazin-1-yl.

In some embodiments, Y is hydrogen, hydroxyl, amino, cyano, carbonyl, carbamoyl, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxyl, ethoxyl, 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 once or independently multiple times with an R ₃ group, each R ₃ being independently selected from hydroxyl, methyl, fluorine, cyano, dimethylamino, dimethylcarbamoyl, hydroxyethyl . hydroxymethyl, methoxyl, trifluoromethyl, trifluoromethoxyl, methylsulfonyl, dimethylamino, methoxymethyl, methylcarbamoyl, phenyl, pyridinyl, cyclopropyl.

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

According to another aspect of the present invention there are provided compounds of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein

ring A is a 6-10 membered saturated or unsaturated mono- or polycyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S;

ring B is a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl;

Z represents a -C _1-12 alkylene- or bond;

Y represents hydrogen, amino, carbamoyl, carbonyl, sulfonyl, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 alkyl-OH, C _1-12 alkyl-cyano, C _1-12 haloalkyl, C _{1- 12} haloalkoxy, N-(C _1-12 amino) ₂ amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl ) ₂ carbamoyl, C _1-12 alkylsulfonyl, C _1-12 alkanoylamino, 3-6 membered saturated or unsaturated carbocyclyl or 3-6 membered saturated or unsaturated heterocyclyl, which may optionally be substituted once or independently multiple times by the group R ₃ ;

each R ₁ is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl, oxetanyl or 1,1-dioxothietanyl, which may optionally be further substituted once or independently multiple times with R ₄ ;

each R ₂ is independently halogen, hydroxyl, amino, C _1-12 alkyl or C _1-12 haloalkyl, and each R ₂ may optionally be further substituted once or independently multiple times by an R ₅ group;

each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxyl, C _1-12 alkyl-OH groups, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-( C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl)phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclial or 3- 10-membered saturated or unsaturated heterocyclyl, wherein each R ₃ may optionally be additionally substituted once or independently multiple times by an R ₆ group;

each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy;

each R ₅ is independently selected from halogen, hydroxyl, cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy;

each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, C _1-12 alkylsulfonyl, C _1-12 haloalkoxy or C _1-12 alkyl-substituted cycloalkyl;

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

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

In some embodiments, Z is a bond, Y is cyclobutyl monosubstituted with C _1-12 alkoxy, optionally methoxy.

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

According to another aspect of the present invention there are provided compounds of formula (Ia-i):

or a pharmaceutically acceptable salt thereof, wherein

ring A is a 6-10 membered saturated or unsaturated mono- or polycyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S;

ring B is a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl;

ring Q is a 3-6 membered saturated or unsaturated carbocyclyl or a 3-6 membered saturated or unsaturated heterocyclyl;

each R ₁ is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl. oxetanyl or 1,1-dioxothietanyl, which may optionally be further substituted once or independently multiple times by the group R4;

each R ₂ is independently halogen, hydroxyl, amino, C _1-12 alkyl or C _1-12 haloalkyl, and each R ₂ may optionally be further substituted once or independently multiple times by an R ₅ group;

each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxyl, C _1-12 alkyl-OH groups, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-( C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl)phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl)amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10- member saturated or unsaturated heterocyclyl, wherein each R ₃ may optionally be further substituted once or independently multiple times by an R ₆ group;

each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C 1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy;

each R ₅ is independently selected from halogen, hydroxyl, cyano, C _1-12 alkyl, C 1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy;

each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, C _1-12 alkylsulfonyl, C _1-12 haloalkoxy or C _1-12 alkyl-substituted cycloalkyl;

R ₇ represents hydrogen, C _1-12 alkyl, C _1-12 alkoxy or C _1-12 alkyl-OH;

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

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

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

In some embodiments, R ₇ is hydrogen, methyl or ethyl.

In some embodiments, the Q ring 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.

According to another aspect of the present invention there are provided compounds of formula (Ia-ii):

or a pharmaceutically acceptable salt thereof, wherein

ring A is a 6-10 membered saturated or unsaturated mono- or polycyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S;

Z represents a -C _1-12 alkylene- or bond;

Y is hydrogen, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 alkyl-OH, 3-6 member saturated or unsaturated carbocyclyl or 3-6 member saturated or unsaturated heterocyclyl, which may optionally be substituted once or independently multiple times with the group R ₃ ;

each R ₁ is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl, oxetanyl or 1,1-dioxothietanyl, which may optionally be further substituted once or independently multiple times with R ₄ ;

each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxyl, C _1-12 alkyl-OH groups, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl)2amino, N-(C _3-12 cycloalkyl)amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, ( C _1-12 alkyl)phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-2 alkyl-OH)amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 -membered saturated or unsaturated heterocyclyl, wherein each R ₃ may optionally be additionally substituted once or independently multiple times by an R ₆ group;

each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy;

each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl)2carbamoyl, C _1-12 alkanoylamino, C _1-12 alkylsulfonyl, C _1-12 haloalkoxy or C _1-12 alkyl-substituted cycloalkyl; And

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

In some embodiments, ring A is pyridonyl or azaindolizinyl.

In some embodiments, m is 1 and R ₁ is C _1-12 alkyl, optionally C _1-12 alkyl, optionally methyl.

In some embodiments, Z is a bond, Y is cyclobutyl monosubstituted with methoxyl.

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

In some embodiments, Z is methylene, Y is phenyl, pyrrolidyl or tetrahydrofuryl, each of which may optionally be substituted singly or independently multiple times with R ₃ .

In some embodiments, R ₃ is halogen or C _1-12 alkyl.

In some embodiments, R ₃ is fluorine or methyl.

According to another aspect of the present invention there are provided compounds of formula (Ib):

or a pharmaceutically acceptable salt thereof,

Where

ring A is a 6-10 membered saturated or unsaturated mono- or polycyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S;

ring B is a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl;

ring Q is a 3-6 membered saturated or unsaturated carbocyclyl or a 3-6 membered saturated or unsaturated heterocyclyl;

R ₇ represents hydrogen, C _1-12 alkyl, C _1-12 alkoxy or C _1-12 alkyl-OH;

each R ₁ is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl, oxetanyl or 1,1-dioxothietanyl, which may optionally be further substituted once or independently multiple times with R ₄ ;

each R ₂ is independently halogen, hydroxyl, amino, C _1-12 alkyl or C _1-12 haloalkyl, and each R ₂ may optionally be further substituted once or independently multiple times by an R ₅ group;

each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxyl, C _1-12 alkyl-OH groups, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-( C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl)phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkylOH)amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10- member saturated or unsaturated heterocyclyl, wherein each R ₃ may optionally be further substituted once or independently multiple times by an R ₆ group;

each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy;

each R ₅ is independently selected from halogen, hydroxyl, cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy or C _1-12 haloalkoxy;

each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, C _1-12 alkylsulfonyl, C _1-12 haloalkoxy or C _1-12 alkyl-substituted cycloalkyl;

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

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

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

In some embodiments, ring A is selected from

In some embodiments, each R ₁ is independently selected from fluorine, chlorine, 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, R ₂ is methyl or fluorine.

In some embodiments, n is 0 or 1.

In some embodiments, the Q ring is selected from:

In some embodiments, each R ₃ is independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxyl, ethoxyl, difluoromethoxyl, trifluoromethoxyl, trifluoroethoxyl, hydroxymethyl, hydroxyethyl, hydroxyethyloxyl, methoxyethyloxyl, amino, methylamino, dimethylamino , ethylamino, isopropylamino, hydroxyethylamino, methylaminoethyloxyl, dimethylaminoethyloxyl, dimethylphosphinyl-methyl, carbamoyl, carbamoylmethoxyl, azetidinyl, pyrrolidyl, morpholinyl, pyrazinyl, dimethylamino azetidinyl, 1-methyl-pyrazin-4-yl, 3-methyl-3,8-diaza- bicyclo[3.2.1]octan-8-yl, 3-methyl-3,6-diaza-bicyclo[3.1.1]heptanyl, 8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3- yl, 6-methyl-2,6-diaza-spiro[3.4]octan-2-yl or 5-methyl-2,5-diaza-spiro[3.3]-heptan-2-yl.

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

According to one aspect of the present invention, there is provided a compound of formula (I) selected from exemplary compounds 1-306 listed below in Table 1.

It will be appreciated that certain features of the present invention, which, for clarity, are described in the context of individual embodiments, may also be provided in combination in a single embodiment. Conversely, other features of the present invention, which, for brevity, are described in the context of a single embodiment, may also be provided individually or in any suitable subcombination.

Connecting substituents are described at various places throughout the present specification. If a structure explicitly requires a joining group, then the Markush variables listed for that group are understood to represent joining groups. For example, if the structure requires a connecting group, and the definition of the Markush group lists "alkyl" for that variable, then "alkyl" obviously represents an alkylene connecting group.

As used herein, the term “substituted” when referring to a chemical group means that the chemical group has one or more hydrogen atoms that have been removed and replaced by a substituent. As used herein, the term “substituent” has the usual meaning known in the art and refers to a chemical moiety that is covalently attached to, or optionally condensed with, the parent group. As used herein, the term “optionally substituted” or “optionally...substituted” means that a chemical group may have no substituents at all (ie, be unsubstituted) or may have one or more substituents (ie, be substituted). It should be understood that substitution at a given atom is limited by valence.

As used herein, the term "C _ij " indicates a carbon number range, wherein i and j are integers, and the carbon number range includes the end points (i.e., i and j) and every integer therebetween, and at the same time j is greater than i. As examples, C _1-6 indicates a range of one to six carbon atoms, 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 _1-12 " indicates 1-12 atoms, including 1-10, 1-8, 1-6, 1-5, 1-4, 1-3, or 1-2 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 a hydrocarbon chain having at least one double or triple bond (alkenyl or alkynyl ). In some embodiments, alkyl refers to a saturated hydrocarbon chain. The above-mentioned hydrocarbon chain may be a straight chain or a branched chain. The term "C _ij alkyl" refers to an alkyl having from i to j carbon atoms. Examples of the saturated alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; higher order homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl 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. Examples of "C _1-12 alkyl" are methyl, ethyl, propyl, isopropyl and butyl. Examples of "C _1-3 alkyl" are methyl, ethyl, propyl and isopropyl.

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

As used herein, the terms “halogen” and “halogen” refer to an atom selected from fluorine, chlorine, bromine or 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 _ij alkoxy" means that the alkyl group of the alkoxy group has from i to j carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxyl, ethoxyl, propoxyl (eg, n-propoxy and isopropoxy), t-butoxy, and the like. Examples of "C _1-12 alkoxyl" are methoxyl, ethoxyl and propoxyl.

As used herein, the term "C _ij alkyl-OH" refers to a group of the formula "-C _ij alkyl-OH", wherein the alkyl group of the group has from i to j carbon atoms, and any carbon atom in this alkyl group can be one or more than one hydroxyl group is attached. In some embodiments, "C _ij alkyl-OH" has one hydroxyl group. Examples of the "C _1-12 alkyl-OH" group are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-hydroxyisopropyl.

As used herein, the term “C _ij haloalkyl” refers to a halogen-substituted (mono- or multiple-substituted) C _ij alkyl group. Examples of "C _1-12 haloalkyl" are fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl and bromisopropyl. Examples of "difluoroethyl" are 1,1-difluoroethyl. Examples of "trifluoroethyl" are 2,2,2-trifluoroethyl and 1,2,2-trifluoroethyl.

As used herein, the term “C _ij haloalkoxy” refers to a halogen-substituted (mono- or multiple-substituted) C _ij alkoxy group. Examples of "C _ij haloalkoxy" are fluoromethoxyl, difluoromethoxyl or trifluoromethoxyl. Examples of "trifluoroethoxy" are 2,2,2-trifluoroethoxy and 1,2,2-trifluoroethoxy.

Examples of "N-(C _1-12 alkyl)amino" are methylamino and ethylamino.

Examples of "N-(C _1-12 haloalkyl)amino" are fluoromethylamino, difluoromethylamino, trifluoromethylamino, 2-chloroethylamino and 1-bromoisopropylamino.

Examples of "N,N-(C _1-12 alkyl) ₂ amino" are di-(N-methyl)amino, di-(N-ethyl)amino and N-ethyl-N-methylamino.

As used herein, the term “C _ij alkanoyl” refers to C _ij alkylcarbonyl. Examples of "C _1-12 alkanoyl" are propionyl and acetyl.

Examples of "C _1-12 alkanoylamino" are formamido, acetamido and propionylamino.

An example of "C _1-12 alkanoyloxy" is acetoxy.

Examples of "C _1-12 alkoxycarbonyl" are methoxycarbonyl, ethoxycarbonyl, n- and tert-butoxycarbonyl.

As used herein, the term “carbamoyl” refers to an aminocarbonyl group. Examples of "N-(C _1-12 alkyl)carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of "N,N-(C _1-12 alkyl) ₂ 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 ring(s) (e.g., having 2 or 3 fused, bridged, or spiro rings), including in which all the ring atoms are carbon atoms, and which contains at least three ring-forming carbon atoms. In some embodiments, the carbocyclyl may contain from 3 to 12 ring-forming carbon atoms (i.e., a 3-12 membered carbon atom system), from 3 to 10 ring-forming carbon atoms, from 3 to 9 ring-forming carbon atoms or from 4 to 8 ring-forming carbon atoms. Carbocyclyl groups may be saturated, partially unsaturated or completely 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 that contains at least one double bond in its ring system. In some embodiments, the unsaturated carbocyclyl group may contain one or more aromatic rings. In some embodiments, one or more ring-forming groups -CH ₂ - of a saturated or unsaturated carbocyclyl may be replaced by a -C(O)- group.

In some embodiments, the carbocyclyl group is a monocyclic alkyl group. In some embodiments, the carbocyclyl group is a saturated monocyclic alkyl group. Examples of monocyclic saturated or unsaturated carbocyclyl 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" rings refers to ring systems having two rings connected through one single common atom; the term "fused" rings refers to ring systems of two rings sharing two adjacent atoms; and the term "bridged" rings refers to ring systems of two rings sharing three or more atoms.

A 3-12-, 3-10-, or 5-6-membered saturated or unsaturated carbocyclyl is a saturated, partially unsaturated, or fully unsaturated mono- or polycyclic ring system having 3-12, 3-10, or 5-6 ring members carbon atoms, respectively, wherein one or more of the ring-forming -CH ₂ - groups can optionally be replaced by a -C(O)- group.

Examples of "3-12 membered saturated or unsaturated carbocyclyl" are C _3-4 cycloalkyl, cyclohexyl, cyclohexenyl, cyclopentyl, phenyl, naphthyl and bicyclo[1.1.1]pentan-1-yl. Examples of "C _3-4 cycloalkyl" are cyclopropyl and cyclobutyl. Examples of a "5-6 membered saturated or unsaturated carbocyclyl" are cyclopentyl and phenyl.

As used herein, the term “heterocyclyl” refers to a carbocyclyl group where one or more (e.g., 1, 2, or 3) ring atoms are replaced by heteroatoms, which include, but are not limited to, O, S, N, P, etc. similar. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in its 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 ring-forming -CH ₂ - groups in the heterocyclyl may optionally be replaced by a -C(O)-, -S-, -S(O)- or -S(O) ₂ - group. In some embodiments, if the heterocyclyl contains a sulfur atom in its ring system, then the ring sulfur atom can optionally be oxidized to form S-oxides. In some embodiments, the heterocyclyl is attached to another portion of the compound through its ring-forming carbon atom. In some embodiments, the heterocyclyl is attached to another portion of the compound through its ring-forming nitrogen atom.

In some embodiments, the 3- to 12-membered saturated or unsaturated mono- or polycyclic heterocyclyl has 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 mono- or polycyclic ring (e.g., having 2 or 3 fused, bridged, or spiro rings) system having 3-12, 3-10 or 5-6 ring-forming atoms, respectively, among which at least one ring atom is selected from nitrogen, sulfur or oxygen, which, unless otherwise indicated, can be attached to the other part of the compound through its ring-forming carbon or nitrogen atom, wherein one or more of the ring-forming -CH ₂ - groups in a saturated or unsaturated heterocyclyl may be replaced by a -C(O)-, -S-, - group S(O)- or -S(O) ₂ -, and if the heterocyclyl contains a sulfur atom in its ring system, then said sulfur atom in the ring can possibly be oxidized to form S-oxides.

Typical monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyra zinil , pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, triazinonyl and the like.

Examples of spiro-heterocyclyl include, but are not limited to, spiropyranyl, spirooxazinyl and the like. Examples of a fused heterocyclyl include, but are not limited to, a fused phenyl ring or a fused pyridinyl ring such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purine yl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3] triazolo[4,3-a]pyridinyl groups and the like. Examples of bridged heterocyclyl include, but are not limited to, morphanyl, hexamethylenetetraminyl, 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.

The term “compound” according to the present invention is intended to include all stereoisomers, geometric isomers and tautomers of the structures provided, unless otherwise indicated.

The term “stereoisomer” refers to any of the various stereoisomeric configurations (eg, enantiomers, diastereomers, and racemates) of an asymmetric compound (eg, those that have one or more asymmetrically substituted carbon atoms or “asymmetric centers”). The compounds of the present invention, which contain asymmetric centers, can be isolated in optically active (as enantiomers or diastereomers) or optically inactive (racemic) forms. The term "enantiomer" includes pairs of stereoisomers that are not mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic mixture.” The terms "diastereomers" or "diastereoisomers" include stereoisomers having at least two asymmetric atoms, but which are not mirror images of each other. Some compounds containing one or more asymmetric centers may promote the formation of enantiomers, diastereomers, or other stereoisomeric forms, which can be defined in terms of absolute configuration as (R)- or (S)-isomers at each asymmetric center according to the R-S rule of the system Kana-Ingolda-Preloga. Allowed connections, the absolute configuration of which is not known, can be indicated by using the term "or" in relation to the asymmetric center. Methods for obtaining optically active forms from racemic mixtures are known in the art, such as separation by high performance liquid chromatography (HPLC), or stereoselective synthesis methods.

The terms "geometric isomers" or "cis and trans isomers" refer to compounds with the same formula, but their functional groups are oriented in different directions in three-dimensional space.

The term "tautomers" includes prototropic tautomers, which are compounds that have the same formula and the same overall charge, but are characterized by isomeric protonation states. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and ring forms in which the proton can occupy two or more positions in the heterocyclic system, such as 1H - and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present invention identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

It is also intended that a "compound" of the present invention includes all isotopes of atoms in such compounds. Isotopes of an atom include atoms that have the same atomic number but different mass numbers. For example, unless otherwise stated, the hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine atoms in a “compound” of the present invention are intended to also include their isotopes, such as, but not limited to: ¹ N, ² N, ³ N, ¹¹ C, ¹² C, ¹³ C, ¹⁴ C, ¹⁴ N, ¹⁵ N, ^{16 O, 17 O} , ¹⁸ O, ³¹ R, ³² R, ³² S, ³³ S, ³⁴ S , ³⁶ S, ¹⁷ F, ¹⁹ F, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, ¹²⁷ I and ¹³¹ I. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, the term “deuterium-substituted” or “deuterium-substituted” means replacing another hydrogen isoform (eg, protium) in a chemical group with deuterium. In some embodiments, carbon includes ¹² C and ¹³ C. In some embodiments, the term “compound” of the present invention covers only isotopes of the hydrogen atom in a given compound. In some embodiments, the term "compound" of the present invention covers only isotopes of atoms that are common in nature.

It is further understood that a “compound” of the present invention may exist in solvated as well as non-solvated forms, such as, for example, hydrated forms, solid forms, and the present invention is intended to cover all such solvated and non-solvated forms.

It is also understood that the “compound” of the present invention may exist in pharmaceutically acceptable salt forms.

As used herein, the term “pharmaceutically acceptable” refers to those compounds, substances, compositions and/or dosage forms that are medically suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic reaction or other problem or another complication commensurate with a reasonable benefit/risk ratio. In some embodiments, compounds, substances, compositions and/or dosage forms that are pharmaceutically acceptable are those that have been approved by a regulatory agency (such as the US Food and Drug Administration, FDA drugs of China or the European Medicines Agency), or listed in a generally accepted pharmacopoeia (such as the US Pharmacopoeia, the Chinese Pharmacopoeia or the European Pharmacopoeia) for use in animals and, more specifically, in humans.

As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present invention wherein the parent compound is modified by converting an existing acid moiety (e.g., carboxyl and the like) or a basic moiety (e.g., amine, alkali, and the like) ) into their salt form. In many cases, the compounds of the present invention are capable of forming salts with acids and/or bases due to the presence of amino and/or carboxyl groups or the like. Pharmaceutically acceptable salts are salts with acids and/or bases that retain the biological effectiveness and properties of the parent compound and are not generally undesirable from a biological or other point of view. Suitable pharmaceutically acceptable salts of the compound of the present invention include, for example, an acid addition salt, which may be derived, for example, from an inorganic acid (for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acid and the like) or an organic acid (for example, formic, acetic, propionic, glycolic, oxalic, maleic, malonic, succinic, fumaric, tartaric, trimesic, citric, lactic, phenylacetic, benzoic, mandelic, methanesulfonic, napadisic, ethanesulfonic, toluenesulfonic, trifluoroacetic, salicylic, sulfosalicylic acids and the like). In some embodiments, the pharmaceutically acceptable salt of a compound of the present invention is a salt of formic acid. In some embodiments, the pharmaceutically acceptable salt of a compound of the present invention is a trifluoroacetic acid (TFA) salt.

Suitable pharmaceutically acceptable salts of the compound of the present invention also include, for example, a base addition salt, which may be derived, for example, from inorganic bases (for example, salts and hydroxides of sodium, potassium, ammonium, carbonate, bicarbonate salts of metals from columns I to XII of the Periodic Table , such as calcium, magnesium, iron, silver, zinc, copper and the like) or organic bases (for example, primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, basic ion exchange resins and the like). Some organic amines include, but are not limited to, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. Those skilled in the art will appreciate that it may also be possible to add acids or bases to form acid/base addition salts other than those shown in the Examples section. Listings of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa. (1985); and in Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).In some embodiments, suitable pharmaceutically acceptable salts of the compounds of the present invention are salts with inorganic bases.

The present invention also includes active intermediates, active metabolites and prodrugs of the compounds of the present invention. As used herein, “active intermediate” means an intermediate in a synthesis process that exhibits the same or substantially the same biological activity as the final synthesized compound.

As used herein, "active metabolite" means a degradation product or end product of a compound of the present invention, or a salt or prodrug thereof, resulting from metabolism or biotransformation in an animal or human body that exhibits the same or substantially the same biological activity. same as the specified connection. Such metabolites may be formed by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, and the like of the administered compound or salt or prodrug.

As used herein, the term “prodrugs” refers to any compounds or conjugates that release the active parent drug when administered to an animal or human subject. Prodrugs can be prepared by modifying the functional groups present in the compounds so that the modifying groups can be cleaved from the parent compounds either conventionally or in vivo. Prodrugs include compounds in which a hydroxyl, amino, sulfhydryl or carboxyl group is linked to any group that is cleaved upon administration to a mammal to form a free hydroxyl, amino, sulfhydryl or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of the compounds of the present invention with alcohol and amino functional groups. The preparation and use of prodrugs are discussed in T. Higuchi and V. Stella, “Prodrugs as New Delivery Systems,” volume 14 of the American Chemical Society (A.C.S.) Symposia Series and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, 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 proposed in this invention, including their pharmaceutically acceptable salts, is illustrated in the synthesis schemes in the Examples section. The compounds proposed in this invention can be prepared using any known methods of organic synthesis and can be synthesized in accordance with any of the numerous possible synthetic routes, and, therefore, these schemes are only illustrative and are not intended to limit other possible methods. which can be used to prepare the compounds of this invention. Additionally, the steps in these diagrams are presented for better illustration and may be modified as necessary. Variants of the compounds shown in the Examples section were synthesized for the purpose of research and possible submission to regulatory authorities.

The reactions necessary to prepare the compounds of the present invention can be carried out in suitable solvents, which can be easily selected by one skilled in the art of organic synthesis. Suitable solvents may have little or no reaction with the starting materials, intermediates, or products at the temperatures at which the reactions are carried out, for example, at temperatures that may range from the freezing point of the solvent to the boiling point of the solvent. This reaction can be carried out in a single solvent or in a mixture consisting of more than one solvent. Depending on the particular reaction step, solvents suitable for a particular reaction step can be selected by one skilled in the art.

The introduction and deprotection of various chemical groups can be used in the preparation of the compounds of the present invention. The need for introducing and deprotecting and the selection of appropriate protecting groups can be readily determined by one skilled in the art. Chemical characteristics of protecting groups can be found, for example, in the book by T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

Monitoring of these reactions can be carried out by any suitable method known in the art. For example, product formation can be detected using spectroscopic means such as nuclear magnetic resonance spectroscopy (eg, ^1H or ^13C ), infrared spectroscopy, spectrophotometry (eg, ultraviolet (UV)-visible), mass spectrometry, or using chromatographic techniques such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS) or thin layer chromatography (TLC). Purification of compounds by those skilled in the art can be accomplished by a variety of methods, including high performance liquid chromatography (HPLC) (see Preparative LC-MS Purification: Improved Compound Specific Method Optimization, Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem., 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and chromatography on silica as the normal phase.

The structures of the compounds in the Examples section were characterized by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). Chemical shift (δ) in NMR spectra is given in units of 10 ^-6 ( ^ppm ). ¹ H-NMR spectra were recorded in dimethyl sulfoxide-d ₆ (DMSO-d ₆ ), or CDCl ₃ , or CD ₃ OD, or D ₂ O, or acetone-d ₆ , or CD ₃ CN (from Innochem, or Sigma- Aldrich, or Cambridge Isotope Lab., Inc.) on Bruker AVANCE NMR spectrometers (300 MHz or 400 MHz) using ICON-NMR software (running TopSpin) with tetramethylsilane as internal standard.

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

High performance liquid chromatography (HPLC) measurement is carried out on a Shimadzu LC-20AD system, or a Shimadzu LC-20ADXR system, or a Shimadzu LC-30AD system, using a C18 Shim-pack XR-ODS column (3.0*50mm , 2.2 µm), or a C18 Ascentis Express column (2.1*50 mm, 2.7 µm), or an Agilent Poroshell HRN-C18 column (3.0*50 mm, 2.7 µm).

Thin layer chromatography was carried out using silica gel plates from Sinopharm Chemical Reagent Beijing Co., Ltd. and Xinnuo Chemical. To carry out thin layer chromatography (TLC), plates with silica gel 175-225 microns are used. To separate and purify products using TLC, silica gel plates with a layer thickness of 1.0 mm are used.

For chromatographic purification, use a silica gel column as a carrier (100-200, 200-300 or 300-400 mesh, manufactured by Rushanshi Shangbang Xincailiao Co., Ltd. or Rushan Taiyang Desiccant Co., Ltd., etc.) or column for flash chromatography (C18 reverse phase chromatography column, 20-45 µm, manufactured by Agela Technologies) in the Agela Technologies flash chromatography system. The size of the columns is adjusted according to the number of connections.

Known starting materials of the present invention can be synthesized using or in accordance with methods known in the art or can be purchased from Alfa Aesar, TCI, Sigma-Aldrich, Bepharm, Bide Pharmatech, PharmaBlock, Enamine, Innochem and JW&Y PharmLab and etc.

Unless otherwise stated, all reactions are carried out under argon or nitrogen. The expression "argon or nitrogen atmosphere" means that the reaction flask is connected to a cylinder of approximately 1 liter of argon or nitrogen. Hydrogenation is usually carried out under pressure. Unless otherwise stated, the temperature at which the reactions in the Examples are carried out is ambient temperature, which is 10°C to 30°C.

Reaction progress is monitored by TLC and/or LC-MS. Eluent systems used for the reactions include the dichloromethane-methanol system and the petroleum ether-ethyl acetate system. Volume ratios of solvents are adjusted according to the different polarities of the compounds.

The column chromatography elution system used to purify compounds and the eluent system for TLC include the dichloromethane-methanol system and the petroleum ether-ethyl acetate system. Volume ratios of solvents are adjusted according to the different polarities of the compounds. Small amounts of alkaline or acidic agents (0.1%-1%) such as formic acid or acetic acid or TFA or ammonia may be added for adjustment purposes.

Abbreviations for the chemical reagents used in the synthesis of the compounds proposed according to this invention are given below.

Pharmaceutical composition

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

In general, pharmaceutically acceptable carriers are those conventional in the medical field and can be prepared by a method well known in the pharmaceutical field. In some embodiments, the compounds of the present invention or a pharmaceutically acceptable salt thereof may be admixed with a pharmaceutically acceptable carrier to formulate a pharmaceutical composition.

The form of pharmaceutical compositions depends on a number of criteria, including, but not limited to, the route of administration, the extent of the disease or the dose to be administered. Pharmaceutical compositions can be prepared for oral, nasal, rectal, transdermal, intravenous or intramuscular administration. According to the required route of administration, pharmaceutical compositions can be prepared in the form of tablets, capsules, pills, powder, granules, sachets, wafers, lozenges, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), spray , ointment, paste, cream, lotion, gel, patch, inhalant or suppository.

In some embodiments, the pharmaceutical compositions contain the compounds of the present invention or a pharmaceutically acceptable salt thereof in an amount of from about 1 mg to about 500 mg, in particular from 1 mg to about 50 mg.

In some embodiments, the pharmaceutical compositions contain one or more compounds of the present invention or a pharmaceutically acceptable salt thereof as a first active ingredient and further contain a second active ingredient. The second active ingredient may be any immunomodulator or antineoplastic agent known in the art, including, without limitation, chemotherapeutic agents, immunotherapeutic agents, cell signal transduction inhibitors, cell signal transduction inhibitors, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, antihormonal agents and so on. Examples of such immunomodulators or antineoplastic agents are platinum-based chemotherapeutic agents (eg, cisplatin (cis-dichlorodiamineplatinum(II) (DDP)), carboplatin (CBP), 1,2-diaminocyclohexane(sulfato)platinum (SHP), nedaplatin, oxaliplatin ( OXA), laboplatin), docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, CTLA-4 inhibitors (cytotoxic T-lymphocyte antigen 4), antibodies to CTLA-4, PD-1 inhibitors (programmed cell death protein 1), inhibitors PD-L1 (PD-1 ligand), anti-PD-1/PD-L1 antibodies, CD39 inhibitors (cluster of differentiation 39), anti-CD39 antibodies, CD73 inhibitors, anti-CD73 antibodies, CCR2 (C-C family chemokine receptor 2) inhibitors , anti-CCR2 antibodies, EGFR (epidermal growth factor receptor) inhibitors, CDK (cyclin-dependent kinase) 4/6 inhibitors, MELK (maternal fetal leucine zipper kinase) inhibitors, OX40 agonists, antiandrogen inhibitors, antibodies to IgG4 isotypes, tyrosine kinase inhibitors , DNA methyltransferase inhibitors, Hsp90 inhibitors (heat shock protein 90), FGFR (fibroblast growth factor receptor) inhibitors, mTOR (mammalian target of rapamycin) inhibitors, aromatase inhibitors, VEGF (vascular endothelial growth factor) inhibitors, LHRH antagonists (releasing luteinizing hormone factor), PI3K inhibitors (phosphatidylinositol 3-kinase), AKT inhibitors (a member of the protein kinase B family), Aurora kinase inhibitors, MEK inhibitors, HDAC inhibitors (histone de acetylase), BET inhibitors (from the English. Bromodomain and Extra-Terminal domain), PIK3CA inhibitors (p110α catalytic subunit of PI3-kinase), proteasome inhibitors, other selective estrogen receptor negative regulators (SERD), farnesyltransferase inhibitors, anti-VEGF-A antibodies, anti-ErbB3 (Her3) antibodies, proteasome inhibitors , protein kinase Cβ inhibitors, antibodies to IGF-1R (insulin-like growth factor receptor 1), antibodies to HER2 (human epidermal growth factor receptor type 2), SERMs (selective estrogen receptor modulators), IGF inhibitors (insulin-like growth factor), antibodies to IgG and the like. Representative examples of antineoplastic agents for the treatment of cancers or tumors may include, but are not limited to, cisplatin, carboplatin, SHP, nedaplatin, oxaliplatin, laboplatin, docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, vincristine, vinblastine, gemcitabine, cyclophosphamide, chlorambucil, karmustin, methotrexate, fluorurasil, actinomycin, epirubicin, anthracycline, bleomicin, mitomycin-s, irinothens, topotle, tenceide, interleukin, interferon, tremumumab, ipilimumab, pimbrolyzumab, nivolumab, Abelumab, durvalumab, and durvalumab, and abdominal, atesolismab IPh 52, iPh 53, CPI- 006, plosalizumab, MLN1202, cetuximab, lapatinib, erlotinib, gefitinib, neratinib, trastuzumab, ado-trastuzumab emtansine, pertuzumab, MCLA-128, anastrazole, raloxifene, G1T38, tamoxifen, goserelin, enzalutamide, vorinostat, entino stat, sunitinib, pazopanib, bevacizumab , ranibizumab, pegaptanib, cediranib, dasatinib, GDC-0980, gedatolisib, alpelisib, VKM120, copanlisib, AZD8835, GDC-0941, taselisib, temsirolimus, everolimus, sapanisertib, AZD5363, MK2206, panitumum b, pembrolizumab, sorafenib, palbociclib, abemaciclib, ribociclib , crizotinib, dovitinib, ruxolitinib, azacitidine, CC-486, HSP90 inhibitor ganetespib, Debio 1347, erdafitinib, vitusertib, alisertib, selumetinib, GS-5829, GSK525762, MLN9708, GDC-0810, AFP464, tipifarni b, seribantumab, bortezomib, enzastaurin, AVE 1642, xentuzumab, dalotuzumab, AMG 479 and the like.

Treatment of adenosine receptor-associated diseases, as defined below, may be administered as monotherapy or may include, in addition to the compound of the invention, conventional surgery, or radiation therapy, or chemotherapy, or immunotherapy. Such chemotherapy may include the use of one or more of the following chemotherapeutic agents: cisplatin (DDP), carboplatin (CBP), 1,2-diaminocyclohexane(sulfato)platinum (SHP), nedaplatin, oxaliplatin (OXA), laboplatin, docetaxel, paclitaxel , doxorubicin, etoposide or mitoxantrone. Such immunotherapies may include one or more of the following antineoplastic agents: (1) anti-CTLA-4 antibody; (2) anti-PD-1 antibody; (3) anti-PD-L1 antibody; (4) anti-CD73 antibody; (5) anti-CD39 antibody; or (6) anti-CCR2 antibody.

In particular, the anti-CTLA-4 antibody is tremelimumab (described in US 6682736). According to another aspect of the invention, in particular, the anti-CTLA-4 antibody is ipilimumab (marketed by Bristol Myers Squib as ^YERVOY® ).

In particular, the anti-PD-L1 antibody is the antibody described in US 20130034559 (MedImmune). According to another aspect of the invention, in particular, the anti-PD-L1 antibody is the antibody described in US 2010/0203056 (Genentech/Roche). According to another aspect of the invention, in particular, the anti-PD-L1 antibody is the antibody described in US 20090055944 (Medarex). According to another aspect of the invention, in particular, the anti-PD-L1 antibody is the antibody described in US 20130323249 (Sorrento Therapeutics).

Specifically, the anti-PD-1 antibody is MRK-3475 (Merck). According to another aspect of the invention, in particular, the anti-PD-1 antibody is nivolumab, or the anti-PD-1 antibody is the antibody described in WO 2006/121168 or US 8008449 (Medarex). According to another aspect of the invention, in particular, the anti-PD-1 antibody is the antibody described in WO 2009/101611 (CureTech). According to another aspect of the invention, in particular, the anti-PD-1 antibody is the antibody described in WO2012/145493 (Amplimmune). According to another aspect of the invention, in particular, the anti-PD-1 antibody is the antibody described in US 7488802 (Wyeth/Medlmmune). According to another aspect of the invention, in particular, the anti-PD-1 antibody is the antibody described in US 20130280275 (Board of Regents, Univ. of Texas). According to another aspect of the invention, in particular, the anti-PD-1 antibody is the antibody described in WO 99/42585 (Agonox), WO 95/12673 and WO 95/21915.

Specifically, an anti-CD39 antibody is IPH52 (Innate Pharmaceuticals).

Specifically, the anti-CD73 antibody is CPI-006 (Corvus Pharmaceuticals) or IPH53 (Innate Pharmaceuticals).

In particular, the anti-CCR2 antibody is plosalizumab (Takeda Pharmaceuticals International Co.) or MLN1202 (Millennium Pharmaceuticals).

According to this aspect of the invention there is provided a combination suitable for use in the treatment of an adenosine receptor-associated disease, in particular cancer, comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and any one or more of the chemotherapeutic agents listed above, and/or any one or more than one of the immunotherapeutic agents listed above under numbers (1)-(6).

For example, the compounds of the present invention may be presented in combination with an anti-PD1/PD-L1 antibody. In some specific embodiments, the compounds of the present invention may be presented in combination with an anti-PD1/PD-L1 antibody and, further, in combination with an anti-CTLA-4, CD38, CD73 or CCR2 antibody.

According to this aspect of the present invention 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 immunomodulators or antitumor agents listed above.

Thus, according to another aspect of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided in combination with an immunomodulator or chemotherapeutic agents selected from those listed above.

When the term “combination” is used herein, it should be understood to refer to simultaneous, separate or sequential administration. In some embodiments, “combination” refers to simultaneous administration. According to another aspect of the present invention, “combination” refers to separate administration. According to another aspect of the present invention, “combination” refers to sequential administration. If administration is carried out sequentially or separately, then a delay in the introduction of the second component should not lead to loss of the positive effect of the combination.

According to another aspect of the present invention, there is provided a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antitumor agent selected from the agents listed above, together with a pharmaceutically acceptable diluent or carrier.

According to another aspect of the present invention, there is provided a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antitumor agent selected from the substances listed above, together with a pharmaceutically acceptable diluent or carrier, for use in the preparation of an immunomodulatory or anticancer agent. effect.

According to another aspect of the present invention, there is provided a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antitumor agent selected from the substances listed above, together with a pharmaceutically acceptable diluent or carrier, for use in the treatment of NSCLC, RCC , prostate cancer or breast cancer (etc.).

According to another aspect of the present invention, there is provided a kit containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antitumor agent selected from the substances listed above.

According to another aspect of the present invention, 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 antitumor agent selected from the substances listed above, in a second unit dosage form; And

c) a container for containing said first and second dosage forms.

In addition to their use in therapeutic medicine, the compounds of formula (I) or a pharmaceutically acceptable salt thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the purpose of assessing the activity or expression of adenosine receptors in laboratory animals such as like cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the case of other features mentioned above regarding the pharmaceutical composition, process, method, use and preparation of a drug, alternative and preferred embodiments of the compounds of the present invention described in this application are also applicable.

Method of treatment

The present invention provides a method of treating a disease associated with adenosine receptors (including, for example, A1, A2a and/or A2b, in particular A2a) by administering to a subject a therapeutically effective amount of one or more compounds, pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to the present invention.

As used herein, the term “adenosine receptor-associated disease” or “AR-associated disease” refers to a disease whose onset or progression, or both, is associated with genomic changes, expression, overexpression, degradation or activity of AR (including eg A1, A2a and/or A2b, especially A2a), as appropriate. Examples include, but are not limited to, inflammatory disorders, cancer, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, HIV infection, ADA-SCID, acute heart failure (AHF) and chronic heart failure, chronic obstructive pulmonary disease (COPD), asthma and other diseases. In some embodiments, an AR-associated disease refers to a disease that will be treated by inhibiting the action of the adenosine receptor.

In some embodiments, the AR-associated disease is a cancer, preferably an AR-expressing cancer or an AR-overexpressing cancer. "AR-expressing cancer" is a cancer that involves cancer cells or tumor cells having a protein such as AR, eg A2a, A1 and/or A2b, present on their cell surface. An “AR-overexpressing cancer” is a cancer that is characterized by significantly higher levels of a protein such as AR, such as A2a, A1 and/or A2b, on the cell surface of a cancer or tumor cell compared to a non-cancerous cell of the same tissue type. Such overexpression may be due to gene amplification or increased transcription or translation. Expression or overexpression of adenosine receptors can be determined in a diagnostic or prognostic assay by assessing increased levels of AR proteins present on the cell surface (eg, through immunohistochemistry (IHC) analysis). Alternatively or additionally, levels of AR-encoding nucleic acid in a cell can be measured, for example, by fluorescence in situ hybridization (FISH; see application WO 98/45479 published October 1998), Southern blot techniques, or polymerase chain reaction ( PCR), such as quantitative real-time PCR (RT-PCR) (Methods, 132: 73-80 (1990)). In addition to the above assays, various in vivo assays are available to one skilled in the art. For example, the cells of a patient's body can be exposed to an antibody, which may be labeled with a detectable label, such as a radioactive isotope, and the binding of the antibody to the patient's cells can be assessed, for example, by externally scanning for radioactivity or by analyzing a biopsy sample taken from a previously exposed patient. of this antibody.

In particular, cancers include, but are not limited to, lung cancer (eg, 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, cholangiocarcinoma, osteosarcoma, lymphoma, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, bladder cancer, liver cancer, stomach cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, types of kidney cancer, mesothelioma, neuroblastoma, thyroid cancer, types of head and neck cancer, types of esophageal cancer, types of eye cancer, nasopharyngeal cancer or oral cancer. In some embodiments, the cancer is NSCLC, RCC, prostate cancer, or breast cancer. The stage of development of cancer mentioned in this description can be of any stage, unless otherwise noted. In some embodiments, the cancer is a cancer in the early stages of development. In some embodiments, the cancer is a locally advanced cancer. In some embodiments, the cancer is 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 existing therapies.

In some embodiments, the compounds or pharmaceutically acceptable salts thereof of the present invention have the ability to treat cancer (eg, NSCLC, RCC, prostate cancer, breast cancer). In addition, the compounds of the present invention or pharmaceutically acceptable salts thereof may also be useful in the treatment of other adenosine receptor-associated diseases, for example, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, HIV infection, ADA-SCID, AHF and chronic heart failure, chronic obstructive pulmonary disease (COPD) or asthma.

As used herein, the terms “treating” and “treating” refer to reversing, alleviating, delaying the onset of, or suppressing the progression of a disease or disorder, or one or more of its symptoms, as set forth herein. In some embodiments, treatment may be administered after the development of one or more symptoms. In other embodiments, treatment may be provided in the absence of symptoms. For example, treatment may be provided to a susceptible individual prior to the onset of symptoms (eg, taking into account symptom history and/or taking into account genetic factors or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to detect or delay their recurrence.

The therapeutically effective amount of a compound or pharmaceutically acceptable salts thereof provided herein will depend on various factors known in the art, such as body weight, age, medical history, currently used drugs, the health status of the subject, and the potential for cross-reaction. reactivity, allergic reactions, sensitivity and adverse side effects, as well as the route of administration and the extent of the disease. Based on these and other circumstances or needs, dosages may be proportionally reduced or increased by one skilled in the art (eg, a physician or veterinarian).

Application of connections

Some embodiments of the present invention provide the use of the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical composition of the present invention in the manufacture of medicaments for the treatment of AR-associated diseases. Typical AR-associated diseases include, but are not limited to, cancers (eg, NSCLC, RCC, prostate or breast cancer) and other diseases.

In such a situation, the present invention also provides a method for screening a patient suitable for treatment with the compounds or pharmaceutical composition of the present invention alone or in combination with other ingredients (eg, a second active ingredient, eg, an antitumor agent). The method includes sequencing material from tumor samples from patients and detecting accumulation or activation of AR.

Thus, according to another aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as previously defined, for use as a drug.

According to another aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as previously defined, in the manufacture of a medicament for modulating adenosine receptors in a warm-blooded animal such as a human.

The term "modulate", "modulate" or "modulation" when used in relation to adenosine receptors refers to the action or result of altering the expression, degradation and/or activity of adenosine receptors.

According to another aspect of the present invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as previously defined, in the manufacture of a medicament for the treatment of AR-associated diseases in a warm-blooded animal such as a human.

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

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

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

According to another feature of this aspect of the present invention, there is provided a method of treating AR-associated diseases in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as previously defined.

According to another feature of this aspect of the present invention, there is provided a method of obtaining an anticancer effect in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as previously defined.

According to another aspect of this aspect of the present invention, there is provided a method of obtaining an anticancer effect in a warm-blooded animal, such as a human, in need of such treatment, comprising (1) determining whether the warm-blooded animal does or does not have an AR-expressing cancer and (2), if so, then administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as previously defined.

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

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

According to another aspect of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, as previously defined, is provided for use in the treatment of AR-associated diseases in a warm-blooded animal such as a human.

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

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

EXAMPLES

The following sections of the description serve to further explain the general methods of the present invention. The compounds of the present invention can be prepared by methods known in the art. The following description illustrates in detail the methods for preparing the preferred compounds of the present invention. However, it does not in any way limit the methods for preparing the compounds of the present invention.

Example 01. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-((3-fluoropyridin-2-yl)methyl)pyrazin-2-carboxamide ( connections 01)

Step 1. Methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxylate

To a solution of methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-carboxylate (200 mg; 0.71 mmol; 1 eq.) and (2,6-dimethylpyridin-4-yl)boronic acid (214.4 mg; 1.42 mmol; 2 eq.) in n-BuOH (25 ml) was added xPhos (67.7 mg; 0.14 mmol; 0.2 eq.) and Pd(OAc) ₂ (31 .9 mg; 0.14 mmol; 0.2 eq.), K ₃ PO ₄ (301.4 mg; 1.42 mmol; 2 eq.). After this, stirring was performed for 2 hours at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 10:1), obtaining methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxylate ( 230 mg; 36.8%) as a yellow solid. LCMS: m/z (ESI (electrospray ionization)), M ⁺ =339.2.

Step 2. 3-Amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-[(3-fluoropyridin-2-yl)methyl]pyrazin-2-carboxamide (compound 01)

Solution/mixture of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-pyrazine-2-carboxylic acid (215 mg; 0.64 mmol; 1 eq.) and 1 -(3-fluoropyridin-2-yl)methanamine (96.2 mg; 0.76 mmol; 1.20 eq.), HATU (483.2 mg; 1.3 mmol; 2.0 eq.), DIEA ( 246.4 mg; 1.9 mmol; 3.0 eq.) in DMF (10 ml) was stirred for 2 hours at 20°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (215 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)+0, 1% NH ₃ .H ₂ O), mobile phase B: ACN (acetonitrile); flow rate: 20 ml/min; gradient: from 53% B to 62% B in 7 min; 220/254 nm; Rt (retention time ): 6.1 min), yielding 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-[(3-fluoropyridin-2-yl)methyl]- pyrazine-2-carboxamide (compound 01) (83.3 mg; 29.3%) as a light yellow solid. LCMS: m/z (ESI), M ⁺ =447.2. ^1H NMR (400 MHz, methanol- _d4 ): δ 2.4 (s, 6H), 4.8 (d, J=1.7 Hz, 2H), 7.1-7.2 (m, 4H), 7.4 (dt, J= 8.6; 4.4 Hz, 1H), 7.4-7.5 (m, 2H), 7.6 (ddd, J=9.9; 8.4; 1.3 Hz, 1H), 8.4 (dt, J=4 .8; 1.4 Hz, 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)pyrazin-2-carboxamide (compound 02)

Step 1. Methyl 6-chloro-3-methyl-5-(5-methylfuran-3-yl)pyrazin-2-carboxylate

A mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (1 g; 4.5 mmol; 1 eq.) and (5-methylfuran-2-yl)boronic acid (0.6 g; 4.8 mmol ) and Pd(dppf)Cl ₂ (0.3 g; 0.5 mmol) and Na ₂ CO ₃ (1.0 g; 9.0 mmol) in a mixture of dioxane/H ₂ O (40 ml) were stirred for 4 hours at 90°C in a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with a mixture of DCM:MeOH (1:1) (3 × 10 ml). The filtrate was extracted with CH ₂ Cl ₂ (3 x 10 ml). The organic layer was then dried using Na ₂ SO ₄ and the solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (CH ₂ Cl ₂ :EtOAc (1:1)) to give methyl 6-chloro-3-methyl-5-(5-methylfuran-3-yl)-pyrazin-2-carboxylate (125 mg; 7.1%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =268.2.

Step 2. Methyl 3-methyl-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(5-methylfuran-3-yl)pyrazin-2-carboxylate

A mixture of methyl 6-chloro-3-methyl-5-(5-methylfuran-3-yl)pyrazin-2-carboxylate (65 mg; 0.24 mmol; 1 eq.) and 1-methyl-5-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (56.4 mg; 0.24 mmol; 1.00 eq.) and Pd(dppf )Cl ₂ (17.5 mg; 0.024 mmol; 0.10 eq.) and Na ₂ CO ₃ (50.88 mg; 0.48 mmol; 2 eq.) in a mixture of dioxane/H20 (6/1, 3 ml ) was stirred for 10 hours at 90°C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with a mixture of CH ₂ Cl ₂ :MeOH (1:1) (3 × 10 ml). The filtrate was washed with 20 ml H ₂ O and extracted with CH ₂ Cl ₂ (3 x 20 ml). The aqueous layer was dried using Na ₂ SO ₄ and concentrated under reduced pressure. The residue was then dissolved in ethyl acetate (10 ml). The precipitated solids were collected by filtration and washed with diethyl ether (3 x 3 ml) and the resulting solid was dried under vacuum to give methyl 3-methyl-6-(1-methyl-2-oxo-1,2-dihydropyridine-4- yl)-5-(5-methylfuran-3-yl)pyrazin-2-carboxylate (55 mg; 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)pyrazin-2-carboxylic acid

Methyl 3-methyl-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(5-methylfuran-3-yl)pyrazin-2-carboxylate (90 mg; 0.3 mmol; 1 equiv.) was dissolved in MeOH (9 ml) and 1 ml was taken for the reaction. To this solution were added LiOH (25.2 mg; 1.1 mmol; 4.0 eq.) and H ₂ O (1.8 ml) at 0° C. and stirred for 6 hours at room temperature. The mixture was adjusted to pH 6 using HCl (aq). The solution was concentrated under reduced pressure to give 3-methyl-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(5-methylfuran-3-yl)pyrazin-2-carboxylic acid (85 mg; 96.6%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =327.1.

Step 4. 3-amino-N-[(2,6-difluorophenyl)methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2 -yl)pyrazin-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)pyrazin-2-carboxylic acid (80 mg; 0.3 mmol; 1 eq.) and DIEA (116.1 mg; 0.9 mmol; 3.00 eq.) in DMSO (4 ml) HATU (342 mg; 0.9 mmol; 3.0 eq.) was added in portions .) at room temperature. The resulting mixture was stirred for 10 minutes at room temperature. 1-(2,6-difluorophenyl)methanamine (107.3 mg; 0.75 mmol; 2.5 eq.) was then added dropwise and stirred for 10 hours at room temperature. The reaction was quenched by adding brine (30 ml) at room temperature. The resulting solid was collected by filtration and purified by preparative TLC (CH ₂ Cl ₂ /EtOAc, 1:1), obtaining 30 mg of crude product, which was purified by preparative HPLC (column: XBridge OBD C18 preparative column, 5 μm, 19 * 150 mm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l) + 0.1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 37% B to 37% B in 8 min; 220/254 nm; Rt: 7.33 min), giving 3-amino-N-[(2,6-difluorophenyl)methyl]-6-(1-methyl-6-oxo-1 ,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)pyrazin-2-carboxamide (compound 02) (7.4 mg; 6.49%) as a yellow solid. LCMS m/z (ESI) [M+H] ⁺ =452.3. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 2.25 (s, 3H), 3.64 (s, 3H), 4.70 (s, 2H), 6.18 (d, J=3.4 Hz, 1H), 6.55 ( d, J=9.2 Hz, 1H), 6.81 (d, J=3.3 Hz, 1H), 6.98 (t, J=7.9 Hz, 2H), 7.39-7.28 (m, 1H), 7.52 (dd, J=9.2; 2.5 Hz, 1H), 7.92 (d, J=2.5 Hz, 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)

Step 1. 3-Amino-5-chloro-6-(5-methylfuran-2-yl)pyrazin-2-carbonitrile

A mixture of 3-amino-5,6-dichloropyrazin-2-carbonitrile (250 mg; 1.3 mmol; 1 eq.) and (5-methylfuran-2-yl)boronic acid (166.6 mg; 1.3 mmol; 1.00 eq.) and Pd(dppf)Cl ₂ (96.8 mg; 0.1 mmol; 0.1 eq.) and Na ₂ CO ₃ (280.4 mg; 2.7 mmol; 2 eq.) in a mixture of dioxane/H ₂ O (15 ml) was stirred for 6 hours at 70°C in a nitrogen atmosphere.

The resulting mixture was filtered, the filter cake was washed with a mixture of CH ₂ Cl ₂ :MeOH (1:1) (3×10 ml). The filtrate was washed with 20 ml H ₂ O and extracted with CH ₂ Cl ₂ (3 x 20 ml). The organic layer was dried using Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:(CH ₂ Cl ₂ /EtOAc (1:1)) (1:1) to give 3-amino-5-chloro-6-(5-methylfuran-2-yl )pyrazine-2-carbonitrile (130 mg; 28.9%) as a yellow solid. 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)pyrazin-2-carbonitrile (240 mg; 1.0 mmol; 1 eq.) in THF (12 ml) was stirred and the mixture was slowly dissolved add DMSO (155.4 mg; 2.1 mmol; 2.0 eq.) at 0°C and stir for 6 hours at room temperature. The reaction was quenched by adding H ₂ O (2 ml) at 0°C, then adding Na ₂ CO ₃ solution and stirring for 30 minutes at room temperature to give 3-(aminomethyl)-6-chloro-5-(5-methylfuran -2-yl)pyrazin-2-amine (240 mg; 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. tert-Butyl N-[[3-amino-5-chloro-6-(5-methylfuran-3-yl)pyrazin-2-yl]methyl]carbamate

To 3-(aminomethyl)-6-chloro-5-(5-methylfuran-2-yl)pyrazin-2-amine (238 mg; 1.0 mmol; 1.0 eq.) in DCM (10 ml) was added ( BOC) ₂ O (438.9 mg; 2.0 mmol; 2.0 eq.) at room temperature. The resulting mixture was stirred for 10 hours at room temperature. The resulting mixture was quenched with water (20 ml) and extracted with CH ₂ Cl ₂ (3 x 20 ml). The combined organic layers were washed with H ₂ O (3 x 10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl N-[[3-amino-5-chloro-6-(5-methylfuran-3-yl)pyrazin-2-yl]methyl]carbamate (150 mg; 41. 83%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =339.2.

Step 4. tert-Butyl N-[[3-amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(5-methylfuran-3-yl)pyrazin-2 -yl]methyl]carbamate

tert-Butyl N-[[3-amino-5-chloro-6-(5-methylfuran-3-yl)pyrazin-2-yl]methyl]-carbamate (120 mg; 0.34 mmol; 1 eq.) was added into a mixture of dioxane/H ₂ O (10 ml), then 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 was added under N ₂ atmosphere, 2-dihydropyridin-2-one (124.9 mg; 0.5 mmol; 1.50 eq.), Pd(dppf)Cl ₂ (25.9 mg; 0.1 mmol) and Na ₂ CO ₃ (75, 1 mg; 0.7 mmol; 2 eq.) and stirred for 10 hours at 90° in a nitrogen atmosphere. The reaction solution was concentrated and purified by preparative TLC (CH ₂ Cl ₂ /EtOAc, 1:1), yielding tert-butyl N-[[3-amino-5-(1-methyl-6-oxo-1,6-dihydropyridine-3 -yl)-6-(5-methylfuran-3-yl)pyrazin-2-yl]methyl]carbamate (35 mg; 23.53%) as a yellow solid. 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-one

tert-Butyl N-[[3-amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(5-methylfuran-3-yl)pyrazin-2-yl] Methyl]carbamate (120 mg; 1 eq.) was added to DCM (5 ml) and TFA (2.5 ml). The resulting solution was stirred for 10 hours at room temperature in an air atmosphere. The mixture was adjusted to pH 7 with a saturated solution of Na ₂ CO ₃ (aq). The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 30 ml). The combined organic layers were washed with H ₂ O (2×10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The result was 5-[6-amino-5-(aminomethyl)-3-(5-methylfuran-3-yl)-pyrazin-2-yl]-1-methyl-1,2-dihydropyridin-2-one (80 mg; 84.58%) as a yellow solid. 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 a stirred solution of 5-[6-amino-5-(aminomethyl)-3-(5-methylfuran-3-yl)pyrazin-2-yl]-1-methyl-1,2-dihydropyridin-2-one (80 mg ; 0.26 mmol; 1 eq.) and 2,6-difluorobenzoic acid (60.9 mg; 0.39 mmol; 1.5 eq.) in DMSO (1 ml) HATU (197 mg; 0.52 mmol; 2.0 eq.) and DIEA (67 mg; 0.52 mmol; 2.0 eq.) at room temperature in an air atmosphere. The resulting solution was stirred for 10 hours at room temperature. The resulting mixture was quenched with brine (20 ml), the aqueous solution was extracted with CH ₂ Cl ₂ (3 × 10 ml). The organic layers were dried over anhydrous Na ₂ SO ₄ , 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]methyl]-2,6-difluorobenzamide (compound 04) (112 mg; 93.7%) as a light yellow solid. LCMS m/z (ESI) [M+H] ⁺ =452.2. ^1H NMR (400 MHz, methanol- _d4 ) δ 2.22-2.33 (m, 3H), 3.36 (s, 14H), 3.63 (s, 3H), 4.66 (s, 2H), 6.12-6.20 (m, 1H ), 6.67 (d, J=3.3 Hz, 1H), 7.09 (t, J=8.2 Hz, 2H), 7.41-7.58 (m, 2H), 7.85 (d, J=2.6 Hz, 1H).

Example 05. Preparation of 3-amino-N-(2,6-difluorobenzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 05)

Step 1. Methyl 3-amino-6-chloro-5-(oxazol-2-yl)pyrazin-2-carboxylate

To a stirred solution of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (500 mg; 2.25 mol; 1 eq.) and 2-(tributylstannyl)-1,3-oxazole (806.5 mg; 2. 25 mol; 1.00 eq.) in 1,4-dioxane (20 ml) LiCl (190.9 mg; 4.50 mmol; 2 eq.), tricyclohexylphosphane (126.3 mg; 0.45 mmol; 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (466.2 mg; 0.45 mmol; 0.20 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 140°C in a nitrogen atmosphere under microwave irradiation. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (160 mg; 27 .9%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =255.1.

Step 2. 3-Amino-6-chloro-5-(oxazol-2-yl)pyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (100 mg; 0.4 mmol; 1 eq.) in MeOH (10 ml) and LiOH.H ₂ O (49.4 mg; 1.2 mmol; 2.0 eq.) was added to water (1 ml) in portions at room temperature. The resulting mixture was stirred for 4 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeOH in water, gradient from 10% to 50% in 35 min; detector: UV, 254 nm, yielding 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (50 mg; 52.9%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =241.1; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.50 (d, J=0.8 Hz, 1H), 8.34 (d, J=0.8 Hz, 1H).

Step 3. 3-Amino-6-chloro-N-(2,6-difluorobenzyl)-5-(oxazol-2-yl)pyrazin-2-carboxamide

To a stirred mixture of 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (150 mg; 0.62 mmol; 1 eq.) and DIEA (241.7 mg ; 1.87 mmol; 3 eq.) in DMSO (10 ml) 1-(2,6difluorophenyl)methanamine (133.9 mg; 0.94 mmol; 1.50 eq.) and HATU (355.6 mg) were added in portions ; 0.94 mmol; 1.5 eq.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), giving 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(1,3-oxazol-2- yl)pyrazine-2-carboxamide (compound 05) (140 mg; 48.51%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =366.1; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.10 (t, J=5.7 Hz, 1H), 8.42 (s, 1H), 7.88 (s, 2H), 7.58 (s, 1H), 7.49- 7.28 (m, 1H), 7.10 (t, J=8.0 Hz, 2H), 4.57 (d, J=5.8 Hz, 2H).

Step 4. 3-Amino-N-(2,6-difluorobenzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 05)

To a stirred mixture of (2,6-dimethylpyridin-4-yl)boronic acid (82.6 mg; 550 mmol; 2.00 eq.) and 3-amino-6-chloro-N-[(2,6-difluorophenyl) methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (100 mg; 270 mmol; 1 eq.) in dioxane (10 ml) Pd(dppf)Cl ₂ .CH ₂ Cl was added in portions ₂ (44.7 mg; 0.05 mmol; 0.2 eq.) and K ₃ PO ₄ (232.2 mg; 1.09 mmol; 4 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 3-amino-N-[(2,6-difluorophenyl)methyl]-6-(2,6-dimethylpyridin-4-yl)-5 -(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 05) (40 mg; 33.2%) as a yellow solid. FCMS: m/z (ESI), [M+H] ⁺ =437.3; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.12 (t, J=5.8 Hz, 1H), 8.26 (s, 1H), 7.95 (s, 2H), 7.46-7.31 (m, 2H), 7.09 (t, J=8.0 Hz, 2H), 7.00 (s, 2H), 4.62 (d, J=5.9 Hz, 2H), 2.40 (s, 6H).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 05.

Example 06. Preparation of 3-amino-N-(2,6-difluorobenzyl)-6-(2,6-dimethylmorpholino)-5-(4-fluorophenyl)pyrazine-2-carboxamide (compound 06)

Step 1. 3-Amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(4-fluorophenyl)pyrazine-2-carboxamide

Solution/mixture of 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylic acid

(1.2 g; 4.48 mmol; 1 eq.) and 1-(2,6-difluorophenyl)methanamine (1.0 g; 6.99 mmol; 1.56 eq.) in DMF (25 ml) were stirred for 2 hours at 15°C in an air atmosphere. The resulting mixture was washed with water (3 × 10 volumes). The precipitated solids were collected by filtration and washed with ethyl ether (3 x 10 ml) to give 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(4-fluorophenyl)pyrazine-2 -carboxamide (1.3 g; 73.82%) as a brown-yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =393.2.

Step 2. tert-Butyl N-[(tert-butoxy)carbonyl]-N-(5-chloro-3-[[(2,6-difluorophenyl)methyl]carbamoyl]-6-(4-fluorophenyl)pyrazine-2 -yl)carbamate

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

Step 3. Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-[[(2,6-difluorophenyl)methyl]carbamoyl]-5-(2,6-dimethylmorpholin-4-yl) -6-(4-fluorophenyl)pyrazin-2-yl)-carbamate

Tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-chloro-3-[[(2,6-difluorophenyl)methyl]carbamoyl]-6-(4- fluorophenyl)pyrazin-2-yl)carbamate (230 mg; 0.39 mmol; 1 eq.), 2,6-dimethylmorpholine (134.0 mg; 1.16 mmol; 3 eq.), Cs ₂ CO ₃ (252 .7 mg; 0.78 mmol; 2 eq.), RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl) (36.2 mg; 0.08 mmol; 0.2 eq.), palladacyclic based on RuPhos 3rd generation (Gen.3) (32.4 mg; 0.04 mmol; 0.1 eq.) and toluene (15 ml) at 100°C for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc, 1:2), yielding tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-[[(2,6-difluorophenyl)methyl]carbamoyl]-5- (2,6-dimethylmorpholin-4-yl)-6-(4-fluorophenyl)pyrazin-2-yl)carbamate (30 mg; 11.51%) as a yellow solid. LCMS: m/z (ESI), [M-Boc+H] ⁺ =572.3.

Step 4. 3-Amino-N-(2,6-difluorobenzyl)-6-(2,6-dimethylmorpholino)-5-(4-fluorophenyl)pyrazine-2-carboxamide (compound 06)

Tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-[[(2,6-difluorophenyl)methyl]carbamoyl]-5-(2,6-dimethylmorpholine-4) was added to a 50 ml round bottom flask -yl)-6-(4-methylphenyl)pyrazin-2-yl)carbamate (50 mg; 0.07 mmol; 1 eq.) and TFA (2 ml) in DCM (10 ml) at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 19*250 mm, 5 μm; mobile phase A: water (with NH ₄ HCOO ₃ (10 mmol/l)+0, 1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 78% B to 78% B in 7 min; 220/254 nm; Rt: 6.68 min) , yielding 3-amino-N-[(2,6-difluorophenyl)methyl]-6-(2,6-dimethylmorpholin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxamide (compound 06) ( 2 mg; 5.6%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =472.3. ¹ H (300 MHz, DMSO-d ₆ ) δ 1.08 (6H, s), 2.35 (2H, t), 3.03 (2H, d), 3.60 (2H, d), 4.60 (2H, d), 7.03-7.15 (4H, t), 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 (500 mg; 2.0 mmol; 1 eq.) in MeOH (100 ml) was added NH ₄ OH (2 ml) in portions. and Raney's Ni (10 mg; 0.1 mmol; 0.1 eq.). The mixture was stirred for 10 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The result was 3-(aminomethyl)-5-chloro-6-(4-fluorophenyl)pyrazin-2-amine (560 mg; 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]-2-fluoro-6-(trifluoromethyl)benzamide

To a mixture of 3-(aminomethyl)-5-chloro-6-(4-fluorophenyl)pyrazin-2-amine (210 mg; 0.8 mmol; 1 eq.) and 2-fluoro-6-(trifluoromethyl)benzoic acid ( 259.4 mg; 1.3 mmol; 1.5 eq.) in DCM (5 ml) HATU (632.0 mg; 1.7 mmol; 2 eq.) and Et ₃ N (252.3 mg; 2 eq.) were added in portions. 2.5 mmol; 3 eq.). The mixture was stirred for 4 hours at room temperature under air and quenched with water (10 ml). The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 20 ml). The combined organic layers were washed with H ₂ O (3 x 10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was then purified by preparative TLC (PE/EtOAc, 2:1), yielding N-[[3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]-2-fluoro-6- (trifluoromethyl)benzamide (457 mg; 49.7%) as a yellow solid. 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)pyrazin-2-yl]methyl]-2 -fluoro-6-(trifluoromethyl)benzamide (compound 07)

To a mixture of N-[[3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide (90 mg; 200 mmol; 1 eq. ) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (167.3 mg; 0.7 mmol; 3.5 eq.) in a dioxane/H ₂ O mixture (10 ml), Pd(dppf)Cl ₂ (44.6 mg; 0.06 mmol; 0.30 eq.) and K ₃ PO ₄ ( 258.9 mg; 1.2 mmol; 6.0 eq.) in a nitrogen atmosphere. The mixture was stirred for 10 hours at 110°C under a nitrogen atmosphere and concentrated in vacuo. The resulting residue was purified by preparative TLC (PE/EtOAc, 5:4), obtaining the products contained in this residue, then this crude product was purified by preparative HPLC (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with NH ₄ HCOO ₃ (10 mmol/l) + 0.1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 34% B to 54% B in 7 min; 220/254 nm; Rt: 7.08 min), yielding N-[[3-amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridine -3-yl)pyrazin-2-yl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide (compound 07) (29 mg; 27.1%) as a white solid. LCMS m/z (ESI) [M+H] ⁺ =516.1. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 3.53 (s, 2H), 4.71 (s, 1H), 6.37 (d, J=9.4 Hz, 1H), 7.13 (t, J=8.8 Hz, 2H), 7.31 (dd, J=9.4; 2.6 Hz, 1H), 7.53 (dt, J=8.8; 6.0 Hz, 2H), 7.63 (d, J=7.6 Hz, 1H), 7.66-7.71 (m, 1H), 7.76 (d, J=2.5 Hz, 1H).

Example 08. Preparation of N-[[3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-yl]methyl]pyridin-2-carboxamide (compound 08)

Step 1. 3-(Aminomethyl)-5-chloro-6-(4-fluorophenyl)pyrazin-2-amine

3-Amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile (500 mg; 2.0 mmol; 1 eq.) was added to MeOH (100 ml) and NH ₄ OH (2 ml) was added. Raney Ni (10 mg; 0.1 mmol; 0.1 eq.) was then slowly added to the above mixture and stirred for 10 hours at room temperature under a hydrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The result was 3-(aminomethyl)-5-chloro-6-(4-fluorophenyl)pyrazin-2-amine (560 mg; 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]pyridin-2-carboxamide

Mixture of 3-(aminomethyl)-5-chloro-6-(4-fluorophenyl)pyrazin-2-amine (45 mg; 0.2 mmol; 1 eq.), pyridine-2-carboxylic acid (32.9 mg; 0 .3 mmol; 1.5 eq.), HATU (135.4 mg; 0.4 mmol; 2.0 eq.) and TEA (60.9 mg; 0.5 mmol; 3.0 eq.) in DCM (3 ml) was stirred for 4 hours at room temperature in an air atmosphere.

The resulting mixture was quenched with water (10 ml) and extracted with CH ₂ Cl ₂ (3 x 20 ml). The combined organic layers were washed with H ₂ O (3 x 10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was then purified by preparative TLC (PE/EtOAc, 1:2), yielding N-[[3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]pyridin-2-carboxamide (53 mg; 79.02%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =358.2.

Step 3. Preparation of N-[[3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-pyrazin-2-yl]methyl]pyridin-2-carboxamide (compound 08 )

To a mixture of N-[[3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]pyridin-2-carboxamide (25 mg; 0.1 mmol; 1 eq.) and (2 Pd( _dppf )Cl ₂ (5 .1 mg; 0.01 mmol; 0.1 eq.) and K ₃ PO ₄ (44.5 mg; 0.21 mmol; 3 eq.) in a nitrogen atmosphere. The mixture was stirred for 10 hours at 90°C under a nitrogen atmosphere. The residue was purified by preparative TLC (PE/EtOAc, 1:1), obtaining the products contained in this residue, then this crude product was purified by preparative HPLC (column: XBridge OBD C18 preparative column, 19 * 250 mm, 5 μm; mobile phase A: water (with NH ₄ HCOO ₃ (10 mmol/l) + 0.1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 36% B to 64% B per 7 min; 220/254 nm; Rt: 6.97 min), yielding N-[[3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2- yl]methyl]pyridine-2-carboxamide (compound 08) (6.7 mg; 9.4%) as a white solid. LCMS m/z (ESI) [M+H] ⁺ =429.2. ^1H NMR (400 MHz, methanol- _d4 ) δ 2.37 (s, 4H), 4.74 (s, 1H), 7.01-7.20 (m, 2H), 7.43 (s, 1H), 7.60 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.69 (s, 1H).

Example 09. Preparation of 3-amino-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2 -carboxamide (compound 09)

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)pyrazin-2-carboxylate (1 g; 3.55 mol; 1 eq.) and (2,6-dimethylpyridin-4-yl)boronic acid (1.1 g; 7.3 mol; 2.1 eq.) in n-BuOH (25 ml) was added x-Phos (0.3 g; 0.7 mmol; 0.2 eq.) and Pd(OAc ) ₂ (0.2 g; 0.7 mmol; 0.2 eq.), K ₃ PO ₄ (301.4 mg; 1.42 mmol; 2 eq.) in a nitrogen atmosphere. The mixture was stirred for 2 hours at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 10:1), yielding 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxylic acid ( 400 mg; 33.30%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =339.0.

Step 2. 3-Amino-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2- carboxamide (compound 09)

To a solution of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxylic acid (150 mg; 0.4 mmol; 1 eq.), 6-( aminomethyl)-N,N-dimethylpyridin-2-amine (134.1 mg; 0.9 mmol; 2.0 eq.), HATU (337.1 mg; 0.9 mmol; 2 eq.) in DMF (5 ml) DIEA (171.9 mg; 1.3 mmol; 3 eq.) was added dropwise over 1 min at 15°C. The resulting mixture was stirred for another 2 hours at 15°C. The resulting mixture was concentrated under reduced pressure. The crude product (150 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 49% B to 69% B in 7 min; 254/220 nm; Rt: 5.8 min), giving 3-amino-N-[[6 -(dimethylamino)pyridin-2-yl]methyl]-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-carboxamide (compound 09) (39.0 mg; 18 .6%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =472.3; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.33 (s, 6H), 2.97 (s, 6H), 4.48 (d, J=5.6 Hz, 2H), 6.52 (dd, J=10.2 ; 7.9 Hz, 2H), 6.99 (s, 2H), 7.16-7.26 (m, 2H), 7.37-7.51 (m, 3H), 9.20 (t, J=5.7 Hz, 1H).

Example 11. Preparation of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)-N-((3-(trifluoromethyl)pyridine -2-yl)methyl)pyrazin-2-carboxamide (compound 11)

Step 1. 3-Amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid

To a solution of methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (400 mg; 1.57 mmol; 1 eq.) in MeOH (2 ml) and THF (8 ml) LiOH.H ₂ O (131.8 mg; 3.14 mmol; 2 eq.) was added. The resulting mixture was stirred for 2 hours at 40°C under a nitrogen atmosphere. The pH of the mixture was adjusted to 8 using HCl.H ₂ O. The solvent was removed under reduced pressure. The residue gave 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (350 mg; 92.6%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =241.1; ^1H NMR: (300 MHz, DMSO- _d6 ) δ 7.60 (s, 1H), 7.76 (s, 2H), 8.44 (s, 1H), 13.68 (s, 1H).

Step 2. 3-Amino-6-chloro-5-(1,3-oxazol-2-yl)-N-[[3-(trifluoromethyl)pyridin-2-yl]methyl]pyrazin-2-carboxamide

To a solution of 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (150 mg; 0.62 mmol; 1 eq.) in DCM (15 ml) was added portionwise 1-[3-(trifluoromethyl)pyridin-2-yl]methanamine (219.6 mg; 1.25 mmol; 2 eq.), HOBT (hydroxybenzotriazole) (168.5 mg; 1.25 mmol; 2 eq.) and EDC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) (239.0 mg; 1.25 mmol; 2 eq.) for 5 min at room temperature. The resulting mixture was stirred for 2 hours at room temperature in an air atmosphere. 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-oxazol-2-yl)-N-[[3-(trifluoromethyl)pyridin-2- yl]methyl]pyrazine-2-carboxamide (20 mg; 8.1%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =399.1; ^1H NMR: (300 MHz, MeOD) δ 4.93 (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-oxazol-2-yl)-N-[[3-( trifluoromethyl)pyridin-2-yl]methyl]pyrazine-2-carboxamide (compound 11)

To a mixture of 3-amino-6-chloro-5-(1,3-oxazol-2-yl)-N-[[3-(trifluoromethyl)-pyridin-2-yl]methyl]pyrazin-2-carboxamide (20 mg ; 0.05 mmol; 1 eq.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (23.6 mg; 0.10 mmol; 2.00 eq.) in 1,4-dioxane (5 ml) Pd(dppf)Cl ₂ (7.3 mg; 0.01 mmol; 0.20 eq.) was added in portions .) and Cs ₂ CO ₃ (32.7 mg; 0.10 mmol; 2 eq.). The mixture was stirred for 5 minutes at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 90°C under a nitrogen atmosphere and concentrated in vacuo. The crude product (40 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 5 μm, 19*150 mm; mobile phase A: water (with NH ₄ HCOO ₃ (10 mmol/l)+0, 1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 40% B in 7 min; 254/220 nm; Rt: 6.55 min) , giving 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)-N-[[3-(trifluoromethyl )pyridin-2-yl]methyl]pyrazin-2-carboxamide (compound 11) (2 mg; 8.5%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =472.3; ^1H NMR: (300 MHz, MeOD) δ 3.66 (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-dihydropyridine -3-yl)pyrazin-2-carboxamide (compound 13)

Step 1. Preparation of 3-amino-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridine -3-yl)pyrazin-2-carboxamide

To a stirred mixture of 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylic acid (350 mg; 1.308 mmol; 1 eq.) and 6-(aminomethyl)-N,N-dimethylpyridine-2- amine (296.62 mg; 1.962 mmol; 1.5 eq.) in DMF (20 ml), HATU (994.47 mg; 2.615 mmol; 2 eq.) and DIEA (338.03 mg; 2.615 mmol; 2 eq.) were added in portions eq.) at 15°C in an air atmosphere. The resulting mixture was stirred for 3 hours and quenched using 50 ml of water. The resulting solid was collected by filtration and dried under reduced pressure to obtain 3-amino-6-chloro-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-5-(4-fluorophenyl)pyrazine-2-carboxamide (300 mg; 57.23%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =401.2.

Step 2. Preparation of 3-amino-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridine -3-yl)pyrazin-2-carboxamide (compound 13)

To a solution of 3-amino-6-chloro-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-5-(4-fluorophenyl)pyrazine-2-carboxamide (50 mg; 0.12 mmol; 1 eq.) and (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid (28.6 mg; 0.19 mmol; 1.50 eq.) in water (0.2 ml) and dioxane (1.8 ml), Cs ₂ CO ₃ (81.3 mg; 0.25 mmol; 2 eq.) and Pd(dppf)Cl ₂ (9.1 mg; 0.01 mmol; 0.1 eq.) were added .) under a nitrogen atmosphere, the resulting mixture was stirred for 2 hours at 90°C under a nitrogen atmosphere and concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 40% B to 48% B in 7 min; 254/220 nm; Rt: 5.37 min), giving 3-amino-N-[[6 -(dimethylamino)pyridin-2-yl]methyl]-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-carboxamide (compound 13 ) (12 mg; 20.3%) as a light yellow solid.

LCMS: m/z (ESI), [M+H] ⁺ =474.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.0 (s, 5H), 3.4 (s, 2H), 4.5 (d, J=5.9 Hz, 1H), 6.2 (d, J=9.3 Hz, 1H), 6.4-6.5 (m, 1H), 7.3 (t, J=8.8 Hz, 1H), 7.5 (t, J=7.9 Hz, 1H), 7.5 (t, J=7, 1 Hz, 2H), 7.9 (d, J=2.5 Hz, 1H), 9.3 (s, 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 13.

Example 14. Preparation of 3-amino-N-((3-fluoropyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol- 2-yl)pyrazin-2-carboxamide (compound 14)

SCHEME 11

Step 1. Methyl 3-((di-tert-butoxycarbonyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin- 2-carboxylate

To a stirred mixture of methyl 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (80 mg; 0.2 mmol; 1 eq.) and (Boc) ₂ O (160.0 mg; 0.7 mmol; 3.0 eq.) in DCM (2 ml) DMAP (5.97 mg; 0.049 mmol; 0.2 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for another 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH, 20:1) to give methyl 3-[bis[(tert-butoxy)carbonyl]amino]-6-(1-methyl-6-oxo-1,6-dihydropyridine-3- yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (84 mg; 65.2%) as a light yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =528.

Step 2. 3-((Di-tert-butoxycarbonyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxylic acid

To the stirred mixture methyl 3-[bis[(tert-butoxy)carbonyl]amino]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol- 2-yl)pyrazin-2-carboxylate (84 mg; 0.2 mmol; 1 eq.) in MeOH (5 ml) was added portionwise with LiOH (7.6 mg; 0.3 mmol; 2 eq.) at room temperature in air atmosphere. The resulting mixture was stirred for another 1 hour at 50°C. The mixture was left 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]amino]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl )-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (75 mg; 91.7%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =514.1.

Step 3. Di-tert-butyl (3-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6 -(oxazol-2-yl)pyrazin-2-yl)carbamate

To a stirred mixture of 3-[bis[(tert-butoxy)carbonyl]amino]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2 -yl)pyrazin-2-carboxylic acid (81 mg; 0.16 mmol; 1 eq.) and 1-(3-fluoropyridin-2-yl)methanamine (39.8 mg; 0.3 mmol; 2.0 eq. .) HATU (120.0 mg; 0.3 mmol; 2 eq.) and DIEA (61.2 mg; 0.47 mmol; 3 eq.) were added in portions to DMF (2 ml) at room temperature in an air atmosphere. The resulting mixture was stirred for another 6 hours at room temperature. The resulting mixture was quenched with water (20 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with water (3 x 50 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The result was tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-[[(3-fluoropyridin-2-yl)methyl]carbamoyl]-5-(1-methyl-6-oxo-1 ,6-dihydropyridin-3-yl)-6-(1,3-oxazol-2-yl)pyrazin-2-yl)carbamate (80 mg; 81.6%) as a yellow solid, which was used directly next stage without additional purification. LCMS: m/z (ESI), [M-Boc+H] ⁺ =522.3.

Step 4. 3-Amino-N-((3-fluoropyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide (compound 14)

To the stirred solution/mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-[[(3-fluoropyridin-2-yl)methyl]carbamoyl]-5-(1-methyl- 6-oxo-1,6-dihydropyridin-3-yl)-6-(1,3-oxazol-2-yl)pyrazin-2-yl)carbamate (70 mg; 0.11 mmol; 1 eq.) and TFA (2 ml) in DCM (2 ml) was added in portions at room temperature in an air atmosphere. The resulting mixture was stirred for another 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (4 ml). NH ₃ .H ₂ O (4 ml) was added in portions at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (4 ml). The residue was purified by preparative TLC (DCM/MeOH, 20:1) to give 3-amino-N-[(3-fluoropyridin-2-yl)methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridine -3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 14) (22 mg; 45.9%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =422.2. ^1H NMR (DMSO-d ₆ , 400 MHz) δ 3.5 (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. Preparation of 3-amino-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5- (1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 15)

SCHEME 12

Step 1. 6-(Dimethylamino)pyridine-2-carbonitrile

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

Step 2. 6-(Aminomethyl)-N,N-dimethylpyridin-2-amine

To a mixture of 6-(dimethylamino)pyridine-2-carbonitrile (1.1 g; 7.5 mmol; 1 eq.) in MeOH (50 ml), NH ₃ .H ₂ O (0.3 g; 7.5 mmol ; 1 eq.) Raney Ni (64.03 mg; 0.747 mmol; 0.10 eq.) was added at room temperature. The mixture was stirred for 30 minutes at 20°C under a hydrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 6-(aminomethyl)-N,N-dimethylpyridin-2-amine (1 g; 88.5%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =152.2.

Step 3. 3-Amino-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 15)

To a mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg ; 0.32 mmol; 1 eq.) and 6-(aminomethyl)-N,N-dimethylpyridin-2-amine (72.4 mg; 0.48 mmol; 1.5 eq.) in DMF (3 ml) in portions HATU (243 mg; 0.64 mmol; 2 eq.) and DIEA (118 mg; 0.96 mmol; 3 eq.) were added at room temperature. The mixture was stirred for 10 minutes at 15°C in an air atmosphere. The precipitated solids were collected by filtration and washed with water (3 x 10 ml). The resulting solid was dried under infrared irradiation to give 3-amino-N-[[6-(dimethylamino)pyridin-2-yl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 15) (66.1 mg; 46.4%) as a light yellow solid.

LCMS: m/z (ESI), [M+H] ⁺ =447.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.9 (s, 5H), 3.3 (s, 2H), 4.4 (d, J=5.7 Hz, 2H), 6.3 (d, J=9.3 Hz, 1H), 6.5 (dd, J=9.2; 7.9 Hz, 2H), 7.3-7.4 (m, 2H), 7.46 (dd, J=8.5; 7.3 Hz, 1H), 7.8 (s, 1H), 8.0 (d, J=2.6 Hz, 1H), 8.3 (d, J=0.8 Hz, 1H), 9.3 (t, J=5.7 Hz, 1H).

Example 16. Preparation of 3-amino-N-((3-(dimethylamino)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5- (oxazol-2-yl)pyrazin-2-carboxamide (compound 16)

DIAGRAM 13

Step 1. 2-(Aminomethyl)-N,N-dimethylpyridin-4-amine

To a solution of 4-(dimethylamino)pyridine-2-carbonitrile (200 mg; 1.4 mmol; 1 eq.) in MeOH (5 ml) was added NH ₃ .H ₂ O (0.1 ml; 2.6 mmol; 1 .9 eq.). The resulting mixture was stirred for 30 minutes at 15°C in a hydrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(aminomethyl)-N,N-dimethylpyridin-4-amine (190 mg; 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-dihydropyridin-3-yl)-5-( Oxazol-2-yl)pyrazin-2-carboxamide (compound 16)

To a mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg ; 0.32 mmol; 1 eq.) and 2-(aminomethyl)-N,N-dimethylpyridin-3-amine (72.4 mg; 0.48 mmol; 1.5 eq.) in DMF (5 ml) in portions HATU (242.7 mg; 0.64 mmol; 2 eq.) and DIE A (165.12 mg; 1.28 mmol; 4 eq.) were added. The mixture was stirred for 60 min at 15°C in an air atmosphere and quenched with water (15 ml). The precipitated solids were collected by filtration and washed with water (3 x 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-(oxazol-2-yl)pyrazin-2-carboxamide (compound 16) (50.6 mg; 35.5%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =447.2; ¹ H NMR (400 MHz, 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, 5 Hz, 2H), 6.3 (d, J=9.4 Hz, 1H), 7.3 (dd, J=8.1; 4.7 Hz, 1H), 7.3-7.4 (m, 2H), 7.5 (dd , J=8.1; 1.5 Hz, 1H), 7.8 (s, 1H), 8.0 (d, J=2.6 Hz, 1H), 8.2 (dd, J=4.7; 1.4 Hz , 1H), 8.3 (d, J=0.7 Hz, 1H), 9.3 (t, J=5.5 Hz, 1H).

Example 17. Preparation of 3-amino-N-((6-methoxypyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol- 2-yl)pyrazin-2-carboxamide (compound 17)

SCHEME 14

Step 1. 3-Amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (1 g; 3.93 mmol; 1 eq.) and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (1.8 g; 7.85 mmol; 2 eq.) in 1 ,4-dioxane (50 ml) Cs ₂ CO ₃ (2.6 g; 7.85 mmol; 2 eq.) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.5 g; 0.59 mmol; 0.15 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 90°C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH ₂ Cl ₂ (1 × 200 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/PE (0-100%), then EA/DCM (0-10%), giving methyl 3-amino-6-(1-methyl-6-oxo-1, 6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (1.1 g; 85.58%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =328.0. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ3.47 (s, 3H), 3.91 (s, 3H), 6.36 (d, J=9.4 Hz, 1H), 7.35 (dd, J=9, 3; 2.6 Hz, 1H), 7.43 (d, J=0.8 Hz, 1H), 7.63 (s, 2H), 7.85 (d, J=2.6 Hz, 1H), 8.32 (d, J =0.8 Hz, 1H).

Step 2. 3-Amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid

To the stirred mixture of methyl 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (7 g; 21.39 mmol; 1 eq.) in THF (500 ml) and methanol (100 ml) a solution of LiOH (1024.4 mg; 42.77 mmol; 2 eq.) in water (20 ml) was added in portions at 35 °C in air atmosphere. The resulting mixture was stirred for 3 hours at 35°C in an air atmosphere. The mixture was neutralized to pH 6 using HCl (aq) 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)pyrazin-2 -carboxylic acid (6.3 g; 94.03%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =314.0.

Step 3. 3-Amino-N-[(6-methoxypyridin-2-yl)methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3 -oxazol-2-yl)pyrazin-2-carboxamide (compound 17)

To a stirred mixture of HATU (24.3 mg; 0.06 mmol; 2 eq.) and 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxylic acid (10 mg; 0.03 mmol; 1 eq.) in DMF (5 ml) was added portionwise with DIEA (10.3 mg; 0.08 mmol; 2. 5 equiv.) at room temperature. The resulting mixture was stirred for 5 minutes at room temperature. 1-(6-methoxypyridin-2-yl)methanamine (6.6 mg; 0.05 mmol; 1.5 eq.) was added in portions. The resulting mixture was stirred for 3 hours at room temperature. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 3:1) to give 3-amino-N-[(6-methoxypyridin-2-yl)methyl]-6-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 17) (30 mg; 27.10%) as yellow solid matter. LCMS: m/z (ESI), [M+H] ⁺ =434.0; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.36 (t, J=6.1 Hz, 1H), 8.29 (d, J=0.8 Hz, 1H), 8.02 (d, J=2.6 Hz, 1H), 7.79 (s, 2H), 7.65 (t, J=7.8 Hz, 1H), 7.48-7.32 (m, 2H), 6.90 (d, J=7.3 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.31 (d, J=9.4 Hz, 1H), 4.53 (d, J=6.0 Hz, 2H), 3.81 (s, 3H), 3.45 ( s, 3H).

Example 18. Preparation of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-[(6-methylpyridin-2-yl)methyl]-5-(1, 3-oxazol-2-yl)pyrazin-2-carboxamide (compound 18)

SCHEME 15

Step 1. Methyl 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)-pyrazin-2-carboxylate

To a mixture of methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (1.1 g; 4.32 mmol; 1 eq.) and 1-methyl-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (2.0 g; 8.64 mmol; 2 eq.) in 1,4-dioxane (40 ml) was added Pd(dppf)Cl ₂ (0.3 g; 0.43 mmol; 0.1 eq.) and Cs ₂ CO ₃ (2.8 g; 8.64 mmol; 2 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 90°C under a nitrogen atmosphere and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /MeOH (4%), giving methyl 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5 -(1,3-oxazol-2-yl)pyrazin-2-carboxylate (1 g; 70.72%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =328.0. ^1H NMR: (400 MHz, DMSO- _d6 ) δ 3.46 (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-oxazol-2-yl)pyrazin-2-carboxylic acid

To a solution of methyl 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (1 g ; 3.06 mmol; 1 eq.) in MeOH (30 ml) and THF (10 ml) was added LiOH (0.1 g; 6.11 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred for 2 hours at 40°C in an air atmosphere. The pH of the mixture was adjusted to 5 using 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)pyrazin-2- carboxylic acid (800 mg; 83.58%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =314.0. ^1H NMR: (400 MHz, DMSO- _d6 ) δ 3.46 (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-yl)methyl]-5-(1,3 -oxazol-2-yl)pyrazin-2-carboxamide (compound 18)

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.32 mmol; 1 eq.), HATU (242.7 mg; 0.64 mmol; 2 eq.) and DIEA (123.8 mg; 0.96 mmol; 3 eq.) in DMF (5 ml ) 1-(6-methylpyridin-2-yl)methanamine (58.5 mg; 0.48 mmol; 1.5 eq.) was added portionwise at room temperature under air. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The mixture was poured into water, filtered, the solid was collected by filtration and washed with MeOH (10 ml), dried under vacuum to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)- N-[(6-methylpyridin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 18) (24 mg; 18.01%) as a yellow solid substances. LCMS: m/z (ESI), [M+H] ⁺ =418.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.48 (s, 3H), 4.58 (d, J=6.1 Hz, 2H), 6.33 (d, J=9.4 Hz, 1H), 7.15 ( d, J=7.7 Hz, 2H), 7.36-7.47 (m, 2H), 7.65 (t, J=7.7 Hz, 1H), 7.81 (s, 2H), 8.06 (d, J=2, 6 Hz, 1H), 31 (d, J=0.8 Hz, 1H), 8 2.47 (s, 3H), 9.45 (t, J=6.1 Hz, 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 18.

Example 19. Preparation of 3-amino-N-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5- (1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 19)

SCHEME 16

Step 1. 1-[3-(Difluoromethoxy)pyridin-2-yl]methanamine

To a stirred mixture of 3-(difluoromethoxy)pyridine-2-carbonitrile (70 mg; 0.41 mmol; 1 eq.) and Raney Ni (7.1 mg; 0.1 mmol; 0.2 eq.) in MeOH (5 ml) NH ₃ .H ₂ O (1 ml) was added in portions at room temperature. The resulting mixture was stirred for another 3 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure. The result was 1-[3-(difluoromethoxy)pyridin-2-yl]methanamine (50 mg, 69.7%) as a purple oil. 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]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 19)

To a stirred solution/mixture of 1-[3-(difluoromethoxy)pyridin-2-yl]methanamine (41.7 mg; 0.24 mmol; 1.5 eq.) and 3-amino-6-(1- methyl 6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (50 mg; 0.16 mmol; 1 eq.) in DMF (4 ml) was added dropwise with HATU (242.7 mg; 0.64 mmol; 4 eq.) and DIEA (82.5 mg; 0.64 mmol; 4 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for another 0.5 h at room temperature. The resulting mixture was added dropwise to water (200 ml). The resulting mixture was filtered, and the filter cake was washed with MeOH (3×10 ml). The result was [3-(difluoromethoxy)pyridin-2-yl]methyl-3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3- Oxazol-2-yl)pyrazin-2-carboxylate (compound 19) (18 mg; 23.7%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =470.2. ^1H NMR (DMSO, 400 MHz) δ 3.5 (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)

DIAGRAM 17

Step 1. N-[[3-Amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]-3-(difluoromethoxy)pyridine-2-carboxamide

To a mixture of 3-(aminomethyl)-5-chloro-6-(4-fluorophenyl)pyrazin-2-amine (40 mg; 0.16 mmol; 1 eq.) and 3-(difluoromethoxy)pyridine-2-carboxylic acid ( 59.9 mg; 0.32 mmol; 2.0 eq.) in DCM (2.5 ml) was added HATU (120.4 mg; 0.32 mmol; 2 eq.) and TEA (48.1 mg; 0 .5 mmol; 3 eq.) and stirred for 6 hours at room temperature in an air atmosphere. The resulting mixture was quenched with water (20 ml) and extracted with CH ₂ Cl ₂ (3 x 20 ml). The combined organic layers were washed with H ₂ O (3 x 3 10 ml), dried over anhydrous Na ₂ SO ₄ . 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]methyl]-3-(difluoromethoxy)pyridin- 2-Carboxamide (30 mg; 42.5%) as a yellow solid. 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)pyrazin-2-yl]methyl]-3 -(difluoromethoxy)pyridine-2-carboxamide (compound 21)

To a mixture of N-[[3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]-3-(difluoromethoxy)pyridine-2-carboxamide (30 mg; 0.07 mmol; 1 eq.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (33.3 mg; 0 .14 mmol; 2.0 eq.) in a mixture of dioxane/H ₂ O (1 ml) was added Pd(dppf)Cl ₂ (10.4 mg; 0.01 mmol; 0.2 eq.) and K ₃ PO ₄ (45.1 mg; 0.21 mmol; 3 eq.) and stirred for 10 hours at 90°C under nitrogen atmosphere. The residue was purified by preparative TLC (PE/EtOAc, 1:1), then the crude product (25 mg) was purified by preparative HPLC (column: preparative column XBridge OBD C18, 5 μm, 19*150 mm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l) + 0.1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 27% B in 8 min; 254 /220 nm; Rt: 7.32 min), yielding N-[[3-amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) pyrazin-2-yl]methyl]-3-(difluoromethoxy)pyridin-2-carboxamide (compound 21) (2.7 mg; 7.61%) as a white solid. LCMS m/z (ESI) [M+H] ⁺ =497.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 3.52 (s, 2H), 4.70 (s, 1H), 7.08-7.23 (m, 1H), 7.33 (dd, J=9.4; 2.6 Hz , 1H), 7.45-7.55 (m, 1H), 7.65 (dd, J=8.4; 4.6 Hz, 1H), 7.74-7.84 (m, 1H), 8.56 (dd, J=4.6; 1.3 Hz, 1H).

Example 23. Preparation of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-[[6-(methylamino)pyridin-2-yl]methyl]-5- (1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 23)

DIAGRAM 18

Step 1. 6-(Methylamino)pyridine-2-carbonitrile

To a solution of 6-bromopyridine-2-carbonitrile (500 mg; 2.7 mmol; 1 eq.) in THF (10 ml) was added methanamine (424.3 mg; 13.6 mmol; 5.0 eq.) at room temperature and stirred for 6 hours at 80°C in an air atmosphere. The residue was purified by preparative TLC (PE/EtOAc 5:1) to give 6-(methylamino)pyridine-2-carbonitrile (80 mg; 21.9%) as a white solid. 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 (80 mg; 0.6 mmol; 1 eq.) and Raney Ni (51.5 mg; 0.6 mmol; 1.0 eq.) in MeOH (5 ml) NH ₃ .H ₂ O (21.1 mg; 0.60 mmol; 1 eq.) was added in portions at RT. The resulting mixture was stirred for 30 min at 15° C. under a hydrogen atmosphere and concentrated under reduced pressure to give 6-(aminomethyl)-N-methylpyridin-2-amine (60 mg; 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)pyridin-2-yl]methyl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 23)

To a stirred solution/mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2 -carboxylic acid (70 mg; 0.22 mmol; 1 eq.) and 6-(aminomethyl)-N-methylpyridin-2-amine (46.0 mg; 0.3 mmol; 1.5 eq.) in DMF ( 3 ml), HATU (169.9 mg; 0.5 mmol; 2 eq.) and DIEA (86.6 mg; 0.6 mmol; 3 eq.) were added dropwise/portionally, stirred for 10 min at 15° C in the air atmosphere. The crude product (60 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30*150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 20% B to 28% B in 7 min; 254/220 nm; Rt: 6.5 min), giving 3-amino-6-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)-N-[[6-(methylamino)-pyridin-2-yl]methyl]-5-(1,3-oxazol-2-yl)pyrazin- 2-carboxamide (compound 23) (8 mg; 8.3%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =433.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 2.8 (s, 2H), 3.6 (s, 2H), 4.5 (s, 1H), 6.4 (d, J=8.2 Hz, 1H), 6.4- 6.6 (m, 1H), 7.3-7.4 (m, 1H), 7.5 (dd, J=9.3; 2.6 Hz, 1H), 8.0 (d, J=2.5 Hz, 1H), 8.0 ( d, J=0.8 Hz, 1H).

Example 24. Preparation of 3-amino-N-[(6-aminopyridin-2-yl)methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1, 3-oxazol-2-yl)pyrazin-2-carboxamide (compound 24)

DIAGRAM 19

Step 1. 6-(Aminomethyl)pyridin-2-amine

To a solution of 6-aminopyridinecarbonitrile (100 mg; 0.84 mmol; 1 eq.) in 20 ml MeOH in a 50 ml round-bottom flask was added Raney Ni (10 mg; 0.12 mmol; 0.14 eq.) under a nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1.5 hours under a hydrogen atmosphere using a hydrogen cylinder. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 6-(aminomethyl)pyridin-2-amine (100 mg; 96.73%) as a brown oil. The crude product was directly used 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-dihydropyridin-3-yl)-5-(1,3 -oxazol-2-yl)pyrazin-2-carboxamide (compound 24)

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (381 .5 mg; 1.22 mmol; 1.5 eq.) and HATU (617.5 mg; 1.62 mmol; 2 eq.) in DMF (15.0 ml) DIEA (314.8 mg; 2 eq.) was added in portions .44 mmol; 3 eq.) and 6-(aminomethyl)pyridin-2-amine (100 mg; 0.81 mmol; 1 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 30 minutes at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (20:1) to give 3-amino-N-[(6-aminopyridin-2-yl)methyl]-6-(1- methyl 6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 24) (57 mg; 16.43%) as yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =419.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.48 (s, 3H), 4.39 (d, J=6.2 Hz, 2H), 5.92 (s, 2H), 6.32 (dd, J=8.8 ; 3.8 Hz, 2H), 6.42 (d, J=7.3 Hz, 1H), 7.28-7.40 (m, 2H), 7.42 (s, 1H), 7.83 (s, 2H), 8.07 (d, J=2.6 Hz, 1H), 8.31 (s, 1H), 9.26 (t, J=6.2 Hz, 1H).

Example 25. Preparation of 3-amino-N-((4-(dimethylamino)pyrimidin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5- (oxazol-2-yl)pyrazin-2-carboxamide (compound 25)

SCHEME 20

Step 1. 4-(Dimethylamino)pyrimidine-2-carbonitrile

4-bromopyrimidine-2-carbonitrile (980 mg; 5.3 mmol; 1 eq.) and NHMe ₂ (15 ml; 30.00 mmol; 5.6 eq.) in THF (10 mg) at 80°C for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with hexane/EtOAc (1:1) to give 4-(dimethylamino)pyrimidine-2-carbonitrile (700 mg; 88.7%) as a white solid. 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 (80 mg; 0.5 mmol; 1 eq.) and Raney Ni (9.3 mg; 0.1 mmol; 0.2 eq.) in MeOH (5 ml) NH ₄ OH (1 ml) was added dropwise at room temperature. The resulting mixture was stirred for another 1 hour at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure to obtain 70 mg of brown oil. The crude product was directly used 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]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-( 1.3-oxazol-2-yl)pyrazin-2-carboxamide (compound 25)

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (50 mg; 0.16 mmol; 1 eq.) and 2-(aminomethyl)-N,N-dimethylpyrimidin-4-amine (36.4 mg; 0.2 mmol; 1.5 eq.) in DMF (5 ml) DIEA (82.5 mg; 0.64 mmol; 4 eq.) and HATU (242.7 mg; 0.6 mmol; 4 eq.) were added in portions at room temperature in an air atmosphere. The resulting mixture was stirred for another 30 minutes at room temperature. The resulting mixture was added to water and filtered, the filter cake was washed with EtOAc (3x5 ml) and MeOH (2x5 ml). The crude product was recrystallized from water/DMF (5:1 in ml) to give 3-amino-N-[[4-(dimethylamino)pyrimidin-2-yl]methyl]-6-(1-methyl-6-oxo- 1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 25) (14 mg; 19.41%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =448.3. ^1H NMR (DMSO, 400 MHz) δ 3.0 (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. Preparation of 3-amino-N-[[6-(azetidin-1-yl)pyridin-2-yl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) )-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 26)

SCHEME 21

Step 1. 6-(Azetidin-1-yl)pyridin-2-carbonitrile

6-bromopyridine-2-carbonitrile (500 mg; 2.732 mmol; 1 eq.), azetidine (202.79 mg; 3.552 mmol; 1.30 eq.) and K ₂ CO ₃ (755 .19 mg; 5.464 mmol; 2.00 eq.) in DMF (20 ml) at room temperature. The mixture was stirred for 2 hours at 80°C and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to give 6-(azetidin-1-yl)pyridin-2-carbonitrile (400 mg; 91.97%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =160.2.

Step 2. 1-[6-(Azetidin-1-yl)pyridin-2-yl]methanamine

Raney Ni (40 mg; 0.47 mmol; 0.32 eq.) and 6-(azetidin-1-yl)pyridin-2-carbonitrile (230 mg; 1.44 mmol; 1 eq.) were added to a 50 mL round bottom flask. .) in MeOH (20 ml) at room temperature. The mixture was stirred for 2 hours under H ₂ atmosphere. Raney Ni was removed by filtration. The filtrate was concentrated under reduced pressure to give 1-[6-(azetidin-1-yl)pyridin-2-yl]methanamine (200 mg; 84.81%) as a yellow oil, 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]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 26)

To a mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (80 mg ; 0.26 mmol; 1 eq.) and 1-[6-(azetidin-1-yl)pyridin-2-yl]methanamine (62.9 mg; 0.39 mmol; 1.5 eq.) in DMF ( 5 ml) HATU (195.4 mg; 0.51 mmol; 2 eq.) and DIEA (99.6 mg; 0.77 mmol; 3 eq.) were added at room temperature. The resulting mixture was stirred for 60 minutes and concentrated in vacuo. The crude product (50 mg) was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 5 μm, 19*150 mm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l) + 0, 1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 43% B in 7 min; 254/220 nm; Rt: 6.68 min) , obtaining 3-amino-N-[[6-(azetidin-1-yl)pyridin-2-yl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)- 5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 26) (11 mg; 9.40%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =459.3. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (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. Preparation of 3-amino-N-(5-(dimethylamino)-2-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide (compound 27)

SCHEME 22

Step 1. Preparation of 5-(dimethylamino)-2-fluorocyclohexa-1,3-diene-1-carbonitrile

To a solution of 5-amino-2-fluorobenzonitrile (2 g; 14.69 mmol; 1 eq.) in DMF (40 ml) was added NaH (1057.7 mg; 44.08 mmol; 3 eq.) at 0°C. After stirring for 5 minutes, MeI (8341.4 mg; 58.77 mmol; 4 equiv.) was added dropwise at 0°C. The resulting solution was stirred for 2 hours at 0°C and quenched with saturated aq. NH ₄ Cl solution (50 ml). The resulting solution was extracted with ethyl acetate (3 x 50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column, eluting with dichloromethane/methanol (40:1). The result was 1.2 g (49.75%) of 5-(dimethylamino)-2-fluorocyclohexa-1,3-diene-1-carbonitrile as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =165.2. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.89 (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's Ni (52.18 mg; 0.609 mmol; 0.20 eq.) and 5-(dimethylamino)-2-fluorobenzonitrile (500 mg; 3.045 mmol; 1 eq.) in MeOH (50 ml) in a round bottom flask with a capacity NH ₄ OH (2 mL; 51.361 mmol; 16.87 eq.) was added to 250 mL. The resulting solution was stirred for 2 hours at room temperature under a hydrogen atmosphere. Raney's Ni was filtered. The filtrate was concentrated to obtain 400 mg (78.08%) of 3-(aminomethyl)-4-fluoro-N,N-dimethylaniline as a solid. LCMS: m/z (ESI), [M-NH2] ⁺ =152.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.83 (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-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide (compound 27)

To a mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (50 mg ; 0.16 mmol; 1 eq.) and 3-(aminomethyl)-4-fluoro-N,N-dimethylaniline (32.2 mg; 0.19 mmol; 1.20 eq.) in DMF (10 ml) in TEA (48.5 mg; 0.48 mmol; 3.0 eq.) and HATU (66.8 mg; 0.18 mmol; 1.1 eq.) were added to a 25 mL round bottom flask. The resulting solution was stirred for 1 hour at room temperature. Then the reaction was quenched by adding 50 ml of water. The resulting solid was collected by filtration and dried under vacuum to give 17.2 mg (23.25%) of 3-amino-N-[[5-(dimethylamino)-2-fluorophenyl]methyl]-6-(1-methyl-6 -oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 27) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =464.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (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. Preparation of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)-N-((6-(pyrrolidin-1 -yl)pyridin-2-yl)methyl)pyrazin-2-carboxamide (compound 28)

SCHEME 23

Step 1. 1-[6-Pyrrolidin-1-yl)pyridin-2-yl]methanamine

To a mixture of 6-(pyrrolidin-1-yl)pyridin-2-carbonitrile (200 mg; 1.1 mmol; 1 eq.) and Raney Ni (98.9 mg; 1.1 mmol; 1.0 eq.) in MeOH (10 ml) was added NH ₃ .H ₂ O (40.5 mg; 1.1 mmol; 1 eq.) and stirred for 30 minutes at 15°C in a hydrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 1-[6-(pyrrolidin-1-yl)pyridin-2-yl]methanamine (120 mg; 58.6%) as a white solid. 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-oxazol-2-yl)-N-[[6-( pyrrolidin-1-yl)pyridin-2-yl]methyl]pyrazine-2-carboxamide (compound 28)

To a mixture of 1-[6-(pyrrolidin-1-yl)pyridin-2-yl]methanamine (100 mg; 0.56 mmol; 1 eq.) and 3-amino-6-(1-methyl-6-oxo- 1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (176.7 mg; 0.56 mmol; 1.00 eq.) in DMF ( 3 ml) HATU (429.0 mg; 1.13 mmol; 2 eq.) and DIEA (218.7 mg; 1.69 mmol; 3 eq.) were added at room temperature. The mixture was stirred for 60 minutes at 15°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l) + 0, 1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 39% B to 40% B in 9 min; 254/220 nm; Rt: 8.3 min) , giving 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)-N-[[6-(pyrrolidine -1-yl)pyridin-2-yl]methyl]pyrazin-2-carboxamide (compound 28) (36.7 mg; 13.17%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =473.3; ¹ H NMR (400 MHz, methanol-d ₄ ) δ 1.8-1.9 (m, 4H), 3.3 (d, J=6.6 Hz, 4H), 4.5 (d, J=5.5 Hz, 2H), 6.3 (dd, J=13.3; 8.9 Hz, 2H), 6.5 (d, J=7.3 Hz, 1H), 7.4-7.5 (m, 3H), 7.8 (s, 1H), 7.9 ( d, J=2.6 Hz, 1H), 8.3 (d, J=0.8 Hz, 1H), 9.3 (t, J=5.6 Hz, 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. 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)

To a mixture of 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(4-fluorophenyl)pyrazine-2-carboxamide (100 mg; 0.25 mmol; 1 eq.) and 1 -methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (119.7 mg; 0.5 mmol; 2 ,0 eq.) in a mixture of dioxane/H ₂ O (2 ml) was added Pd(dppf)Cl ₂ (37.3 mg; 0.1 mmol; 0.2 eq.) and K ₃ PO ₄ (162.1 mg ; 0.8 mmol; 3 eq.) in a nitrogen atmosphere at room temperature. The mixture was stirred for 10 hours at 90°C under a nitrogen atmosphere. The residue was purified by preparative TLC (PE/EtOAc, 1:2), then the crude product was purified by preparative HPLC (column: XBridge OBD C18 preparative column, 30x150 mm, 5 µm; mobile phase A: water (with 0.05% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 39% B to 49% B in 7 min; 254/220 nm; Rt: 6.18 min), giving 3-amino- N-[(2,6-difluorophenyl)methyl]-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-carboxamide (compound 29 ) (7 mg; 5.85%) as a yellow solid. LCMS m/z (ESI) [M+H] ⁺ =466.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 3.55 (s, 2H), 4.73 (s, 2H), 6.38 (d, J=9.2 Hz, 1H), 6.93-7.05 (m, 2H), 7.10-7.19 (m, 2H), 7.30 (dd, J=9.4; 2.6 Hz, 1H), 7.32-7.42 (m, 1H), 7.50-7.61 (m, 2H), 7.88 (d, J =2.5 Hz, 1H).

Example 30. Preparation of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)-N-[[3- (trifluoromethoxy)pyridin-2-yl]methyl]pyrazine-2-carboxamide (compound 30)

SCHEME 25

Step 1. 3-(Trifluoromethoxy)pyridine-2-carbonitrile

To a stirred mixture of 2-bromo-3-(trifluoromethoxy)pyridine (300 mg; 1.24 mmol; 1 eq.) and Zn(CN) ₂ (291.2 mg; 2.48 mmol; 2 eq.) in THF ( 15 ml) and H ₂ O (3 ml) t-BuXantPhos-Pd-G3 (197.0 mg; 0.25 mmol; 0.2 eq.) and t-BuXantPhos (171.3 mg; 0.25 mmol) were added ; 0.2 eq.) in a nitrogen atmosphere at RT. The resulting mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 3-(trifluoromethoxy)pyridine-2-carbonitrile (200 mg; 85.76%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =188.9.

Step 2. 1-[3-(Trifluoromethoxy)pyridin-2-yl]methanamine

To a solution of 3-(trifluoromethoxy)pyridine-2-carbonitrile (100 mg; 0.53 mmol; 1 eq.) and NH ₃ .H ₂ O (1.0 ml; 28.54 mmol; 48.31 eq.) in MeOH (10 ml) was added Raney Ni (22.8 mg; 0.27 mmol; 0.5 eq.) under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure. The result was 1-[3-(trifluoromethoxy)pyridin-2-yl]methanamine (80 mg, 78.32%) as a purple oil. 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-oxazol-2-yl)-N-[[3-( trifluoromethoxy)pyridin-2-yl]methyl]pyrazine-2-carboxamide (compound 30)

To a solution of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (80 mg ; 0.26 mmol; 1 eq.) and 1-[3-(trifluoromethoxy)pyridin-2-yl]methanamine (98.1 mg; 0.51 mmol; 2 eq.) in DMF (10 ml) was added HATU ( 194.2 mg; 0.51 mmol; 2 eq.) and DIEA (66.0 mg; 0.51 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 30 minutes at room temperature in an air atmosphere. The solvent was removed under reduced pressure. The crude product (80 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 5 μm, 19*150 mm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l) + 0, 1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 46% B in 7 min; 254/220 nm; Rt: 6.83 min) , giving 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)-N-[[3-(trifluoromethoxy )pyridin-2-yl]methyl]pyrazin-2-carboxamide (compound 30) (10 mg; 8.03%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =488.2. ^1H NMR: (400 MHz, MeOD) δ 3.65 (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. Preparation of 3-amino-6-[1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl]-N-[(3-fluoropyridin-2-yl)methyl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 31)

SCHEME 26

Step 1. Methyl 3-amino-6-[1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate

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-dioxaborolane (340.1 mg; 1.34 mmol; 2 eq.) and 5-bromo-1-(difluoromethyl)-1,2-dihydropyridin-2-one (150 mg; 0.67 mmol; 1 eq.) in THF (20 ml) KOAc (197.2 mg; 2.01 mmol; 3.00 eq.) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (82.0 mg; 0.10 mmol; 0.15 eq.) were added in portions at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 75°C 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 (20 ml ) methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (84.5 mg; 0.33 mmol; 0.50 eq.), Cs ₂ was added in portions CO ₃ (432.7 mg; 1.33 mmol; 2 eq.) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ ; (70.5 mg; 0.09 mmol; 0.13 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 75°C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH ₂ Cl ₂ (2 × 20 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1) to give methyl 3-amino-6-[1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxylate (100 mg; 18.65%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =364.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.87 (s, 3H), 6.51 (d, J=9.7 Hz, 1H), 7.41 (s, 1H), 7.59 (dd, J=9.6 ; 2.5 Hz, 1H), 7.69 (s, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 8.32 (d, J= 0.8 Hz, 1H).

Step 2. 3-Amino-6-[1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-6-[1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (90 mg; 0.25 mmol; 1 eq.) in THF (15 ml) was added dropwise LiOH (11.9 mg; 0.50 mmol; 2.01 eq.) in water (1 ml) at room temperature. The resulting mixture was stirred for 3 hours at room temperature in an air atmosphere. The mixture was neutralized to pH 6 using 1 N. aq. HCl solution and concentrated in vacuo to give crude 3-amino-6-[1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1,3-oxazol-2-yl )pyrazine-2-carboxylic acid (85 mg; 98.24%) as a yellow solid, 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-fluoropyridin-2-yl)methyl]-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 31)

To a stirred mixture of 3-amino-6-[1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (10 mg; 0.03 mmol; 1 eq.), DIEA (11.1 mg; 0.09 mmol; 3.00 eq.) and HATU (21.8 mg; 0.06 mmol; 2.00 eq.) ) in DMF (8 ml) was added dropwise 1-(3-fluoropyridin-2-yl)methanamine (5.4 mg; 0.04 mmol; 1.50 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 3 hours at room temperature in an air atmosphere. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 3-amino-6-[1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3- yl]-N-[(3-fluoropyridin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 31) (30 mg; 28.64%) in as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =458.2; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.30 (t, J=5.9 Hz, 1H), 8.35 (dd, J=4.0; 2.3 Hz, 1H), 8.30 (d, J =0.8 Hz, 1H), 8.10 (s, 0H), 7.97 (d, J=2.5 Hz, 1H), 7.87 (d, J=13.8 Hz, 2H), 7.75-7.64 (m, 2H), 7.41 (q, J=4.3 Hz, 2H), 6.50 (d, J=9.7 Hz, 1H), 4.68 (dd, J=5.7; 1.5 Hz, 2H).

Example 32. Preparation of 3-amino-N-[(2,6-difluorophenyl)methyl]-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2- yl)pyrazin-2-carboxamide (compound 32)

DIAGRAM 27

Step 1. Methyl 3-amino-6-(imidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (300 mg; 1.18 mmol; 1 eq.) and 6-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (431.4 mg; 1.77 mmol; 1.5 eq.) in dioxane (18 ml ) and H ₂ O (2 ml), Cs ₂ CO ₃ (767.7 mg; 2.36 mmol; 2 eq.) and Pd(dppf)Cl ₂ (172.4 mg; 0.24 mmol; 0. 2 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C. The mixture was left to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH, 20:1) to give methyl 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl )pyrazine-2-carboxylate (165 mg; 41.6%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =337.2. ^1H NMR (DMSO-d ₆ , 400 MHz) δ 3.9 (3H, s), 7.1 (1H, dd, J=9.4; 1.8 Hz), 7.4 (1H, s), 7.5 (1H, d , J=9.3 Hz), 7.6 (1H, d, J=1.2 Hz), 7.7 (1H, d, J=19.0 Hz), 8.0 (1H, d, J=1.1 Hz) , 8.3 (1H, s), 8.7 (1H, t, J=1.4 Hz).

Step 2. 3-Amino-6-(imidazo[2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-6-[imidazo[1,2-a]pyridin-7-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (160 mg; 0. 48 mmol; 1 eq.) in THF (20 ml) and water (2 ml) LiOH (13.7 mg; 0.57 mmol; 1.2 eq.) was added portionwise at room temperature. The resulting mixture was stirred for 4 hours at room temperature and the pH was adjusted to 5 using 1N. aq. 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]-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl) )pyrazine-2-carboxamide (compound 32)

To a stirred mixture of 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (80 mg; 0. 25 mmol; 1 equiv.) and 1-(2,6-difluorophenyl)methanamine (71.1 mg; 0.50 mmol; 2 equiv.) in DMF (5 ml) HATU (377.5 mg; 1 mmol) was added in portions ; 4 eq.) and DIEA (128.3 mg; 1 mmol; 4 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 0.5 h at room temperature. The resulting mixture was quenched with water, the resulting solid was collected by filtration and suspended using MeOH (5 ml). The resulting solid was collected by filtration and dried under vacuum to give 3-amino-N-[(2,6-difluorophenyl)methyl]-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 32) (30 mg; 25.8%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =448.2. ^1H NMR (DMSO-d ₆ , 400 MHz) δ 4.6 (2H, d, J=5.8 Hz), 7.1 (2H, t, J=7.9 Hz), 7.2 (1H, dd, J=9 ,4; 1.8 Hz), 7.3-7.4 (2H, m), 7.5 (1H, d, J=9.3 Hz), 7.6 (1H, d, J=1.3 Hz), 7.9 (3H, d, J=23.3 Hz), 8.3 (1H, s), 8.7 (1H, t, J=1.3 Hz), 9.2 (1H, t, J=5.9 Hz).

Example 33. Preparation of 3-amino-N-(3-(dimethylamino)-2-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide (compound 33)

SCHEME 28

Step 1. 3-(Dimethylamino)-2-fluorobenzonitrile

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

Step 2. 3-(Aminomethyl)-2-fluoro-N,N-dimethylaniline

To a stirred mixture of 3-(dimethylamino)-2-fluorobenzonitrile (160 mg; 0.97 mmol; 1 eq.) and Raney Ni (16.7 mg; 0.19 mmol; 0.20 eq.) in MeOH (20 ml ) NH ₄ OH (2 ml) was added in portions at room temperature. The resulting mixture was stirred for another 1 hour at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure. The resulting 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-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide (compound 33)

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (80 mg; 0.26 mmol; 1 eq.) and 3-(aminomethyl)-2-fluoro-N,N-dimethylaniline (85.9 mg; 0.5 mmol; 2.0 eq.) in DMF (5 ml) HATU (194.2 mg; 0.51 mmol; 2.00 eq.) and DIE A (132.0 ml; 1.02 mmol; 4.00 eq.) were added in portions at room temperature in an air atmosphere. The resulting mixture was stirred for 3 hours at room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH, 20:1) to give the crude product 3-amino-3-(3-(dimethylamino)-2-fluorobenzyl)-6-(1-methyl-6-oxo-1,6- Dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (100 mg) as a brown-yellow oil. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: Xselect CSH OBD, 30*150 mm, 5 µm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate : 60 ml/min; gradient: from 16% B to 27% B in 7 min; 254/220 nm; Rt: 4.40 min), giving 3-amino-N-(3-(dimethylamino)-2-fluorobenzyl )-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 33) (44 mg; 37.06% ) as a brown-yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =464.2. ^1H NMR (DMSO-d ₆ , 400 MHz) δ 2.8 (5H, s), 4.6 (2H, d, J=6.3 Hz), 6.3 (1H, d, J=9.4 Hz), 6.9- 7.0 (2H, m), 7.1 (1H, t, J=7.8 Hz), 7.4-7.4 (2H, m), 7.8 (1H, s), 8.0 (1H, d, J=2.6 Hz) , 8.3 (1H, d,J=0.8 Hz), 9.3 (1H, t, J=6.4 Hz).

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)pyrazin-2-carboxamide (compound 35)

DIAGRAM 29

Step 1. Methyl 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate

To a stirred solution of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (2.5 g; 11.26 mmol; 1 eq.) and 2H-1,2,3-triazole (1555.4 mg; 22. 52 mmol; 2 eq.) in DMSO (50 ml) tert-BuONa (1082.1 mg; 11.26 mmol; 1 eq.) was added in portions at RT. The resulting mixture was stirred for 3 hours at 60°C in an oil bath, cooled to RT and quenched with water (200 ml). The resulting solid was collected by filtration, dried under vacuum and purified on a silica gel column (DCM:EA, 0-20%) to obtain 1.6 g of crude product. The crude product was further purified by preparative TLC (DCM:EA, 6:1) to give methyl 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (800 mg; 29%). ^1H NMR (300 MHz, chloroform-d) δ 4.06 (s, 3H), 8.03 (s, 2H).

Step 2. 3-Amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylic acid

To a stirred mixture of methyl 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (200 mg; 0.79 mmol; 1 eq.) in THF ( 50 ml) a solution of LiOH (38.0 mg; 1.59 mmol; 2.02 eq.) in water (2 ml) was added dropwise at room temperature. The resulting mixture was stirred for 3 hours at 40°C. The resulting mixture was concentrated to a volume of 10 ml under vacuum. The mixture was acidified to pH 6 using HCl (aq). The precipitated solids were collected by filtration and dried under vacuum to give 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylic acid (120 mg; 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]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxamide

To a stirred solution of 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylic acid (130 mg; 0.54 mmol; 1 eq.), DIE A (209.5 mg; 1.62 mmol; 3.00 eq.) and 1-(2,6-difluorophenyl)methanamine (116.0 mg; 0.81 mmol; 1.50 eq.) in DMF (10 ml ) 50% (by weight) T ₃ P (687 mg; 1.08 mmol; 2.00 eq.) was added dropwise at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(2H -1,2,3-triazol-2-yl)pyrazin-2-carboxamide (110 mg; 55.67%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =366.0. ^1H NMR (300 MHz, chloroform-d) δ 8.00 (s, 3H), 7.38-7.30 (m, 1H), 6.98 (t, J=7.8 Hz, 2H), 4.77 (d, J=6, 0 Hz, 2H).

Step 4. 3-Amino-N-[(2,6-difluorophenyl)methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(2H-1,2 ,3-triazol-2-yl)pyrazin-2-carboxamide (compound 35)

To a stirred mixture of 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxamide (100 mg; 0.27 mmol; 1 eq.), Cs ₂ CO ₃ (267.3 mg; 0.82 mmol; 3 eq.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (128.6 mg; 0.55 mmol; 2.00 eq.) in 1,4-dioxane (20 ml) was added portionwise with Pd( dppf)Cl ₂ .CH ₂ Cl ₂ (44.7 mg; 0.05 mmol; 0.2 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 90°C under a nitrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), giving 3-amino-N-[(2,6-difluorophenyl)methyl]-6-(1-methyl-6-oxo-1,6- Dihydropyridin-3-yl)-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxamide (compound 35) (40 mg; 33.04%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =439.2; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.18 (t, J=5.9 Hz, 1H), 8.13 (s, 2H), 7.93 (s, 2H), 7.76 (d, J=2.6 Hz, 1H), 7.48-7.25 (m, 1H), 7.08 (t, J=8.0 Hz, 2H), 6.73 (dd, J=9.5; 2.7 Hz, 1H), 6.20 (d, J=9.5 Hz, 1H), 4.61 (d, J=5.9 Hz, 2H), 3.39 (s, 3H).

Example 36. Preparation of 3-amino-N-((3-(hydroxymethyl)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5- (oxazol-2-yl)pyrazin-2-carboxamide (compound 36)

SCHEME 30

Step 1. Methyl 2-(((tert-butoxycarbonyl)amino)methyl)nicotinate

To a mixture of methyl 2-(aminomethyl)pyridine-3-carboxylate (1 g; 6.02 mmol; 1 eq.) and TEA (1826.8 mg; 18.05 mmol; 3.0 eq.) in DCM (30 ml ) in a 250 ml round bottom flask, Boc ₂ O (1379.0 mg; 6.32 mmol; 1.05 eq.) was added in portions at room temperature. The resulting solution was stirred for 16 hours at room temperature. The resulting solution was diluted using 50 ml of water. The resulting solution was extracted with dichloromethane (3 x 50 ml), dried over anhydrous sodium sulfate and concentrated. The result was 1.5 g (93.61%) of methyl 2-([[(tert-butoxy)carbonyl]amino]methyl)pyridine-3-carboxylate as a solid. LCMS: m/z (ESI), [M+H] ⁺ =267.1.

Step 2. tert-Butyl ((3-(hydroxymethyl)pyridin-2-yl)methyl)carbamate

A solution of methyl 2-([[(tert-butoxy)carbonyl]amino]methyl)pyridine-3-carboxylate (100 mg; 0.38 mmol; 1 eq.) in THF (5 mL) was placed in a 50 mL round bottom flask. LiAlH ₄ (42.8 mg; 1.13 mmol; 3 eq.) was then added in portions at 0°C. The resulting solution was stirred for 1 hour at 0°C in an ice bath. The reaction was then quenched by adding 0.043 ml of water and 0.172 ml of NaOH solution (15% aq.). The resulting solids were filtered off. The filtrate was concentrated to give 85 mg (94.9%) tert-butyl N-[[3-(hydroxymethyl)pyridin-2-yl]methyl]carbamate as a solid. LCMS: m/z (ESI), [M+H] ⁺ =239.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.40 (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

A solution of tert-butyl N-[[3-(hydroxymethyl)pyridin-2-yl]methyl]carbamate (50 mg; 0.21 mmol; 1 eq.), TFA (1 mL) in DCM was placed in a 10 mL round bottom flask. (3 ml). The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was concentrated to provide 28 mg (96.6%) of [2-(aminomethyl)pyridin-3-yl]methanol TFA salt as a solid. LCMS: m/z (ESI), [M+H] ⁺ =139.3. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 4.25 (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-dihydropyridin-3-yl)-5-( Oxazol-2-yl)pyrazin-2-carboxamide (compound 36)

To a mixture of [2-(aminomethyl)pyridin-3-yl]methanol (52.9 mg; 0.38 mmol; 2.0 eq.), 3-amino-6-(1-methyl-6-oxo-1, 6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (60 mg; 0.19 mmol; 1 eq.) in DMF (15 ml) in a round bottom flask HATU (87.4 mg; 0.23 mmol; 1.2 eq.) and DIEA (74.3 mg; 0.57 mmol; 3.0 eq.) were added to a 50 mL container at room temperature. The resulting solution was stirred for 1 hour at room temperature. Then the reaction was quenched by adding 20 ml of water. The resulting solution was extracted with ethyl acetate (3 x 25 ml) and the organic layers were combined. The resulting mixture was washed with water saturated with salt (1 x 10 ml). The resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 5 μm, 19*150 mm; mobile phase A: water (with NH ₄ HCOO ₃ (10 mmol/l) + 0.1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 30% B in 7 min; 254/220 im; Rt: 6.35 min). As a result, 20 mg (24.09%) of 3-amino-N-[[3-(hydroxymethyl)pyridin-2-yl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin- 3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 36) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =434.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.47 (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 shown in the table below were prepared using the methods described for the preparation of compound 36.

Example 38. Preparation of 3-amino-6-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-N-[(2,6-difluorophenyl)methyl]-5-(1,3- Oxazol-2-yl)pyrazin-2-carboxamide (compound 38)

SCHEME 31

Step 1. 5-Bromo-1-cyclopropyl-1,2-dihydropyridin-2-one

To a mixture of 5-bromo-1,2-dihydropyridin-2-one (2 g; 11.49 mmol; 1 eq.), cyclopropylboronic acid (2.0 g; 23.28 mmol; 2.03 eq.) and Cu (AcO) ₂ (2.1 g; 0.01 mmol; 1 eq.) in CH ₂ ClCH ₂ Cl (50 ml) was added Na ₂ CO ₃ (2.4 g; 0.02 mmol; 2 eq.) and 4,4-di-tert-butyl-2,2-dipyridyl (3.1 g; 0.01 mmol; 1 eq.) at room temperature under nitrogen. The resulting mixture was stirred for 12 hours at 70°C under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /MeOH (20:1) to give 5-bromo-1-cyclopropyl-1,2-dihydropyridin-2-one (600 mg; 24.39%) in as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =213.9; 215.9. ^1H NMR: (300 MHz, CDCl ₃ ) δ 0.86 (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]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide

To a solution of 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (50 mg; 0.21 mmol; 1 eq.) and 1-(2,6- difluorophenyl)methanamine (44.6 mg; 0.31 mmol; 1.5 eq.) in DMF (5 ml) was added T ₃ P (132.2 mg; 0.42 mmol; 2.00 eq.) and DIEA ( 80.6 mg; 0.62 mmol; 3 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature in an air atmosphere and concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), giving 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(1,3-oxazol-2- yl)pyrazine-2-carboxamide (120 mg; 39.47%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =366.0. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 4.53 (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-dihydropyridin-2-one

To a solution of 5-bromo-1-cyclopropyl-1,2-dihydropyridin-2-one (100 mg; 0.47 mmol; 1 eq.) and 4,4,5,5-tetramethyl-2-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (177.9 mg; 0.70 mmol; 1.50 eq.) in THF (10 ml) was added KOAc (137.5 mg; 1.40 mmol; 3.00 eq.) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (38.1 mg; 0.05 mmol; 0.1 eq.) in air atmosphere at room temperature. The mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere. 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 (10 ml) was used directly at the next stage without additional 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]-5-(1,3-oxazole -2-yl)pyrazin-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 (100 mg; 0.38 mmol; 1 equiv.) in THF (10 ml) was added 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (280.1 mg; 0.77 mmol; 2 eq.), Cs ₂ CO ₃ (249.5 mg; 0.77 mmol; 2.00 eq.) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ ( 31.3 mg; 0.04 mmol; 0.1 eq.) in a nitrogen atmosphere. The mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere and concentrated in vacuo. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 3-amino-6-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-N-[(2, 6-difluorophenyl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 38) (20 mg; 11.25%) as a yellow solid.

LCMS: m/z (ESI), [M+H] ⁺ =465.2. ^1H NMR: (300 MHz, MeOD) δ 0.93 (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. Preparation of 3-amino-N-[[2-fluoro-6-(morpholin-4-yl)phenyl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl )-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 39)

SCHEME 32

Step 1. 2-Fluoro-6-(morpholin-4-yl)benzonitrile

DIEA ( 1858.2 mg; 14.38 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred for 2.5 hours at 80°C in an air atmosphere. The resulting mixture was diluted with water (200 ml). The resulting mixture was extracted with EtOAc (2 x 300 ml). The combined organic layers were washed with water (2 x 100 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 2-fluoro-6-(morpholin-4-yl)benzonitrile (637 mg; 42.97%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =207.0. ^1H NMR (400 MHz, chloroform-d) δ 3.21-3.28 (m, 4H), 3.85-3.92 (m, 4H), 6.78 (dt, J=8.4; 4.2 Hz, 2H), 7.47 ( td, J=8.4; 6.6 Hz, 1H).

Step 2. 1-[2-Fluoro-6-(morpholin-4-yl)phenyl]methanamine

To a solution of 2-fluoro-6-(morpholin-4-yl)benzonitrile (200 mg; 0.97 mmol; 1 eq.) in MeOH was added Raney Ni (166.2 mg; 1.94 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 1.5 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2×10 ml). The filtrate was concentrated under reduced pressure to give 1-[2-fluoro-6-(morpholin-4-yl)phenyl]methanamine (150 mg; 73.56%) as a white oil, 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]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 39)

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (200 mg; 0.64 mmol; 1 eq.) and 1-[2-fluoro-6-(morpholin-4-yl)phenyl]methanamine (134.2 mg; 0.64 mmol; 1 eq.) in DMF (10 ml) T ₃ P (812.5 mg; 2.55 mmol; 4 eq.) and DIEA (247.5 mg; 1.92 mmol; 3 eq.) were added in portions at room temperature in an air atmosphere. The resulting mixture was stirred for 2 hours at room temperature in an air atmosphere. The resulting mixture was poured into water (30 ml). The resulting solid was collected by filtration and suspended in 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]methyl]-6-(1-methyl-6-oxo-1 ,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 39) (120 mg; 37.18%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =506.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.88 (t, J=4.5 Hz, 4H), 3.34 (s, 3H), 3.64 (t, J=4.5 Hz, 4H), 4.72 ( d, J=5.8 Hz, 2H), 6.32 (d, J=9.4 Hz, 1H), 7.00 (dd, J=9.8; 8.4 Hz, 1H), 7.07 (d, J= 8.1 Hz, 1H), 7.29-7.43 (m, 3H), 7.83 (s, 2H), 7.97 (d, J=2.6 Hz, 1H), 8.30 (d, J=0.8 Hz, 1H ), 9.14 (t, J=5.8 Hz, 1H).

Preparation 40. Preparation of 3-amino-N-(1-(2,6-difluorophenyl)ethyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol- 2-yl)pyrazin-2-carboxamide (compound 40)

SCHEME 33

Step 1. 3-Amino-N-[1-(2,6-difluorophenyl)ethyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3 -oxazol 2-yl)pyrazine-2-carboxamide

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.32 mmol; 1 eq.), T3P (242.7 mg; 0.76 mmol; 2.39 eq.) and DIE A (123.8 mg; 0.96 mmol; 3 eq.) in DMF (10 ml) 1-(2,6-difluorophenyl)ethane-1-amine (75.3 mg; 0.48 mmol; 1.5 eq.) was added portionwise at room temperature under air. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The resulting mixture was poured into water (30 ml). The resulting solid was collected by filtration and suspended in MeOH (10 ml). The resulting solid was collected by filtration and dried under vacuum to give 3-amino-N-[1-(2,6-difluorophenyl)ethyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl )-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (40 mg; 27.42%) as a yellow solid. 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-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide (compound 40-1 and compound 40-2)

The racemic product (60 mg) was purified by preparative chiral HPLC using an eluent. Column: CHIRALPAK IG, 20*250 mm, 5 µm; mobile phase A: Hex:DCM=5:1 (with 10 mM NH ₃ -MEOH) for HPLC, mobile phase B: EtOH for HPLC; flow rate: 16 ml/min; gradient: from 50 V to 50 V in 16 minutes; 220/254 nm; RT1: 10.8; RT2: 12.8. The result was 3-amino-N-(1-(2,6-difluorophenyl)ethyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide (isomer 1) (compound 40-1) (15 mg) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =453. ^1H NMR: (400 MHz, MeOD) δ 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). For a chiral compound: tR=1.967 min; and 3-amino-N-(1-(2,6-difluorophenyl)ethyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl) )pyrazine-2-carboxamide (isomer 2) (compound 40-2) (15 mg) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =453.2. ^1H NMR: (400 MHz, MeOD) δ 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). For a chiral compound: tR=2.500 min, for a mixture of chiral compounds: tR=1.981 min; 2,480 min.

Example 41. Preparation of 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide (compound 41)

SCHEME 34

Stage 1. 5-Bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one

To a mixture of 5-bromo-1,2-dihydropyridin-2-one (2 g; 11.49 mmol; 1 eq.), 2-ioodethan-1-ol (4.0 g; 22.98 mmol; 1.999 eq. ) in DMSO (30 ml) in a 50 ml round bottom flask was added K ₂ CO ₃ (4.8 g; 34.47 mmol; 2.999 eq.) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. Then the reaction was quenched by adding 50 ml of water. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers were combined. The resulting organic layers were washed with sat. NaCl solution (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was applied to a 1:2 ethyl acetate/petroleum ether silica gel column to give 330 mg (12%) of 5-bromo-1-(2-hydroxyethyl)-1,2-dihydropyridin-2-one as a white solid. substances. LCMS: m/z (ESI), [M+H] ⁺ =218.1. ^1H NMR (400 MHz, chloroform-d) δ 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-dihydropyridin-3-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide (compound 41)

5-Bromo-1-(2-hydroxyethyl)-1,2-dihydropyridin-2-one (298.1 mg; 1.37 mmol; 5 eq.), 4,4,5, was placed in a 50 mL round bottom flask. 5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (416.6 mg; 1.64 mmol; 6 equiv .), Pd(dppf)Cl ₂ (120.0 mg; 0.16 mmol; 0.60 eq.), KOAc (80.5 mg; 0.82 mmol; 3 eq.), dioxane (15 ml). The resulting solution was stirred for 2 hours at 80°C in an oil bath. The resulting mixture was directly used in the next step. To this mixture was added 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (100 mg; 0.27 mmol; 1 eq.), Pd(dppf)Cl ₂ (100.0 mg; 0.14 mmol; 0.5 eq.), K ₃ PO ₄ (348.2 mg; 1.64 mmol; 6.00 eq. .), dioxane (15 ml) and water (10 ml). The resulting solution was left to react with stirring in an N ₂ atmosphere for another 16 hours at 80°C in an oil bath. The resulting mixture was concentrated. The resulting solution was extracted with ethyl acetate (3×30 ml). The organic layers were concentrated. The crude product was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 5 μm, 30*150 mm; mobile phase A: water (with NH ₄ HCO ₃ , 10 mmol/l), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 18% B to 42% B in 7 min; 254/220 nm; Rt: 6.42 min). The result was 3-amino-N-[(2,6-difluorophenyl)methyl]-6-[1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 41) (20 mg; 15.3%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =469.2. ^1H NMR (300 MHz, DMSO-J6) δ 3.61-3.63 (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. Preparation of 3-amino-N-[(2,6-difluorophenyl)methyl]-5-(1,3-oxazol-2-yl)-6-[1-(oxetan-3-yl)-6- oxo-1,6-dihydropyridin-3-yl]pyrazin-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 (200 mg; 1.15 mmol; 1 eq.) and 3-bromooxetane (629.8 mg; 4.60 mmol; 4 eq.) in DMF (10 ml) K ₂ CO ₃ (476.6 mg; 3.45 mmol; 3 eq.) was added in portions at RT in an air atmosphere. The resulting mixture was stirred for 3 hours at 100°C in an air atmosphere. The resulting mixture was poured into water. The resulting mixture was extracted with CH ₂ Cl ₂ (2×100 ml). The combined organic layers were washed with water (1×30 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (10:1) to give 5-bromo-1-(oxetan-3-yl)-1,2-dihydropyridin-2-one (120 mg; 45.38 %) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =230.0. ^1H NMR (400 MHz, chloroform-d) δ 4.66-4.74 (m, 2H), 4.96 (ddd, J=7.3; 6.2; 1.0 Hz, 2H), 5.55 (tt, J=6 ,3; 5.3 Hz, 1H), 6.71 (dd, J=8.8; 0.7 Hz, 1H), 7.67 (dd, J=8.7; 2.5 Hz, 1H), 8.11 (dd , J=2.6; 0.7 Hz, 1H).

Step 2. 1-(Oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3.2-dioxaborolan-2-yl)pyridin-2(1H)-one

To a stirred mixture of 5-bromo-1-(oxetan-3-yl)-1,2-dihydropyridin-2-one (230 mg; 1.00 mmol; 1 eq.) and 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (507.7 mg; 2.00 mmol; 2 eq.) in THF (7 ml) KOAc (294.3 mg; 3.00 mmol; 3 eq.) and Pd(dppf)Cl ₂ (146.3 mg; 0.20 mmol; 0.2 eq.) were added in portions at RT in atmosphere nitrogen. The resulting mixture was stirred for 3 hours at 80°C 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]-5-(1,3-oxazol-2-yl)-6-[1-(oxetan-3-yl)-6-oxo -1,6-dihydropyridin-3-yl]pyrazin-2-carboxamide (compound 42)

To a stirred solution/mixture of 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (200 mg ; 0.55 mmol; 1 eq.) and 1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2 -dihydropyridin-2-one (151.6 mg; 0.55 mmol; 1 eq.) in THF (20 ml) Pd(dppf)Cl ₂ (80.0 mg; 0.11 mmol; 0.20 eq.) was added in portions .) and Cs ₂ CO ₃ (534.5 mg; 1.64 mmol; 3.00 eq.) at RT in a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 80°C under a nitrogen atmosphere. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30*150 mm, 5 µm; mobile phase A: water (with 0.05% NH ₃ .H ₂ O), mobile phase B: ACN ; flow rate: 60 ml/min; gradient: from 25% B to 50% B in 7 min; 254/220 nm; Rt: 5.20 min), giving 3-amino-N-[(2,6-difluorophenyl )methyl]-5-(1,3-oxazol-2-yl)-6-[1-(oxetan-3-yl)-6-oxo-1,6-dihydropyridin-3-yl]pyrazin-2-carboxamide (5 mg; 1.90%) (compound 42) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =481.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.58 (d, J=5.8 Hz, 2H), 4.66 (t, J=7.0 Hz, 2H), 4.83 (t, J=7.4 Hz, 2H), 5.56 (p, J=7.3 Hz, 1H), 6.37 (d, J=9.4 Hz, 1H), 7.07 (t, J=8.0 Hz, 2H), 7.28-7.45 (m, 2H), 7.60 (dd, J=9.4; 2.5 Hz, 1H), 7.75 (s, 2H), 7.96 (d, J=2.5 Hz, 1H), 8.29 (d, J =0.8 Hz, 1H), 9.11 (t, J=5.9 Hz, 1H).

Example 45. Preparation of 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[(1,3-thiazol- 4-yl)methyl]pyrazin-2-carboxamide (compound 45)

SCHEME 36

Step 1. Methyl 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (1200 mg; 4.71 mmol; 1 eq.) and 6-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (1725.6 mg; 7.07 mmol; 1.50 eq.) in dioxane (20 ml ) and water (2 ml), Pd(dppf)Cl ₂ (689.7 mg; 0.94 mmol; 0.2 eq.) and Cs ₂ CO ₃ (3071.0 mg; 9.43 mmol; 2 eq.) were added in portions .) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C. The mixture was left to cool to room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3×10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /MeOH (50:1) to give methyl 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxylate (1200 mg; 75.71%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =337. ^1H NMR (DMSO-d ₆ , 400 MHz) δ 3.9 (3H, s), 7.1 (1H, dd, J=9.4; 1.8 Hz), 7.4 (1H, s), 7.5 (1H, d , J=9.3 Hz), 7.6 (1H, d, J=1.2 Hz), 7.7 (2H, s), 8.0 (1H, s), 8.3 (1H, s), 8.7 (1H, t, J=1.4 Hz).

Step 2. 3-Amino-6-[imidazo[1.2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (2.5 g; 7.4 mmol; 1 eq.) in THF (30 ml) LiOH (0.2 g; 8.4 mmol; 1.12 eq.) and H ₂ O (5 ml) were added in portions at room temperature in an air atmosphere. The resulting mixture was stirred for another 4 hours at room temperature and acidified to pH 6 using 1N. aq. HCl solution, the resulting solid was collected by filtration and dried under vacuum to give 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazine -2-carboxylic acid (2 g; 83.5%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =323.2. ^1H NMR (DMSO-d ₆ , 400 MHz) δ 3.9 (3H, s), 7.1 (1H, dd, J=9.4; 1.8 Hz), 7.4 (1H, s), 7.5 (1H, d , J=9.3 Hz), 7.6 (1H, d, J=1.2 Hz), 7.7 (2H, s), 8.0 (1H, s), 8.3 (1H, s), 8.7 (1H, t, J=1.4 Hz).

Step 3. 3-Amino-6-[imidazo[1,2-a]pyridin-6-yl1-5-(1,3-oxazol-2-yl)-N-[(1,3-thiazol-4- yl)methyl]pyrazine-2-carboxamide (compound 45)

To a stirred mixture of 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0. 31 mmol; 1 eq.) and 1-(1,3-thiazol-4-yl)methanamine (70.9 mg; 0.6 mmol; 2.0 eq.) in DMF (3 ml) was added portionwise with HATU (471 .9 mg; 1.2 mmol; 4.0 eq.) and DIE A (160.4 mg; 1.2 mmol; 4.0 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for another 60 minutes at room temperature. The resulting mixture was poured into water (30 ml), the resulting solid was collected by filtration and suspended in MeOH (16 ml), the resulting solid was collected by filtration and dried under vacuum to give 3-amino-6-[imidazo[1,2-a] pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[(1,3-thiazol-4-yl)methyl]pyrazin-2-carboxamide (compound 45) (43 mg; 32.8%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =419.2. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.6 (3H, s), 4.6 (2H, d, J=6.2 Hz), 7.2 (1H, s), 7.3-7.4 (2H, m), 7.6 (1H, d, J=9.3 Hz), 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=6.1 Hz).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 45.

Example 46. Preparation of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((3-(methylamino)pyridin-2-yl)methyl)-5- (oxazol-2-yl)pyrazin-2-carboxamide (compound 46)

SCHEME 37

Step 1. 3-(Methylamino)picolinonitrile

To a solution of 3-fluoropyridine-2-carbonitrile (500 mg; 4.09 mmol; 1 eq.) in THF (20 ml) was added methanamine (190.8 mg; 6.14 mmol; 1.50 eq.) at room temperature . The resulting mixture was stirred for 3 hours at 50°C. The reaction was quenched by adding water (10 ml) at room temperature. The precipitated solids were collected by filtration and dried under reduced pressure to give 3-(methylamino)pyridine-2-carbonitrile (300 mg; 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 (100 mg; 0.75 mmol; 1 eq.) in THF (15 ml) was added Raney Ni (128.7 mg; 1.50 mmol; 2.00 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 5 hours at room temperature under a hydrogen atmosphere. 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 (90 mg; 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)pyridin-2-yl)methyl)-5-( Oxazol-2-yl)pyrazin-2-carboxamide (compound 46)

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (70 mg; 0.22 mmol; 1 eq.) and 2-(aminomethyl)-N-methylpyridin-3-amine (36.8 mg; 0.27 mmol; 1.20 eq.) in DMF (10 ml) were added in portions DIEA (86.6 mg; 0.67 mmol; 3 eq.) and T ₃ P (142.2 mg; 0.45 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The reaction was quenched with water (40 ml) at room temperature. The precipitated solids were collected by filtration and washed with water (10 ml). The product had poor solubility and was purified by trituration with DMF (5 ml). The resulting yellow solid was collected by filtration, washed with methanol (10 ml) and dried under infrared radiation to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-[[ 3-(methylamino)pyridin-2-yl]methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 46) (20 mg; 19.46%) as a yellow solid . LCMS: m/z (ESI), [M+H] ⁺ =433.2; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.74 (d, J=4.5 Hz, 3H), 3.47 (s, 3H), 4.46 (d, J=5.3 Hz, 2H), 5.68 ( d, J=5.0 Hz, 1H), 6.33 (d, J=9.4 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 7.13 (dd, J=8.0; 4.8 Hz, 1H), 7.30-7.47 (m, 2H), 7.69-7.90 (m, 3H), 8.01 (d, J=2.6 Hz, 1H), 8.29 (s, 1H), 9.40 (d , J=5.4 Hz, 1H).

Example 47. Preparation of 3-amino-6-(1H-1,3-benzodiazol-5-yl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(1,3-oxazol-2- yl)pyrazin-2-carboxamide (compound 47)

SCHEME 38

Step 1. 3-Amino-6-chloro-N-[(3-fluoropyridin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide

To a stirred mixture of 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (2000 mg; 8.31 mmol; 1 eq.) and 1-(3-fluoropyridine -2-yl)methanamine (1572.7 mg; 12.47 mmol; 1.5 eq.) in DMF (20 ml) was added in portions with DIEA (4297.4 mg; 33.25 mmol; 4 eq.) and T ₃ R (10579.6 mg; 33.25 mmol; 4 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. 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]-5-(1,3-oxazol-2-yl)pyrazin- 2-carboxamide (2.2 g; 75.89%) as a yellow-green substance. LCMS: m/z (ESI), [M+H] ⁺ =349.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.68 (dd, J=5.7; 1.7 Hz, 2H), 7.43 (dt, J=8.6; 4.4 Hz, 1H), 7.59 (s, 1H), 7.73 (ddd, J=10.0; 8.4; 1.3 Hz, 1H), 7.92 (s, 2H), 8.38-8.46 (m, 2H), 9.17 (t, J= 5.7 Hz, 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)

To a solution of 3-amino-6-chloro-N-[(3-fluoropyridin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (100 mg; 0.29 mmol; 1 eq.) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,3-benzodiazole (140.0 mg; 0.57 mmol ; 2 eq.) in 1,4-dioxane (10 ml) and H ₂ O (1 ml), Cs ₂ CO ₃ (186.9 mg; 0.57 mmol; 2 eq.) and Pd(dppf)Cl ₂ were added (21.0 mg; 0.03 mmol; 0.1 eq.) in an atmosphere of N ₂ . The resulting mixture was stirred for 24 hours at 90°C under a nitrogen atmosphere and concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 µm; mobile phase A: water (with 0.05% NH ₃ .H ₂ O), mobile phase B: ACN ; flow rate: 60 ml/min; gradient: from 21% B to 31% B in 7 min; 254/220 nm; Rt: 6.45 min), giving 3-amino-6-(1H-1,3- benzodiazol-5-yl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 47) (12 mg; 16, 20%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =431.1. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 4.73 (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 shown in the table below were prepared using the methods described for the preparation of compound 47.

Example 48. Preparation of 5-(2,6-dimethylpyridin-4-yl)-6-(4-fluorophenyl)-N4-(2-((3-fluoropyridin-2-yl)amino)ethyl)pyrimidin-2,4 -diamine (compound 48)

SCHEME 39

Step 1. 6-(Aminomethyl)pyridin-2-amine

To a mixture of 6-aminopyridine-2-carbonitrile (100 mg; 0.8 mmol; 1 eq.) and Raney Ni (21.6 mg; 0.3 mmol; 0.3 eq.) in THF (10 ml) dropwise NH ₄ OH (1 ml) was added at room temperature. The resulting mixture was stirred for another 40 minutes at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 6-(aminomethyl)pyridin-2-amine (80 mg; 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-oxazol-2 -yl)pyrazin-2-carboxamide (compound 48)

To a stirred solution/mixture of 3-amino-6-[imidazo[1,2-a]pyridin-6 yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.3 mmol; 1 eq.) and 6-(aminomethyl)pyridin-2-amine (76.4 mg; 0.6 mmol; 2.0 eq.) in DMF (3 ml) was added dropwise/portionally HATU (471.9 mg; 1.2 mmol; 4.0 eq.) and DIEA (160.4 mg; 1.2 mmol; 4.0 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for another 30 minutes at room temperature. The resulting mixture was added dropwise to water. The resulting mixture was filtered, the filter cake was washed with water (3×10 ml). The crude product was recrystallized from DCM/MeOH (5:1, 6 ml) to give 3-amino-N-[(6-aminopyridin-2-yl)methyl]-6-[imidazo[1,2-a]pyridin- 6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 48) (89 mg; 66.1%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =428.1. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.4 (2H, d, J=6.1 Hz), 5.9 (2H, d, J=6.0 Hz), 6.3 (1H, d, J=8 ,1 Hz), 6.4 (1H, d, J=7.2 Hz), 7.2 (1H, dd, J=9.4; 1.8 Hz), 7.3 (1H, t, J=7.8 Hz) , 7.4 (1H, s), 7.5 (1H, d, J=9.4 Hz), 7.6 (1H, d, J=1.3 Hz), 7.9 (3H, s), 8.3 (1H, s), 8.8 (1H, t, J=1.4 Hz), 9.3 (1H, t, J=6.2 Hz).

Example 49. Preparation of 3-amino-N-((6-amino-3-fluoropyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5 -(oxazol-2-yl)pyrazin-2-carboxamide (compound 49)

SCHEME 40

Step 1. tert-Butyl (6-amino-3-fluoropyridin-2-yl)methylcarbamate

To a stirred mixture of 6-bromo-5-fluoropyridin-2-amine (19 mg; 0.10 mmol; 1 eq.), Na ₂ CO ₃ (42.2 mg; 0.40 mmol; 4 eq.) and tert. butyl N-[(trifluoroboranuidyl)methyl]potassium carbamate (70.7 mg; 0.30 mmol; 3 eq.) in toluene (20 ml) and water (3 ml) was added portionwise with S-Phos (12.3 mg; 0 .03 mmol; 0.3 eq.) and Pd(AcO) ₂ (6.7 mg; 0.03 mmol; 0.3 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1), giving tert-butyl N-[(6-amino-3-fluoropyridin-2-yl)methyl]carbamate (130 mg; 41.17%) in as a brown solid. LCMS: m/z (ESI), [M+H] ⁺ =242.1.

Step 2. 6-(Aminomethyl)-5-fluoropyridin-2-amine

To a stirred solution of tert-butyl N-[(6-amino-3-fluoropyridin-2-yl)methyl]carbamate (120 mg; 0.50 mmol; 1 eq.) in DCM (5 ml), a solution of HCl ( gas.) in 1,4-dioxane (362.7 mg; 9.95 mmol; 20 eq.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature in an air atmosphere. The resulting mixture was concentrated to give 6-(aminomethyl)-5-fluoropyridin-2-amine (100 mg; 142.44%) as an off-white solid, which was used in the next step without purification. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.98 (d, J=5.8 Hz, 2H), 6.64 (dd, J=9.1; 3.3 Hz, 1H), 7.53 (t, J =9.1 Hz, 1H).

Step 3. 3-Amino-N-((6-amino-3-fluoropyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5- (oxazol-2-yl)pyrazin-2-carboxamide (compound 49)

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (90 mg; 0.29 mmol; 1 eq.), 6-(aminomethyl)-5-fluoropyridin-2-amine (61.2 mg; 0.43 mmol; 1.51 eq.) and DIEA (149.3 mg; 1.15 mmol; 4.02 eq.) in DMF (10 ml) was added dropwise T ₃ P (182.8 mg; 0.57 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The reaction was quenched by adding water (40 ml) at room temperature. The precipitated solids were collected by filtration and washed with methanol (20 ml) to give 3-amino-N-[(6-amino-3-fluoropyridin-2-yl)methyl]-6-(1-methyl-6-oxo- 1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 49) (30 mg; 15.95%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =437.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.48 (s, 3H), 4.50 (dd, J=5.8; 2.1 Hz, 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=2.6 Hz, 1H), 8.31 (d, J=0.8 Hz, 1H), 9.09 ( t, J=5.8 Hz, 1H).

Example 50. Preparation of 3-amino-N-[[3-fluoro-6-(methylamino)pyridin-2-yl]methyl]-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) )-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 50)

SCHEME 41

Step 1. 6-Bromo-5-fluoro-N-methylpyridin-2-amine

To a stirred mixture of copper(II) acetate (1.64 g; 9.03 mmol; 2.5 eq.) and methyl boronic acid (540.6 mg; 9.03 mmol; 2.5 eq.) in dioxane (30 ml ) pyridine (1 g; 12.64 mmol; 3.5 eq.) and 6-bromo-5-fluoropyridin-2-amine (690 mg; 3.61 mmol; 1 eq.) were added in portions at room temperature in an air atmosphere . The resulting mixture was stirred for 3 hours at 100°C in an air atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (2×30 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 (120 mg; 16.20%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺ =205.1; 207.1.

Step 2. tert-Butyl (3-fluoro-6-(methylamino)pyridin-2-yl)methylcarbamate

To a stirred mixture of mpem-butyl N-[(trifluoroboranuidyl)methyl]potassium carbamate (346.9 mg; 1.46 mmol; 3 eq.) and 6-bromo-5-fluoro-N-methylpyridin-2-amine (100 mg ; 0.49 mmol; 1 eq.) in toluene (20 ml) and water (3 ml), S-Phos (60.1 mg; 0.15 mmol; 0.3 eq.), Pd(AcO) ₂ was added in portions (32.9 mg; 0.15 mmol; 0.3 eq.) and Na ₂ CO ₃ (206.8 mg; 1.95 mmol; 4.00 eq.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 95°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1) to give tert-butyl N-[[3-fluoro-6-(methylamino)pyridin-2-yl]methyl]carbamate (90 mg; 72.28 %) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺ =256.3.

Step 3. 6-(Aminomethyl)-5-fluoro-N-methylpyridin-2-amine

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

Step 4. 3-Amino-N-((3-fluoro-6-(methylamino)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 50)

To a stirred mixture of 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (70 mg; 0.22 mmol; 1 eq.) and 6-(aminomethyl)-5-fluoro-N-methylpyridin-2-amine (38.1 mg; 0.25 mmol; 1.10 eq.) in DMF (10 ml) DIEA (86.6 mg; 0.67 mmol; 3 eq.) and (3H3)phosphane (17.9 mg; 0.45 mmol; 2.00 eq.) 50% in EA ( ethyl acetate) at room temperature. The resulting mixture was stirred for 3 hours at room temperature in an air atmosphere. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with MeOH (20 ml) to give 3-amino-N-[[3-fluoro-6-(methylamino)pyridin-2-yl]methyl]-6-(1-methyl-6 -oxo-1,6-dihydropyridin-3-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 50) (25 mg; 24.59%) as a yellow solid . LCMS: m/z (ESI), [M+H] ⁺ =451.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.63 (d, J=4.7 Hz, 3H), 3.43 (s, 3H), 4.51 (dd, J=5.3; 2.1 Hz, 2H ), 6.21-6.42 (m, 2H), 6.49 (p, J=4.5; 4.0 Hz, 1H), 7.22-7.46 (m, 3H), 7.82 (s, 2H), 7.95 (d, J =2.6 Hz, 1H), 8.28 (d, J=0.8 Hz, 1H), 9.21 (t, J=5.2 Hz, 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. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(4-fluoro-2-methoxybenzyl)-5-(4-fluorophenyl)-pyrazine-2-carboxamide (compound 52 )

To a mixture of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxylic acid (0.05 g, 0.15 mmol), (4-fluoro- 2-methoxyphenyl)methanamine (0.03 g, 0.22 mmol) in DMF (5 ml) was added with DIEA (0.06 g, 0.44 mmol) and HATU (0.06 g, 0.15 mmol) at 20 °C. The mixture was then stirred at this temperature for 1 hour. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then purified using an RP-C18 column 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) (0.04 g; yield: 56.9%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =476.1. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.3 (s, 6H), 3.9 (s, 3H), 4.5 (d, J=6.3 Hz, 2H), 6.7 (td, J= 8.4; 2.4 Hz, 1H), 6.9 (d, J=11.2 Hz, 1H), 7.0 (s, 2H), 7.2-7.2 (m, 3H), 7.4 (dd, J=8, 8; 5.7 Hz, 2H), 9.1 (t, J=6.3 Hz, 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 52.

Example 56 Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(1H-pyrazol-1-yl)pyrazin-2-carboxamide (compound 56)

SCHEME 43

Step 1. Preparation of 3-amino-5,6-dichloropyrazine-2-carboxylic acid

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

Step 2. Preparation of 5-((3H-[1,2,31 triazolo[4,5-b]pyridin-3-yl)oxy)-3-amino-6-chloro-N-(2-methoxybenzyl)pyrazin- 2-carboxamide

To a mixture of 3-amino-5,6-dichloropyrazine-2-carboxylic acid (2.5 g; 12.08 mmol), (2-methoxyphenyl)methanamine (1.99 g; 14.5 mmol) in DMF (20 ml ) DIEA (4.67 g; 36.24 mmol) and HATU (4.59 g; 12.08 mmol) were added at 20°C. The mixture was then stirred at this temperature for 1 hour. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was 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 5-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-3-amino-6-chloro -N-(2-methoxybenzyl)pyrazine-2-carboxamide (5 g; yield: 97.1%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =427.2.

Step 3. Preparation of 3-amino-6-chloro-N-(2-methoxybenzyl)-5-(1H-pyrazol-1-yl)pyrazin-2-carboxamide

To a stirred solution of 5-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-3-amino-6-chloro-N-(2-methoxybenzyl)pyrazin- 2-carboxamide (0.2 g; 0.47 mmol) in DMF (5 ml) was added 1H-pyrazole (0.05 g; 0.7 mmol) and K ₂ CO ₃ (0.33 g; 2.35 mmol ) at 110°C. The mixture was then stirred at 110°C for 3 hours. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was 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)pyrazin-2-carboxamide (0.14 g ; yield: 83.3%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =359.1.

Step 4. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(1H-pyrazol-1-yl)pyrazin-2-carboxamide (compound 56)

To a mixture of 3-amino-6-chloro-N-(2-methoxybenzyl)-5-(1H-pyrazol-1-yl)pyrazin-2-carboxamide (0.07 g; 0.2 mmol), (2-methoxyphenyl )methanamine (0.07 g, 0.29 mmol) in dioxane (10 ml), K ₃ PO ₄ (0.12 g, 0.59 mmol) and Pd ₂ dba ₃ (0.02 g, 0.02 mmol) were added ) at 120°C. The mixture was then stirred at this temperature for 0.5 hours. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then concentrated and purified using RP-C18 to give the product 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(1H-pyrazol-1- yl)pyrazin-2-carboxamide (compound 56) (0.017 g; yield: 20.3%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =429.5. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm ^2.3 (s, 6H), 2.7-2.8 (m, 2H), 3.5 (br d, J=6.0 Hz, 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=8.7 Hz, 2H) , 7.2 (br t, J=7.1 Hz, 3H).

Example 57 Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(1H-pyrazol-1-yl)pyrazin-2-carboxamide (compound 57)

SCHEME 44

Step 1. Preparation of 3-(difluoromethoxy)picolinonitrile

To a stirred solution of 3-hydroxypicolinonitrile (2.2 g; 18.33 mmol) in ACN (10 ml) and water was added dimethyl(bromodifluoromethyl)phosphonate (8.72 g; 36.66 mmol) and KOH (3.08 g; 54.99 mmol) at -78°C. The mixture was then stirred at -78°C for 16 hours. LCMS indicated completion of the reaction. Water was added and the mixture was extracted with EA and concentrated to give 3-(difluoromethoxy)picolinonitrile as a dark oil. LCMS: m/z (ESI), [M+H] ⁺ =171.4.

Step 2. Preparation of (3-(difluoromethoxy)pyridin-2-yl)methanamine

To a stirred solution of 3-(difluoromethoxy)picolinonitrile (1.5 g, 8.82 mmol) in THF (20 mL) was added LiAlH ₄ (0.5 g, 13.23 mmol) at 0°C. The mixture was then stirred at 0°C for 1 hour. LCMS indicated the presence of the desired product. Water was added and the mixture was extracted with EA. Concentrated to give a yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =175.1.

Step 3. Preparation of 3-amino-N-((3-(difluoromethoxy)pyridin-2-yl)methyl)-6-(2.6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-carboxamide (connections 57)

To a mixture of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxylic acid (0.03 g, 0.09 mmol), (3-(difluoromethoxy )pyridin-2-yl)methanamine (0.02 g; 0.13 mmol) in DMF (5 ml) was added DIEA (0.03 g; 0.27 mmol) and HATU (0.03 g; 0.09 mmol ) at 20°C. The mixture was then stirred at this temperature for 1 hour. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then purified using 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) (0.03 g; yield: 68.4%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =495.6. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm ^2.3 (s, 6H), 4.7 (d, J=6.0 Hz, 2H), 7.0 (s, 2H), 7.2-7.3 (m, 3H), 7.3-7.5 (m, 4H), 7.7 (d, J=8.5 Hz, 1H), 8.4 (d, J=3.5 Hz, 1H), 9.2 (t, J=5.7 Hz , 1H).

Example 58 Preparation of 3-amino-N-((3-(difluoromethoxy)pyridin-2-yl)methyl)-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridine -3-yl)pyrazin-2-carboxamide (compound 58)

SCHEME 45

Step 1. Preparation of 3-amino-6-chloro-N-((3-(difluoromethoxy)pyridin-2-yl)methyl)-5-(4-fluorophenyl)pyrazine-2-carboxamide

To a mixture of 3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-carboxylic acid (0.12 g, 0.45 mmol), (3-(difluoromethoxy)pyridin-2-yl)methanamine (0 .08 g; 0.45 mmol) in DMF (5 ml) were added DIEA (0.17 g; 1.35 mmol) and HATU (0.17 g; 0.45 mmol) at 20°C. The mixture was then stirred at this temperature for 1 hour. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then purified using RP-C18 and concentrated to give the product 3-amino-6-chloro-N-((3-(difluoromethoxy)pyridin-2-yl)methyl)-5-(4-fluorophenyl)pyrazin- 2-Carboxamide (0.07 g; yield: 36.8%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =424.2.

Step 2. Preparation of 3-amino-N-((3-(difluoromethoxy)pyridin-2-yl)methyl)-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,b-dihydropyridine -3-yl)pyrazin-2-carboxamide (compound 58)

To a mixture of 3-amino-6-chloro-N-((3-(difluoromethoxy)pyridin-2-yl)methyl)-5-(4-fluorophenyl)pyrazine-2-carboxamide (0.06 g, 0.14 mmol ), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.05 g; 0.21 mmol) in dioxane (3 ml), K ₃ PO ₄ (0.09 g, 0.43 mmol) and Pd ₂ dba ₃ (0.01 g, 0.01 mmol) were added at 120°C. The mixture was then stirred at this temperature for 0.5 hours. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then concentrated and purified using 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)pyrazin-2-carboxamide (compound 58) (0.025 g; yield: 35.5%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =497.2. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm ^3.4 (s, 3H), 4.7 (d, J=5.7 Hz, 2H), 6.2 (d, J=9.5 Hz, 1H) , 7.1 (dd, J=9.5; 2.5 Hz, 1H), 7.2-7.3 (m, 3H), 7.4 (s, 1H), 7.4 (dd, J=8.5; 4.7 Hz, 1H), 7.5-7.6 (m, 3H), 7.7 (d, J=8.2 Hz, 1H), 8.0 (d, J=2.5 Hz, 1H), 8.4 (d, J=4.4 Hz , 1H), 9.2 (t, J=6.0 Hz, 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)pyrazin-2-carboxamide (compound 59)

SCHEME 46

Step 1. Preparation of 3-amino-6-chloro-N-(2-(difluoromethoxy)phenyl)-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide

To a mixture of 3-amino-6-chloro-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxylic acid (0.1 g; 0.4 mmol), 2-(difluoromethoxy)aniline ( 0.1 g; 0.59 mmol) in DMF (5 ml) was added DIEA (0.15 g; 1.19 mmol) and HATU (0.15 g; 0.4 mmol) at 20°C. The mixture was then stirred at this temperature for 1 hour. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then purified using 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 (0.05 g; yield: 30.7%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =413.4.

Step 2. 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)pyrazin-2-carboxamide (compound 59)

To a mixture of 3-amino-6-chloro-N-(2-(difluoromethoxy)phenyl)-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide (0.03 g; 0.07 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.03 g; 0.11 mmol ) in dioxane (3 ml), K ₃ PO ₄ (0.05 g, 0.22 mmol) and Pd ₂ dba ₃ (0.01 g, 0.01 mmol) were added at 120°C. The mixture was then stirred at this temperature for 0.5 hours. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then concentrated and purified using 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)pyrazin-2-carboxamide (compound 59) (0.02 g; yield: 56.6%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =486.1. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.2 (s, 3H), 3.5 (s, 3H), 6.3 (d, J=9.5 Hz, 1H), 6.4 (d, J= 2.5 Hz, 1H), 7.0 (dd, J=9.5; 2.5 Hz, 1H), 7.1-7.5 (m, 5H), 7.8-7.9 (m, 2H), 8.1 (d, J= 2.2 Hz, 1H), 8.3-8.3 (m, 1H), 10.3 (s, 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 59.

Example 61 Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(5-methylfuran-3-yl)pyrazin-2-carboxamide (compound 61)

SCHEME 47

Step 1. Preparation of methyl 3-amino-6-chloro-5-(5-methylfuran-3-yl)pyrazin-2-carboxylate

To a mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (0.5 g; 2.26 mmol), 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)- 1,3,2-dioxaborolane (0.71 g; 3.39 mmol) in dioxane (20 ml) was added Na ₂ CO ₃ (0.94 g; 4.53 mmol) and Pd(dppf)Cl ₂ (0. 83 g; 1.13 mmol) at 100°C. The mixture was then stirred at this temperature for 2 hours. LCMS indicated completion of the reaction, and the reaction mixture was purified by silica gel chromatography to give the desired product methyl 3-amino-6-chloro-5-(5-methylfuran-3-yl)pyrazin-2 -carboxylate.LCMS: m/z (ESI), [M+H] ⁺ =268.4.

Step 2. Preparation of methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(5-methylfuran-2-yl)pyrazin-2-carboxylate

To a mixture of methyl 3-amino-6-chloro-5-(5-methylfuran-3-yl)pyrazin-2-carboxylate (0.26 g, 1 mmol), 2,6-dimethyl-4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.23 g; 1 mmol) in dioxane (20 ml) was added Na ₂ CO ₃ (0.94 g; 4.53 mmol) and Pd(dppf)Cl ₂ (0.073 g; 0.1 mmol) at 100°C. The mixture was then stirred at this temperature for 2 hours. LCMS indicated completion of the reaction and the reaction mixture was purified by silica gel chromatography to give the desired product methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(5 -methylfuran-2-yl)pyrazin-2-carboxylate. LCMS: m/z (ESI), [M+H] ⁺ =339.5.

Step 3. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(5-methylfuran-2-yl)pyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(5-methylfuran-2-yl)pyrazin-2-carboxylate (0.4 g; 1.18 mmol) in MeOH (20 ml) was added NaOH (0.09 g; 2.37 mmol) at 25°C. The mixture was then stirred at this temperature for 16 hours. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was 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)pyrazin-2-carboxylic acid (0.3 g; yield: 78.2%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =325.2.

Step 4. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(5-methylfuran-2-yl)pyrazin-2-carboxamide (compound 61)

To a mixture of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(5-methylfuran-2-yl)pyrazin-2-carboxylic acid (0.05 g, 0.15 mmol), ( 2-methoxyphenyl)methanamine (0.021 g; 0.15 mmol) in DMF (5 ml) was added with DIEA (0.058 g; 0.45 mmol) and HATU (0.057 g; 0.15 mmol) at 20°C. The mixture was then stirred at this temperature for 1 hour. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then purified using RP-C18 and concentrated to give the product 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(5-methylfuran-2- yl)pyrazin-2-carboxamide (compound 61) (0.021 g; yield: 32%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =444.1. 1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.2 (s, 3H), 2.4 (s, 6H), 3.8 (s, 3H), 4.5 (d, J=6.3 Hz, 2H), 6.2 (d, J=3.2 Hz, 1H), 6.5 (d, J=3.2 Hz, 1H), 6.9 (t, J=7.4 Hz, 1H), 7.0 (d, J=8, 2 Hz, 1H), 7.1-7.2 (m, 3H), 7.2 (t, J=7.1 Hz, 1H), 8.9 (t, J=6.3 Hz, 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 61.

Example 63 Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxamide (connections 63)

SCHEME 48

Step 1. Preparation of methyl 3-amino-6-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxylate

To a mixture of methyl 3-amino-5,6-dichloropyrazin-2-carboxylate (0.5 g; 2.26 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (0.43 g; 3 .39 mmol) in dioxane (20 ml), Na ₂ CO ₃ (0.57 g; 4.53 mmol) and Pd(dppf)Cl ₂ (0.83 g; 1.13 mmol) were added at 100°C. The mixture was then stirred at this temperature for 2 hours. LCMS indicated completion of the reaction, and the reaction mixture was purified by silica gel chromatography to give 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. Preparation of methyl 3-amino-6-(2,b-dimethylpyridin-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxylate

To a mixture of methyl 3-amino-6-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxylate (0.4 g, 1.5 mmol), (2,6-dimethylpyridin- 4-yl)boronic acid (0.34 g; 2.25 mmol) in dioxane (20 ml) was added Na ₂ CO ₃ (0.45 g; 3 mmol) and Pd(dppf)Cl ₂ (0.55 g; 0.75 mmol) at 100°C. The mixture was then stirred at this temperature for 2 hours. LCMS indicated completion of the reaction and the reaction mixture was purified by silica gel chromatography to give the desired product methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(1 -methyl-1H-pyrazol-4-yl)pyrazin-2-carboxylate. LCMS: m/z (ESI), [M+H] ⁺ =339.2.

Step 3. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxylate (0.4 g; 1. 18 mmol) in MeOH (20 ml) was added NaOH (0.09 g, 2.37 mmol) at 25°C. The mixture was then stirred at this temperature for 16 hours. LCMS indicated completion of the reaction. Next, the mixture was concentrated, the residue was 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)pyrazin-2-carboxylic acid (0 .3 g; yield: 78.2%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =325.5.

Step 4. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxamide (connections 63)

To a mixture of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxylic acid (0.05 g; 0.15 mmol), (2-methoxyphenyl)methanamine (0.021 g; 0.15 mmol) in DMF (5 ml) was added DIEA (0.058 g; 0.45 mmol) and HATU (0.057 g; 0.15 mmol) at 20°C . The mixture was then stirred at this temperature for 1 hour. LCMS indicated completion of the reaction. The mixture was then concentrated, the residue was poured into water and then extracted with EA (2×25 ml). The organic solution was then purified using 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)pyrazin-2-carboxamide (compound 63) (0.004 g; yield: 6%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =444.2. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.2 (s, 3H), 2.4 (s, 6H), 3.8 (s, 3H), 4.5 (d, J=6.3 Hz, 2H) , 6.2 (d, J=3.2 Hz, 1H), 6.5 (d, J=3.2 Hz, 1H), 6.9 (t, J=7.4 Hz, 1H), 7.0 (d, J=8 ,2 Hz, 1H), 7.1-7.2 (m, 3H), 7.2 (t, J=7.1 Hz, 1H), 8.9 (t, J=6.3 Hz, 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of 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)pyrazin- 2-carboxamide (compound 72)

SCHEME 49

Step 1. Preparation of methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylate

To a mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (4.4 g; 19.91 mmol), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (3.07 g; 21.9 mmol) in dioxane (50 ml) and water (5 ml) was added Na ₂ CO ₃ (4.22 g; 39.82 mmol) and dppfPdCl ₂ (2.84 g ; 3.98 mmol). The mixture was then stirred at 100°C for 1 hour under N ₂ atmosphere. Next, the mixture was concentrated, the residue was poured into water (100 ml) and then extracted with EA (100 ml × 3). The organic solution was then concentrated to give the crude product (5.5 g; 98% yield) as a yellow solid, which was used in the next step without further purification. MS m/z (ESI) [M+H] ⁺ =282.2.

Step 2. Preparation of 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylic acid

LiOH (0 .3 g; 12 mmol). The mixture was then stirred at 20°C for 3 hours. The mixture was then diluted with citric acid solution (2N; 50 ml) and then filtered. The solid was dried to give 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylic acid (0.95 g; 91% yield) as a yellow solid. MS m/z (ESI) [M+H] ⁺ =268.2.

Step 3. Preparation of 3-amino-6-chloro-N-(2-(difluoromethoxy)benzyl)-5-(4-fluorophenyl)-pyrazine-2-carboxamide

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

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

To a mixture of 3-amino-6-chloro-N-(2-(difluoromethoxy)benzyl)-5-(4-fluorophenyl)-pyrazine-2-carboxamide (90 mg; 0.21 mmol), 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (50 mg; 0.21 mmol), Pd ₂ (dba) ₃ (8 mg ; 0.0087 mmol), tricyclohexylphosphine (11 mg; 0.039 mmol) and K ₃ PO ₄ (75 mg; 0.35 mmol) in dioxane (3 ml) water (1 ml) was added. The resulting mixture was hermetically sealed and heated at 120°C for 15 minutes in a microwave reactor. The mixture was filtered and the filtrate was purified on 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)pyrazin-2-carboxamide (compound 72) (82 mg; 78% yield) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =496.3. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 3.42 (s, 3H), 4.57 (d, J=6.31 Hz, 2H), 6.20 (d, J=9.46 Hz, 1H) , 7.10 (dd, J=9.30; 2.68 Hz, 1H), 7.16-7.30 (m, 5H), 7.30-7.36 (m, 2H), 7.44-7.83 (m, 3H), 7.64 (br d ,J=16.08 Hz, 1H), 7.99 (d, J=2.52 Hz, 1H), 9.23 (t, J=6.31 Hz, 1H).

The compound shown in the table below was prepared using the methods described for the preparation of compound 72.

Example 75. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide (75 connections)

SCHEME 50

Step 1. Preparation of 3-amino-6-chloro-X-(2-methoxybenzyl)-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide

To a mixture of 5-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-3-amino-6-chloro-N-(2-methoxybenzyl)pyrazine- 2-carboxamide (500 mg; 1.2 mmol) in DMF (5 ml) was added 3-methyl-1H-pyrazole (120 mg; 1.5 mmol) and K ₂ CO ₃ (350 mg; 2.5 mmol). The resulting mixture was heated at 120°C for 1 hour. The mixture was purified on C18 (40 g; MeCN/water, 5%-80%) to give 3-amino-6-chloro-N-(2-methoxybenzyl)-5- (3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide (200 mg; yield 46%) and 3-amino-6-chloro-N-(2-methoxybenzyl)-5-(5-methyl- 1H-pyrazol-1-yl)pyrazin-2-carboxamide (40 mg; yield 7%) as yellow solids. LCMS m/z (ESI) [M+H] ⁺ =373.2.

Step 2. Preparation of 3-amino-6-(2,b-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide (75 connections)

To a mixture of 3-amino-6-chloro-N-(2-methoxybenzyl)-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide (45 mg; 0.12 mmol), (2 ,6-dimethylpyridin-4-yl)boronic acid (20 mg; 0.13 mmol), Pd ₂ (dba) ₃ (7 mg; 0.0076 mmol), tricyclohexylphosphine (13 mg; 0.046 mmol) and K ₃ PO ₄ (45 mg; 0.21 mmol) in dioxane (3 ml) was added water (1 ml). The resulting mixture was hermetically sealed and heated at 120°C for 15 minutes in a microwave reactor. The mixture was filtered and the filtrate was purified on 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)pyrazin-2-carboxamide (compound 75) (36 mg; 67% yield) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =444.3. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.10 (s, 3H), 2.34 (s, 6H), 3.84 (s, 3H), 4.50 (d, J=6.31 Hz, 2H) , 6.34 (d, J=2.52 Hz, 1H), 6.86 (s, 2H), 6.89 (t, J=7.41 Hz, 1H), 7.00 (d, J=8.20 Hz, 1H), 7.15 (d, J=7.25 Hz, 1H), 7.23 (t, J=7.90 Hz, 1H), 7.98 (d, J=2.21 Hz, 3H), 9.04 (t, J=6, 42 Hz, 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of 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)pyrazin- 2-carboxamide (compound 77)

SCHEME 51

Step 1. Preparation of 5-bromo-1-(oxetan-3-yl)pyridin-2(1H)-one

To a mixture of 5-bromopyridin-2(1H)-one (1.2 g, 6.9 mmol) in DMF (10 ml) was added 3-iodoxetane (1.3 g, 7.1 mmol) and Cs ₂ CO ₃ ( 2.7 g; 8.3 mmol). The resulting mixture was heated at 100°C for 4 hours. The mixture was filtered and the filtrate was purified on C18 (40 g; MeCN/water, 5%-40%), yielding 5-bromo-1-(oxetan-3-yl)pyridin- 2(1H)-one (310 mg; 20% yield) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =230.1.

Step 2. Preparation of 1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

To a mixture of 5-bromo-1-(oxetan-3-yl)pyridin-2(1H)-one (260 mg; 1.1 mmol), 4,4,4',4',5,5,5', 5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (300 mg; 1.2 mmol) and PdCl ₂ (dppf) (30 mg; 0.041 mmol) in dioxane (5 ml) added KOAc (250 mg; 2.6 mmol). The mixture was then heated at 90°C for 30 minutes in a microwave reactor. The mixture was then diluted with water (50 ml) and extracted with EA (50 ml). The organic layer was dried using brine and anhydrous Na ₂ SO ₄ then concentrated to give the crude product (250 mg; 80% yield) as a brown solid. MS m/z (ESI) 278.3 [M+H] ⁺ .

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

To a mixture of 1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (20 mg; 0.072 mmol), 3-amino-6-chloro-N-(2,6-difluorobenzyl)-5-(4-fluorophenyl)pyrazine-2-carboxamide (35 mg; 0.89 mmol), Pd ₂ (dba) ₃ ( 7 mg; 0.0076 mmol), tricyclohexylphosphine (13 mg; 0.046 mmol) and K ₃ PO ₄ (45 mg; 0.21 mmol) in dioxane (3 ml) water (1 ml) was added. The resulting mixture was hermetically sealed and heated at 120°C for 15 minutes in a microwave reactor. The mixture was filtered and the filtrate was purified on 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)pyrazin-2-carboxamide (compound 77) (21 mg; 57% yield) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =508.3. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 4.30 (s, 2H), 4.64 (t, J=6.94 Hz, 2H), 4.94 (t, J=7.41 Hz, 2H) , 5.62 (quin, J=7.01 Hz, 1H), 6.40 (d, J=9.14 Hz, 1H), 6.99 (br t, J=7.72 Hz, 2H), 7.10 (br t,J =8.67 Hz, 2H), 7.24 (dd, J=9.46; 2.21 Hz, 1H), 7.30-7.37 (m, 1H), 7.54 (br dd, J=8.51; 5.36 Hz, 2H),7.86 (d, J=2.21 Hz, 1H).

Example 78 Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-fluorobenzyl)-5-(4-fluorophenyl)pyrazine-2-carboxamide (compound 78)

SCHEME 52

Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-fluorobenzyl)-5-(4-fluorophenyl)-pyrazin-2-carboxamide (compound 78)

To a stirred mixture of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxylic acid (20 mg; 0.059 mmol), (2-fluorophenyl)methanamine (7 .4 mg; 0.059 mmol) and DIPEA (15 mg; 0.118 mmol) were added as one portion of HATU (25 mg; 0.065 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The solution was purified on 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) (16.3 mg; 61.94% yield) as an off-white solid. LCMS: m/z (ESI), [M+H] ⁺ =446.4. ¹ H NMR (500 MHz, CDCl ₃ ) δ ^ppm 1.9 (brs, 2H), 2.5 (s, 6H), 4.7 (d, J=6.3 Hz, 2H), 6.9 (s, 2H), 7.0 (t, J=8.7 Hz, 2H), 7.1-7.2 (m, 2H), 7.25-7.30 (m, 1H), 7.3-7.4 (m, 3H), 8.3 (brt, J=6.1 Hz , 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of 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)pyrazin-2 -carboxamide (compound 82)

SCHEME 53

Suspension of 3-amino-6-chloro-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazine-2-carboxamide (30 mg; 0.078 mmol), 1,3-dimethyl-5-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (23 mg; 0.093 mmol) and K ₃ PO ₄ (28 mg; 0.132 mmol) in a mixture of dioxane (1 .50 ml)/water (0.375 ml) was degassed and purged with N ₂ 3 times, then PCy ₃ (tricyclohexylphosphine) (6.5 mg; 0.023 mmol) and Pd ₂ (dba) ₃ (7 mg; 0.008 mmol) were added. The resulting mixture was again degassed and purged with N ₂ 3 times. The reaction mixture was sealed and heated at 120°C for 1 hour using a microwave reactor. The solution was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on C18 (40 g) eluting with a gradient of 0% to 60% MeCN in water (with 0.05% ammonium 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) (25 mg; 68.08% yield) as a yellow solid substances. LCMS: m/z (ESI), [M+H] ⁺ =474.4. ¹ H NMR (500 MHz, CDCl ₃ ) δ ^ppm 1.7 (s, 2H), 2.1 (s, 3H), 3.5 (s, 3H), 3.9 (s, 3H), 4.7 (d, J=6, 3 Hz, 2H), 6.9 (d, J=8.2 Hz, 1H), 6.9 (t, J=7.4 Hz, 1H), 7.1 (t, J=8.7 Hz, 2H), 7.1 ( d, J=2.2 Hz, 1H), 7.2 (s, 1H), 7.3-7.3 (m, 1H), 7.3-7.4 (m, 1H) 7.5 (dd, J=8.8; 5.4 Hz , 2H), 8.4 (brt, J=6.0 Hz, 1H).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 82.

Example 83 Preparation of 3-amino-6-(2-amino-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazine-2-carboxamide (compound 83)

SCHEME 54

Step 1. Preparation of (2-amino-6-methylpyridin-4-yl) boronic acid

Suspension of 4-bromo-6-methylpyridin-2-amine (80 mg; 0.428 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (130 mg; 0.513 mmol) and KOAc (50 mg; 0.51 mmol) in dioxane (4 ml) were degassed and purged with N ₂ 3 times, then PdCl ₂ (dppf) (16 mg; 0.021 mmol). The resulting mixture was again degassed and purged with N ₂ 3 times. The reaction mixture was sealed and heated at 100°C for 16 hours. The solution was filtered and evaporated under reduced pressure to give (2-amino-6-methylpyridin-4-yl)boronic acid (96 mg; crude), which was used as follows. stage without additional 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)-pyrazine-2-carboxamide (compound 83)

Suspension of 3-amino-6-chloro-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazin-2-carboxamide (30 mg; 0.078 mmol), (2-amino-6-methylpyridin-4-yl) boronic acid (48 mg; 0.093 mmol) and K ₃ PO ₄ (48 mg; 0.244 mmol) in a mixture of dioxane (1.50 ml)/water (0.37 ml) were degassed and purged with N ₂ 3 times, then PCy ₃ was added (6.5 mg; 0.023 mmol) and Pd ₂ (dba) ₃ (7 mg; 0.008 mmol). The resulting mixture was again degassed and purged with N ₂ 3 times. The reaction mixture was sealed and heated at 120°C for 1 hour using a microwave reactor. The solution was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on C18 (40 g) eluting with a gradient of 0% to 100% MeCN in water (with 0.05% ammonium hydroxide) to give 3-amino-6-(2-amino-6-methylpyridinium-4 -yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)-pyrazine-2-carboxamide (compound 83) (7.6 mg; 21.3% yield) as an off-white solid. LCMS: m/z (ESI), [M+H] ⁺ =495.3. ¹ H NMR (500 MHz, CDCl ₃ ) δ ^ppm 1.9 (brs, 2H), 2.3 (s, 3H), 3.9 (s, 3H), 4.7 (d, J=6.3 Hz, 2H), 4.7 (brs, 2H), 6.3 (s, 1H), 6.5 (s, 1H), 6.9 (d, J=8.2 Hz, 1H), 6.9-7.0 (m, 1H), 7.0 (t, J=8 .5 Hz, 2H), 7.3-7.4 (m, 2H), 7.4-7.5 (m, 2H), 8.4 (brt, J=6.1 Hz, 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. Preparation of 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile

In the reaction mixture to a solution of 3-amino-5,6-dichloropyrazine-2-carbonitrile (300 mg; 1.5 mmol) and (4-fluorophenyl)boronic acid (233 mg; 1.6 mmol) in dioxane (14 ml) 2 M Na ₂ CO ₃ solution (1.6 ml) was added. The resulting mixture was degassed and purged with N ₂ 3 times, then PdCl ₂ (dppf) (58 mg; 0.079 mmol) was added. The resulting mixture was again degassed and purged with N ₂ 3 times. The resulting mixture was heated at 80°C under nitrogen using a balloon for 6 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to give 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile (395 mg; crude) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺ =249.2.

Step 2. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carbonitrile

A solution of 3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-carbonitrile (395 mg; 1.5 mmol) and (2,6-dimethylpyridin-4-yl)boronic acid (288 mg; 1 .9 mmol) in dioxane (14 ml). Then a 2 M Na ₂ CO ₃ solution (1.6 ml) was added to the reaction mixture. The resulting mixture was degassed and purged with N ₂ 3 times, then PdCl ₂ (dppf) (58 mg; 0.079 mmol) was added. The resulting mixture was again degassed and purged with N ₂ 3 times. The resulting mixture was heated at 90°C under nitrogen using a balloon for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, the filtrate was 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 (311 mg; 61% yield) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺ =320.3.

Step 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 (60 mg; 0.188 mmol) in anhydrous THF (0.5 ml) was added dropwise into a stirred suspension of LiAlH ₄ (14 mg; 0.376 mmol) in anhydrous THF (1.5 ml) at 0°C in an ice/water bath. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. The reaction mixture was diluted with anhydrous THF (10 ml), cooled and stirred at 0°C in an ice/water bath. Sodium sulfate decahydrate (500 mg; three portions) was then added and the resulting mixture was stirred at this temperature for 30 minutes. The filtrate was then filtered and concentrated in vacuo to give 3-(aminomethyl)-5-(2,6-dimethylpyridin-4-yl)-6-(4-fluorophenyl)pyrazin-2-amine (50 mg; 82% yield) the form of brown butter. LCMS: m/z (ESI), [M+H] ⁺ =324.4.

Step 4. Preparation of N-((3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-yl)methyl)-2-methoxybenzamide (compound 86)

A solution of 3-(aminomethyl)-5-(2,6-dimethylpyridin-4-yl)-6-(4-fluorophenyl)pyrazin-2-amine (50 mg; 0.15 mmol) and TEA (47 mg; 0. 46 mmol) in NMP (1 ml) was cooled in an ice/water bath at 0°C, then a solution of 2-methoxybenzoyl chloride (26 mg; 0.155 mmol) in NMP (1.0 ml) was added dropwise to the reaction mixture. The resulting mixture was stirred and slowly warmed to room temperature over 2 hours. The solution was purified by flash chromatography on C18 (40 g) eluting with a gradient of 0% to 50% MeCN in water (with 0.05% ammonium hydroxide) to give N- ((3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-yl)methyl)-2-methoxybenzamide (compound 86) (15 mg; 46% yield ) as a whitish solid. LCMS: m/z (ESI), [M+H] ⁺ =458.3. ^1H NMR (500 MHz, CDCl ₃ ) δ ^ppm 2.5 (s, 6H), 3.9 (s, 3H), 4.8 (d, J=6.3 Hz, 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; 1.6 Hz, 1H), 8.7 (brt, J=6.0 Hz, 1H).

Example 87. Preparation of 3-amino-6-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(2,6-difluorobenzyl)-5-(4-fluorophenyl)pyrazin-2 -carboxamide (compound 87)

SCHEME 56

Step L Preparation of 3-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 (200 mg; 0.74 mmol), (2,6-difluorophenyl)methanamine (107 mg; 0.74 mmol ) and DIPEA (93 mg; 1.49 mmol) were added as one portion of HATU (313 mg; 0.82 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The solution was purified on C18 (40 g; MeCN/water, 0%-60%) to give 3-amino-6-chloro-N-(2,6-difluorobenzyl)-5-(4-fluorophenyl)pyrazine-2-carboxamide (290 mg; 99% yield) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =393.2.

Step 2. Preparation of 3-amino-6-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(2,6-difluorobenzyl)-5-(4-fluorophenyl)pyrazin-2 -carboxamide (compound 87)

Suspension of 3-amino-6-chloro-N-(2,6-difluorobenzyl)-5-(4-fluorophenyl)pyrazine-2-carboxamide (50 mg; 0.12 mmol), 1-cyclopropyl-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (40 mg; 0.15 mmol) and K ₃ PO ₄ (46 mg; 0.21 mmol ) in a mixture of dioxane (2.0 ml)/water (0.4 ml) was degassed and purged with N ₂ 3 times, then PCy ₃ (11 mg; 0.039 mmol) and Pd ₂ (dba) ₃ (12 mg; 0.013 mmol) were added ). The resulting mixture was again degassed and purged with N ₂ 3 times. The reaction mixture was sealed and heated at 120°C for 15 minutes using a microwave reactor. The solution was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on C18 (40 g) eluting with a gradient of 0% to 70% MeCN in water (with 0.05% ammonium 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) (40 mg; 64% yield) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =492.3. ^1H NMR (500 MHz, CDCl ₃ ) δ ^ppm 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=6.3 Hz, 2H), 6.5 (d, J=9.1 Hz, 1H), 6.9 (t, J=7.9 Hz, 2H), 7.1 (t, J=8.5 Hz, 2H), 7.2-7.3 (m, 1H), 7.3-7.3 (m, 2H), 7.4-7.5 (m, 2H), 8.2 (brt, J=6.3 Hz, 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. Preparation of 3-amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-carbonitrile

In the reaction mixture to a solution of 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile (395 mg; 1.587 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (448 mg; 1.905 mmol) in dioxane (14 ml) was added 2 M solution of Na ₂ CO ₃ (336 mg; 1.6 ml) . The resulting mixture was degassed and purged with N ₂ 3 times, then PdCl ₂ dppf) (58 mg; 0.079 mmol) was added. The resulting mixture was again degassed and purged with N ₂ 3 times. The resulting mixture was heated at 90°C under nitrogen using a balloon for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, the filtrate was 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)pyrazin-2-carbonitrile (235 mg; 46% yield) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺ =322.3.

Step 2. Preparation of 5-(5-amino-6-(aminomethyl)-3-(4-fluorophenyl)pyrazin-2-yl)-1-methylpyridin-2(1H)-one

A solution of 3-amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-carbonitrile (51 mg; 0.159 mmol) in anhydrous THF ( 0.5 ml) was added dropwise to a stirred suspension of LiAlH ₄ (12 mg; 0.317 mmol) in anhydrous THF (1.5 ml) at 0°C in an ice/water bath. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. The reaction mixture was diluted with anhydrous THF (10 ml), cooled and stirred at 0°C in an ice/water bath. Sodium sulfate decahydrate (500 mg; three portions) was then added and the resulting mixture was stirred at this temperature for 30 minutes. Next, it was 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 (52 mg; yield 100%) in the form of brown oil. LCMS: m/z (ESI), [M+H] ⁺ =326.5.

Step 3. 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)

A solution of 5-(5-amino-6-(aminomethyl)-3-(4-fluorophenyl)pyrazin-2-yl)-1-methylpyridin-2(1H)-one (52 mg; 0.16 mmol) and TEA ( 49 mg; 0.48 mmol) in NMP (1 ml) was cooled in an ice/water bath at 0°C, then a solution of 2,6-difluorobenzoyl chloride (34 mg; 0.19 mmol) in NMP (1.0 ml). The resulting mixture was stirred and slowly warmed to room temperature over 2 hours. The solution was purified by flash chromatography on C18 (40 g) eluting with a gradient of 0% to 60% MeCN in water (with 0.05% ammonium 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) (8 mg; 11% yield) as an off-white solid. LCMS: m/z (ESI), [M+H] ⁺ =466.3. ¹ H NMR (500 MHz, CDCl ₃ ) δ ^ppm 3.5 (s, 3H), 4.8 (d, J=6.3 Hz, 2H), 5.5 (brs, 2H), 6.4 (d, J=9, 5 Hz, 1H), 7.0-7.0 (m, 3H), 7.1 (t, J=8.7 Hz, 2H), 7.1 (dd, J=9.5; 2.5 Hz, 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

Step 1. Preparation of methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylate

To a mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (4.4 g; 19.91 mmol), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (3.07 g; 21.9 mmol) in dioxane (50 ml) and water (5 ml) was added Na ₂ CO ₃ (4.22 g; 39.82 mmol) and dppfPdCl ₂ (2.84 g ; 3.98 mmol). The mixture was then stirred at 100°C for 1 hour under N ₂ atmosphere. Next, the mixture was concentrated, the residue was poured into water (100 ml) and then extracted with EA (100 ml × 3). The organic solution was then concentrated to give the crude product (5.5 g; 98% yield) as a yellow solid, which was used in the next step without further purification. MS m/z (ESI) [M+H] ⁺ =282.2.

Step 2. Preparation of methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxylate

To a mixture of methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylate (2.8 g; 9.96 mmol), (2,6-dimethylpyridin-4-yl)boronic acid (1 .51 g; 9.96 mmol) in dioxane (50 ml) and water (5 ml), Na ₂ CO ₃ (3.01 g; 19.93 mmol) and Pd(PPh ₃ ) ₄ (1.42 g; 1.99 mmol). The mixture was then stirred at 80°C for 8 hours under N ₂ atmosphere. The mixture was then concentrated and the residue was poured into water (100 ml) and then extracted with EA (100 ml x 3). The organic solution was then concentrated to give the crude product, which was further purified by flash column chromatography to give the desired methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin- 2-carboxylate (2.5 g; 71% yield) as a yellow solid. MS m/z (ESI) [M+H] ⁺ =353.4. ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.33 (s, 6H), 3.89 (s, 3H), 6.89 (s, 2H), 7.22 (t, J=8.29 Hz, 2H) , 7.43 (t, J=6.58 Hz, 2H), 7.61 (br s, 2H).

Step 3, Preparation of 3-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 (2.3 g; 6.53 mmol) in methanol (25 ml ) and water (5 ml) sodium hydroxide (1.3 g; 32.66 mmol) was added. The mixture was then stirred at 45°C for 2 hours. Next, the solution was concentrated and the residue was suspended in 25 ml of water. The solution was washed twice with 15 ml DCM. Then the inorganic layer was acidified with 0.5 N. HCl solution to pH 3. The resulting solid was collected and dried to give the desired product (1.70 g; 77% yield) as a white solid. MS m/z (ESI) [M+H] ⁺ =339.4. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.31-2.38 (m, 6H), 6.94 (s, 2H), 7.22 (t, J=8.41 Hz, 2H), 7.43 (t, J=6.73 Hz, 2H), 7.64 (br s, 2H), 12.56-13.99 (m, 1H).

Step 4. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)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 (25 mg; 0.07 mmol), (2-methoxyphenyl)methanamine (20 mg; 0.15 mmol) and DIEA (15 mg; 0.118 mmol) in DMF (2 ml) were added as one portion of HATU (40 mg; 0.11 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The solution was purified on 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) (19.8 mg; 59.2% yield) as an off-white solid. MS m/z (ESI) [M+H] ⁺ =458.4. ^1H NMR (500 MHz, CDCl ₃ ) δ ^ppm 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 shown in the table below were prepared using
methods described for the preparation of compound 89.

Example 93; Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-phenylpyrazine-2-carboxamide (compound 93)

SCHEME 59

Step 1. Preparation of methyl 3-amino-6-chloro-5-phenylpyrazine-2-carboxylate

To a mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (0.22 g; 1.0 mmol), phenylboronic acid (0.13 g; 1.05 mmol) in dioxane (3 ml) and water ( 0.3 ml) Na ₂ CO ₃ (0.21 g; 1.99 mmol) and Pd(dppf)Cl ₂ (0.14 g; 0.20 mmol) were added. The mixture was then stirred at 100°C for 1 hour under N ₂ atmosphere. Next, the mixture was concentrated, the residue was poured into water (100 ml) and then extracted with EA (10 ml × 3). The organic solution was then concentrated to give the crude product (0.24 g; 91% yield) as a yellow solid, which was used in the next step without further purification. MS m/z (ESI) [M+H] ⁺ =263.3.

Step 2. Preparation of methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-phenylpyrazin-2-carboxylate

To a mixture of methyl 3-amino-6-chloro-5-phenylpyrazin-2-carboxylate (0.24 g; 0.91 mmol), (2,6-dimethylpyridin-4-yl)boronic acid (0.14 g; 0 .96 mmol) in dioxane (5 ml) and water (0.5 ml), Na ₂ CO ₃ (0.19 g; 1.82 mmol) and Pd(PPh ₃ ) ₄ (0.14 g; 0.20) were added mmol). The mixture was then stirred at 80°C for 8 hours under N ₂ atmosphere. Next, the mixture was concentrated, the residue was poured into water (10 ml) and then extracted with EA (10 ml × 3). The organic solution was then concentrated to give the crude product, which was further purified by flash column chromatography to give the desired methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-phenylpyrazine-2-carboxylate (0 .30 g; yield 98%) as a yellow solid. MS m/z (ESI) [M+H] ⁺ =335.4.

Step 3. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-phenylpyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-phenylpyrazin-2-carboxylate (0.30 g; 0.90 mmol) in methanol (10 ml) and water (2 ml) sodium hydroxide (0.18 g; 4.49 mmol) was added. The mixture was then stirred at 45°C for 2 hours. Next, the solution was concentrated and the residue was suspended in 5 ml of water. The solution was washed with DCM (2×5 ml). Then the inorganic layer was acidified with 0.5 N. HCl solution to pH 3. The resulting solid was collected and dried to give the desired product (0.14 g; 49% yield) as a white solid. MS m/z (ESI) [M+H] ⁺ =321.4.

Step 4 Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-phenylpyrazine-2-carboxamide (compound 93)

To a stirred solution of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-phenylpyrazin-2-carboxylic acid (35 mg; 0.11 mmol), (2-methoxyphenyl)methanamine (22 mg; 0 .16 mmol) and DIEA (28 mg; 0.22 mmol) in DMF (2 ml) was added in one portion to HATU (50 mg; 0.13 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The solution was purified on C18 (40 g; MeCN/water, 5%-60%) to give 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-phenylpyrazin- 2-carboxamide (compound 93) (23.0 mg; 48% yield) as an off-white solid. MS m/z (ESI) [M+H] ⁺ =440.4. ¹ H NMR (500 MHz, CDCl ₃ ) δ ^ppm 2.30 (s, 6H), 3.86 (s, 3H), 4.52 (d, J=6.31 Hz, 2H), 6.91 (t, J=7, 36 Hz, 1H), 6.99-7.04 (m, 3H), 7.18 (d, J=7.57 Hz, 1H), 7.25 (t, J=7.87 Hz, 1H), 7.35-7.45 (m, 5H ),7.82 (br s, 2H), 9.06 (t, J=6.31 Hz, 1H).

Example 94. Preparation of 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-N-[(5-methyl-1,3-thiazol-4-yl)methyl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 94)

SCHEME 60

Step 1. tert-Butyl N-[(5-methyl-1,3-thiazol-4-yl)methyl]carbamate

To a stirred mixture of 4-bromo-5-methyl-1,3-thiazole (400 mg; 2.3 mmol; 1 eq.) and tert-butyl N-[(trifluoro-lambda4-boranyl)methyl]potassium carbamate (639, 11 mg; 2.7 mmol; 1.2 eq.) in toluene (16 ml), Na ₂ CO ₃ (714.3 mg; 6.7 mmol; 3.0 eq.), S-Phos (368, 9 mg; 0.9 mmol; 0.4 eq.), water (2 ml) and Pd(AcO) ₂ (100.9 mg; 0.45 mmol; 0.2 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C. The mixture was left to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc, 5:1) to give tert-butyl N-[(5-methyl-1,3-thiazol-4-yl)methyl]carbamate (280 mg; 54.6%) as crude yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =229.2.

Step 2. 1-(5-Methyl-1,3-thiazol-4-yl)methanamine

To a stirred solution of tert-butyl N-[(5-methyl-1,3-thiazol-4-yl)methyl]carbamate (270 mg; 1.2 mmol; 1 eq.) in DCM (5 ml) was added dropwise n. a solution of HCl in dioxane (5 ml) at room temperature in an air atmosphere. The resulting mixture was stirred for another 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The result was 1-(5-methyl-1,3-thiazol-4-yl)methanamine (150 mg; 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]-5-(1.3-oxazole) -2-yl)pyrazin-2-carboxamide (compound 94)

To a stirred mixture of 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0. 3 mmol; 1 eq.) and 1-(5-methyl-1,3-thiazol-4-yl)methanamine (79.6 mg; 0.6 mmol; 2.0 eq.) in DMF (5 ml) portions HATU (471.9 mg; 1.24 mmol; 4.0 eq.) and DIEA (160.4 mg; 1.2 mmol; 4.0 eq.) were added at room temperature in an air atmosphere. The resulting mixture was stirred for another 60 minutes at room temperature. The resulting mixture was poured into water (20 ml), the resulting solid was collected by filtration and washed with water (10 ml). The crude product was suspended in MeOH (5 ml) to give 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-N-[(5-methyl-1,3-thiazol-4-yl )methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 94) (106 mg; 77.9%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =433.2. ^1H NMR (methanol- _d4 , 400 MHz) δ 2.6 (3H, s), 4.7 (2H, s), 7.2 (1H, dd, J=9.3; 1.8 Hz), 7.3 (1H , s), 7.5 (1H, d, J=9.3 Hz), 7.6 (1H, d, J=1.3 Hz), 7.9 (1H, s), 8.0 (1H, s), 8.7 (1H, d, J=1.5 Hz), 8.8 (1H, s).

Example 95. Preparation of 3-amino-N-[(4-aminopyrimidin-2-yl)methyl]-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol- 2-yl)pyrazin-2-carboxamide (compound 95)

SCHEME 61

Step 1. 2-(Aminomethyl)pyrimidin-4-amine

To a stirred mixture of 4-aminopyrimidine-2-carbonitrile (200 mg; 1.67 mmol; 1 eq.) in THF (10 ml) was added Raney Ni (71.3 mg; 0.83 mmol; 0.5 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 1.5 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with THF (2×5 ml). The filtrate was concentrated under reduced pressure to give 2-(aminomethyl)pyrimidin-4-amine (200 mg; 96.75%) as a light yellow solid, which was directly 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-oxazol-2 -yl)pyrazin-2-carboxamide (compound 95)

To a stirred mixture of 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0. 31 mmol; 1 eq.) and 2-(aminomethyl)pyrimidin-4-amine (77.0 mg; 0.62 mmol; 2 eq.) in DMF (10 ml) T ₃ P (394.9 mg; 2 eq.) was added in portions. 1.24 mmol; 4 eq.) and DIEA (120.3 mg; 0.93 mmol; 3 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred overnight at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (60 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 15% B to 25% B in 7 min; 254/220 nm; Rt: 5.77 min), giving 3-amino-N-[(4- aminopyrimidin-2-yl)methyl]-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 95) ( 13 mg; 9.78%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =429.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.33-4.77 (m, 2H), 6.29 (d, J=5.9 Hz, 1H), 7.18 (dd, J=9.3; 1.8 Hz , 2H), 7.37 (d, J=0.8 Hz, 1H), 7.52 (d, J=9.3 Hz, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.96 (d, J=1.1 Hz, 1H), 8.00 (d, J=5.9 Hz, 4H), 8.28 (d, J=0.8 Hz, 1H), 8.80 (t, J=1.4 Hz, 1H ), 9.18 (t, J=5.8 Hz, 1H).

Example 96. Preparation of 3-amino-N-[[2-(dimethylphosphoryl)-6-fluorophenyl]methyl]-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3- Oxazol-2-yl)pyrazin-2-carboxamide (compound 96)

SCHEME 62

Step 1. 2-(Dimethylphosphoryl)-6-fluorobenzonitrile

To a mixture of 2-bromo-6-fluorobenzonitrile (1 g; 5.00 mmol; 1 eq.) and (methylphosphonoyl)methane (0.4 g; 1.00 eq.) in 1,4-dioxane (15 ml) Pd(AcO) ₂ (0.1 g; 0.1 eq.), XantPhos (0.6 g; 0.2 eq.) and K ₃ PO ₄ (2.1 g; 0.01 mmol; 2.00 eq.) in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 2-(dimethylphosphoryl)-6-fluorobenzonitrile (620 mg; 62.90%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =198.0. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 1.83 (s, 3H), 1.87 (s, 3H), 7.80 (m, 2H), 7.95 (m, 1H).

Step 2. 1-[2-(Dimethylphosphoryl)-6-fluorophenyl]methanamine

To a solution of 2-(dimethylphosphoryl)-6-fluorobenzonitrile (600 mg; 3.04 mmol; 1 eq.) and NH ₃ .H ₂ O (0.1 ml; 3.82 mmol; 1.13 eq.) in MeOH (10 mL) Raney Ni (130.4 mg; 1.52 mmol; 0.5 eq.) was added at room temperature under nitrogen. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3×10 ml). The filtrate was concentrated under reduced pressure to give 1-[2-(dimethylphosphoryl)-6-fluorophenyl]methanamine (550 mg; 89.83%) as a purple oil, which was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺ =202.2. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 1.82 (m, 6H), 3.17 (s, 3H), 4.02 (d, 2H), 7.45 (s, 3H).

Stage 3; 3-Amino-N-[[2-(dimethylphosphoryl)-6-fluorophenyl]methyl]-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2- yl)pyrazine-2-carboxamide (compound 96)

To a solution of 1-[2-(dimethylphosphoryl)-6-fluorophenyl]methanamine (10 mg; 0.05 mmol; 1 eq.) and 3-amino-6-[imidazo[1,2-a]pyridin-6-yl ]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (16.0 mg; 0.05 mmol; 1.00 eq.) in DMF (5 ml) was added T ₃ P (31 .6 mg; 0.10 mmol; 2 eq.) and DIEA (19.3 mg; 0.15 mmol; 3 eq.) at room temperature. The resulting solution was stirred for 60 min at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 5 µm, 19*150 mm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN ; flow rate: 20 ml/min; gradient: from 25% B to 35% B in 8 min; 254/220 nm; Rt: 6.27 min), giving 3-amino-N-[[2-(dimethylphosphoryl) -6-fluorophenyl]methyl]-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 96) (95 mg; 37.81%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =506.2. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 1.85 (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. Preparation of 3-amino-N-((3-fluoropyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2- yl)pyrazin-2-carboxamide (compound 101)

SCHEME 63

Step 1. 3-Methylimidazo[1,2-a]pyridin-6-yl-boronic acid

A mixture of 2-bromo-1,1-dimethoxypropane (500 mg; 2.73 mmol; 1 eq.) in 2.5 ml of 1 N. aq. HCl solution was stirred for 1 hour at 80°C. The mixture was cooled to RT and neutralized to pH 7 using NaHCO ₃ (solid). The aqueous layer was extracted with CHCl ₃ (3×5 ml). To the resulting solution in CHCl ₃ , 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (180.3 mg; 0.82 mmol; 0 .30 eq.) at room temperature. The resulting mixture was stirred overnight at 80°C. The resulting mixture was concentrated under reduced pressure to obtain the crude products 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]pyridin-6-yl)-5-(oxazol-2-yl) )pyrazine-2-carboxamide (compound 101)

To a stirred mixture of 3-amino-6-chloro-N-[(3-fluoropyridin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (100 mg; 0. 29 mmol; 1 eq.) and [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (100.9 mg; 0.57 mmol; 2.00 eq.) in 1,4-dioxane (20 ml) Cs ₂ CO ₃ (467.2 mg; 1.43 mmol; 5 eq.) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (70.3 mg; 0.09 mmol; 0. 3 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred overnight at 105°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 3-amino-N-[(3-fluoropyridin-2-yl)methyl]-6-[3-methylimidazo[1,2-a] pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 101) (23 mg; 18.05%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =445.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.44 (d, J=0.9 Hz, 3H), 4.72 (dd, J=5.8; 1.7 Hz, 2H), 7.25 (dd, J =9.4; 1.8 Hz, 1H), 7.31-7.47 (m, 3H), 7.50 (dd, J=9.4; 1.0 Hz, 1H), 7.72 (ddd, J=10.0; 8.3; 1.3 Hz, 1H), 7.90 (s, 2H), 8.29 (d, J=0.8 Hz, 1H), 8.33-8.42 (m, 2H), 9.36 (t, J=5, 9 Hz, 1H).

Example 102 Preparation of 3-amino-N-[(2,6-difluorophenyl)methyl]-6-[1-(3-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-( 1,3-oxazol-2-yl)pyrazin-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 (1 g; 5.75 mmol; 1 eq.) and 3-iodopropan-1-ol (2.1 g; 11.49 mmol; 2 eq. ) in DMF (15 ml) was added K ₂ CO ₃ (1.6 g; 11.49 mmol; 2 eq.) at room temperature. The mixture was stirred for 4 hours at 80°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl ₃ /MeOH, 20:1) to give 5-bromo-1-(3-hydroxypropyl)-1,2-dihydropyridin-2-one (300 mg; 22.49%) as a yellow solid substances. LCMS: m/z (ESI), [M+H] ⁺ =232.1; 234.1. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 1.12 (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 (200 mg; 0.86 mmol; 1 eq.) and 4,4,5,5-tetramethyl-2-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (437.7 mg; 1.72 mmol; 2 eq.) in THF (15 ml ) added KOAc (137.5 mg; 1.40 mmol; 3.00 eq.) and Pd(dppf)Cl ₂ (63.1 mg; 0.09 mmol; 0.1 eq.) at room temperature under nitrogen atmosphere . The mixture was stirred for 2 hours at 80°C under nitrogen atmosphere. 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]-6-[1-(3-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1 ,3-oxazol-2-yl)pyrazin-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 (305.3 mg ; 1.09 mmol; 2.00 eq.) in THF (15 ml) was added 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(1,3-oxazol-2 -yl)pyrazin-2-carboxamide (200 mg; 0.55 mmol; 1 eq.), Cs ₂ CO ₃ (356.4 mg; 1.09 mmol; 2.00 eq.) and Pd(dppf)Cl ₂ (40.0 mg; 0.05 mmol; 0.10 eq.) under nitrogen atmosphere at room temperature. The mixture was stirred for 2 hours at 80°C under nitrogen atmosphere, the residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), obtaining 3-amino-N-[(2,6-difluorophenyl)methyl]-6 -[1-(3-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 102) (60 mg ; 22.74%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =483.3. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 1.76 (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 Preparation of 3-amino-N-[(2,6-difluorophenyl)methyl]-6-[1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-( 1,3-oxazol-2-yl)pyrazin-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 (500 mg; 2.87 mmol; 1 eq.) and 1-bromo-2-methoxyethane (1597.6 mg; 11.49 mmol; 4 eq. .) in DMF (15 ml) K ₂ CO ₃ (1191.4 mg; 8.62 mmol; 3 eq.) was added in portions at 80°C in an air atmosphere. The resulting mixture was stirred for 5 hours at 80°C in an air atmosphere. The resulting mixture was poured into water. The resulting mixture was extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with water (1 x 40 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to give 5-bromo-1-(2-methoxyethyl)-1,2-dihydropyridin-2-one (200 mg; 29.99%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =231.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.24 (s, 3H), 3.56 (t, J=5.3 Hz, 2H), 4.04 (t, J=5.3 Hz, 2H), 6.38 (d, J=9.6 Hz, 1H), 7.53 (dd, J=9.7; 2.8 Hz, 1H), 7.91 (d, J=2.8 Hz, 1H).

Step 2. 1-(2-Methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

To a stirred mixture of 5-bromo-1-(2-methoxyethyl)-1,2-dihydropyridin-2-one (150 mg; 0.65 mmol; 1 eq.) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (328.3 mg; 1.29 mmol; 2 eq.) in THF (5 ml) Pd(dppf)Cl ₂ (94.6 mg; 0.13 mmol; 0.2 eq.) and KOAc (190.3 mg; 1.94 mmol; 3 eq.) were added in portions at 80°C in the atmosphere nitrogen. The resulting mixture was stirred for 3 hours at 80°C 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]-6-[1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl]-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 103)

To a stirred mixture of 3-amino-6-chloro-N-[(2,6-difluorophenyl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (100 mg; 0.27 mmol ; 1 eq.) and 1-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one ( 152.7 mg; 0.55 mmol; 2.00 eq.) in THF (8 ml) Pd(dppf)Cl ₂ (40.0 mg; 0.05 mmol; 0.2 eq.) and Cs ₂ were added in portions CO ₃ (356.4 mg; 1.09 mmol; 4 eq.) at 100°C in a nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /MeOH (20:1) to give 3-amino-N-[(2,6-difluorophenyl)methyl]-6-[1-(2-methoxyethyl) -6-oxo-1,6-dihydropyridin-3-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 103) (33 mg; 24.77%) as yellow -green solid. LCMS: m/z (ESI), [M+H] ⁺ =483.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.22 (s, 3H), 3.57 (t, J=5.4 Hz, 2H), 4.04 (t, J=5.5 Hz, 2H), 4.61 (d, J=5.9 Hz, 2H), 6.35 (d, J=9.4 Hz, 1H), 7.10 (t, J=8.0 Hz, 2H), 7.34-7.46 (m, 2H) , 7.47 (dd, J=9.4; 2.6 Hz, 1H), 7.75-7.80 (m, 2H), 7.88 (d, J=2.6 Hz, 1H), 8.30 (d, J=0, 8 Hz, 1H), 9.07 (t, J=5.9 Hz, 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)pyrazin-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)pyrazin-2-carboxylic acid

To a stirred mixture of methyl 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (300 mg; 1.178 mmol; 1 eq.) and 6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (431.39 mg; 1.767 mmol; 1.5 eq.) in dioxane (20 ml ) Pd(dppf)Cl ₂ (172.41 mg; 0.236 mmol; 0.2 eq.), water (2 ml) and Cs ₂ CO ₃ (1151.62 mg; 3.535 mmol; 3 eq.) were added in portions at room temperature in a nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 ml). The filtrate was acidified to pH 5 using 2N. aq. HCl solution. The resulting solid was collected by filtration and dried under vacuum to give 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-triazol-2-yl) pyrazine-2-carboxylic acid (290 mg; 76.37%) as a crude brown solid, which was directly used in the next step without further purification. 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)pyrazin-2-carboxamide (compound 104)

To a stirred mixture of 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.31 mmol; 1 eq.) and 1-(3-fluoropyridin-2-yl)methanamine (67.1 mg; 0.62 mmol; 2 eq.) in DMF (3 ml) HATU (471 .9 mg; 1.24 mmol; 4 eq.) and DIEA (160.4 mg; 1.24 mmol; 4 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was quenched with water (10 ml), the resulting solid was collected by filtration and washed with water (3 x 10 ml). The crude product was suspended in MeOH (6 ml), the resulting solid was collected by filtration and dried under vacuum to give 3-amino-N-[(3-fluoropyridin-2-yl)methyl]-6-[imidazo[1,2-a ]pyridin-6-yl]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxamide (compound 104) (48 mg; 35.5%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =431.2. ^1H NMR (DMSO-d ₆ , 400 MHz) δ 4.7 (2H, d, J=5.9 Hz), 6.7 (1H, dd, J=9.4; 1.8 Hz), 7.4 (2H, dd , J=8.8; 4.4 Hz), 7.6 (1H, d, J=1.2 Hz), 7.7 (1H, ddd, J=10.0; 8.3; 1.3 Hz), 7.9 (1H, s), 8.1 (3H, s), 8.4 (1H, dt, J=4.7; 1.5 Hz), 8.6-8.7 (1H, m), 9.4 (1H, t, J=6, 0 Hz).

Example 107. Preparation of 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide

Example 108. Preparation of 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide

Step 1. 5-Bromo-1-(2-hydroxypropyl)-1,2-dihydropyridin-2-one

A solution of 5-bromo-1,2-dihydropyridin-2-one (1 g; 5.75 mmol; 1 eq.) and 1-bromopropan-2-ol (1.6 g; 0.01 mmol; 2.00 eq. .), K ₂ CO ₃ (1.6 g; 0.01 mmol; 2.00 eq.) in DMF (15 ml) was stirred for 4 hours at 80°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 5-bromo-1-(2-hydroxypropyl)-1,2-dihydropyridin-2-one (0.9 g, 67.48%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =232.1; 234.1. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 1.05 (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-(4,45,5-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 (300 mg; 1.29 mmol; 1 eq.) and 4,4,5,5-tetramethyl-2-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (656.5 mg; 2.59 mmol; 2 eq.) in THF (15 ml ) KOAc (137.5 mg; 1.40 mmol; 3.00 eq.) and Pd(dppf)Cl ₂ (94.6 mg; 0.13 mmol; 0.10 eq.) were added. The mixture was stirred for 2 hours at 80°C under nitrogen atmosphere. 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-dihydropyridin-3-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide

To a solution of methyl 3-amino-6-bromo-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (200 mg; 0.67 mmol; 1 eq.) and 1-methyl -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (314.4 mg; 1.34 mmol; 2.00 eq.) in THF (15 ml) was added Cs ₂ CO ₃ (435.8 mg; 1.34 mmol; 2 eq.) and Pd(dppf)Cl ₂ (48.9 mg; 0.07 mmol; 0.1 eq.). After stirring for 2 hours at 80°C under nitrogen atmosphere, the residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), obtaining 3-amino-N-(2,6-difluorobenzyl)-6-(1- (2-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (racemate; 10 mg; 4.77%) as a yellow solid substances. LCMS: m/z (ESI), [M+H] ⁺ =483.3. ^1H NMR: (300 MHz, 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).

Step 4. 3-Amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2- yl)pyrazin-2-carboxamide (absolute configuration unknown, peak L compound 107) and 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxypropyl)-6-oxo-1, 6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (absolute configuration unknown, peak 2. compound 108)

The racemic product (100 mg) was purified by preparative chiral HPLC using an eluent. Column: (R,R) Whelk-O 1; 21.1*250 mm, 5 microns; mobile phase A: Hex (with NH ₃ .MeOH (8 mmol/l)) for HPLC, mobile phase B: EtOH for HPLC; flow rate: 20 ml/min; gradient: from 50 V to 50 V in 26 minutes; 254/220 nm; Rt1: 16.649; Rt2: 19.223. The result was 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2- yl)pyrazin-2-carboxamide (isomer 1) (compound 107) (30 mg; 30%) as a yellow solid LCMS: m/z (ESI), [M+H] ⁺ =483.3. ^1H NMR: (300 MHz, 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). For a chiral compound: tR=2.59 min; and 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide (isomer 2) (compound 108) (30 mg; 30%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =483.3. ^1H NMR: (300 MHz, 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). For a chiral compound: tR=3.03 min, for a mixture of chiral compounds: tR=2.59 min, 3.03 min.

Example 111. Preparation of 3-amino-N-((6-(3-(dimethylamino)azetidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin- 6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 111)

SCHEME 67

Step 1. 6-(3-(Dimethylamino)azetidin-1-yl)picoliponitrile

6-chloropyridine-2-carbonitrile (1.5 g; 10.826 mmol; 1 eq.), N,N-dimethylazetidine-3-amine dihydrochloride (1.87 g; 10.826 mmol; 1 eq.) was placed in a 50 ml round-bottom flask. ), DMF (10 ml; 129.218 mmol; 11.94 eq.), K ₂ CO ₃ (4.49 g; 32.479 mmol; 3 eq.). The resulting solution was stirred for 16 hours at 80°C. The resulting solution was extracted with dichloromethane (3 x 20 ml). The residue was applied to a silica gel column using dichloromethane/methanol (50:1) for separation. The result was 6-[3-(dimethylamino)azetidin-1-yl]pyridin-2-carbonitrile (compound 111) (475 mg; 21.69%) as a light brown solid. ^1H NMR (400 MHz, 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 (6Н, 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

6-(3-(dimethylamino)azetidin-1-yl)picolinonitrile was placed in a 25 ml round bottom flask. MeOH (10 mL; 246.989 mmol; 111.01 eq.), NH ₄ OH (2 mL; 51.361 mmol; 23.09 eq.) and Raney Ni were then added at RT. The resulting mixture was stirred for 1 hour at room temperature. Solids were filtered off. The resulting mixture was concentrated. The result was 290 mg of 1-[6-(aminomethyl)pyridin-2-yl]-N,N-dimethylazetidin-3-amine (63.18%) as a solid. LCMS: m/z (ESI), [M+H] ⁺ =207.1. ^1H NMR (300 MHz, methanol- _d4 ) δ 2.24 (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-(oxazol-2-yl)pyrazin-2-carboxamide (compound 111)

3-Amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid was placed in a 25 ml round bottom flask. (130 mg), DMF (5 ml), T ₃ P (750 mg), DIEA (530 mg), 1-[6-(aminomethyl)pyridin-2-yl]-N,N-dimethylazetidin-3-amine ( 130 mg). The resulting solution was stirred for 16 hours at room temperature. The resulting solution was extracted with ethyl acetate (3 x 10 ml), the organic layers were combined and concentrated. The residue was applied to a silica gel column using dichloromethane/methanol (8:1) for separation. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 31% B to 41% B in 7 min; 254/220 nm; Rt: 5.10 min) and the product was obtained. The result was 3-amino-N-([6-[3-(dimethylamino)azetidin-1-yl]pyridin-2-yl]methyl)-6-[3-methylimidazo[1,2-a]pyridin-6 -yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 111) (51.6 mg) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =525.3. ^1H NMR (300 MHz, methanol- _d6 ) δ 2.03 (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. Preparation of 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl )-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 112)

SCHEME 68

Step 1. 6-(4-Methylpiperazin-1-yl)picolinonitrile

6-Fluoropyridine-2-carbonitrile (500 mg; 4.095 mmol; 1 eq.), 1-methylpiperazine (615.25 mg; 6.142 mmol; 1.5 eq.), K ₂ CO ₃ (1131.89 mg; 8.190 mmol ; 2 eq.) were dissolved in 3 ml DMF. The mixture was stirred at 50°C for 8 hours. LCMS indicated completion of the reaction. The crude product was purified on a silica gel column eluting with DCM: _CH3OH (15:1), the product was further purified by preparative HPLC to give 6-(4-methylpiperazin-1-yl)picolinonitrile (158 mg; 19.08%) in the form of brown butter. LCMS: m/z (ESI), [M+H] ⁺ =203.3.

Step 2. (6-(4-Methylpiperazin-1-yl)pyridin-2-yl)methanamine

6-(4-Methylpiperazin-1-yl)pyridin-2-carbonitrile (140 mg; 0.692 mmol; 1 eq.), Raney Ni (118.60 mg; 1.384 mmol; 2.00 eq.) was dissolved in 3 ml NH ₄ OH and MeOH. The mixture was stirred at room temperature under H ₂ atmosphere for 3 hours. LCMS indicated completion of the reaction. The crude product was purified on a silica gel column eluting with DCM: _CH3OH (15:1), the product was further purified by preparative HPLC to give (6-(4-methylpiperazin-1-yl)pyridin-2-yl)methanamine (40 mg ; 28.01%) in the form of gray oil. 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-(oxazol-2-yl)pyrazin-2-carboxamide (compound 112)

1-[6-(4-Methylpiperazin-1-yl)pyridin-2-yl]methanamine (29.44 mg; 0.143 mmol; 1.20 eq.), 3-amino-6-[3-methylimidazo[1, 2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (40 mg; 0.119 mmol; 1 eq.), EDCI (1-ethyl-3- (3-dimethylaminopropyl)carbodiimide) (45.60 mg; 0.238 mmol; 2.00 eq.), HOBT (32.14 mg; 0.238 mmol; 2.00 eq.), DIEA (92.23 mg; 0.714 mmol; 6.00 eq.) was dissolved in 3 ml DMF. The mixture was stirred at room temperature for 2 hours. LCMS indicated completion of the reaction. The crude product was purified on a silica gel column eluting with DCM: _CH3OH (15:1), the product was further purified by preparative HPLC to give 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl )-N-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (26.5 mg; 42.47% ) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =525.3. ¹ H-NMR (300 MHz, methanol) 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)pyrazin-2-carboxamide (compound 113)

SCHEME 69

Step 1. 3-(2-Hydroxyethoxy)pyridine-2-carbonitrile

To a mixture of 3-fluoropyridine-2-carbonitrile (1.5 g; 12.3 mmol; 1 eq.) and ethane-1,2-diol (1.5 g; 24.5 mmol; 2 eq.) in 1, Cs ₂ CO ₃ (8.0 g; 24.5 mmol; 2 eq.) was added to 4-dioxane (25 ml). The resulting mixture was stirred for 4 hours at 80°C in an air 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 3-(2-hydroxyethoxy)pyridine-2-carbonitrile (1 g; 49.6%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =166.1. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 3.75 (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]ethan-1-ol

Raney _'s Ni ₍ 469.7 mg; 5.5 mmol; 3 eq.). The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure. The result was 2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethan-1-ol (200 mg) as a purple oil. 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]-6-(1-methyl-1H-1,3-benzodiazol- 6-yl)pyrazin-2-carboxamide (compound 113)

To a solution of 2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethan-1-ol (200 mg; 1.2 mmol; 1 eq.) and 3-amino-5-(4-fluorophenyl)- 6-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxylic acid (302.4 mg; 0.8 mmol; 0.7 eq.) in DMF (15 ml) was added portionwise T ₃ P (756.7 mg; 2.4 mmol; 2 eq.), DIEA (307.4 mg; 2.4 mmol; 2 eq.). The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (60 mg) was purified by preparative HPLC under the following conditions (column: Xselect CSH OBD, 30*150 mm, 5 µm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate : 60 ml/min; gradient: from 35% B to 45% B in 7 min; 254/220 nm; Rt: 7.02 min), giving 3-amino-5-(4-fluorophenyl)-N-[[ 3-(2-hydroxyethoxy)pyridin-2-yl]methyl]-6-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxamide (compound 113) (20 mg; 6, 55%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =514.3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.76 (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). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -74.48, -112.25.

The compounds shown in the table below were prepared using the methods described for the preparation of 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- benzodiazol-6-yl)pyrazin-2-carboxamide (compound 114)

SCHEME 70

Step 1. N-[2-[(2-Cyanopyridin-3-yl)oxy]ethyl]-N-methylcarbamate

To a mixture of 3-fluoropyridine-2-carbonitrile (1.5 g; 12.2 mmol; 1 eq.) and tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (4.3 g; 24.5 mmol; 2 eq.) in 1,4-dioxane (25 ml) was added Cs ₂ CO ₃ (8.01 g; 24.6 mmol; 2.0 eq.) at room temperature. The resulting mixture was stirred for 4 hours at 80°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to give tert-butyl N-[2-[(2-cyanopyridin-3-yl)oxy]ethyl]-N-methylcarbamate (1.8 g; 52.8%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =179.0. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 1.36 (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]methanamine

Raney _Ni (288 _, 4 mg; 3.3 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure. The result was 1-[3-(2-methoxyethoxy)pyridin-2-yl]methanamine (200 mg; 65.2%) as a purple oil. 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]methyl]-6-(1-methyl-1H-1,3-benzodiazol- 6-yl)pyrazin-2-carboxamide (compound 114)

To a solution of 1-[3-(2-methoxyethoxy)pyridin-2-yl]methanamine (180 mg; 1 mmol; 1 eq.) and 3-amino-5-(4-fluorophenyl)-6-(1-methyl- 1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxylic acid (251.2 mg; 0.7 mmol; 0.7 eq.) in DMF (15 ml) was added in portions T ₃ P (628.6 mg; 2 mmol; 2 eq.) and DIEA (255.3 mg; 2 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (60 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 35% B to 45% B in 7 min; 254/220 nm; Rt: 6.83 min), yielding 3-amino-5-(4-fluorophenyl )-N-[[3-(2-methoxyethoxy)pyridin-2-yl]methyl]-6-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxamide (compound 114) (48.1 mg; 9.2%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =528.3. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 3.29 (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 Preparation of 3-amino-5-(4-fluorophenyl)-6-(1-methyl-1H-1,3-benzodiazol-6-yl)-N-([3-[2-(methylamino)ethoxy] pyridin-2-yl]methyl)pyrazin-2-carboxamide (compound 115)

SCHEME 71

Step 1. tert-Butyl N-[2-[(2-cyanopyridin-3-yl)oxy]ethyl]-N-methylcarbamate

To a mixture of 3-fluoropyridine-2-carbonitrile (1.5 g; 12.2 mmol; 1 eq.) and tert-butyl X-(2-hydroxyethyl)-N-methylcarbamate (4.3 g; 24.5 mmol; 2 eq.) in 1,4-dioxane (25 ml) was added portionwise Cs ₂ CO ₃ (8.01 g; 24.5 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 4 hours at 80°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to give tert-butyl N-[2-[(2-cyanopyridin-3-yl)oxy]ethyl]-N-methylcarbamate (1.8 g; 52.8%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =278.0. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 1.36 (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. tert-Butyl N-(2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate

To a solution of tert-butyl N-[2-[(2-cyanopyridin-3-yl)oxy]ethyl]-N-methylcarbamate (300 mg; 1.08 mmol; 1 eq.) in MeOH (5 ml) and NH ₃ H ₂ O (1 ml) was added Raney's Ni (185.3 mg; 2.1 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure. The result was tert-butyl N-(2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate (200 mg; 65.7%) as a purple oil. 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]formamido]methyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate

To a solution of tert-butyl N-(2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate (200 mg; 0.7 mmol; 1 eq.) and 3-amino-5 -(4-fluorophenyl)-6-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxylic acid (180.8 mg; 0.5 mmol; 0.7 eq.) in DMF (15 ml) was added in portions with T ₃ P (452.3 mg; 1.4 mmol; 2 eq.) and DIEA (183.7 mg; 1.4 mmol; 2.0 eq.) at room temperature. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), yielding tert-butyl N-(2-[[2-([[3-amino-5-(4-fluorophenyl)-6-(1- methyl 1H-1,3-benzodiazol-6-yl)pyrazin-2-yl]formamido]methyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate (150 mg; 33.6%) as yellow solid matter. 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]pyridine -2-yl]methyl)pyrazin-2-carboxamide (compound 115)

By 4 n. tert-butyl N-(2-[[2-([[3-amino-5-(4-fluorophenyl)-6-(1- methyl 1H-1,3-benzodiazol-6-yl)pyrazin-2-yl]formamido]methyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate (150 mg; 0.2 mmol; 1 eq. ) at room temperature. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 µm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 33% B to 43% B in 7 min; 254/220 nm; Rt: 5.8 min), giving 3-amino-5-(4-fluorophenyl )-6-(1-methyl-1H-1,3-benzodiazol-6-yl)-N-([3-[2-(methylamino)ethoxy]pyridin-2-yl]methyl)pyrazin-2-carboxamide ( compound 115) (51 mg; 40.5%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =527.3. ^1H NMR (300 MHz, DMSO- _d6 ) δ 2.31 (3H, s), 2.85 (2H, m), 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-benzodiazol-6-yl)pyrazin-2-carboxamide (compound 116)

SCHEME 72

Step 1. 3-[2-(Dimethylamino)ethoxy]pyridine-2-carbonitrile

To a mixture of 3-fluoropyridin-2-carbonitrile (1 g; 8.1 mmol; 1 eq.) and 2-(dimethylamino)ethan-1-ol (1.4 g; 0.02 mmol; 2.0 eq.) in 1,4-dioxane (25 ml) was added Cs ₂ CO ₃ (5.3 g; 0.02 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 4 hours at 80°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (2:3) to give 3-[2-(dimethylamino)ethoxy]pyridine-2-carbonitrile (1.2 g; 76.6%) as a yellow oil. . LCMS: m/z (ESI), [M+H] ⁺ =192.1. ^1H NMR (300 MHz, DMSO- _d6 ) δ 2.21 (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]methanamine

Raney's _{Ni (} 403.2 mg; 4.7 mmol; 3 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure. The result was 1-[3-[2-(dimethylamino)ethoxy]pyridin-2-yl]methanamine (200 mg; 65.3%) as a purple oil. 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)pyrazin-2-carboxamide (compound 116}

To a solution of 1-[3-[2-(dimethylamino)ethoxy]pyridin-2-yl]methanamine (200 mg; 1.02 mmol; 1 eq.) and 3-amino-5-(4-fluorophenyl)-6- (1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxylic acid (260.5 mg; 0.7 mmol; 0.7 eq.) in DMF (15 ml) was added portionwise T ₃ P (651.8 mg; 2.04 mmol; 2 eq.) and DIEA (264.7 mg; 2.04 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 33% B to 43% B in 7 min; 254/220 nm; Rt: 7.08 min), giving 3-amino-N-([3-[2-( dimethylamino)ethoxy]pyridin-2-yl]methyl)-5-(4-fluorophenyl)-6-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxamide (compound 116) ( 46.5 mg; 8.40%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =541.4. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 2.20 (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. Preparation of 3-amino-5-(4-fluorophenyl)-N-([3-[(2-hydroxyethyl)amino]pyridin-2-yl]methyl)-6-(1-methyl-1H-1, 3-benzodiazol-6-yl)pyrazin-2-carboxamide (compound 117)

SCHEME 73

Step 1. 3-[(2-Hydroxyethyl)amino]pyridine-2-carbonitrile

To a mixture of 3-fluoropyridin-2-carbonitrile (1.5 g; 12.3 mmol; 1 eq.) and 2-aminoethan-1-ol (1.5 g; 24.5 mmol; 2 eq.) in DMSO ( 25 ml) Cs ₂ CO ₃ (8.01 g; 24.5 mmol; 2 eq.) was added in portions at room temperature. The resulting mixture was stirred for 4 hours at 80°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to give 3-[(2-hydroxyethyl)amino]pyridine-2-carbonitrile (1 g; 49.8%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =164.2. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (2H, q), 3.54 (2H, t), 483 (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]ethan-1-ol

Raney's _{Ni (} 472.5 mg; 5.5 mmol; 3 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 ml). The filtrate was concentrated under reduced pressure. The result was 2-[[2-(aminomethyl)pyridin-3-yl]amino]ethan-1-ol (230 mg; 74.8%) as a purple oil. 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]pyridin-2-yl]methyl)-6-(1-methyl-1H-1,3 -benzodiazol-6-yl)pyrazin-2-carboxamide (compound 117)

To a solution of 2-[[2-(aminomethyl)pyridin-3-yl]amino]ethan-1-ol (200 mg; 1.2 mmol; 1 eq.) and 3-amino-5-(4-fluorophenyl)- 6-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxylic acid (304.2 mg; 0.8 mmol; 0.7 eq.) in DMF (15 ml) was added portionwise T ₃ P (761.1 mg; 2.3 mmol; 2 eq.) and DIEA (309.1 mg; 2.4 mmol; 2 eq.). The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction mixture (60 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 35% B to 36% B in 7 min; 254/220 nm; Rt: 5.57 min), giving 3-amino-5-(4-fluorophenyl )-N-([3-[(2-hydroxyethyl)amino]pyridin-2-yl]methyl)-6-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxamide ( compound 117) (33.3 mg; 5.4%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =513.4. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 3.17 (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. Preparation of 3-amino-N-((4-(dimethylamino)pyridin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazole -2-yl)pyrazin-2-carboxamide (compound 118)

SCHEME 74

Step 1. 4-(Dimethylamino)nicotinonitrile

Dimethylamine (295.63 mg; 6.557 mmol; 2.00 eq.), 4-bromopyridine-3-carbonitrile (600 mg; 3.279 mmol; 1 eq.) and K ₂ CO ₃ (1.36 g; 9.836 mmol; 3.00 eq.) at room temperature. The resulting mixture was stirred for 2 hours at 40°C. The resulting mixture was filtered, the filter cake was washed with DCM (2×20 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to give 4-(dimethylamino)pyridine-3-carbonitrile (470 mg; 97.40%) as an off-white solid (crude). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.26 (6H, s), 6.55 (1H, d), 8.23 (1H, d), 8.47 (1H, s).

Step 2. 3-(Aminomethyl)-N,N-dimethylpyridin-4-amine

A solution of 4-(dimethylamino)pyridine-3-carbonitrile (470 mg; 3.193 mmol; 1 eq.) and Raney nickel (957.56 mg; 11.177 mmol; 3.50 eq.), NH ₃ H ₂ O (1.12 g; 31.958 mmol; 10.01 eq.) in MeOH was stirred for 7 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (2×10 ml). The filtrate was concentrated under reduced pressure. The result was 3-(aminomethyl)-N,N-dimethylpyridin-4-amine (467 mg; 96.71%) as a green oil. LCMS: m/z (ESI), [M+H] ⁺ =152.3. ^1H NMR (300 MHz, MeOD-d ₄ ) δ 2.75-3.05 (6H, m), 3.93 (2H, s), 6.95 (1H, s), 7.90-8.51 (2H, m).

Stage 3; 3-Amino-N-((4-(dimethylamino)pyridin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl )pyrazine-2-carboxamide (compound 118)

To a stirred solution of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (70 mg; 0.208 mmol; 1 eq.) and DIEA (80.70 mg; 0.624 mmol; 3.00 eq.), T ₃ P (132.45 mg; 0.416 mmol; 2.00 eq.) 3- (aminomethyl)-N,N-dimethylpyridin-4-amine (62.95 mg; 0.416 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give a yellow solid. The crude product (90 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 15% B to 50% B in 7 min; 254/220 nm; Rt: 5.82 min), giving 3-amino-N-[[4 -(dimethylamino)pyridin-3-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2- carboxamide (compound 118) (45 mg; 46.05%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =470.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 2.42 (3H, d), 2.80 (6H, s), 457 (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)pyrazin-2-carboxamide (compound 119)

SCHEME 75

Step 1. 2-[(2-Cyanopyridin-3-yl)oxy]acetamide

A mixture of K ₂ CO ₃ (448.75 mg; 3.247 mmol; 3 eq.), 2-chloroacetamide (121.45 mg; 1.299 mmol; 1.2 eq.) and 3-hydroxypyridine-2-carbonitrile (130 mg; 1.082 mmol; 1 eq.) in DMF (6 ml) was stirred for 16 hours at 80°C in an air atmosphere. The resulting mixture was diluted with water (30 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (3 x 30 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 12:1) to give 2-[(2-cyanopyridin-3-yl)oxy]acetamide (100 mg; 52.15%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =178.0. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 478 (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]acetamide

A mixture of Raney nickel (26.98 mg; 0.315 mmol; 0.62 eq.) and 2-[(2-cyanopyridin-3-yl)oxy]acetamide (90 mg; 0.508 mmol; 1 eq.) in MeOH (5 ml ) was stirred for 1 hour at room temperature under a hydrogen atmosphere. The precipitated solids were collected by filtration and washed with MeOH (3×10 ml). The resulting mixture was concentrated under reduced pressure to give 2-[[2-(aminomethyl)pyridin-3-yl]oxy]acetamide (60 mg; 65.18%) as a purple solid. LCMS: m/z (ESI), [M+H] ⁺ =182.1.

Step 3. 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)

A mixture of T ₃ P (100 mg; 1.344 mmol; 4 eq.), DIEA (470.5 mg; 1.344 mmol; 4.00 eq.), 3-amino-5-(4-fluorophenyl)-6-(1- methyl 1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxylic acid (120 mg; 0.336 mmol; 1.00 eq.) and 2-[[2-(aminomethyl)pyridin-3-yl] oke i] acetamide (59.8 mg; 0.336 mmol; 1 eq.) in DMF (0.2 ml) was stirred for 4 hours at room temperature in an air atmosphere. The crude product (70 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 31% B to 45% B in 8 min; 254/220 nm; Rt: 7.30 min), giving 3-amino-N-[[3- (carbamoylmethoxy)pyridin-2-yl]methyl]-5-(4-fluorophenyl)-6-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazin-2-carboxamide (compound 119) (20 mg; 12.14%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =527.3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.80 (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). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ: -112.591.

Examples 120/121. Preparation of (R/S)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazole -2-yl)pyrazin-2-carboxamide (compounds 120/121)

SCHEME 76

Step 1. 3-Amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2-yl) )pyrazine-2-carboxamide

To a stirred solution of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (300 mg; 0.892 mmol; 1 eq.), Et ₃ N (270.79 mg; 2.676 mmol; 3.00 eq.) and T ₃ P (851.48 mg; 2.676 mmol; 3.00 eq.) were added dropwise to DMF 1-(1-methylpyrrolidin-2-yl)methanamine (203.73 mg; 1.784 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred overnight at room temperature. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give a yellow solid. The crude product (260 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 23% B to 38% B in 7 min; 254/220 nm; Rt: 6.33 min), giving 3-amino-6-[3-methylimidazo [1,2-a]pyridin-6-yl]-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (120 mg ; 31.10%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =433.3. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.55-1.67 (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-methylpyrrolidin-2-yl)methyl)-5- (oxazol-2-yl)pyrazin-2-carboxamide (compounds 120/121)

The crude product was purified by preparative HPLC under the following conditions (column: CHIRALPAK IG, 20*250 mm, 5 µm; mobile phase A: Hex:DCM, 3:1 (with 10 mM NH ₃ -MEOH) for HPLC, mobile phase B: EtOH for HPLC; flow rate: 18 ml/min; gradient: 50 V to 50 V in 25 min; 220/254 nm; Rt1: 13.303; Rt2: 19.802), giving 3-amino-6-[3-methylimidazo[ 1,2-a]pyridin-6-yl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (isomer 1) (compound 120) (42 mg; 42.00%), LCMS: m/z (ESI), [M+H] ⁺ =433.2. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.60 (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]pyridin-6-yl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-5-(1,3- Oxazol-2-yl)pyrazin-2-carboxamide (isomer 2) (compound 121) (40 mg; 40%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =433.2. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.59 (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. Preparation of (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(pyrrolidin-2-ylmethyl) )pyrazine-2-carboxamide (compound 122)

SCHEME 77

Step 1. (R)-tert-Butyl 2-((3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamido)methyl)pyrrolidine-1-carboxylate

To a stirred solution of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (140 mg; 0.416 mmol; 1 eq.) and tert-butyl (2R)-2-(aminomethyl)pyrrolidine-1-carboxylate (125.06 mg; 0.624 mmol; 1.50 eq.), DIEA (161.40 mg; 1.249 mmol ; 3.00 eq.) T ₃ P (264.91 mg; 0.833 mmol; 2.00 eq.) was added dropwise to DMF at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was diluted with water (100 ml). The resulting mixture was extracted with CH ₂ Cl ₂ (4 x 100 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), yielding tert-butyl (2R)-2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridine-6 -yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]pyrrolidine-1-carboxylate (156 mg; 72.26%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =519.2.

Step 2. (2R)-3-Amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (compound 122)

Tert-butyl(2R)-2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3- oxazol-2-yl)pyrazin-2-yl)formamido]methyl]pyrrolidine-1-carboxylate (140 mg; 0.270 mmol; 1 eq.) and TFA (2.00 ml; 17.541 mmol; 99.74 eq.) at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 ml). The reaction was quenched with a saturated solution of NaHCO ₃ at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 100 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l) + 0, 1% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 10% B to 30% B in 7 min; 254/220 nm; Rt: 6.82 min), yielding 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[[(2R)-pyrrolidin-2 -yl]methyl]pyrazin-2-carboxamide (compound 122) (60 mg; 53.11%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =419.2. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.32-1.44 (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. Preparation of (S)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(pyrrolidin-2-ylmethyl) )pyrazine-2-carboxamide (compound 123)

SCHEME 78

Step 1. (S)-tert-Butyl 2-((3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamido)methyl)pyrrolidine-1-carboxylate

3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid ( 140 mg; 0.416 mmol; 1 eq.) and tert-butyl (2S)-2-(aminomethyl)pyrrolidine-1-carboxylate (125.06 mg; 0.624 mmol; 1.50 eq.) and DIEA (161.40 mg ; 1.249 mmol; 3.00 eq.), T ₃ P (264.91 mg; 0.833 mmol; 2.0 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was diluted with water (100 ml). The resulting mixture was extracted with CH ₂ Cl ₂ (4 x 100 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), yielding tert-butyl (2S)-2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridine-6 -yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]pyrrolidine-1-carboxylate (170 mg; 78.75%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =519.4.

Step 2. (S)-3-Amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (compound 123)

Tert-butyl (2S)-2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3- Oxazol-2-yl)pyrazin-2-yl)formamido]methyl]pyrrolidine-1-carboxylate (170 mg; 0.328 mmol; 1 eq.) and TFA (3 ml; 40.389 mmol; 123.21 eq.) at room temperature . The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 ml). The reaction was quenched with saturated NaHCO ₃ solution at room temperature and the reaction mixture was extracted with CH ₂ Cl ₂ (3 x 100 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 17% B to 37% B in 7 min; 254/220 nm; Rt: 5.73 min), yielding 3-amino-6-[3-methylimidazo [1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[[(2S)-pyrrolidin-2-yl]methyl]pyrazin-2-carboxamide ( compound 123) (60 mg, yield (Y) 43.74%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =419.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.38 (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. Preparation of (R)-3-amino-6-(3-ethylpyrazolo[1,5-a]pyridin-5-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-( Oxazol-2-yl)pyrazin-2-carboxamide (compound 128)

SCHEME 79

Step 1. 1-[5-Bromopyrazolo[1,5-a]pyridin-3-yl]ethan-1-ol

CH ₃ MgBr (2.12 g, 17.8 mmol, 4.00 eq) was added to a stirred solution of 5-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde (1 g; 4.444 mmol; 1 eq.) in THF (20 ml) at -50°C under nitrogen atmosphere. The reaction was quenched by adding sat. solution (aq.) NH ₄ Cl (5 ml) at 0°C. The aqueous layer was extracted with CH ₂ Cl ₂ (3 x 30 ml). The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to give 1-[5-bromopyrazolo[1,5-a]pyridin-3-yl]ethan-1-ol (600 mg; 56. 01%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =241.2.

Step 2. 5-Bromo-3-ethylpyrazolo[1,5-a]pyridine

Triethylsilane (1852.03 mg; 15. 93 mmol; 6.0 eq.) in TFA (10 ml) at room temperature under air. 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]pyridine (490 mg; 82.0%) as a white solid. 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

To a solution of 5-bromo-3-ethylpyrazolo[1,5-a]pyridine (430 mg; 1.9 mmol; 1 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (970.2 mg; 3.81 mmol; 2.0 eq.) in dioxane (10 ml) was added K ₃ PO ₄ (1216.5 mg; 5.73 mmol; 3.0 eq.) and Pd(dppf)Cl ₂ (279.6 mg; 0.38 mmol; 0.2 eq.). After stirring for 2 hours at 90°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 12:1), yielding 3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine (420 mg; 80.78%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =273.2.

Step 4. Methyl 3-amino-6-[3-ethylpyrazolo[1,5-a]pyridin-5-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate

To a solution of methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (400 mg; 1.571 mmol; 1 eq.) and 3-ethyl-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (641.31 mg; 2.356 mmol; 1.50 eq.) in dioxane (10 ml) and water (1 ml), K ₃ PO ₄ (1000.35 mg; 4.713 mmol; 3 eq.) and Pd(dppf)Cl ₂ (229.89 mg; 0.314 mmol; 0.2 eq.) were added. After stirring for 2 hours at 85°C under nitrogen, the residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 15:1) to give methyl 3-amino-6-[3-ethylpyrazolo[1,5-a]pyridine -5-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (300 mg; 52.4%) as a brown-yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =365.3.

Step 5. 3-Amino-6-(3-ethylpyrazolo[1,5-a]pyridin-5-yl)-5-(oxazol-2-yl)pyrazin-2-carboxylic acid

Solution of methyl 3-amino-6-[3-ethylpyrazolo[1,5-a]pyridin-5-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (280 mg; 0. 77 mmol; 1 eq.) and LiOH (36.8 mg; 1.54 mmol; 2.0 eq.) in THF (20 ml) were stirred for 1 h at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified to pH 5 using HCl (aq) solution. The precipitated solids were collected by filtration and concentrated in vacuo to give 3-amino-6-[3-ethylpyrazolo[1,5-a]pyridin-5-yl]-5-(1,3-oxazol-2-yl) pyrazine-2-carboxylic acid (240 mg; 89.15%) as a brown-yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =351.3.

Step 6. 3-Amino-6-[3-ethylpyrazolo[1,5-a]pyridin-5-yl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl1-5-(1.3- Oxazol-2-yl)pyrazin-2-carboxamide (compound 128)

Solution of 3-amino-6-[3-ethylpyrazolo[1,5-a]pyridin-5-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (70 mg; 0. 2 mmol; 1 eq.), 1-[(2R)-1-methylpyrrolidin-2-yl]methanamine (34.22 mg; 0.3 mmol; 1.5 eq.), HATU (151.95 mg; 0 .4 mmol; 2 eq.), DIEA (77.5 mg; 0.6 mmol; 3 eq.) in DMF (2 ml) was stirred for 30 min at room temperature in an air atmosphere. The reaction mixture was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 50% B in 8 min; 254/220 nm; Rt: 7.25 min), giving 3-amino-6-[3-ethylpyrazolo[1,5 -a]pyridin-5-yl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 128 ) (20.1 mg; 22.42%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =447.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.2 (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. Preparation of (S)-3-amino-6-(3-ethylpyrazolo[1,5-a]pyridin-5-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-( Oxazol-2-yl)pyrazin-2-carboxamide (compound 129)

SCHEME 80

Step 1. 3-Amino-6-[3-ethylpyrazolo[1.5-a]pyridin-5-yl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-5-(1.3-oxazole -2-yl)pyrazin-2-carboxamide (compound 129)

3-Amino-6-[3-ethylpyrazolo[1,5-a]pyridin-5-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid solution (70 mg; 0.200 mmol ; 1 eq.), 1-[(2S)-1-methylpyrrolidin-2-yl]methanamine (34.22 mg; 0.300 mmol; 1.5 eq.), HATU (151.95 mg; 0.400 mmol; 2. 00 eq.), DIEA (77.47 mg; 0.599 mmol; 3 eq.) in DMF (2 ml) was stirred for 30 min at room temperature in an air atmosphere. The crude product (70 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: 39% B to 51% B in 8 min; 254/220 nm; Rt: 7.67 min), yielding 3-amino-6-[3-ethylpyrazolo [1,5-a]pyridin-5-yl]-N-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)pyrazin-2- carboxamide (compound 129) (29.8 mg; 22.42%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =447.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.2 (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)pyrazin-2-carboxamide (compound 232)

SCHEME 81

Step 1. 3-Amino-6-(1-methyl-1H-1,3-benzodiazol-6-yl)-5-(1,3-oxazol-2-yl)-N-[(1,3-thiazole -4-yl)methyl]pyrazin-2-carboxamide (compound 130)

To a stirred solution of 3-amino-6-(1-methyl-1H-1,3-benzodiazol-6-yl)-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylic acid (300 mg; 0.892 mmol; 1 eq.) and 1-[(2S)-1-methylpyrrolidin-2-yl]methanamine (101.86 mg; 0.892 mmol; 1 eq.) in DMF, T ₃ was added dropwise/portionally P (851.47 mg; 2.676 mmol; 3 eq.) and DIEA (576.44 mg; 4.460 mmol; 5 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 4 hours at room temperature in an air atmosphere. The resulting mixture was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (3 x 10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 18% B to 35% B in 7 min; 254/220 nm; Rt: 7.08 min), giving 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) (20 mg; 5.18%) as a yellow solid. LCMS m/z (ESI) [M+H] ⁺ =433.2; ^1H NMR (400 MHz, MeOD-d ₄ ) δ 1.68-1.81 (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)pyrazin-2-carboxamide (compound 233)

SCHEME 82

Step 1. 3-Amino-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylic acid

Solution of methyl 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (500 mg; 1.964 mmol; 1 eq.), 1-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,3-benzodiazole (608.25 mg; 2.356 mmol; 1.20 eq.), Pd(dppf )Cl ₂ (287.36 mg; 0.393 mmol; 0.2 eq.) and Cs ₂ CO ₃ (2559.16 mg; 7.855 mmol; 4.0 eq.) in dioxane (40 ml) and water (5 ml) stirred for 16 hours at 100°C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3×40 ml). The aqueous solution was acidified to pH 6 using HCl solution (1 M). The precipitated solids were collected by filtration and washed with water (2×10 ml). As a result, 3-amino-6-(1-methyl-1H-1,3-benzodiazol-6-yl)-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylic acid was obtained (240 mg; 36.34%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =337.1. ¹ H-NMR (300 MHz, MeOD-d ₄ ) δ 3.93 (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-methylpyrrolidin-2-yl)methyl)-5-(2H -1,2,3-triazol-2-yl)pyrazin-2-carboxamide (compound 131)

A mixture of 3-amino-6-(1-methyl-1H-1,3-benzodiazol-6-yl)-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.297 mmol; 1 eq.), 1-[(2R)-1-methylpyrrolidin-2-yl]methanamine (67.91 mg; 0.595 mmol; 2.0 eq.), T ₃ R (473.04 mg ; 1.487 mmol; 5 eq.) and DIEA (384.29 mg; 2.973 mmol; 10 eq.) in DMF (5 ml) were stirred for 2 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Kinetex EVO CIS column, 30*150.5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 20% B to 35% B in 7 min; 254/220 im; Rt: 5.73 min), giving 3-amino-6-(1-methyl-1H-1 ,3-benzodiazol-6-yl)-N-[[(2R)-l-methylpyrrolidin-2-yl]methyl]-5-(2H-l,2,3-triazol-2-yl)pyrazin-2- carboxamide (compound 131) (20 mg; 15.55%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =433.3. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 1.67-1.69 (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, t).

The compounds shown in the table below were prepared using the methods described for the preparation of compound 131.

Examples 134/135. Preparation of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[[(2R/2S)-oxetane -2-yl]methyl]pyrazin-2-carboxamide (compounds 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-carboxamide

To a stirred mixture of T ₃ P (946.09 mg; 2.973 mmol; 5.00 eq.) and 1-(oxetan-2-yl)methanamine (77.72 mg; 0.892 mmol; 1.50 eq.) in DMF ( 5 ml), 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid ( 200 mg; 0.595 mmol; 1 eq.) and DIEA (307.44 mg; 2.379 mmol; 4.00 eq.) at 25°C in a nitrogen atmosphere. The resulting mixture was stirred for 6 hours at 25°C under a nitrogen atmosphere. The reaction was quenched by adding water (50 ml) at 25°C. The aqueous layer was extracted with EtOAc (3x50 ml). The aqueous layer was evaporated. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 19% B to 29% B in 7 min; 254/220 nm; Rt: 6.45 min), yielding 3-amino-6-[3-methylimidazo [1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[(oxetan-2-yl)methyl]pyrazin-2-carboxamide (90 mg; 37 .33%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =406.2.

Step 2. Preparation of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[[(2R/2S )-oxetan-2-yl]methyl]pyrazin-2-carboxamide (compounds 134/135)

The crude product (150 mg) was purified by preparative HPLC under the following conditions (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: MTBE (with 10 mM NH ₃ -MEOH) for HPLC, mobile phase B: EtOH for HPLC; flow rate: 20 ml/min; gradient: from 20 V to 20 V in 18 min; 220/254 nm; Rt1: 12.678; Rt2: 14.094), giving 3-amino-6-[3-methylimidazo[1, 2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[[(2R)-oxetan-2-yl]methyl]pyrazin-2-carboxamide (isomer 1) (compound 134) (60 mg; 40%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =406.1. ¹ H NMR (300 MHz, MeOD-d ₄ ) 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]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[[(2R)-oxetan-2 -yl]methyl]-pyrazin-2-carboxamide (isomer 2) (compound 135) (60 mg; 40%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =406.1. ^1H NMR (300 MHz, MeOD-d ₄ ) δ 2.50 (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. Preparation of (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)

SCHEME 84

Step 1. (R)-3-Amino-6-(3-methylimidazo[2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydrofuran-3-yl)methyl )pyrazine-2-carboxamide (compound 136)

3-Amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid was placed in a 25 ml round bottom flask. (100 mg; 0.297 mmol; 1 eq.), DIEA (384.30 mg; 2.973 mmol; 10 eq.) and (R)-(tetrahydrofuran-3-yl)methanamine (90.23 mg; 0.892 mmol; 3 eq. .) in DMF (4 ml). T ₃ P (378.44 mg; 1.189 mmol; 4 eq.) was added to the above solution at 0°C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 30×150 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l) + 0.1% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 17% B to 37% B in 7 min; 254/220 nm; Rt: 5.85 min). The result was 67 mg (53.72%) of (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N -((tetrahydrofuran-3-yl)methyl)pyrazin-2-carboxamide (compound 136) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =420.2. ¹ H-NMR (400 MHz, MeOD-d ₄ ) δ 1.75 (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. Preparation of (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)

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)

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.297 mmol; 1 eq.) and (S)-(tetrahydrofuran-3-yl)methanamine (130 mg; 1.285 mmol; 4.32 eq.) DIEA (1.04 ml; 5.946 mmol; 20 eq.) was added dropwise to DMF .) and T ₃ P (473.05 mg; 1.487 mmol; 5 eq.) at room temperature in an air atmosphere. The reaction mixture was diluted with water (25 ml). The aqueous layer was extracted with EtOAc (2 x 25 ml). The combined organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 30 × 150 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l) + 0.1% NH ₃ . H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 15% B to 35% B in 7 min; 254/220 nm; Rt: 6.48 min), obtaining (S) -3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydrofuran-3-yl)methyl)pyrazin-2 -carboxamide (compound 137) (70 mg; 56.00%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =420.3; ¹ H-NMR (400 MHz, MeOD-d ₄ ) δ 1.75 (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 shown in the table below were prepared using the methods described for the preparation of 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]pyrazin-2-carboxylic acid

3-Amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylic acid (1 g; 3.736 mmol; 1 eq.), [ 3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (1.12 g; 6.364 mmol; 1.70 eq.), Cs ₂ CO ₃ (3.04 g; 9.330 mmol; 2.50 eq.), dioxane (25 ml), Pd(dppf)Cl ₂ (273.39 mg; 0.374 mmol; 0.10 eq.). The resulting solution was stirred for 16 hours at 100°C. The resulting solution was diluted with 20 ml of H ₂ O. The resulting solution was extracted with ethyl acetate (3 x 20 ml) and the aqueous layers were combined. The pH value of the solution was adjusted to 4 using HCl solution (1 mol/L). Solids were collected by filtration. As a result, 500 mg (36.83%) of 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylic acid was obtained in the form brown solid. LCMS: m/z (ESI), [M+H] ⁺ =364. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.37 (3H, s), 6.97 (1H, d), 7.21 (2H, t), 7.38 (2H, t), 7.51 (2H, d), 7.62 ( 2Н, s), 8.26 (1Н, s).

Step 2. 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)

3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylic acid (130 mg; 0.358 mmol; 1 eq.), 1-[(2R)-1-methylpyrrolidin-2-yl]methanamine (81.71 mg; 0.716 mmol; 2.00 eq.), DMF (6 ml), DIEA (0.31 ml; 2.396 mmol; 3.42 eq.), T ₃ P (569.19 mg; 1.789 mmol; 5.00 eq.). The resulting solution was stirred for 16 hours at 20°C. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (column: preparative column XBridge OBD C18, 30×150 mm, 5 µm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 34% B to 49% B in 7 min; 254/220 nm; Rt: 6.52 min). The result was 54.29 mg (33.02%) of 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[[( 2R)-1-methylpyrrolidin-2-yl]methyl]pyrazin-2-carboxamide (compound 138) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =460. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.61 (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). ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) -112.225 (1F).

Example 147. Preparation of 3-amino-N-(2-methoxyethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (connections 147)

SCHEME 87

Step 1. 3-Amino-N-(2-methoxyethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide ( connection 147)

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (90 mg; 0.268 mmol; 1 eq.) and 2-methoxyethane-1-amine (60.30 mg; 0.803 mmol; 3 eq.) DIEA (164.08 mg; 1.270 mmol; 5 eq.) and T ₃ were added dropwise to DMF P (323.16 mg; 1.016 mmol; 4 eq.) at room temperature in an air atmosphere. The resulting solution was stirred for 1 hour at room temperature. Water (25 ml) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with brine (1x15 ml), dried over anhydrous Na ₂ SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 30×150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; speed flow: 60 ml/min; gradient: from 18% B to 32% B in 7 min; 254 nm; Rt: 6.83 min), giving 3-amino-N-(2-methoxyethyl)-6-[3- methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 147) (50 mg; 49.78%) as a yellow solid substances. LCMS: m/z (ESI), [M+H] ⁺ =394.2. ¹ H-NMR (400 MHz, MeOD-d ₄ ) δ 2.52 (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 shown in the table below were prepared using the methods described for the preparation of compound 147.

Example 149. Preparation of 3-amino-N-(3-methoxypropyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazine -2-carboxamide (compound 149)

SCHEME 88

Step 1. Methyl 3-amino-6-[3-methylimidazo[1,2-a]iridin-6-yl1-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (3000 mg; 11.8 mmol; 1 eq.) and [3-methylimidazo[1 ,2-a]pyridin-6-yl]boronic acid (4146.7 mg; 23.6 mmol; 2 eq.) in dioxane (300 ml) Cs ₂ CO ₃ (11516.2 mg; 35.3 mmol) was added in portions ; 3 eq.) and Pd(dppf)Cl ₂ (1724.1 mg; 2.4 mmol; 0.2 eq.) at 80°C in a nitrogen atmosphere. The resulting mixture was stirred for 1.5 hours at 95°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /EtOAc (1:4) to give methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxylate (1500 mg; 36.3%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =351.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.12 (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-oxazol-2-yl)pyrazin-2-carboxylic acid

Mixture of methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylate (1500 mg; 4. 3 mmol; 1 eq.) and LiOH (205.1 mg; 8.6 mmol; 2 eq.) in THF (100 ml) and MeOH (20 ml) were stirred for 1.5 h at 45°C. The resulting mixture stirred for 2.5 hours at 45°C in an air atmosphere. The mixture was acidified to pH 5 using HCl (aq) solution. The resulting mixture was concentrated in vacuo to give 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (1200 mg; 83.3%) as a yellow solid. 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-oxazol-2-yl)pyrazin- 2-carboxamide (compound 149)

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.3 mmol; 1 eq.) and 3-methoxypropan-1-amine (53 mg; 0.6 mmol; 2 eq.) in DMF (8 ml) HATU (226.1 mg; 0.6 mmol; 2 equiv.) and DIEA (115.3 mg; 0.9 mmol; 3 equiv.) at room temperature in an air atmosphere. The resulting mixture was stirred for 2.5 hours at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 21% B to 34% B in 7 min; 254/220 nm; Rt: 6.67 min), giving 3-amino-N-(3-methoxypropyl )-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 149) (10 mg; 8. 3%) as a yellow-green solid. LCMS: m/z (ESI), [M+H] ⁺ =408.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.78 (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]boronic acid

5-(3,3,4,4-Tetramethylborolan-1-yl)pyridin-2-amine (20.0 g; 92.5 mmol; 1.0 eq.) was added to the HCl solution (1.0 mol/L ), stirred for 1 hour at 80°C in an air atmosphere. The mixture was made alkaline to pH 7 using NaHCO ₃ (tv). The resulting mixture was extracted with CHCl ₃ (5 x 40 ml) and dried over anhydrous N ₂ SO ₄ . After filtration, 2-bromo-1,1-dimethoxypropane (49.9 g; 272.9 mmol; 2.9 eq.) was added to the above mixture. The resulting mixture was stirred for 10 hours at 100°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was recrystallized from EtOAc/MeOH (20:1, 50 ml) to give [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (14.6 g; 87.8%) as white solid matter. LCMS: m/z (ESI), [M+H] ⁺ =177.2.

Step 2. Methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylate

A mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (20 g; 90.1 mmol; 1.0 eq.), (4-fluorophenyl)boronic acid (13.9 g; 99.1 mmol; 1 ,1 eq.), Pd(dppf)Cl ₂ (6.6 g; 9.0 mmol; 0.1 eq.) and Na ₂ CO ₃ (19.1 g; 180.2 mmol; 2.0 eq. ) in a mixture of 1,4-dioxane/H ₂ O (300 ml) was stirred for 2 hours at 90°C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with H ₂ O (3 x 80 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was recrystallized from MeOH (100 mL) to give methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylate (19.2 g, 74.2%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =282.2.

Step 3. Methyl 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl!pyrazin-2-carboxylate

A mixture of methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylate (9.2 g; 32.6 mmol; 1.0 eq.), [3-methylimidazo[1,2-a ]pyridin-6-yl]boronic acid (11.5 g; 65.3 mmol; 2.0 eq.), Pd(dppf)Cl ₂ (2.4 g; 3.3 mmol; 0.1 eq.) and K ₃ PO ₄ (13.9 g; 65.3 mmol; 2.0 eq.) in a mixture of 1,4-dioxane/H ₂ O (200 ml) was stirred for 2 hours at 90°C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (4 x 80 ml). The combined organic layers were washed with H ₂ O (3 x 30 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /EtOAc (2:1) to give methyl 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridine -6-yl]pyrazin-2-carboxylate (9.5 g; 76.1%) as a brownish-yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =378.3.

Step 4. 3-Amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylate (3.0 g; 7.9 mmol ; 1.0 eq.) lithium hydroxide (380.8 mg; 15.9 mmol; 2.0 eq.) was added to a mixture of 20:1 THF/H ₂ O (82 ml). The resulting mixture was stirred for 4.0 hours at room temperature in an air atmosphere. The desired product could be detected by LCMS. The mixture was acidified to pH 3 using a solution of HCl (in dioxane). The precipitated solids were collected by filtration and washed with water (2 x 10 ml) to give 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazine -2-carboxylic acid (2.1 g; 72.7%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =364.2. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.35-2.42 (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]-5-(4-fluorophenyl)-6-[3-methylimidazo[1.2-a]pyridin-6-yl]pyrazin-2- carboxamide (compound 154)

Mixture of 3-amino-5-(4-fluorophenyl)-6-[imidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylic acid (100.0 mg; 0.3 mmol; 1.0 eq.), 1-(aminomethyl)-N,N-dimethylcyclopropan-1-amine (49.0 mg; 0.4 mmol; 1.5 eq.), HATU (217.6 mg; 0.6 mmol; 2 .0 eq.) and DIEA (111.0 mg; 0.9 mmol; 3.0 eq.) in DMF (2.5 ml) were stirred for 1 h at room temperature in an air atmosphere. The reaction was quenched with water at room temperature. The solids were separated, then the crude product was recrystallized from EtOH (4 ml) to give 3-amino-N-[[1-(dimethylamino)cyclopropyl]methyl]-5-(4-fluorophenyl)-6-[3-methylimidazo[1 ,2-a]pyridin-6-yl]pyrazin-2-carboxamide (compound 154) (25 mg; 18.6%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =460.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.43-0.52 (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 shown in the table below were prepared using the methods described for the preparation of 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

Methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylate (2.0 g; 7.10 mmol; 1 eq.) and a solution of NH ₃ (gas) were added to a hermetically sealed 50 ml test tube. .) in MeOH (30 ml; 7.0 mmol/l) at room temperature, heated for 5 hours at 50°C, concentrated to give 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2 -carboxamide (1.5 g; 79%) as a light yellow solid. 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 (1.5 g; 5.63 mmol; 1 eq.) and POCl ₃ (10 mL; 107) were added to a 25 mL round bottom flask. .28 mmol; 19.07 eq.) at room temperature, heated for 3 hours at 90°C. Cool to room temperature, pour into NaHCO ₃ (aq, 200 ml), filter and dry to give 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile (1.2 g; 86 %) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =249.2.

Step 3. 3-(Aminomethyl)-5-chloro-6-(4-fluorophenyl)pyrazin-2-amine

Add 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile (1.4 g; 5.63 mmol; 1 eq.) and Raney Ni (0.3 g) to a 500 mL round bottom flask. ; 3.50 mmol; 0.62 eq.) in methanol (150 ml) at room temperature, stirred for 15 h under H ₂ atmosphere (about 1.5 at (147 kPa)), filtered and concentrated to give 3- (aminomethyl)-5-chloro-6-(4-fluorophenyl)pyrazin-2-amine (1.1 g; crude) 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]pyrazin-2-yl]methyl] -1-methylpyrrolidine-2-carboxamide

To a stirred mixture of (2S)-1-methylpyrrolidine-2-carboxylic acid (168.68 mg; 1.31 mmol; 1.10 eq.), 3-(aminomethyl)-5-chloro-6-(4-fluorophenyl) pyrazin-2-amine (300 mg; 1.19 mmol; 1 eq.) and HATU (496.58 mg; 1.31 mmol; 1.1 eq.) in DMF (3.0 ml) was added dropwise with DIEA ( 306.89 mg; 2.38 mmol; 2.0 eq.) at 0°C under nitrogen, stirred for 3 hours at room temperature, added water (15 ml), filtered and dried to give (2S)-N -[[3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]-1-methylpyrrolidine-2-carboxamide (250 mg; 57.88%) as a light yellow solid . 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]pyrazin-2-yl]methyl] -1-methylpyrrolidine-2-carboxamide (compound 156)

Mixture of (2S)-N-[[3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]-1-methylpyrrolidine-2-carboxamide (180.0 mg; 0.5 mmol ; 1.0 eq.), [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (174.1 mg; 0.9 mmol; 2.0 eq.), Pd(dppf)Cl ₂ (36.2 mg; 0.1 mmol; 0.1 eq.) and K ₃ PO ₄ (315.1 mg; 1.5 mmol; 3.0 eq.) in a mixture of 1,4-dioxane/H ₂ O (4.0 ml) was stirred for 10 hours at 90°C under nitrogen atmosphere. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 40:1), then the crude product (80.0 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 30% B to 43% B in 7 min; 254/220 nm ; Rt: 6.70 min), yielding (2S)-N-[[3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazine -2-yl]methyl]-1-methylpyrrolidin-2-carboxamide (compound 157) (20.0 mg; 8.6%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =460.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.73 (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]pyrazin-2-yl]methyl] -1-methylpyrrolidine-2-carboxamide (compound 157)

Mixture of (2R)-N-[[3-amino-6-chloro-5-(4-fluorophenyl)pyrazin-2-yl]methyl]-1-methylpyrrolidine-2-carboxamide (180.0 mg; 0.5 mmol ; 1.0 eq.), [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (174.1 mg; 0.9 mmol; 2.0 eq.), Pd(dppf)Cl ₂ (36.2 mg; 0.1 mmol; 0.2 eq.) and K ₃ PO ₄ (315.1 mg; 1.5 mmol; 3.0 eq.) in a mixture of 1,4-dioxane/H ₂ O (4.0 ml) was stirred for 10 hours at 90°C under nitrogen atmosphere. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 40:1), then the crude product (80.0 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 30% B to 43% B in 7 min; 254/220 nm ; Rt: 6.70 min), yielding (2R)-N-[[3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazine -2-yl]methyl]-1-methylpyrrolidin-2-carboxamide (compound 157) (20.0 mg; 8.6%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =460.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.73 (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 shown in the table below were prepared using the methods described for the preparation of compound 157.

Example 161. Preparation of (S)-3-amino-N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6- yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 161)

SCHEME 92

Step 1. (S)-tert-Butyl 2-((3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamido)methyl)-4.4-difluoropyrrolidine-1-carboxylate

To a stirred solution of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (150 mg; 0.446 mmol; 1 eq.) and tert-butyl (28)-2-(aminomethyl)-4,4-difluoropyrrolidine-1-carboxylate (210.75 mg; 0.892 mmol; 2.00 eq.), DIEA (172, 93 mg; 1.338 mmol; 3.00 eq.) T ₃ P (283.83 mg; 0.892 mmol; 2.00 eq.) was added dropwise to DMF at 0°C in an air atmosphere. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The resulting mixture was diluted with EtOAc (40 ml). The resulting mixture was washed with water (2×40 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and the solid was filtered and concentrated in vacuo. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 200:15), yielding tert-butyl (2S)-2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridine-6 -yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]-4,4-difluoropyrrolidine-1-carboxylate (220 mg; 88.95%) as a yellow solid substances. 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-a1pyridin-6-yl)-5-(oxazole -2-yl)pyrazin-2-carboxamide

Tert-butyl (2S)-2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3- Oxazol-2-yl)pyrazin-2-yl)formamido]methyl]-4,4-difluoropyrrolidine-1-carboxylate (220 mg; 0.397 mmol; 1 eq.) and TFA (2 ml; 26.926 mmol; 67.87 eq. .) at room temperature. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. The solvent and TFA were evaporated to give 3-amino-N-[(4,4-difluoropyrrolidin-2-yl)methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (180 mg; 99.84%) as a yellow solid (crude). 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-(oxazol-2-yl)pyrazin-2-carboxamide (compound 161)

To a stirred mixture of 3-amino-N-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5- (1,3-oxazol-2-yl)pyrazin-2-carboxamide (180 mg; 0.396 mmol; 1 eq.) and HCHO (118.93 mg; 3.961 mmol; 10.00 eq.), DIEA (510.9 mg; 3.961 mmol; 10.00 eq.) in CH ₂ Cl ₂ (6 ml) and MeOH (3 ml) NaBH ₃ CN (149.35 mg; 2.377 mmol; 6.00 eq.) was added in portions at room temperature in air atmosphere. The reaction mixture was stirred at RT for 2 hours. Quenched with water (50 ml) and extracted with DCM (2×50 ml), the organic layer was combined and dried over anhydrous Na ₂ SO ₄ , the solid was filtered and the solvent was evaporated. The residue was purified by preparative TLC (DCM:MeOH, 20:1) to give a yellow solid. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18 column, 30*150.5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B : ACN; flow rate: 60 ml/min; gradient: from 27% B to 40% B in 7 min; 254/220 nm; R _t : 6.05 min), giving 3-amino-N-[[(2S )-4,4-difluoro-1-methylpyrrolidin-2-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2- yl)pyrazin-2-carboxamide (compound 161) (60 mg; 32.34%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =469.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 2.19 (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. Preparation of (R)-3-amino-N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6- yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 162)

SCHEME 93

Step 1. (R)-tert-Butyl 2-((3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamido)methyl)-4,4-difluoropyrrolidine-1-carboxylate

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (150 mg; 0.446 mmol; 1 eq.) and tert-butyl (2R)-2-(aminomethyl)-4,4-difluoropyrrolidine-1-carboxylate (210.75 mg; 0.892 mmol; 2.00 eq.), DIEA (172, 93 mg; 1.338 mmol; 3.00 eq.) T ₃ P (283.83 mg; 0.892 mmol; 2.00 eq.) was added dropwise to DMF at 0°C in an air atmosphere. The resulting mixture was diluted with EtOAc (50 ml). The resulting mixture was washed with water (2×50 ml) and saturated NaCl solution (2×50 ml), and the organic layer was dried over anhydrous Na ₂ SO ₄ . The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), yielding tert-butyl (2R)-2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridine-6 -yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]-4,4-difluoropyrrolidine-1-carboxylate (220 mg; 88.95%) as a yellow solid substances. LCMS: m/z (ESI), [M+H] ⁺ =555.2; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.28 (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), 8.3 (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- (oxazol-2-yl)pyrazin-2-carboxamide

To a stirred solution of tert-butyl (2R)-2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2- yl)pyrazin-2-yl)formamido]methyl]-4,4-difluoropyrrolidine-1-carboxylate (220 mg; 0.397 mmol; 1 eq.) TFA (2 mL; 26.926 mmol; 67.87 eq.) was added to DCM at room temperature in an air atmosphere. The resulting mixture was stirred for 1 hour at room temperature in an air atmosphere. DCM and TFA were evaporated to give 3-amino-N-[[(2R)-4,4-difluoropyrrolidin-2-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl] -5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (99.84%) as a yellow solid (crude). LCMS: m/z (ESI), [M+H] ⁺ =455.2. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.40 (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-(oxazol-2-yl)pyrazin-2-carboxamide (compound 162)

To a stirred mixture of 3-amino-N-[[(2R)-4,4-difluoropyrrolidin-2-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5- (1,3-oxazol-2-yl)pyrazin-2-carboxamide (180 mg; 0.396 mmol; 1 eq.), HCHO (118.93 mg; 3.961 mmol; 10.00 eq.) and DIEA (307.15 mg; 2.377 mmol; 6.00 eq.) in a mixture of CH ₂ Cl ₂ (6 ml)/MeOH (3 ml) NaBH ₃ CN (149.35 mg; 2.377 mmol; 6.00 eq.) was added dropwise at room temperature in the air atmosphere. The resulting mixture was stirred for 2 hours at room temperature in an air atmosphere. The reaction was quenched by adding water (50 ml) at room temperature. The aqueous layer was extracted with CH ₂ Cl ₂ (2×50 ml). The organic layer was combined, dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give a yellow solid. The crude product (160 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN; flow rate: 20 ml/min; gradient: 32% B to 45% B in 8 min; 254/220 nm; Rt: 7.67 min), giving 3-amino-N-[[( 2R)-4,4-difluoro-1-methylpyrrolidin-2-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2 -yl)pyrazin-2-carboxamide (compound 162) (40 mg; 21.56%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =469.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 2.19 (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. Preparation of 3-amino-H-[(6-[1-methyl-1,6-diazaspiro[3.3]heptan-6-yl]pyridin-2-yl)methyl]-6-[3-methylimidazo[1 ,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 171)

SCHEME 94

Step 1. tert-butyl 6-(6-cyanopyridin-2-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate

Mixture of 6-fluoropyridine-2-carbonitrile (1.5 g; 12.29 mmol; 1 eq.), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (2.92 g; 14.73 mmol ; 1.20 eq.) and K ₂ CO ₃ (5.09 g; 36.829 mmol; 3.00 eq.) in DMF (20 ml) were stirred for 10 h at 50°C in an air atmosphere. The resulting mixture was extracted with EtOAc (4×20 ml). The combined organic layers were washed with H ₂ O (2×10 ml), dried over anhydrous Na ₂ SO ₄ . 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 tert-butyl 6-(6-cyanopyridin-2-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (2 .69 g; 72.17%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =301.3.

Step 2. 1-(6-[1-Methyl-1,6-diazaspiro[3.3]heptan-6-yl)pyridin-2-yl)methanamine

A mixture of tert-butyl 6-(6-cyanopyridin-2-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (0.5 g; 1.665 mmol; 1 eq.) and LiAlH ₄ (0.13 g ; 3.425 mmol; 2.06 eq.) in THF (10 ml) was stirred for 6 hours at 50°C in an air atmosphere. The reaction mixture was quenched by adding EtOAc (20 ml) at room temperature and then extracted with EtOAc (4×20 ml). The combined organic layers were washed with water (3×10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The result was 1-(6-[1-methyl-1,6-diazaspiro[3.3]heptan-6-yl]pyridin-2-yl)methanamine (200 mg; 53.93%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =219.2.

Step 3. 3-Amino-N-[(6-[1-methyl-1,6-diazaspiro[3.3]heptan-6-yl]pyridin-2-yl)methyl]-6-[3-methylimidazo[1, 2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 171)

To a stirred solution/mixture of 3-amino-6-[imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid ( 100 mg; 0.31 mmol; 1 eq.) and 1-(6-[1-methyl-1,6-diazaspiro[3.3]heptan-6-yl]pyridin-2-yl)methanamine (101.6 mg; 0.465 mmol; 1.50 eq.) in DMF (3 ml) HATU (235.96 mg; 0.621 mmol; 2.00 eq.) and DIEA (120.31 mg; 0.931 mmol; 3.0 eq.) were added dropwise. ) at room temperature in an air atmosphere. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 60 ml/min; gradient : 28% B to 40% B in 7 min; 254/220 nm; Rt: 6.37 min), yielding 3-amino-N-[(6-[1-methyl-1,6-diazaspiro[3.3] heptan-6-yl]pyridin-2-yl)methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin- 2-carboxamide (compound 171) (20 mg; 12.01%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =537.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.1 (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. Preparation of 3-amino-N-((6-((8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-6-(3- methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 172)

SCHEME 95

Step 1. 6-((1R,5S)-3-Methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)picolinonitrile

To a stirred solution of 6-fluoropyridine-2-carbonitrile (594 mg; 4.865 mmol; 1 eq.) and 3-methyl-3,8-diazabicyclo[3.2.1]octane (675.35 mg; 5.351 mmol; 1.10 eq. .) K ₂ CO ₃ (2756.59 mg; 19.946 mmol; 4.10 eq.) was added portionwise to DMF (10.5 ml) at room temperature in an air atmosphere. The resulting mixture was stirred for 6.0 hours at 50°C in an air atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (hexane/EtOAc, 1:1) to give 6-[3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-carbonitrile (613 mg, 55.19 %) in the form of a light yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =229.3.

Step 2. (6-((1R,5S)-3-Methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methanamine

To a stirred solution of 6-[8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridin-2-carbonitrile (613 mg; 2.685 mmol; 1 eq.) and NH ₃ .H ₂ O ( 1.2 ml; 190.218 mmol; 65.14 eq.) into MeOH (15 ml) was added dropwise Raney Ni (345.07 mg; 4.028 mmol; 1.50 eq.) at room temperature under a hydrogen atmosphere. The resulting mixture was stirred for 1.0 h at room temperature under a hydrogen atmosphere.

The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give 1-(6-[8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridin-2-yl)methanamine (580 mg; 94.99%) in the form of a yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =233.3.

Step 3. 3-Amino-N-((6-((1R,5S)-3-methyl-3.8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-6-( 3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide

To a stirred solution of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (200 mg; 0.596 mmol; 1 eq.) and 1-(6-[3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)methanamine (207.85 mg; 0.895 mmol; 1 .50 eq.) in DMF (4.00 ml; 205.218 mmol; 324.98 eq.) HATU (453.56 mg; 1.193 mmol; 2.00 eq.) and DIEA (308.34 mg; 2.386 mmol) were added in portions ; 4.00 eq.) at room temperature in an air atmosphere. The desired product could be detected by LCMS. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 3-amino-N-[(6-[3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridine -2-yl)methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (100 mg; 30.45%) as a dark yellow solid. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 31% B to 43% B in 7 min; 254/220 nm; Rt: 6.77 min), giving 3-amino-N-[(6- [3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]- 5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 172) (39 mg; 23.9%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =551.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 1.57 (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. Preparation of 3-amino-N-((6-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1 ,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 175)

SCHEME 96

Step 1. 6-(6-Methyl-2,6-diazaspiro[3.4]octan-2-yl)picolinonitrile

6-fluoropyridine-2-carbonitrile (500 mg; 4.095 mmol; 1 eq.) tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate, oxalic acid salt, (1609, 41 mg; 5.323 mmol; 1.3 eq.), K ₂ CO ₃ (1697.83 mg; 12.285 mmol; 3 eq.) and DMF (10 ml) at room temperature. The resulting mixture was stirred for 3 hours at 50°C. The reaction was quenched by adding sat. NaCl (aq) solution (250 ml) at room temperature. The resulting mixture was extracted with EtOAc (2×125 ml). The combined organic layers were washed with sat. NaCl (aq) solution (250 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1) to give 6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridin-2 -carbonitrile (700 mg; 79.78%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =259.2.

Step 2. (6-(6-Methyl-2.b-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)methanamine

Add tert-butyl 2-(6-cyanopyridin-2-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (500 mg; 1.590 mmol; 1 eq.) in THF ( 10 ml), then LiAlH ₄ (301.81 mg; 7.952 mmol; 5 eq.) was added at 0°C. This solution was stirred at 70°C for 2 hours. The desired product could be detected by LCMS. The reaction was quenched by adding water (0.5 ml) at 0°C. The solid was filtered off. The filtrate was concentrated in vacuo to give 1-(6-[6-methyl-2,6-diazaspiro[3.4]octan-2-yl]pyridin-2-yl)methanamine (250 mg; 67.66%) as a yellow oil . LCMS: m/z (ESI), [M+H] ⁺ =233.3.

Step 3. 3-Amino-N-((6-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1, 2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide

1-(6-[6-methyl-2,6-diazaspiro[3.4]octan-2-yl]pyridin-2-yl)methanamine (150 mg; 0.646 mmol; 1 eq.) was added to a hermetically sealed 10 mL tube. , 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (65.14 mg; 0.194 mmol; 1.50 eq.), HATU (490.98 mg; 1.291 mmol; 2.00 eq.) and DIEA (333.77 mg; 2.583 mmol; 4 eq.) in DMF (10 ml) at room temperature within 2 hours. The desired product could be detected by LCMS. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A:, mobile phase B: MeOH for HPLC; flow rate: 20 ml/min ; gradient: 66% B to 70% B in 7 min; 254/220 nm; Rt: 6.32 min), yielding 3-amino-N-[(6-[6-methyl-2,6-diazaspiro[ 3.4]octan-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) (15 mg; 14.3%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =551.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.87 (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. Preparation of 3-amino-6-(3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluoropyridin-2-yl)methyl)-5-(oxazole -2-yl)pyrazin-2-carboxamide (compound 198)

SCHEME 97

Step 1. (S)-2-Methyl-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin- 3-yl)methyl)propan-2-sulfinamide

Mixture of tert-butyl N-([6-bromoimidazo[1,2-a]pyridin-3-yl]methyl)carbamate (700 mg; 2.146 mmol; 1 eq.), 4,4,5,5-tetramethyl-2 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (817.42 mg; 3.219 mmol; 1.50 eq.), Pd( dppf)Cl ₂ (157.02 mg; 0.215 mmol; 0.1 eq.) and AcOK (421.22 mg; 4.292 mmol; 2 eq.) in 1,4-dioxane (10 ml) were stirred for 2 hours at 90°C in a nitrogen atmosphere. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1), yielding tert-butyl N-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazo[1,2-a]pyridin-3-yl]methyl]carbamate (500 mg; 49.94%) as a brown-yellow solid. LCMS: m/z (ES), [M+H] ⁺ =432.3.

Step 2. (S)-3-Amino-6-(3-(((tert-butylsulfinyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluoropyridin- 2-yl)methyl)-5-(oxazol-2-yl)pyrazin-2-carboxamide

To a stirred solution of (S)-2-methyl-N-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin- 3-yl]methyl]propan-2-sulfinamide (649.19 mg; 1.721 mmol; 2.00 eq.) and 3-amino-6-chloro-N-[(3-fluoropyridin-2-yl)methyl]- 5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (300 mg; 0.860 mmol; 1 eq.) in a 7:1 dioxane/H ₂ O mixture (16 ml) was added dropwise/portionwise with K ₃ PO ₄ (547.83 mg; 2.581 mmol; 3.0 eq.) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (147.53 mg; 0.181 mmol; 0.21 eq.) at room temperature in a hydrogen atmosphere . The resulting mixture was stirred for 2.0 hours at 80°C under a nitrogen atmosphere. The desired product could 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-(oxazol- 2-yl)pyrazin-2-carboxamide

3-Amino-N-[(3-fluoropyridin-2-yl)methyl]-6-[3-([[(S)-2-methylpropan-2-sulfinyl]amino was added to a hermetically sealed 10.0 ml test tube. ]methyl)-imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (150 mg) and dioxane/HCl mixture (6.0 ml) at room temperature. The resulting mixture was stirred for 60 minutes at room temperature in an air atmosphere. The desired product could 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. Purification of the crude product (100 mg) by preparative HPLC was carried out under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 µm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: 21% B to 31% B in 8 min; 254/220 nm; Rt: 7.53 min), yielding 3-amino-6-[3 -(aminomethyl)imidazo[1,2-a]pyridin-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2 -carboxamide (compound 198) (20 mg; 6.12%) as a yellow solid. LCMS: m/z (ES+), [M+H] ⁺ =460.2. ^1H NMR (DMSO-d ₆ , 40 MHz) δ 4.01 (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 ]pyridin-6-yl]pyrazin-2-carboxamide (compound 199)

SCHEME 98

Step 1. tert-butyl N-[2-[(2-cyanopyridin-3-yl)oxy]ethyl]-N-methylcarbamate

3-fluoropyridine-2-carbonitrile (800 mg; 6.552 mmol; 1 eq.), tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (1.38 g; 7.875 mmol; 1. 20 eq.), DMF (4 ml), K ₂ CO ₃ (2.26 g; 16.352 mmol; 2.50 eq.). The resulting mixture was stirred for 16 hours at 80°C. The resulting mixture was diluted using 20 ml H ₂ O. The resulting solution was extracted with ethyl acetate (3×8 ml) and the organic layers were combined. The resulting solution was washed with brine (3×10 ml), 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). The result was 738 mg (40.62%) of tert-butyl N-[2-[(2-cyanopyridin-3-yl)oxy]ethyl]-N-methylcarbamate as a purple solid. LCMS: m/z (ESI), [M+H-tBu] ⁺ =222.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.34 (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).

Step 2. tert-butyl N-(2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate

In a 25 mL round bottom flask, degassed and maintained under an inert atmosphere of hydrogen, was placed tert-butyl N-[2-[(2-cyanopyridin-3-yl)oxy]ethyl]-N-methylcarbamate (738 mg; 2.661 mmol; 1 eq.), MeOH (10 ml), NH ₃ .H ₂ O (1 ml; 25.681 mmol; 9.65 eq.), Raney Ni (227.99 mg; 2.661 mmol; 1.00 eq.). The resulting solution was stirred for 2 hours at 16°C. Solids were filtered off. The resulting mixture was concentrated under vacuum. The result was 700 mg (93.49%) of tert-butyl N-(2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate as a purple solid. LCMS: m/z (ESI), [M+H] ⁺ =282.2.

Step 3. tert-butyl N-(2-[[2-([[3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazine -2-yl]formamido]methyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate

Tert-butyl N-(2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate (154.87 mg; 0.550 mmol; 2.00 eq.) was placed in a 6 ml vial. , 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylic acid (100 mg; 0.275 mmol; 1 eq.), DIEA (0.34 ml; 2.061 mmol; 7.49 eq.), DMF (2.5 ml), T ₃ P (262.70 mg; 0.826 mmol; 3.00 eq.). The resulting solution was stirred for 16 hours at 16°C. The resulting solution was diluted with 20 ml H ₂ O. The resulting solution was extracted with ethyl acetate (3×10 ml) and the organic layers were combined. The resulting solution was extracted with brine (3×10 ml), the organic layers were combined and dried over anhydrous sodium sulfate. The residue was purified by preparative TLC (DCM:MeOH, 7:1). The result was 93 mg (53.92%) tert-butyl N-(2-[[2-([[3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a ]pyridin-6-yl]pyrazin-2-yl]formamido]methyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate as a yellow solid. 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)pyrazin-2-carboxamide 2.2.2-trifluoroacetate (compound 199)

Tert-butyl N-(2-[[2-([[3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6- yl]pyrazin-2-yl]formamido]methyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate (80 mg; 0.128 mmol; 1 eq.), DCM (3.00 ml), TFA (1, 00 ml; 13.46 mmol; 105.2 eq.). The resulting solution was stirred for 2 hours at 20°C. The resulting mixture was concentrated under vacuum. The pH of the solution was adjusted to 9 with saturated sodium bicarbonate solution. The resulting solution was extracted with ethyl acetate (3×10 ml) and the organic layers were combined. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH, 3:1). The crude product was purified by preparative HPLC (column: Sunfire C18 OBD preparative column, 10 µm, 19*250 mm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 10% B to 25% B in 10 min; 254/220 nm; Rt: 8.7 min). The result was 20.22 mg of 3-amino-5-(4-fluorophenyl)-N-((3-(2-(methylamino)ethoxy)pyridin-2-yl)methyl)-6-(3-methylimidazo[1 ,2-a]pyridin-6-yl)pyrazin-2-carboxamide 2,2,2-trifluoroacetate (compound 199) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =527.3. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 2.52-2.54 (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). ¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ -111.615 (1F), -74.101 (7.27F).

Examples 202/206. 3-Amino-N-[[1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)-6-[3-(trifluoromethyl)imidazo[1,2-a]pyridine -6-yl]pyrazin-2-carboxamide (compound 202),

3-amino-N-[1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)-6-[3-(trifluoromethyl)imidazo[1,2-a]pyridin- 6-yl]pyrazin-2-carboxamide (compound 206)

SCHEME 99

Step 1. 6-Bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine

A mixture of 6-bromo-3-iodimidazo[1,2-a]pyridine (1.5 g; 4.645 mmol; 1 eq.), 15-(trifluoromethyl)-1lambda4,12lambda4-diaza-15-cupratetetracyclo[10.2.1.0 ^∧ [5,14].0 ^∧ [8,13]]pentadeca-1,3,5(14),6,8,10,12-heptaene-15-ylium (1.74 g; 5.574 mmol; 1.2 eq.) in DMF (15 ml) was stirred overnight at 50°C. The resulting mixture was diluted with CH ₂ Cl ₂ (100 ml). The resulting mixture was filtered, the filter cake was washed with DCM (2×50 ml). The resulting mixture was washed with water (2×150 ml). The organic phase was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (detection was carried out by absorption at 220 nm in 10 ^-3 optical density units (mAU; from English milli Absorption Unit)), eluted with a mixture of CH ₂ Cl ₂ /PE (40:60), obtaining 6 -bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine (780 mg; 63.36%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =267.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.7 (1H, dd), 7.7-7.8 (1H, m), 8.2-8.2 (1H, m), 8.6-8.8 (1H, m).

Step 2. [3-(Trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]boronic acid

To a solution of 6-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine (500 mg; 1.887 mmol; 1 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (958.14 mg; 3.773 mmol; 2.00 eq.) in dioxane (20 ml) was added AcOA (555 .45 mg; 5.660 mmol; 3 eq.) and Pd(dppf)Cl ₂ (276.08 mg; 0.377 mmol; 0.2 eq.). After stirring for 2 hours at 90°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeOH in water; gradient: from 10% to 50% in 10 minutes; detector: UV, 254 nm, yielding [3-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]boronic acid (370 mg; 85.29%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =231.1.

Step 3. 3-Amino-N-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)-6-[3-(trifluoromethyl)imidazo[ 1,2-a]pyridin-6-yl]pyrazine-2-carboxamide

To a solution of [3-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]boronic acid (350 mg; 1.522 mmol; 1 eq.) and 3-amino-6-chloro-N-[(1- methylpyrrolidin-2-yl)methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (512.60 mg; 1.522 mmol; 1.00 eq.) in dioxane (20 ml) and H ₂ O (2 ml) K ₃ PO ₄ (969.25 mg; 4.566 mmol; 3 eq.) and Pd(dppl)Cl ₂ (222.74 mg; 0.304 mmol; 0.2 eq.) were added. After stirring for 2 hours at 90°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (15:1) to give 3-amino-N-[[1-methylpyrrolidin-2-yl]methyl]-5-(1, 3-oxazol-2-yl)-6-[3-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxamide (200 mg; 27.01%) as light yellow solid matter. LCMS: m/z (ESI), [M+H] ⁺ =487.3.

Step 4. 3-Amino-N-[[1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)-6-[3-(trifluoromethyl)imidazo[1,2- a]pyridin-6-yl]pyrazin-2-carboxamide (compound 202)/(compound 206)

The crude product (100 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IG, i.d. (ID) 2.0 cm, length (L) 25 cm (5 μm); mobile phase A: CO ₂ : 75, mobile phase B: EtOH:ACN=1:25; flow rate: 40 ml/min; 220 nm; Rt1: 10; Rt2: 12.65), giving 3-amino-H-[1-methylpyrrolidine-2 -yl]methyl]-5-(1,3-oxazol-2-yl)-6-[3-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxamide (compound 202 ) (50 mg; 27.78%) and 3-amino-N-[1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)-6-[3-(trifluoromethyl )imidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxamide (compound 206) as a yellow solid. 3-Amino-N-[1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)-6-[3-(trifluoromethyl)imidazo[1,2-a]pyridin- 6-yl]pyrazin-2-carboxamide.

(Compound 202) LCMS: m/z (ESI), [M+H] ⁺ =487.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.6 (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 (400 MHz, DMSO-d ₆ ) δ 1.6 (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).

Examples 214/209. Preparation of 3-amino-6-(3-chloroimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2-yl)pyrazine -2-carboxamide (compounds 214/209)

SCHEME 100

Step 1. (3-Chloroimidazo[1,2-a]pyridin-6-yl)boronic acid

[Imidazo[1,2-a]pyridin-6-yl]boronic acid (600 mg; 3.705 mmol; 1 eq.) and NCS (1.24 g; 9.262 mmol; 2.50 eq.) were dissolved in 3 ml DMF . The mixture was stirred at room temperature for 3 hours. LCMS indicated completion of the reaction.

The crude product was purified by reverse phase HPLC to give [3-chloroimidazo[1,2-a]pyridin-6-yl]boronic acid (235 mg; 32.3%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =197.2.

Step 2. 3-Amino-6-(3-chloroimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxylic acid

[3-Chloroimidazo[1,2-a]pyridin-6-yl]boronic acid (169.69 mg; 0.864 mmol; 1.00 eq.), methyl 3-amino-6-chloro-5-(1,3 -oxazol-2-yl)pyrazin-2-carboxylate (220 mg; 0.864 mmol; 1 eq.), Pd(dppf)Cl ₂ (126.44 mg; 0.173 mmol; 0.2 eq.) and Cs ₂ CO ₃ (1126.03 mg; 3.456 mmol; 4 eq.) was dissolved in 2.4 ml of a mixture of dioxane/H ₂ O (5:1). The mixture was stirred at 70°C for 2 hours. LCMS indicated completion of the reaction. The mixture was concentrated, acidified with acetic acid and purified by reverse phase HPLC to give methyl 3-amino-6-[3-chloroimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2- yl)pyrazine-2-carboxylate (100 mg; 31.22%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =371.2.

Step 3. 3-Amino-6-[3-chloroimidazo[1,2-a]pyridin-6-yl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-5-(1.3 -oxazol-2-yl)pyrazin-2-carboxamide (compound 214)

3-Amino-6-[3-chloroimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.280 mmol; 1 eq.), 1-[(2R)-1-methylpyrrolidin-2-yl]methanamine (48.02 mg; 0.420 mmol; 1.5 eq.), DIEA (253.61 mg; 1.962 mmol; 7 eq. ) and T ₃ P (267.58 mg; 0.841 mmol; 3 eq.) were added to DMF (3 ml). The resulting suspension was stirred at room temperature for 3 hours. The reaction mixture was quenched with a saturated solution of NH ₄ Cl (15 ml) and extracted with EtOAc (3×50 ml), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated, obtaining a yellow resinous substance . The residue was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 µm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 29% B to 37% B in 8 min; 254/220 nm; Rt: 6.57/7.42 min), yielding 3-amino-6-[3-chloroimidazo[1,2-a]pyridin-6-yl] -N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 214) (23.9 mg; 18. 8%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =453.2. ^1H NMR (400 MHz, methanol- _d4 ) δ 1.66-1.84 (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-methylpyrrolidin-2-yl]methyl]-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 209)

3-Amino-6-[3-chloroimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.280 mmol; 1 eq.), 1-[(2R)-1-methylpyrrolidin-2-yl]methanamine (48.02 mg; 0.420 mmol; 1.5 eq.), DIEA (253.61 mg; 1.962 mmol; 7 eq. ), T ₃ P (267.58 mg; 0.841 mmol; 3 eq.) was added to DMF (3 ml). The resulting suspension was stirred at room temperature for 3 hours. The reaction mixture was quenched with a saturated solution of NH ₄ Cl (15 ml), extracted with EtOAc (3×50 ml), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated, obtaining a yellow resinous substance . The residue was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 µm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 29% B to 37% B in 8 min; 254/220 nm; Rt: 6.57/7.42 min), yielding 3-amino-6-[3-chloroimidazo[1,2-a]pyridin-6-yl] -N-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (18.9 mg; 14.8%) in as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =453.2. ^1H NMR (400 MHz, methanol- _d4 ) δ 1.72-1.84 (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. Preparation of 3-amino-N-[[(3R)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 219)

SCHEME 101

Step 1. tert-butyl N-[[(3R-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]carbamate

A mixture of TEA (757.86 mg; 7.489 mmol; 3 eq.), cyclopropanecarbonyl chloride (391.44 mg; 3.745 mmol; 1.5 eq.) and tert-butyl N-[[(3S)-pyrrolidin-3-yl] Methyl]carbamate (500 mg; 2.496 mmol; 1 eq.) in DCM (15 ml) was stirred for 16 hours at room temperature under air. The reaction mixture was diluted with DCM (90 ml), the organic layers were washed with water (2×100 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl N-[[(3R)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]carbamate (750 mg; 111.95%) as a brown oil. ^1H NMR (300 MHz, chloroform-d) δ 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]methanamine

A mixture of TFA (1 ml) and tert-butyl N-[[(3R)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]carbamate (300 mg; 1.118 mmol; 1 eq.) in DCM (3 ml) was stirred for 1 h at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was made alkaline to pH 7 with a saturated solution of NaHCO ₃ (aq). The resulting mixture was extracted with CH ₂ Cl ₂ (2×50 ml). The combined organic layers were washed with water (2×50 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 1-[(3R)-1-cyclopropanecarbonylpyrrolidin-3-yl]methanamine (180 mg; 95.71%) as a brown oil. LCMS: m/z (ESI), [M+H] ⁺ =169.1. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 0.64-0.79 (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-ciutopropanecarbonylpyrrolidin-3-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 219)

A mixture of DIEA (215.21 mg; 1.665 mmol; 7 eq.), T ₃ R (378.44 mg; 1.189 mmol; 5 eq.), 1-[(3R)-1-cyclopropanecarbonylpyrrolidin-3-yl]methanamine ( 160.08 mg; 0.952 mmol; 4 eq.) and 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl) pyrazine-2-carboxylic acid (80 mg; 0.238 mmol; 1 eq.) in DMF (3 ml) was stirred overnight at room temperature under air. The desired product could be detected by LCMS. The residue was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 30×150 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 28% B to 28% B in 7 min; 254/220 nm; Rt: 5.37 min), giving 3-amino-N-[[(3R)-1- cyclopropanecarbonylpyrrolidin-3-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 219 ) (60 mg; 50.81%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =487.3. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 0.68 (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. Preparation of 3-amino-N-[[(3S)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 221)

SCHEME 102

Step 1. tert-butyl N-[[(3S)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]carbamate

To a stirred mixture of TEA (1515.71 mg; 14.979 mmol; 6.00 eq.) and cyclopropanecarbonyl chloride (521.91 mg; 4.993 mmol; 2.00 eq.) in DCM (10 ml) was added portionwise tert-butyl N-[ [(3R)-pyrrolidin-3-yl]methyl]carbamate (500 mg; 2.496 mmol; 1 eq.) at 25°C under nitrogen. The resulting mixture was stirred for 2 hours at 25°C in an air atmosphere. The resulting mixture was extracted with CH ₂ Cl ₂ (3×20 ml) and then the organic phase was dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl N-[[(3S)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]carbamate (670 mg; 100.01%) as a yellow solid. ¹ H NMR (300 MHz, MeOD-d ₄ ) δ 0.85 (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-G(38)-1-Cyclopropanecarbonylpyrrolidin-3-yl]methanamine

To a stirred mixture of tert-butyl N-[[(3S)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]carbamate (300 mg; 1.118 mmol; 1 eq.) in DCM (3 ml) was added TFA (1 ml) at 25 °C in a nitrogen atmosphere. The resulting mixture was stirred for 20 minutes at 25°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 1-[(3S)-1-cyclopropanecarbonylpyrrolidin-3-yl]methanamine (170 mg; 90.39%) as a yellow oil. LCMS: m/z (ESI), [2M+H] ⁺ =337.2.

Step 3. 3-Amino-N-[[(3S)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1 ,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 221)

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (99.95 mg; 0.297 mmol; 0.50 eq.) and DIEA (153.64 mg; 1.189 mmol; 2 eq.) in DMF (5 ml) T ₃ P (472.81 mg; 1.486 mmol; 2.50 eq.) was added in portions .) and 1-[(3S)-1-cyclopropanecarbonylpyrrolidin-3-yl]methanamine (100 mg; 0.594 mmol; 1 eq.) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 25°C under a nitrogen atmosphere. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 28% B to 28% B in 7 min; 254/220 nm; Rt: 5.37 min), giving 3-amino-N-[[( 3S)-1-cyclopropanecarbonylpyrrolidin-3-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2 -carboxamide (60 mg; 20.75%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =487.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.69 (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. Preparation of 3-amino-N-[(3-fluoropyridin-2-yl)methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(morpholine-4- yl)pyrazin-2-carboxamide (compound 223)

SCHEME 103

Step 1. Methyl 3-amino-6-chloro-5-(morpholin-4-yl)pyrazin-2-carboxylate

Morpholine (39 .24 mg; 0.450 mmol; 2 eq.) at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with water (1×100 ml), dried under vacuum to give methyl 3-amino-6-chloro-5-(morpholin-4-yl)pyrazin-2-carboxylate (1.8 g ; 97.71%) as a yellow solid. ¹ H NMR (400 MHz, chloroform-s/) 5 3.61-3.72 (4H, m), 3.75-3.88 (4H, m), 3.94 (3H, s).

Step 2. Methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(morpholin-4-yl)pyrazin-2-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-(morpholin-4-yl)pyrazin-2-carboxylate (600 mg; 2,200 mmol; 1 eq.) and [3-methylimidazo[1,2-a]pyridine -6-yl]boronic acid (580.81 mg; 3.300 mmol; 1.5 eq.) in dioxane (50 ml), Cs ₂ CO ₃ (2150.70 mg; 6.601 mmol; 3 eq.) and Pd( dppf)Cl ₂ (321.99 mg; 0.440 mmol; 0.2 eq.) at 95°C in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 95°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (20:1) to give methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5- (morpholin-4-yl)pyrazin-2-carboxylate (400 mg; 49.35%) as a yellow-green solid. LCMS: m/z (ESI), [M+H] ⁺ =369.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 3.26 (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)pyrazin-2-carboxylic acid

To a solution of methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(morpholin-4-yl)pyrazin-2-carboxylate (400 mg; 1.086 mmol; 1 eq. .) in THF (50 ml) and methanol (10 ml) was added portionwise LiOH (156.01 mg; 6.515 mmol; 6 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature in an air atmosphere. The mixture was acidified to pH 6 using HCl (aq). The resulting mixture was concentrated in vacuo to give 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(morpholin-4-yl)pyrazin-2-carboxylic acid (350 mg; 90.96%) as a yellow solid. 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]pyridin-6-yl1-5-(morpholin-4-yl) pyrazine-2-carboxamide (compound 223)

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(morpholin-4-yl)pyrazin-2-carboxylic acid (100 mg; 0.282 mmol; 1 eq.) and 1-(3-fluoropyridin-2-yl)methanamine (71.19 mg; 0.564 mmol; 2 eq.) in DMF (10 ml) HATU (214.59 mg; 0.564 mmol; 2 eq.) was added in portions. ) and DIE A (109.41 mg; 0.847 mmol; 3 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 2.5 hours at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: 5% ammonia in water, mobile phase B: ACN; flow rate: 20 ml /min; gradient: from 33% B to 48% B in 8 min; 254/220 nm; Rt: 7.47 min), giving 3-amino-N-[(3-fluoropyridin-2-yl)methyl]- 6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(morpholin-4-yl)pyrazin-2-carboxamide (9 mg; 6.83%) (compound 223) as white solid matter. LCMS: m/z (ESI), [M+H] ⁺ =463.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.54 (3H, d), 3.63 (4H, t), 461-4.74 (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).

Examples 227/224. Preparation of trans/cis-3-amino-N-((6-((3-(dimethylamino)cyclobutyl)amino)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin- 6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compounds 227/224)

SCHEME 104

Step 1. 6-((3-(Dimethylamino)cyclobutyl)amino)picolinonitrile

A mixture of 6-fluoropyridine-2-carbonitrile (136 mg; 1.114 mmol; 1 eq.), N1,N1-dimethylcyclobutane-1,3-diamine dihydrochloride (250 mg; 1.336 mmol; 1.20 eq.) and potassium dicarbonate (462 mg; 3.343 mmol; 3.00 eq.) in 3 ml DMF was stirred at 50°C for 18 hours. After cooling to room temperature, water was added and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ . After filtration and concentration, the residue was purified by column (DCM/MeOH, 3/1) to give 6-[[3-(dimethylamino)cyclobutyl]amino]pyridine-2-carbonitrile (155 mg; 64.3%) as a white solid substances. LCMS: m/z (ESI), [M+H] ⁺ =217.3.

Step 2. N1-(6-(Aminomethyl)pyridin-2-yl)-N3,N3-dimethylcyclobutane-1,3-diamine

A mixture of 6-[[3-(dimethylamino)cyclobutyl]amino]pyridine-2-carbonitrile (155 mg; 0.717 mmol; 1 eq.), 1 ml ammonia solution and Raney Ni (100 mg) in methanol (10 ml) was hydrogenated in atmosphere H ₂ (1 at (98.1 kPa)) at room temperature for 3 hours. After filtration through celite, the filtrate was concentrated to dryness under vacuum 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-(oxazol-2-yl)pyrazin-2-carboxamide (compounds 224/227)

To a mixture of 3-amino-6-(1-methyl-1H-1,3-benzodiazol-6-yl)-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (150 mg; 0.446 mmol; 1 eq.) and N3-[6-(aminomethyl)pyridin-2-yl]-N1,N1-dimethylcyclobutane-1,3-diamine (145 mg; 0.66 mmol; 1.48 eq.) in N ,N-dimethylformamide (5 ml) was added DIEA (0.39 ml; 2.239 mmol; 5.02 eq.) and a 50% (by weight) solution of T ₃ P in ethyl acetate (860 mg; 1.351 mmol; 3.03 eq.). The mixture was stirred at room temperature for 18 hours. After concentration to dryness, the residue was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 29% B to 37% B in 8 min; 254/220 nm; Rt: 6.57/7.42 min), yielding trans-3-amino-6-[3 -methyl-imidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[(6-[[3-(dimethylamino)cyclo-butyl]amino ]pyridin-2-yl)methyl]pyrazin-2-carboxamide (compound 227) (6.6 mg; 2.7%) (compound 227). LCMS: m/z (ESI), [M+H] ⁺ =539.4. ^1H NMR (300 MHz, MeOH-d ₄ ) 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]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[(6-[[3 -(di-methylamino)cyclobutyl]amino]pyridin-2-yl)methyl]pyrazine-2-carboxamide (compound 224) (6.1 mg; 2.5%) as a yellow solid (compound 224). LCMS: m/z (ESI), [M+H] ⁺ =539.3. ^1H NMR (300 MHz, MeOH-d ₄ ) δ 1.39-1.48 (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. Preparation of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[[(2R)-oxolan-2-yl]methyl]-5-(2H- 1,2,3-triazol-2-yl)pyrazin-2-carboxamide (compound 229)

SCHEME 105

Step 1. Methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (1 g; 3.927 mmol; 1 eq.) and [3-methylimidazo [1,2-a]pyridin-6-yl]boronic acid (1.38 g; 7.855 mmol; 2 eq.) in 1,4-dioxane (15 ml) and H ₂ O (1.5 ml) were added in portions Cs ₂ CO ₃ (2.56 g; 7.855 mmol; 2.00 eq.) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.64 g; 0.785 mmol; 0.2 eq.) at room temperature in nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), obtaining methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1, 2,3-triazol-2-yl)pyrazin-2-carboxylate (1 g; 72.68%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =351.1. ¹ H NMR: (300 MHz, DMSO-d ₆ ) δ 2.31 (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)pyrazin-2-carboxylic acid

To a stirred solution of methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (950 mg; 2.712 mmol; 1 eq.) to MeOH (15 ml) and THF (3 ml) was added portionwise LiOH (97.42 mg; 4.067 mmol; 1.5 eq.) at room temperature. The resulting mixture was stirred for 4 hours at room temperature. The residue was acidified to pH 5 using HCl (aq). The resulting solid was collected by filtration and dried under vacuum to give 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-triazol-2- yl)pyrazine-2-carboxylic acid (400 mg; 43.86%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =337.1.

Step 3. 3-Amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[[(2R)-oxolan-2-yl]methyl]-5-(2H-1 ,2,3-triazol-2-yl)pyrazin-2-carboxamide (compound 229)

To a stirred mixture of 1-[(2R)-oxolan-2-yl]methanamine (60.15 mg; 0.595 mmol; 2 eq.) and 3-amino-6-[3-methylimidazo[1,2-a]pyridinium- 6-yl]-5-(2H-1,2,3-triazol-2-yl)-pyrazin-2-carboxylic acid (100 mg; 0.297 mmol; 1 eq.) in DMF (10 ml) was added dropwise with DIEA (76.86 mg; 0.595 mmol; 2 eq.) and T ₃ R (23.80 mg; 0.595 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 19*250 mm, 5 µm; mobile phase A:, mobile phase B:; flow rate: 20 ml/min; gradient: from 30% B to 41% B in 8 min; 254/220 nm; Rt: 7.17 min), yielding 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[[ (2R)-oxolan-2-yl]methyl]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxamide (compound 229) (43 mg; 34.48%) as yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =420.3. ¹ H NMR: (300 MHz, DMSO-d ₆ ) δ 1.78 (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).

Examples 230-1/230-2. Preparation of 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 (compounds 230-1/230-2)

SCHEME 106

Step 1. tert-butyl 2-((3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamido)methyl )-4,4-dimethylpyrrolidine-1-carboxylate

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (200 mg; 0.595 mmol; 1 eq.), DIEA (230.58 mg; 1.784 mmol; 3 eq.) and tert-butyl 2-(aminomethyl)-4,4-dimethylpyrrolidine-1-carboxylate (271.58 mg; 1.189 mmol; 2 eq.) in DMF (12 ml) was added dropwise T ₃ P (378.44 mg; 1.189 mmol; 2 eq.) at 0°C in a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. The reaction was quenched by adding water (20 ml) at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (3×20 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1), yielding tert-butyl 2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]- 5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]-4,4-dimethylpyrrolidine-1-carboxylate (180 mg; 55.37%) as a yellow solid. 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-(oxazol-2 -yl)pyrazin-2-carboxamide

To a stirred solution of tert-butyl 2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin- 2-yl)formamido]methyl]-4,4-dimethylpyrrolidine-1-carboxylate (160 mg; 0.293 mmol; 1 eq.) in DCM (8 ml) was added dropwise with TFA (3 ml; 40.389 mmol; 137.99 eq. .) at room temperature in an air atmosphere. The resulting mixture was stirred for 30 minutes at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure to give 3-amino-N-[(4,4-dimethylpyrrolidin-2-yl)methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5 -(1,3-oxazol-2-yl)pyrazin-2-carboxamide (135 mg; 98.12%) as a yellow oil. 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 a stirred mixture of 3-amino-N-[(4,4-dimethylpyrrolidin-2-yl)methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3 -oxazol-2-yl)pyrazin-2-carboxamide (155 mg; 0.347 mmol; 1 eq.), DIEA (89.73 mg; 0.694 mmol; 2 eq.) and paraformaldehyde (PFA; 312.69 mg; 3.471 mmol ; 10 eq.) into DCM (12 ml) and MeOH (4 ml) NaBH ₃ CN (65.44 mg; 1.041 mmol; 3 eq.) was added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 12 hours at room temperature under a nitrogen atmosphere. The reaction was quenched by adding water (20 ml) at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (3×15 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 10:1), obtaining 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazole -2-yl)-N-[(1,4,4-trimethylpyrrolidin-2-yl)methyl]pyrazin-2-carboxamide (130 mg; 81.32%) as a yellow solid. 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)pyrazin-2-carboxamide (230-1/230-2)

The crude product (100 mg) was purified by chiral preparative HPLC under the following conditions (column: CHIRALPAK ID-03, 2.0 cm i.d., 25 cm length (5 µm); mobile phase A: Hex:DCM, 5:1 (with 10 mM NH ₃ -MEOH) for HPLC, mobile phase B: IPA (isopropyl alcohol) for HPLC; flow rate: 20 ml/min; gradient: from 25 V to 25 V in 22 min; 220/254 nm; Rt1 : 15.342; Rt2: 17.566), yielding 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[ (1,4,4-trimethylpyrrolidin-2-yl)methyl]pyrazin-2-carboxamide (compound 230-1) (45 mg; 43.41%), LCMS: m/z (ESI), [M+H] ⁺ = 461.3. ^1H NMR (400 MHz, 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-oxazol-2-yl)-N-[(1,4,4-trimethylpyrrolidine -2-yl)methyl]pyrazin-2-carboxamide (compound 230-2) (45 mg; 45%), LCMS: m/z (ESI), [M+H] ⁺ = 461.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.01 (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. Preparation of methyl 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carboxylate

To a stirred mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (1.5 g; 6.756 mmol; 1 eq.) and (3-fluorophenyl)boronic acid (0.95 g; 6.790 mmol; 1.00 eq.) in 1,4-dioxane (100 ml) and H ₂ O (5 ml), Cs ₂ CO ₃ (6.60 g; 0.020 mmol; 3 eq.) and Pd(dppf)Cl ₂ (0. 74 g; 0.001 mmol; 0.15 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 70°C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH ₂ Cl ₂ (1×30 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /EtOAc (4:1) to give methyl 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carboxylate (900 mg; 47. 30%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 282.0. ^1H NMR (300 MHz, chloroform-d) δ 4.03 (3H, s), 7.22 (1H, m), 7.41-7.59 (2H, m), 7.65 (1H, ddd).

Step 2. Methyl 3-amino-5-(3-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carboxylate (400 mg; 1.420 mmol; 1 eq.) and [3-methylimidazo[1,2-a]pyridine-6 -yl]boronic acid (324.88 mg; 1.846 mmol; 1.30 eq.) in 1,4-dioxane (20 ml) and H ₂ O (2 ml) Cs ₂ CO ₃ (1388.09 mg; 4.260 mmol; 3 eq.) and Pd(dppf)Cl ₂ (155.86 mg; 0.213 mmol; 0.15 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 90°C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH ₂ Cl ₂ (1×20 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give methyl 3-amino-5-(3-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl] pyrazine-2-carboxylate (300 mg; 55.98%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 378.1.

¹ H NMR (300 MHz, chloroform-d) δ 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-carboxylic acid

To a stirred solution of methyl 3-amino-5-(3-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylate (300 mg; 0.795 mmol; 1 eq. ) in THF (20 ml) and H ₂ O (4 ml) was added portionwise LiOH (38.08 mg; 1.590 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The mixture was acidified to pH 5 using HCl (aq) solution. The resulting mixture was concentrated under reduced pressure to give 3-amino-5-(3-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylic acid (280 mg; 96 .94%) as a yellow solid, which was used directly 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 a stirred mixture of 1-[(2R)-1-methylpyrrolidin-2-yl]methanamine (62.85 mg; 0.550 mmol; 2.00 eq.) and 3-amino-5-(3-fluorophenyl)-6-[ 3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylic acid (100 mg; 0.275 mmol; 1 eq.) in DMF (10 ml) was added portionwise with DIEA (106.71 mg; 0.826 mmol ; 3.00 eq.) and T ₃ P (175.14 mg; 0.550 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A (5% NH ₄ HCO ₃ in water), mobile phase B: ACN; flow rate: 20 ml/min; gradient: 37% B to 51% B in 8 min; 254/220 nm; Rt: 7.27 min), yielding 3-amino-5-(3-fluorophenyl)-6-[3-methylimidazo [1,2-a]pyridin-6-yl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]pyrazin-2-carboxamide (compound 231) (20 mg; 15.81%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 460.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.65 (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).

Examples 235/232. Preparation of 3-amino-N-((6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl )-5-(oxazol-2-yl)pyrazin-2-carboxamide (compounds 235/232)

SCHEME 109

Step 1.16-[3-(Dimethylamino)pyrrolidin-1-yl]pyridin-2-carbonitrile

To a mixture of 6-fluoropyridine-2-carbonitrile (500 mg; 4.095 mmol; 1 eq.) and N,N-dimethylpyrrolidin-3-amine (701.41 mg; 6.142 mmol; 1.5 eq.) in 2 ml DMF was added potassium carbonate (1.14 g; 8.190 mmol; 2.00 eq.). The mixture was stirred at 50°C for 8 hours. After concentration to dryness, the residue was purified by silica gel column chromatography eluting with DCM/CH ₃ OH (10/1) to give 6-[3-(dimethylamino)pyrrolidin-1-yl] pyridine-2-carbonitrile (810 mg; 80.0%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 217.1.

Step 2. 1-[6-(Aminomethyl)pyridin-2-yl]-N,N-dimethylpyrrolidin-3-amine

A mixture of 6-[3-(dimethylamino)pyrrolidin-1-yl]pyridin-2-carbonitrile (200 mg; 0.925 mmol; 1 eq.), Raney Ni (158.45 mg; 1.849 mmol; 2 eq.) and NH ₄ OH (50 mg) in methanol (16 ml) was hydrogenated under H ₂ (1 at (98.1 kPa)) 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] ⁺ = 221.1.

Step 3. 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-oxazol-2-yl)pyrazin-2-carboxamide (compounds 235/232)

To a mixture of 1-[6-(aminomethyl)pyridin-2-yl]-N,N-dimethylpyrrolidin-3-amine (185 mg; 0.840 mmol; 1 eq.), 3-amino-6-[3-methylimidazo[1 ,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (423 mg; 1.260 mmol; 1.50 eq.) in N,N-dimethylformamide (5 ml) DIEA (651.14 mg; 5.038 mmol; 6 eq.), HOBt (226.92 mg; 1.679 mmol; 2 eq.) and EDCl (321.94 mg; 1.679 mmol; 2 eq.) were added. The mixture was stirred at room temperature for 3 hours. After concentration to dryness, the residue was purified by chiral preparative HPLC under the following conditions (column: CHIRAL ART Cellulose-SB S-5 um, 2*25 cm, 5 µm; mobile phase A: Hex (c NH ₃ .MeOH, 8 mmol/l) for HPLC, mobile phase B: MeOH:EtOH (1:1, for HPLC); flow rate: 20 ml/min; gradient: from 50 V to 50 V in 13 min; 220 /254 nm; R _T1 : 8.028 min; R _T2 : 10.436 min), yielding 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-oxazol-2-yl)pyrazin-2-carboxamide (compound 235) (77 mg; 17.0%) , LCMS: m/z (ESI), [M+H] ⁺ = 539.4. ¹ H NMR (300 MHz, 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-oxazol-2-yl)pyrazin-2-carboxamide (compound 232) (30 mg; 6.63%) , LCMS: m/z (ESI), [M+H] ⁺ = 539.3. ¹ H NMR (300 MHz, methanol-d ₄ ) δ 1.39-1.59 (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. Preparation of rac-3-amino-N-(2-(methyl(tetrahydrofuran-3-yl)amino)ethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5 -(oxazol-2-yl)pyrazin-2-carboxamide (compound 233)

SCHEME 110

Step 1. tert-butyl (2-(methyl(tetrahydrofuran-3-yl)amino)ethyl)carbamate

A mixture of tert-butyl N-(2-bromoethyl)carbamate (400 mg; 1.785 mmol; 1 eq.), N-methyloxolan-3-amine (180.54 mg; 1.785 mmol; 1 eq.) and K ₂ CO ₃ ( 740.06 mg; 5.355 mmol; 3.0 eq.) in DMF (30 ml) was stirred for 16 hours at 65°C. The resulting mixture was diluted with water (30 ml). The resulting mixture was extracted with EtOAc (3×30 ml). The combined organic layers were washed with saturated brine (20 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The result was tert-butyl N-[2-[methyl(oxolan-3-yl)amino]ethyl]carbamate (410 mg; 94.0%) as a light yellow oil. LCMS: m/z (ESI), [M+H] ⁺ = 245.1. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 0.62 (9H, s), 1.02-1.05 (1H, m), 1.35-1.18 (1H, m), 1.45 (2H, s), 1.80-1.56 (2H , m), 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

A solution of tert-butyl N-[2-[methyl(oxolan-3-yl)amino]ethyl]carbamate (200 mg; 0.819 mmol; 1 eq.) and TFA (3 mL) in DCM (6 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was neutralized to pH 7 with saturated (aq) NaHCO ₃ solution. The aqueous layer was extracted with EtOAc (3×20 ml). The resulting mixture was concentrated under reduced pressure. The result was N-(2-aminoethyl)-N-methyloxolan-3-amine (105 mg; 88.95%) as a light yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =145.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.41-1.44 (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-methylimidazo[1,2-a]pyridin-6-yl)-5- (oxazol-2-yl)pyrazin-2-carboxamide

3-Amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid solution (80 mg; 0.238 mmol ; 1 eq.), N-(2-aminoethyl)-N-methyloxolan-3-amine (41.17 mg; 0.285 mmol; 1.2 eq.), T ₃ P (227.06 mg; 0.714 mmol; 3 .0 eq.) and DIEA (92.23 mg; 0.714 mmol; 3.0 eq.) in DMF (2 ml) were stirred for 2 h at room temperature. The resulting mixture was diluted with water (30 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with saturated brine (10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: preparative column XBridge C18 OBD 19x150 mm, 5 μm; mobile phase A, mobile phase B: ACN; flow rate: 20 ml/min; gradient: 20% B to 37% B in 7 min; 254/220 nm; Rt: 6.58 min), yielding 3-amino-N-[2-[methyl(oxolan-3-yl)amino]ethyl]-6-[3-methylimidazo [1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 233) (12.2 mg; 11.09%) as yellow solid matter. LCMS: m/z (ESI), [M+H] ⁺ = 463.4. ^1H NMR (300 MHz, MeOD-d ₄ ) δ 1.81-1.85 (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. Preparation of (3S)-3-[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazine -2-yl)formamido]-N,N-dimethylbutanamide (compound 234)

SCHEME 111

Step 1. (S)-tert-Butyl 4-(dimethylamino)-4-oxobutan-2-ylcarbamate

To a stirred mixture of (3S)-3-[[(tert-butoxy)carbonyl]amino]butanoic acid (500 mg; 2.460 mmol; 1 eq.) and dimethylamine (221.83 mg; 4.920 mmol; 2 eq.) in DCM add HATU (1870.86 mg; 4.920 mmol; 2 eq.) portionwise and DIEA (1.59 g; 12.301 mmol; 5 eq.) dropwise at room temperature under air. The resulting mixture was stirred overnight at room temperature in an air atmosphere. The residue was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN in water; gradient: from 5% to 20% in 10 minutes; detector: UV 220 nm. This resulted in tert-butyl N-[(2S)-1-(dimethylcarbamoyl)propan-2-yl]carbamate (550 mg, 64.07%) as a pink solid. LCMS (ESI) m/z [M+H] ⁺ = 231.1; ^1H NMR (400 MHz, CDCl ₃ -d) δ 1.27 (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).

Step 2. (S)-3-Amino-N,N-dimethylbutanamide

Add tert-butyl N-[(2S)-1-(dimethylcarbamoyl)propan-2-yl]carbamate (200 mg; 0.868 mmol; 1 eq.) and TFA (0.99 g; 8.684 mmol) to a 50 mL round bottom flask. ; 10 eq.) at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. ECMS (ESI) m/z [M+H] ⁺ = 131.1; ^1H NMR (300 MHz, CDCl ₃ -d) δ 1.40 (3H, d), 2.70 (2H, d), 2.95 (3H, s), 3.01 (3H, s), 3.74 (1H, s), 7.78 ( 3Н, s), 11.00 (2Н, s).

Step 3. (S)-3-Amino-N-(4-(dimethylamino)-4-oxobutan-2-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5 -(oxazol-2-yl)pyrazin-2-carboxamide (compound 234)

To a stirred solution/mixture of (3S)-3-amino-N,N-dimethylbutanamide (77.42 mg; 0.595 mmol; 2 eq.) and 3-amino-6-[3-methylimidazo[1,2-a]pyridine -6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.297 mmol; 1 eq.) was added dropwise to DMF with DIEA (768.59 mg; 5.947 mmol ; 20.00 eq.) and T ₃ P (946.09 mg; 2.973 mmol; 10.00 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred overnight at room temperature in an air atmosphere. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A:, mobile phase B: MeOH for HPLC; flow rate: 20 ml/min ; gradient: 49% B to 59% B in 8 min; 254/220 nm; Rt: 6.97 min), yielding (3S)-3-[(3-amino-6-[3-methylimidazo[1, 2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]-N,N-dimethylbutanamide (15 mg; 11.15%) as yellow solid matter. LCMS (ESI) [M+H] ⁺ = 449.3; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (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 Preparation of (3R)-3-[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazine -2-yl)formamido]-N,N-dimethylbutanamide (compound 236)

SCHEME 112

Step 1. tert-butyl N-[(2R)-1-(dimethylcarbamoyl)propan-2-yl]carbamate

Mixture of DIEA (1589.80 mg; 12.301 mmol; 5 eq.), HATU (1870.86 mg; 4.920 mmol; 2 eq.), dimethylamine hydrochloride (401.20 mg; 4.920 mmol; 2 eq.) and (3R) -3-[[(tert-Butoxy)carbonyl]amino]butanoic acid (500 mg; 2.460 mmol; 1 eq.) in DCM (15 ml; 1 eq.) was stirred overnight at room temperature under air. The resulting mixture was concentrated under reduced pressure. The crude product (1000 mg) was purified by preparative HPLC under the following conditions (0-20% H ₂ O in ACN) to give tert-butyl N-[(2R)-1-(dimethylcarbamoyl)propan-2-yl]carbamate (550 mg; 1.35%) as a colorless oil. LCMS: m/z (ESI), [M+H] ⁺ = 231.0. ^1H NMR (300 MHz, 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

A mixture of TFA (1.00 ml; 13.463 mmol; 15.50 eq.) and tert-butyl N-[(2R)-1-(dimethylcarbamoyl)propan-2-yl]carbamate (200 mg; 0.868 mmol; 1 eq. ) in DCM (3 ml) was stirred for 1 hour at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure to give (3R)-3-amino-N,N-dimethylbutanamide (100 mg; 88.45%) as rose oil. ^1H NMR (300 MHz, chloroform-d) δ 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-oxazol-2-yl)pyrazin- 2-yl)formamido]-N,N-dimethylbutanamide (compound 236)

A mixture of DIEA (245.95 mg; 1.903 mmol; 8 eq.), T ₃ P (454.12 mg; 1.427 mmol; 6 eq.), (3R)-3-amino-N,N-dimethylbutanamide (123.88 mg; 0.952 mmol; 4 eq.) and 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2 α-carboxylic acid (80 mg; 0.238 mmol; 1 eq.) in DMF (3 ml) was stirred overnight at room temperature in an air atmosphere. The desired product could be detected by LCMS. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A:, mobile phase B: MeOH for HPLC; flow rate: 20 ml/min ; gradient: 47% B to 59% B in 8 min; 254/220 nm; Rt: 7.40 min), yielding (3R)-3-[(3-amino-6-[3-methylimidazo[1, 2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]-N,N-dimethylbutanamide (compound 236) (60 mg; 55.12% ) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 449.3. ¹ H NMR (300 MHz, DMSC-d ₆ ) δ 1.23 (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).

Examples 247-1/247-2. Preparation of 3-amino-N-((1,2-dimethylpyrrolidin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl) )pyrazine-2-carboxamide (compounds 247-1/247-2)

SCHEME 113

Step 1. tert-butyl 2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin- 2-yl)formamido]methyl]-2-methylpyrrolidine-1-carboxylate

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (200 mg; 0.595 mmol; 1 eq.) and tert-butyl 2-(aminomethyl)-2-methylpyrrolidine-1-carboxylate (254.89 mg; 1.189 mmol; 2 eq.) T ₃ P (946.09 mg) was added dropwise to DMF ; 2.973 mmol; 5 eq.) and DIEA (307.44 mg; 2.379 mmol; 4 eq.) at 25°C in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 25°C under a nitrogen atmosphere. The resulting mixture was diluted with water (50 ml), extracted with CH ₂ Cl ₂ (3×50 ml). The combined organic layers were washed with brine (3×50 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TGS (CH ₂ Cl ₂ /MeOH, 20:1), obtaining tert-butyl 2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]- 5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]-2-methylpyrrolidine-1-carboxylate (280 mg; 88.40%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 533.3. ^1H NMR (300 MHz, MeOD- _d4 ) δ 1.18 (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]-5-(1,3-oxazole -2-yl)pyrazin-2-carboxamide

To a stirred solution of tert-butyl 2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin- 2-yl)formamido]methyl]-2-methylpyrrolidine-1-carboxylate (280 mg) in DCM was added to TFA (1.5 ml) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at 25°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[(2-methylpyrrolidin-2-yl)methyl]-5-( 1,3-oxazol-2-yl)pyrazin-2-carboxamide (200 mg; 87.96%). LCMS: m/z (ESI), [M+H] ⁺ = 433.2.

Step 3. tert-butyl 2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin- 2-yl)formamido]methyl]-2-methylpyrrolidine-1-carboxylate

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[(2-methylpyrrolidin-2-yl)methyl]-5-(1,3-oxazole -2-yl)pyrazin-2-carboxamide (200 mg; 0.462 mmol; 1 eq.) and PFA (138.73 mg; 4.624 mmol; 10 eq.) in MeOH (8 ml) NaBH ₃ CN (145 .30 mg; 2.312 mmol; 5 eq.) and DIE A (239.07 mg; 1.850 mmol; 4 eq.) at 25°C in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 25°C under a nitrogen atmosphere. The reaction mixture was purified by preparative HPLC under the following conditions (column: preparative Atlantis T3 OBD, 19*150 mm, 5 µm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 10% B to 20% B in 7 min; 254/220 nm; Rt: 6.08 min), yielding 3-amino-N-[(1,2-dimethylpyrrolidin-2-yl)methyl]-6-[3-methylimidazo [1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (100 mg; 58.12%) as a yellow solid.

Step 4. tert-butyl 2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin- 2-yl)formamido]methyl]-2-methylpyrrolidine-1-carboxylate (compounds 247-1/247-2)

The product (100 mg) was purified by chiral preparative HPLC under the following conditions (column: CHIRALPAK IG, 5*25 cm, 5 μm; mobile phase A: Hex:DCM, 3:1 (with 10 mM NH ₃ -MEOH) for HPLC, mobile phase B: HPLC EtOH; flow rate: 20 ml/min; gradient: 40 V to 40 V in 10 min; 220/254 nm; Rt1: 6.193, Rt2: 7.693), yielding 3-amino-N-[ (1,2-dimethylpyrrolidin-2-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2 -carboxamide (compound 247-1) (30 mg; 30.0%) and 3-amino-N-[(1,2-dimethylpyrrolidin-2-yl]methyl]-6-[3-methylimidazo[1,2- a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 247-2) (30 mg; 30.0%) as a yellow solid.

(Compound 247-1): LCMS: m/z (ESI), [M+H] ⁺ = 447.2. ^1H NMR (300 MHz, MeOD-d ₄ ) δ 1.05 (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): ECMS: m/z (ESI), [M+H] ⁺ = 447.4. ^1H NMR (300 MHz, MeOD-d ₄ ) δ 1.05 (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)

SCHEME 114

Step 1. 3-Amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carboxamide

To a solution of NH ₃ (gas) in MeOH (15 ml) methyl 3-amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carboxylate (1000 mg; 3.337 mmol; 1 eq.) was added in portions. at room temperature. The mixture was stirred for 5 hours at 50°C in an air atmosphere. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carboxamide (930 mg; 97.90%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺ = 285.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55-7.67 (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 trichloride (5 ml) was added 3-amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carboxamide (900 mg; 3.162 mmol; 1 eq.) in portions at room temperature. The resulting mixture was stirred for 2 hours at 90°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved using CH ₂ Cl ₂ (100 ml) and made alkaline to pH 8 with saturated (aq) NaHCO ₃ solution. The resulting mixture was extracted with CH ₂ Cl ₂ (2×100 ml). The combined organic layers were washed with water (2×30 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (6:1) to give 3-amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carbonitrile (550 mg; 65.24% ) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 267.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56-7.68 (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]pyrazin-2-carbonitrile

To a stirred mixture of 3-amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carbonitrile (400 mg; 1,500 mmol; 1 eq.) and [3-methylimidazo[1,2-a]pyridine- 6-yl]boronic acid (395.99 mg; 2.250 mmol; 1.5 eq.) in dioxane (50 ml) Cs ₂ CO ₃ (977.56 mg; 3.000 mmol; 2 eq.) and Pd(dppf) were added in portions )Cl ₂ (219.53 mg; 0.300 mmol; 0.2 eq.) at 90°C in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 90°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give 3-amino-5-(3,4-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl ]pyrazine-2-carbonitrile (400 mg; 55.19%) as a yellow solid. 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]pyrazin-2-amine

To a solution of 3-amino-5-(3,4-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carbonitrile (400 mg; 1.104 mmol; 1 eq. ) Raney Ni (189.16 mg; 2.208 mmol; 2.00 eq.) was added portionwise to MeOH (50 mL) at room temperature. The mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2×50 ml). The filtrate was concentrated in vacuo to give 3-(aminomethyl)-6-(3,4-difluorophenyl)-5-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-amine (300 mg; 74.17%) as a beige solid. 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]pyridin-6-yl]pyrazin-2-yl] methyl]-1-methylpyrrolidine-2-carboxamide (compound 257)

To a stirred mixture of 3-(aminomethyl)-5-chloro-6-(3,4-difluorophenyl)pyrazin-2-amine (100 mg; 0.369 mmol; 1 eq.) and (2R)-1-methylpyrrolidine-2-carboxylic acid acid (95.44 mg; 0.739 mmol; 2 eq.) in DMF (10 ml), HATU (210.72 mg; 0.554 mmol; 1.5 eq.) and DIEA (191.00 mg; 1.478 mmol; 4 eq.) were added in portions eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 2 hours at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18, 30*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: 5.95 min), yielding (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 (41 mg; 23.17%) (compound 257) as white solid matter. LCMS: m/z (ESI), [M+H] ⁺ = 478.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.64-1.83 (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. Methyl 3-amino-6-chloro-5-phenylpyrazine-2-carboxylate

To a stirred mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (600 mg; 2.702 mmol; 1 eq.) and phenylboronic acid (336.09 mg; 2.756 mmol; 1.02 eq.) in dioxane (20 ml) K ₃ PO ₄ (1147.23 mg; 5.405 mmol; 2 eq.) and Pd(dppf)Cl ₂ (395.46 mg; 0.540 mmol; 0.2 eq.) were added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 70°C 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 (400 mg; 56.14%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 264.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 3.89 (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-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-phenylpyrazin-2-carboxylate (150 mg; 0.569 mmol; 1 eq.) and [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (200.22 mg; 1.138 mmol; 2 eq.) in dioxane (10 ml), Cs ₂ CO ₃ (556.05 mg; 1.707 mmol; 3 eq.) and Pd(dppf)Cl ₂ (83.25 mg) were added in portions ; 0.114 mmol; 0.2 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-phenylpyrazine-2-carboxylate (130 mg; 63.59%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 360.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.27 (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 a solution of methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-phenylpyrazin-2-carboxylate (130 mg; 0.417 mmol; 1 eq.) in THF (15 ml ) and methanol (5 ml) was added LiOH (19.99 mg; 0.835 mmol; 2.00 eq.) at room temperature. The mixture was stirred for 2.5 hours at 50°C in an air atmosphere. The mixture was acidified to pH 6 using HCl (aq). The resulting solid was collected by filtration and dried under vacuum to give 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-phenylpyrazin-2-carboxylic acid (100 mg; 80.05 %) as a yellow solid. 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-methylpyrrolidin-2-yl]methyl]-5-phenylpyrazin- 2-carboxamide (compound 259)

To a stirred mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-phenylpyrazin-2-carboxylic acid (100 mg; 0.290 mmol; 1 eq.) and 1-[ (2R)-1-methylpyrrolidin-2-yl]methanamine (66.13 mg; 0.579 mmol; 2 eq.) in DMF (5 ml) was added portionwise with DIEA (112.27 mg; 0.869 mmol; 3 eq.) and T ₃ R (368.52 mg; 1.158 mmol; 4 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 2.5 hours at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 µm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 38 %B to 50%B in 8 min; 254/220 nm; Rt: 7.65 min), yielding 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N- [[(2R)-1-methylpyrrolidin-2-yl]methyl]-5-phenylpyrazine-2-carboxamide (compound 259) (33 mg; 25.81%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 442.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.54-1.71 (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. Preparation of 3-amino-N-((6-(3-((dimethylamino)methyl)azetidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a ]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 261)

SCHEME 116

Step 1. 6-(3-((Dimethylamino)methyl)azetidin-1-yl)picolinonitrile

6-bromopyridine-2-carbonitrile (423.10 mg; 2.312 mmol; 1.10 eq.), DMF (4 mL; 51.687 mmol; 24.59 eq.), K ₂ CO ₃ ( 871.41 mg; 6.305 mmol; 3 eq.), [(azetidin-3-yl)methyl]dimethylamine (240 mg; 2.102 mmol; 1 eq.). The resulting solution was stirred for 16 hours at 50°C. The resulting solution was extracted with ethyl acetate (3×10 ml), the organic layers were combined and concentrated. The residue was applied to a silica gel column using dichloromethane/methanol (8:1). The result was 190 mg (41.80%) of 6-[3-[(dimethylamino)methyl]azetidin-1-yl]pyridin-2-carbonitrile as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 217.1. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.13 (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-dimethylmethanamine

A 50 mL round bottom flask was filled with MeOH (5 mL; 0.094 mmol; 2.03 eq.), Raney Ni (0.75 mg; 0.009 mmol; 0.01 eq.), 6-[3-[(dimethylamino)methyl ]azetidin-1-yl]pyridin-2-carbonitrile (190 mg; 0.878 mmol; 1 eq.), NH ₄ OH (1 ml; 25.681 mmol; 29.23 eq.). The resulting solution was stirred for 1 hour at room temperature. The result was 40 mg (20.67%) of 1-(6-[3-[(dimethylamino)methyl]azetidin-1-yl]pyridin-2-yl)methanamine as a brown-yellow oil. LCMS: m/z (ESI), [M+H] ⁺ = 220.95. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 2.13 (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)azetidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a] pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 261)

3-Amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid was placed in a 25 ml round bottom flask. (80 mg; 0.238 mmol; 1 eq.), DMF (0.041 mmol; 0.17 eq.), DIEA (307.44 mg; 2.379 mmol; 10 eq.), T ₃ P (454.12 mg; 1.427 mmol ; 6 eq.), 1-(6-[3-[(dimethylamino)methyl]azetidin-1-yl]pyridin-2-yl)methanamine (104.82 mg; 0.476 mmol; 2 eq.). The resulting solution was stirred for 16 hours at room temperature. The resulting solution was diluted with water (15 ml), extracted with dichloromethane (3×10 ml), the organic layers were combined and concentrated. The crude product was purified by preparative HPLC under the following conditions (column: C18-column Kinetex EVO, 30*150.5 µm; mobile phase A:, mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 30% B to 40% B in 7 min; 254/220 nm; Rt: 5.82 min) and the product was obtained. The result was 23.6 mg (18.42%) of 3-amino-N-[(6-[3-[(dimethylamino)methyl]azetidin-1-yl]pyridin-2-yl)methyl]-6-[ 3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 261) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 539.5. ^1H NMR (400 MHz, methanol- _d4 ) δ 2.23 (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-imidazo-[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

Methyl 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxylate (2.0 g; 7.10 mmol; 1 eq.) and NH ₃ (gas.) were added to a hermetically sealed 50 ml test tube. ) in MeOH (30 ml; 7.0 mmol/l) at room temperature, heated for 5 hours at 50°C, concentrated to give 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2- carboxamide (1.5 g; 79%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 267.0.

Step 2. 3-Amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile

To a stirred solution of POCl ₃ (20 ml), 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carboxamide (5.0 g; 18.750 mmol; 1 eq.) was added in portions at 0°C, stirred for 3 hours at 90°C, concentrated. The residue was dissolved in DCM (300 ml), NaHCO ₃ (aq) solution was added to pH 8.0. The aqueous layer was extracted with DCM (3×50 ml), the combined organic layer was dried and concentrated to give 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile (3.5 g; 75%) as light brown solid. 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]pyrazin-2-carbonitrile

To a stirred mixture of 3-amino-6-chloro-5-(4-fluorophenyl)pyrazine-2-carbonitrile (500 mg; 2.01 mmol; 1 eq.), [3-methylimidazo[1,2-a]pyridine- 6-yl]boronic acid (530.81 mg; 3.02 mmol; 1.5 eq.) and Pd(dppf)Cl ₂ (147 mg; 0.20 mmol; 0.1 eq.) in dioxane (15 ml ) K ₃ PO ₄ (854 mg; 4.02 mmol; 2.0 eq.) in H ₂ O (2.5 ml) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90°C, concentrated and purified with preparative TLC (DCM/MeOH, 40/1) to give 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2 -a]pyridin-6-yl]pyrazin-2-carbonitrile (300 mg; 43%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 345.2.

Step 4. (2S)-N-[[3-Amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-yl]methyl] -1-methylpyrrolidine-2-carboxamide

To a stirred mixture of 3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carbonitrile (500 mg; 1.45 mmol; 1 eq. .) and Raney Ni (62 mg; 0.73 mmol; 0.5 eq.) in ethanol (10 ml), NH ₃ .H ₂ O (1.0 ml) was added at room temperature in a hydrogen atmosphere, stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3×30 ml). The filtrate was concentrated under reduced pressure to give 3-(aminomethyl)-6-(4-fluorophenyl)-5-[3-methyl-imidazo[1,2-a]pyridin-6-yl]pyrazin-2-amine (450 mg ; 89%) as a light brown solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (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]pyrazin-2-yl]methyl] oxolane-2-carboxamide (compound 268)

A solution of (2S)-oxolane-2-carboxylic acid (66.66 mg; 0.57 mmol; 2.0 eq.) in DMF (2.0 ml) was treated with HATU (218 mg; 0.57 mmol; 2.0 eq.) for 20 min at room temperature, then 3-(aminomethyl)-6-(4-fluorophenyl)-5-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin- 2-amine (100 mg; 0.29 mmol; 1 eq.), DIEA (111 mg; 0.86 mmol; 3.0 eq.) at room temperature, stirred for 2 h, quenched with water (20 ml), extracted with DCM (3x20 ml), dried and concentrated, then purified by preparative TLC to give (2S)-N-[[3-amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2- a]pyridin-6-yl]pyrazin-2-yl]methyl]oxolan-2-carboxamide (compound 268) (45.2 mg; 35%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ = 447.3. ^1H NMR (300 MHz, DMSO- _d6 ) δ 1.80 (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 (1Н, 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]pyrazin-2-carboxamide (compound 272)

SCHEME 118

Step 1. Methyl 3-amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carboxylate

To a stirred mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (2000 mg; 9.008 mmol; 1 eq.) and (3,4-difluorophenyl)boronic acid (1450.87 mg; 9.188 mmol; 1.02 eq.) in dioxane (100 ml), K ₃ PO ₄ (3824.10 mg; 18.016 mmol; 2 eq.) and Pd(dppf)Cl ₂ (1318.20 mg; 1.802 mmol; 0.2 eq.) were added in portions. at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 70°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to give methyl 3-amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carboxylate (1500 mg; 55.57 %) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 300.2. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 3.89 (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]pyrazin-2-carboxylate

To a stirred mixture of methyl 3-amino-6-chloro-5-(3,4-difluorophenyl)pyrazine-2-carboxylate (400 mg; 1.335 mmol; 1 eq.) and [3-methylimidazo[1,2-a]pyridine -6-yl]boronic acid (469.81 mg; 2.670 mmol; 2 eq.) in dioxane (40 ml) Cs ₂ CO ₃ (869.84 mg; 2.670 mmol; 2 eq.) and Pd(dppf) were added in portions Cl ₂ (195.34 mg; 0.267 mmol; 0.2 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 20:1) to give methyl 3-amino-5-(3,4-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridine-6- yl]pyrazine-2-carboxylate (300 mg; 56.84%) as a yellow solid. 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]pyrazin-2-carboxylic acid

To a solution of methyl 3-amino-5-(3,4-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylate (200 mg; 0.506 mmol; 1 eq. .) in THF (20 ml) and methanol (5 ml) was added LiOH (48.46 mg; 2.023 mmol; 4 eq.) at room temperature. The mixture was stirred for 3 hours at room temperature under air and acidified to pH 6 using HCl (aq). The resulting solid was collected by filtration and dried under vacuum to give 3-amino-5-(3,4-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylic acid (150 mg; 77.76%) as a yellow solid. 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]pyrazine-2-carboxamide (compound 272)

To a stirred mixture of 3-amino-5-(3,4-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carboxylic acid (150 mg; 0.393 mmol; 1 eq.) and 1-[(2R)-1-methylpyrrolidin-2-yl]methanamine (89.83 mg; 0.787 mmol; 2 eq.) in DMF (15 ml) DIEA (152.51 mg; 1.180 mmol) was added portionwise ; 3 eq.) and T ₃ P (500.62 mg; 1.573 mmol; 4 eq.) at room temperature in an air atmosphere. The resulting mixture was stirred for 3 hours at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: preparative column XBridge OBD C18, 30×150 mm, 5 µm; mobile phase A: 5% aqueous ammonia solution, mobile phase B: ACN; flow rate: 60 ml/ min; gradient: 36% B to 49% B in 7 min; 254/220 nm; Rt: 6.83 min), yielding 3-amino-5-(3,4-difluorophenyl)-6-[3-methylimidazo [1,2-a]pyridin-6-yl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]pyrazin-2-carboxamide (compound 272) (23 mg; 12.25%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 478.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.53-1.70 (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. Preparation of 3-amino-N-[[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]- 5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 273)

SCHEME 119

Step 1. tert-butyl N-[[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]methyl]carbamate

A mixture of TEA (854.86 mg; 8.448 mmol; 5 eq.), dimethylamine hydrochloride (206.66 mg; 2.534 mmol; 1.50 eq.), 4-nitrophenyl chloroformate (408.67 mg; 2.028 mmol; 1. 20 eq.) and tert-butyl N-[[(3R)-pyrrolidin-3-yl]methyl]carbamate hydrochloride (400 mg; 1.690 mmol; 1 eq.) in ACN (20 ml) stirred overnight at 70° C in the air atmosphere. The resulting mixture was diluted with water (50 ml) and extracted with EtOAc (3×50 ml). The combined organic layers were washed with brine (3×50 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc, 1:1), yielding tert-butyl N-[[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]methyl]carbamate (370 mg; 80.70%) in in the form of yellow oil. LCMS: m/z (ESI), [M+H] ⁺ = 272.1. ¹ H-NMR (300 MHz, chloroform-d) δ 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

A mixture of TFA (2 ml; 26.926 mmol; 42.98 eq.) and tert-butyl N-[[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]methyl]carbamate (170 mg; 0.626 mmol; 1 eq. .) in DCM (5 ml) was stirred for 1 hour at room temperature in an air atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give (3S)-3-(aminomethyl)-N,N-dimethylpyrrolidine-1-carboxamide (100 mg; 93.21%) as a colorless oil. LCMS: m/z. ^1H NMR (300 MHz, chloroform-d) δ 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]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5 -(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 273)

Mixture of DIEA (184.46 mg; 1.427 mmol; 6 eq.), T ₃ P (227.06 mg; 0.714 mmol; 3 eq.), (3S)-3-(aminomethyl)-N,N-dimethylpyrrolidine-1 -carboxamide (81.47 mg; 0.476 mmol; 2 eq.) and 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2 -yl)pyrazin-2-carboxylic acid (80 mg; 0.238 mmol; 1 eq.) in DMF (3 ml) was stirred overnight at room temperature under air. The resulting mixture was diluted with water (30 ml) and sat. NaHCO ₃ solution (30 ml), extracted with CH ₂ Cl ₂ (3×40 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 12:1) to give the crude product. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18, 30*150.5 µm; mobile phase A:, mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 15 % B to 35% B in 7 min; 254/220 nm; Rt: 6.93 min), giving 3-amino-N-[[(3S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl]methyl]- 6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 273) (20 mg; 17.00% ) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 490.4. ^1H NMR (300 MHz, DMSO- _d6 ) δ 1.60 (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. Preparation of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[[6-(morpholin-4-yl)pyridin-2-yl]methyl]- 5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 276)

SCHEME 120

Step 1. 6-(Morpholin-4-yl)pyridin-2-carbonitrile

6-fluoropyridine-2-carbonitrile (1 g; 8.190 mmol; 1 eq.), morpholine (1.43 g; 0.016 mmol; 2 eq.) and K ₂ CO ₃ (2.26 g) were added to a 40 ml round bottom flask. ; 0.016 mmol; 2 eq.) in DMF (15 ml) at room temperature. The resulting mixture was stirred for 6 hours at 80°C. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with water (1×100 ml), dried under vacuum to give 6-(morpholin-4-yl)pyridin-2-carbonitrile (1.5 g; 96.79%) as white solid matter. LCMS: m/z (ESI), [M+H] ⁺ = 190.3. ^1H NMR (300 MHz, DMSO- _d6 ) δ 3.46 (4H, dd), 3.66 (4H, dd), 7.18 (2H, m), 7.70 (1H, dd).

Step 2. 1-[6-(Morpholin-4-yl)pyridin-2-yl]methanamine

To a solution of 6-(morpholin-4-yl)pyridin-2-carbonitrile (200 mg; 1.057 mmol; 1 eq.) in MeOH (15 ml) and NH ₃ .H ₂ O (1 ml) was added in portions Raney Ni (271 .67 mg; 3.171 mmol; 3 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3×10 ml). The filtrate was concentrated under reduced pressure to give 1-[6-(morpholin-4-yl)pyridin-2-yl]methanamine (150 mg; 73.44%) as a purple oil, 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)pyridin-2-yl]methyl]-5 -(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 276)

To a solution of 1-[6-(morpholin-4-yl)pyridin-2-yl]methanamine (172.39 mg; 0.892 mmol; 2 eq.) and 3-amino-6-[3-methylimidazo[1,2- a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (150 mg; 0.446 mmol; 1 eq.) in DMF (15 ml) T ₃ was added dropwise P (283.83 mg; 0.892 mmol; 2 eq.) and DIEA (115.29 mg; 0.892 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 30 minutes at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN ; flow rate: 20 ml/min; gradient: from 31% B to 50% B in 8 min; 220/254 nm; Rt: 8.15 min), giving 3-amino-6-[3-methylimidazo[1, 2-a]pyridin-6-yl]-N-[[6-(morpholin-4-yl)pyridin-2-yl]methyl]-5-(1,3-oxazol-2-yl)pyrazin-2- carboxamide (compound 276) (60 mg; 26.30%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 512.4. ^1H NMR: (300 MHz, DMSO- _d6 ) δ 2.40 (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. Preparation of 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carboxamide

To a stirred 30% solution of NH ₃ (gas) in MeOH (20 ml) methyl 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carboxylate (900 mg) was added in portions at room temperature. The resulting mixture was stirred for 4 hours at 50°C. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carboxamide (600 mg) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 267.0. ^1H NMR (400 MHz, chloroform-d) δ 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 trichloride (2 ml) was added 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carboxamide (30 mg) in portions at room temperature. The resulting mixture was stirred for 3 hours at 90°C. The resulting mixture was concentrated under reduced pressure and diluted with DCM (20 ml). The reaction was quenched sat. solution (aq.) NaHCO ₃ at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (2×30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /EtOAC, 5:1) to give 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carbonitrile (400 mg) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 249.0. ^1H NMR (300 MHz, chloroform-d) δ 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-carbonitrile

To a stirred mixture of 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carbonitrile (350 mg; 1.408 mmol; 1 eq.) and [3-methylimidazo[1,2-a]pyridine-6- yl]boronic acid (371.56 mg; 2.111 mmol; 1.50 eq.) in dioxane (20 ml) and H ₂ O (2 ml) Cs ₂ CO ₃ (1375.87 mg; 4.223 mmol; 3 eq.) was added in portions .) and Pd(dppf)Cl ₂ (205.99 mg; 0.282 mmol; 0.2 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 90°C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH ₂ Cl ₂ (1×10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 40:1) to give 3-amino-5-(3-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazine -2-carbonitrile (300 mg; 61.89%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 345.2.

Step 4. 3-(Aminomethyl)-6-(3-fluorophenyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-amine

To a stirred solution of 3-amino-5-(3-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carbonitrile (20 mg; 0.058 mmol; 1 eq.) and NH ₃ .H ₂ O (4.07 mg; 0.116 mmol; 2.00 eq.) in EtOH (2 ml) Raney Ni (9.95 mg; 0.116 mmol; 2.00 eq.) was added in portions at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH (1×10 ml). The filtrate was concentrated under reduced pressure to give 3-(aminomethyl)-6-(3-fluorophenyl)-5-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-amine (180 mg; 71 .17%) in the form of a brown-yellow solid. 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)pyrazin-2-yl)methyl) -1-methylpyrrolidine-2-carboxamide (compound 278)

To a stirred mixture of (2R)-1-methylpyrrolidine-2-carboxylic acid (36.70 mg; 0.284 mmol; 1.10 eq.) in DMF (10 ml) was added portionwise HATU (196.45 mg; 0.517 mmol; 2 eq. .) and DIEA (133.55 mg; 1.033 mmol; 4 eq.) at room temperature. The resulting mixture was stirred for 10 minutes at room temperature. To this stirred solution was added 3-(aminomethyl)-6-(3-fluorophenyl)-5-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-amine (90 mg; 0.258 mmol) in portions ; 1 eq.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: 5% NH ₃ in water, mobile phase B: ACN; flow rate : 60 ml/min; gradient: from 31% B to 43% B in 7 min; 254/220 nm; Rt: 6.48 min), giving (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) (26 mg; 21.90 %) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ = 460.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.40-1.92 (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 ).

Examples 279/280. Preparation of 3-amino-N-((3-methoxytetrahydrofuran-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide (compounds 279/280)

SCHEME 122

Step 1. 3-Methoxyfuran-2-carbaldehydeoxime

A mixture of 3-methoxyfuran-2-carbaldehyde (252 mg; 1.998 mmol; 1 eq.) and hydroxylamine hydrochloride (210 mg; 3.022 mmol; 1.51 eq.) in pyridine (4 ml) was stirred at room temperature for 18 h. After concentration to dryness, the residue was purified on a (PE/EA, 2/1) column to give N-[(3-methoxyfuran-2-yl)methylidene]hydroxylamine (200 mg; 70.9%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ = 142.2.

Stage 2. (3-Methoxytetrahydrofuran-2-yl)methanamine

A mixture of N-[(3-methoxyfuran-2-yl)methylidene]hydroxylamine (460 mg; 3.26 mmol; 1 eq.) and Raney Ni (300 mg; 3.502 mmol; 1.07 eq.) in ethanol (70 ml ) were hydrogenated under H ₂ (1 atm (98.1 kPa)) at room temperature for 1 hour. After filtering 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-(oxazol-2-yl) )pyrazine-2-carboxamide

To a mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-pyrazin-2-carboxylic acid (313 mg; 0.931 mmol; 1 eq.) and 1-(3-methoxyoxolan-2-yl)methanamine (366 mg; 2.790 mmol; 3.00 eq.) in 5 ml DMF was added DIEA (1.62 ml; 9.300 mmol; 9. 99 eq.) and a 50% (by weight) solution of T ₃ R in ethyl acetate (1.77 g; 2.793 mmol; 2.99 eq.). The mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by preparative HPLC (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 23% B to 33% B in 7 min; 254/220 nm; Rt: 6.45 min) and separation on a chiral support (column: CHIRALPAK IG , 20x250 mm, 5 µm; mobile phase A: Hex:DCM, 3:1 (with 10 mM NH ₃ -MeOH) for HPLC, mobile phase B: EtOH for HPLC; flow rate: 20 ml/min; gradient: 30 V to 30 V in 50 min; 254/220 nm; Rt1: 15.377; Rt2: 24.388), giving 3-amino-N-((3-methoxytetrahydrofuran-2-yl)methyl)-6-(3-methylimidazo [1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 279) (15 mg; 3.5%) and 3-amino-N-(( 3-methoxytetrahydrofuran-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 280) ( 15 mg; 3.5%) as a yellow solid. (Compound 279) LCMS: m/z (ESI), [M+H] ⁺ = 450.2. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.93-2.00 (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. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.93-1.99 (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. Preparation of 3-[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl )formamido]-N,N,2,2-tetramethylpropanamide (compound 281)

SCHEME 123

Step 1. 2-(5-Bromo-2-oxo-1,2-dihydropyridin-1-yl)propanenitrile

To a stirred mixture of 3-[[(tert-butoxy)carbonyl]amino]-2,2-dimethylpropanoic acid (250 mg; 1.151 mmol; 1 eq.), HATU (525.02 mg; 1.381 mmol; 1.2 eq. ) and DIEA (743.58 mg; 5.753 mmol; 5 eq.) in DMF (5 ml), a solution of dimethylamine (1.15 ml; 2.301 mmol; 2 eq.) was added dropwise at 0°C, then stirred for 2 hours at 0°C. The resulting mixture was diluted with EtOAc (30 ml). The combined organic layers were washed with water (3×10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl N-[2-(dimethylcarbamoyl)-2,2-dimethylethyl]carbamate (200 mg; 71.1%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 245.4.

Stage 2. 3-Amino-N,N,2,2-tetramethylpropanamide

Tert-butyl N-[2-(dimethylcarbamoyl)-2,2-dimethylethyl]carbamate (190 mg; 0.778 mmol; 1 eq.) and a solution of hydrogen chloride in dioxane (4 M; 5 ml) were added to a 6 ml vial and dioxane (3 ml) at room temperature. The mixture was then stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to give 3-amino-N,N,2,2-tetramethylpropanamide (110 mg; 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-oxazol-2-yl)pyrazin-2-yl) formamido]-N,N,2,2-tetramethylpropanamide

3-Amino-N,N,2,2-tetramethylpropanamide (110 mg; 0.72 mmol; 2 eq.), 3-amino-6-[3-methylimidazo[1,2-a] was added to a 6 ml vial. pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (120 mg; 0.36 mmol; 1 eq.), HATU (164 mg; 0.432 mmol; 1, 2 equiv.), DIEA (140 mg; 1.08 mmol; 3 equiv.) and DMF (1.5 ml) at room temperature. 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 (3×10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 25% B to 40% B in 7 min; 254/220 nm; t _R : 5.77 min), giving 3-[(3-amino-6-[3- methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]-N,N,2,2-tetramethylpropanamide (10 mg; 6.0%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 463.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 1.26 (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. Preparation of 3-amino-N-[(6-[6-methyl-2,6-diazaspiro[3.3]heptan-2-yl]pyridin-2-yl)methyl]-6-[3-methylimidazo[1 ,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 284)

SCHEME 124

Step 1. tert-butyl 6-(6-cyanopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

To a mixture of 6-fluoropyridine-2-carbonitrile (1 g; 8.190 mmol; 1 eq.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.25 g; 16.380 mmol; 2 eq.) in DMF (25 ml) K ₂ CO ₃ (2.26 g; 16.380 mmol; 2 eq.) was added in portions at room temperature. The resulting mixture was stirred for 3 hours at 50°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2:1) to give tert-butyl 6-(6-cyanopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1 .2 g; 48.78%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ = 301.2. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.38 (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]heptan-2-yl]pyridin-2-yl)methanamine

To a solution of tert-butyl 6-(6-cyanopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg; 0.999 mmol; 1 eq.) in THF (15 ml) was added portionwise LiAlH ₄ ; (189.54 mg; 4.994 mmol; 5 eq.) at 0°C in an air atmosphere. The mixture was stirred for 1 hour at room temperature. The resulting mixture was stirred for 3 hours at 70°C in an air atmosphere. The reaction mixture was quenched using water/ice at room temperature and extracted with EtOAc (3×50 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give 1-(6-[6-methyl-2,6-diazaspiro[3.3]heptan-2-yl]pyridin-2-yl)methanamine (100 mg; 45.86%) in in the form of yellow oil. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (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]heptan-2-yl]pyridin-2-yl)methyl]-6-[3-methylimidazo[1, 2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 284)

To a solution of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (90 mg; 0.268 mmol; 1 eq.) and 1-(6-[6-methyl-2,6-diazaspiro[3.3]heptan-2-yl]pyridin-2-yl)methanamine (116.84 mg; 0.535 mmol; 2 eq. ) in DMF (10 ml) T ₃ P (170.30 mg; 0.535 mmol; 2 eq.) and DIEA (69.17 mg; 0.535 mmol; 2 eq.) were added dropwise at room temperature. The resulting mixture was stirred for 30 minutes at room temperature in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 29% B to 38% B in 8 min; 254/220 nm; Rt: 6.95 min), giving 3-amino-N-[(6-[6-methyl -2,6-diazaspiro[3.3]heptan-2-yl]pyridin-2-yl)methyl]-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3 -oxazol-2-yl)pyrazin-2-carboxamide (compound 284) (30 mg; 20.89%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 537.4. ^1H NMR (300 MHz, DMSO- _d6 ) δ 2.14 (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 pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 285)

SCHEME 125

Step 1. 6-[(3R)-3,4-Dimethylpiperazin-1-yl]pyridin-2-carbonitrile

(2R)-1,2-dimethylpiperazine (607.9 mg; 5.32 mmol; 1.3 eq.), 6-fluoropyridine-2-carbonitrile (500 mg; 4.095 mmol; 1 eq.), K ₂ CO ₃ (1131.89 mg; 8.190 mmol; 2 eq.) and DMF (10 ml) at room temperature. The resulting mixture was stirred for 3 hours at 50°C. The reaction was quenched by adding sat. NaCl (aq) solution (250 ml) at room temperature. The resulting mixture was extracted with EtOAc (2×125 ml). The combined organic layers were washed with sat. NaCl (aq.) solution (250 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1), giving 6-[(3R)-3,4-dimethylpiperazin-1-yl]pyridin-2-carbonitrile (540 mg; 60.97%) in in the form of a colorless oil. LCMS: m/z (ESI), [M+H] ⁺ = 217.3.

Step 2. 1-[6-[(3R)-3,4-Dimethylpiperazin-1-yl]pyridin-2-yl]methanamine

To a stirred mixture of 6-[(3R)-3,4-dimethylpiperazin-1-yl]pyridin-2-carbonitrile (200 mg; 0.925 mmol; 1 eq.) in MeOH (5 ml) and NH ₃ .H ₂ O ( 0.5 ml) Raney Ni (15.84 mg; 0.185 mmol; 0.20 eq.) was added dropwise/portionally at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The result was 1-[6-[(3R)-3,4-dimethylpiperazin-1-yl]pyridin-2-yl]methanamine (162 mg; 79.52%) as a crude product/mixture in the form of a colorless oil and 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-methylimidazo[1,2-a] pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide

To a stirred solution/mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.297 mmol; 1 eq.) and 1-[6-[(3R-3,4-dimethylpiperazin-1-yl]pyridin-2-yl]methanamine (98.27 mg; 0.446 mmol; 1, 5 eq.) in DMF (5 ml) HATU (226.12 mg; 0.595 mmol; 2 eq.) and DIEA (115.29 mg; 0.892 mmol; 3 eq.) were added dropwise/portionally at room temperature in an air atmosphere The resulting mixture was extracted with CH ₂ Cl ₂ (3×20 ml).The combined organic layers were washed with water (3×10 ml), dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 15:1) The crude product (80 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A:, mobile phase B: ACN ; flow rate: 20 ml/min; gradient: from 34% B to 45% B in 8 min; 254/220 nm; Rt: 7.53 min), giving 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-oxazol- 2-yl)pyrazin-2-carboxamide (compound 285) (20 mg; 12.49%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ = 539.4. ¹ H-NMR (DMSO-d ₆ , 40 MHz) δ 1.7 (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-(oxazol-2-yl)pyrazin-2-carboxamide (compound 287-2)

Step 1. 6-[(3S)-3.4-Dimethylpiperazin-1-yl]pyridin-2-carbonigril

(3S)-1,3-Dimethylpiperazine (607.89 mg; 5.323 mmol; 1.3 eq.), 6-fluoropyridine-2-carbonitrile (500 mg; 4.095 mmol; 1 eq.) was added to a hermetically sealed 40 ml tube. ), K ₂ CO ₃ (1131.89 mg; 8.190 mmol; 2 eq.) and DMF (10 ml) at room temperature. The resulting mixture was stirred for 3 hours at 50°C. The reaction was quenched by adding sat. NaCl (aq) solution (250 ml) at room temperature. The resulting mixture was extracted with EtOAc (2 x 125 ml). The combined organic layers were washed with sat. NaCl (aq.) solution (250 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1), giving 6-[(2S)-2,4-dimethylpiperazin-1-yl]pyridin-2-carbonitrile (280 mg; 31.61%) in in the form of a colorless oil. LCMS: m/z (ESI), [M+H] ⁺ =217.3.

Step 2. 1-[6-[(2S)-2,4-Dimethylpiperazin-1-yl]pyridin-2-yl]methanamine

To a stirred solution/mixture of 6-[(2S)-2,4-dimethylpiperazin-1-yl]pyridin-2-carbonitrile (280 mg; 1.295 mmol; 1 eq.) in MeOH (5 ml) and NH ₂ NH ₂ ⋅H ₂ O (0.5 ml) was added dropwise/portionally with Raney's Ni (22.18 mg; 0.259 mmol; 0.2 eq.) at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure to give 1-[6-[(2S)-2,4-dimethylpiperazin-1-yl]pyridin-2-yl]methanamine (200 mg; 70.12%) as a colorless solid. substances. LCMS: m/z (ESI), [M+H] ⁺ =221.4.

Step 3. 3-Amhho-N-([6-[(2S)-2,4-dimethylpiperazin-1-yl]pyridin-2-

yl]methyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide (compound 287-2)

To a stirred solution/mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.297 mmol; 1 eq.) and 1-[6-[(2S)-2,4-dimethylpiperazin-1-yl]pyridin-2-yl]methanamine (98.27 mg; 0.446 mmol; 1 .50 eq.) in DMF (10 ml) HATU (226.12 mg; 0.595 mmol; 2 eq.) and DIEA (115.29 mg; 0.892 mmol; 3 eq.) were added dropwise/portionwise at room temperature in air atmosphere. The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 20 ml). The combined organic layers were washed with water (3x20 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 15:1). The crude product (80 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 19*250 mm, 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 20 ml/min; gradient : 36% B to 47% B in 8 min; 254/220 nm; Rt: 7.65 min), yielding 3-amino-N-([6-[(2S)-2,4-dimethylpiperazine-1- yl]pyridin-2-yl]methyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide ( compound 287-2) (20 mg; 12.49%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =539.4. ^1H NMR (400 MHz, DMSO- _d6 ) δ 0.9 (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 shown in the table below were prepared using the methods described for the preparation of compound 287-2.

Example 290. Preparation of (2S)-N-[[3-Amino-5-(4-fluorophenyl)-6-[3-methyl-imidazo-[1,2-a]pyridin-6-yl]pyrazin-2- yl]methyl]oxolane-2-carboxamide (compound 290)

Step 1. Methyl 3-methyl-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-triazol-2-yl)pyrazine

A solution of methyl 3-amino-6-chloro-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (3.0 g; 11.8 mmol; 1 eq.) in dioxane ( 50 ml) were treated with [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (4.15 g; 23.6 mmol; 2.00 eq.), Pd(dppf)Cl ₂ (0. 86 g; 1.19 mmol; 0.1 eq.) and K ₃ PO ₄ (7.50 g; 35.3 mmol; 3.0 eq.) in H ₂ O (5.0 ml) in a nitrogen atmosphere at room temperature, heated for 2 hours at 90°C, cooled to room temperature, concentrated. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /MeOH (20/1) to give methyl 3-methyl-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5- (2H-1,2,3-triazol-2-yl)pyrazin-2-carboxylate (1.8 g; 44%) as a light yellow solid. 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)pyrazin-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)pyrazin-2-carboxylate (1 .0 g; 2.85 mmol; 1 eq.) in THF (20 ml) was treated with LiAlH ₄ (162.5 mg; 4.28 mmol; 1.5 eq.) at -70°C, stirred for 2 hours , quenched with EA (2.5 ml), purified with preparative TLC to give 3-methyl-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3- triazol-2-yl)pyrazin-2-carbaldehyde (280 mg; 31%) as a light yellow solid. 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-triazol-2-yl)pyrazin-2- yl)methyl1-2-methylpropane-2-sulfinamide

Mixture of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-carbaldehyde (260 mg ; 0.81 mmol; 1 eq.) and 2-methylpropane-2-sulfinamide (195 mg; 1.62 mmol; 2.0 eq.) in THF (2.5 ml) were treated with Ti(Oi-Pr) ₄ ( 2.5 ml) at room temperature, heated at 70°C for 2 hours, cooled to room temperature, NaBH ₄ was added; (123 mg; 3.25 mmol; 4.0 eq.), stirred for 2 hours, quenched with water (2.0 ml), filtered. The solid was washed with DCM/MeOH (5/1, 20 ml), combined with the organic layer, concentrated, purified by preparative TLC (DCM/MeOH, 50/1) to give N-[(3-amino-6-[3- methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-yl)methyl]-2-methylpropan-2-sulfinamide (230 mg; 67%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =426.3.

Step 4. (2S)-N-[[3-Amino-5-(4-fluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-yl]methyl] -1-methylpyrrolidine-2-carboxamide

A solution of N-[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(2H-1,2,3-

triazol-2-yl)pyrazin-2-yl)methyl]-2-methylpropan-2-sulfinamide (160 mg; 0.36 mmol; 1 eq.) in DCM (2.0 ml) was treated with HCl (gas) solution in 1,4-dioxane (2.0 ml; 4.0 mol/l) at room temperature, stirred for 2 hours, 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 (160 mg; crude). 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]pyrazin-2-yl]methyl] oxolane-2-carboxamide (compound 290)

A solution of (2R)-1-methylpyrrolidine-2-carboxylic acid (112.5 mg; 0.87 mmol; 2.0 eq.) in DMF (3.0 ml) was treated with HATU (331 mg; 0.87 mmol; 2 .00 equiv.) for 20 min at room temperature, then 3-(aminomethyl)-5-[3-methylimidazo[1,2-a]pyridin-6-yl]-6-(2H-1, 2,3-triazol-2-yl)pyrazin-2-amine (140 mg; 0.44 mmol; 1 eq.), DIEA (167 mg; 1.31 mmol; 3.0 eq.) at room temperature, stirred for 2 h. The residue was purified by preparative TLC (DCM/MeOH, 30/1) to give (2R)-N-[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl ]-5-(2H-1,2,3-triazol-2-yl)pyrazin-2-yl)methyl]-1-methylpyrrolidine-2-carboxamide (65 mg; 35%) as a white solid. LCMS [M+H]=433.3. ^1H NMR (400 MHz, DMSO- _d6 ) δ 1.74 (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)

Step 1. Methyl 3-amino-6-chloro-5-(3,5-difluorophenyl)pyrazine-2-carboxylate

To a stirred mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (4 g; 18.016 mmol; 1 eq.) and (3,5-difluorophenyl)boronic acid (2.90 g; 18.376 mmol; 1.02 eq.) in 1,4-dioxane (100 ml) and H ₂ O (5 ml), K ₃ PO ₄ (7.65 g; 36.031 mmol; 2 eq.) and Pd(dppf)Cl ₂ (2, 64 g; 3.603 mmol; 0.2 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 70°C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH ₂ Cl ₂ (1x30 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /EtOAc (4:1) to give methyl 3-amino-6-chloro-5-(3,5-difluorophenyl)pyrazine-2-carboxylate (4 g; 74.09%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =300.2. ^1H NMR (300 MHz, DMSO- _d6 ) δ 3.89 (3H, s), 7.47 (3H, dd), 7.66 (2H, s).

Step 2. 3-Amino-6-chloro-5-(3,5-difluorophenyl)pyrazine-2-carboxamide

To a stirred solution of 30% NH ₃ in MeOH (100 ml) methyl 3-amino-6-chloro-5-(3,5-difluorophenyl)pyrazine-2-carboxylate (4 g; 13.348 mmol; 1 eq.) was added in portions. ) at room temperature. The resulting mixture was stirred for 4 hours at 50°C. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5-(3,5-difluorophenyl)pyrazine-2-carboxamide (3.5 g; 92.11%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =285.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.43 (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 trichloride (40 mL) was added 3-amino-6-chloro-5-(3,5-difluorophenyl)pyrazine-2-carboxamide (2 g; 7.026 mmol; 1 eq.) in portions at room temperature. The resulting mixture was stirred for 12 hours at 90°C. The resulting mixture was concentrated under reduced pressure and diluted with DCM (20 ml). The reaction was quenched sat. solution (aq) NaHCO ₃ at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . 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 (700 mg; 37.36%) as a yellow solid substances. ¹ H-NMR: (300 MHz, DMSO-d ₆ ) δ 7.43 (3H, m), 7.73 (2H, s).

Step 4. 3-Amino-5-(3,5-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carbonitrile

To a stirred mixture of 3-amino-6-chloro-5-(3,5-difluorophenyl)pyrazine-2-carbonitrile (600 mg; 2.250 mmol; 1 eq.) and [3-methylimidazo[1,2-a]pyridine- 6-yl]boronic acid (791.99 mg; 4.500 mmol; 2.00 eq.) in 1,4-dioxane (30 ml) and H ₂ O (4 ml) was added in portions of Cs ₂ CO ₃ (1466.34 mg ; 4.500 mmol; 2 eq.) and Pd(dppf)Cl ₂ (329.30 mg; 0.450 mmol; 0.2 eq.) at room temperature in a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 90°C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH ₂ Cl ₂ (1x10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1) to give 3-amino-5-(3,5-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl ]pyrazine-2-carbonitrile (300 mg; 36.79%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =363.3. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 2.37 (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]pyrazin-2-amine

To a stirred solution of 3-amino-5-(3,5-difluorophenyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-carbonitrile (100 mg; 0.276 mmol; 1 eq. .) and NH ₃ ⋅H2O (1 ml) in MeOH (15 ml), Raney Ni (47.29 mg; 0.552 mmol; 2 eq.) was added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (1x10 ml). The filtrate was concentrated under reduced pressure to give 3-(aminomethyl)-6-(3,5-difluorophenyl)-5-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-amine (90 mg ; 89.01%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =367.3.

Step 6. (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)

To a stirred mixture of (2R)-1-methylpyrrolidine-2-carboxylic acid (56.41 mg; 0.437 mmol; 2.00 eq.) in DMF (10 ml) was added portionwise HATU (166.05 mg; 0.437 mmol; 2 eq. .) and DIEA (56.44 mg; 0.437 mmol; 2 eq.) at room temperature. The resulting mixture was stirred for 10 minutes at room temperature. 3-(Aminomethyl)-6-(3,5-difluorophenyl)-5-[3-methylimidazo[1,2-a]pyridin-6-yl]pyrazin-2-amine (80 mg) was then added to this stirred solution in portions ; 0.218 mmol; 1 equiv.) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: preparative column XBridge C18 OBD, 5 µm, 19*150 mm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 35 %B to 48%B in 7 min; 254/220 nm; Rt: 6.77 min), yielding (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) (7 mg; 6.71%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =478.4. ^1H NMR (300 MHz, DMSO- _d6 ) δ 1.72 (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. Preparation of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-H-[(28)-1-(1H -1,2,3-triazol-1-yl)propan-2-yl]pyrazin-2-carboxamide (compound 296-1)

Step 1. (S)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

To a stirred solution of tert-butyl N-[(2S)-1-hydroxypropan-2-yl]carbamate (5.0 g; 28.534 mmol; 1 eq.) and TEA (3753.60 mg; 37.095 mmol; 1.3 eq. .) MsCl (4.90 g; 42.801 mmol; 1.5 eq.) was added dropwise to DCM at 0°C under a nitrogen atmosphere. The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 20 ml). The combined organic layers were washed with water (2 x 20 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The result was (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (6.5 g, 89.9%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ - MS signal is not provided.

Step 2. tert-butyl (S)-(1-(1H-1,2,3-triazol-1-yl)propan-2-yl)carbamate

To a stirred solution of tert-butyl N-[(2S)-1-(methanesulfonyloxy)propan-2-yl]carbamate (3 g; 11.843 mmol; 1 eq.) and 1H-1,2,3-triazole (1.23 g; 17.765 mmol; 1.50 eq.) in DMF (50 ml) K ₂ CO ₃ (3.27 g; 23.686 mmol; 2.00 eq.) was added in portions. The resulting mixture was stirred at 90°C under a nitrogen atmosphere. The resulting mixture was diluted with EA (10 ml), washed with water (2 x 10 ml). The resulting mixture was concentrated under vacuum. 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 (1.2 g; 44.7% ) and tert-butyl (8)-(1-(1H-1,2,3-triazol-1-yl)propan-2-yl)carbamate (0.62 g; 23.1%) as a white solid .

tert-Butyl-(S)-(1-(2H-1,2,3-triazol-2-yl)propan-2-yl)carbamate. ¹ H-NMR (300 MHz, chloroform-d) δ 1.09 (3H, d), 1.43 (9H, s), 4.21 (1H, s), 4.51 (2H, d), 7.63 (2H, s).

tert-Butyl-(S)-(1-(1H-1,2,3-triazol-1-yl)propan-2-yl)carbamate. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.02 (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 a stirred solution of tert-butyl (S)-(1-(1H-1,2,3-triazol-1-yl)propan-2-yl)carbamate (280 mg; 1 eq.) in 1,4-dioxane ( 5 ml), a 4 M solution of HCl in 1,4-dioxane (5 ml) was added dropwise at 25°C. 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 (266 mg; 90.5%) as a white solid. The crude product was used directly in the next step without further purification. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.13 (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]pyrazin-2-carboxamide

To a stirred mixture of (2S)-1-(1H-1,2,3-triazol-1-yl)propan-2-amine (45 mg; 0.357 mmol; 1.50 eq.), 3-amino-6-[ 3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (80 mg; 0.238 mmol; 1 eq.) and DIEA ( 184.46 mg; 1.427 mmol; 6.00 eq.) T ₃ P (454.12 mg; 0.714 mmol; 3.00 eq.; 50%) was added dropwise to DMF at 0°C. The reaction mixture was purified preparative HPLC under the following conditions (column: Shiseido CAPCELLCORE C18, 2.1*50 mm, 2.7 µm; mobile phase A: water/0.05% TFA, mobile phase B: ACN/0.05% TFA; speed flow: 1.0 ml/min; gradient: from 5% B to 95% B in 2.0 min; hold for 0.7 min; 254 nm), giving 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)propane -2-yl]pyrazin-2-carboxamide (compound 296-1) (75 mg; 70.9%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =445.3 ^.1H NMR (300 MHz, DMSO- _d6 ) δ 1.19 (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. Preparation of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[(2R)-1-(2H -1,2,3-triazol-2-yl)propan-2-yl]pyrazin-2-carboxamide (compound 296-2)

Step 1. ®-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

To a stirred solution of tert-butyl N-[(2R)-1-hydroxypropan-2-yl]carbamate (3 g; 17.121 mmol; 1 eq.) and MsCl (2.55 g; 22.257 mmol; 1.3 eq.) TEA (3.46 g; 34.241 mmol; 2 eq.) was added to DCM (50 ml) in portions at 0°C for 2 hours. The reaction mixture was quenched by adding H ₂ O with NaHCO ₃ (10 ml), extracted with DCM ( 3 x 20 ml), the organic layer was dried over Na ₂ SO ₄ . The result was (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (6.5 g, 89.9%) as a white solid. LCMS: m/z (ESI), [M+H-tBu+MeCN] ⁺ =239.1.

Step 2. tert-butyl N-[(2R)-1-(2H-1,2,3-triazol-2-yl)propan-2-yl]carbamate

Tert-butyl N-[(2R)-1-(2H-1,2,3-triazol-2-yl)propan-2-yl]carbamate (5 g; 19.739 mmol; 1 eq.) was added to a 10 mL vial. ), 1H-1,2,3-triazole (2.04 g; 29.608 mmol; 1.50 eq.), K ₂ CO ₃ (5.46 g; 39.477 mmol; 2.00 eq.) and DMF (50 ml) at 0°. The mixture was then stirred at 90°C under nitrogen atmosphere for 1 hour. The resulting mixture was diluted with EtOAc (50 ml). The organic layers were washed with brine (3x10 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC under the following conditions: column: C ₁₈ silica gel; mobile phase: MeOH in water; gradient: from 10% to 50% in 10 minutes; detector: UV 254 nm, receiving:

tert-butyl-N-[(2R)-1-(1H-1,2,3-triazol-1-yl)propan-2-yl]carbamate (1 g; 22.3%) ¹ H NMR (300 MHz , DMSO-d ₆ ) δ 0.99 (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);

tert-butyl-N-[(2R)-1-(2H-1,2,3-triazol-2-yl)propan-2-yl]carbamate (2.9 g; 64.9%) as a white solid substances. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.94 (3H, d), 1.31 (9H, s), 3.94 (1H, p), 4.24-4.43 (2H, m), 6.84 (1H, d), 7.74 (2H, s).

Stage 3. ®-1-(1H-1,2,3-triazol-1-yl)propan-2-amine dihydrochloride

To a stirred solution of tert-butyl (R)-(1-(1H-1,2,3-triazol-1-yl)propan-2-yl)carbamate (280 mg; 1.24 mmol; 1 eq.) in 1 ,4-dioxane (5 ml) was added dropwise with a 4 M solution of HCl in 1,4-dioxane (5 ml) at 25°C. 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 (266 mg; quantitative yield) as 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]pyrazin-2-carboxamide

3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid ( 100 mg; 0.297 mmol; 1 eq.), (2R)-1-(1H-1,2,3-triazol-1-yl)propan-2-amine (56.27 mg; 0.446 mmol; 1.5 eq. .), T ₃ P (283.83 mg; 0.892 mmol; 3 eq.), DIEA (192.15 mg; 1.487 mmol; 5 eq.) and DMF (10 ml) at 0°C. The mixture was then stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 10% B to 50% B in 7 min; 254/220 nm; Rt: 5.48 min), yielding 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]pyrazin-2-carboxamide (compound 296-2) (20 mg; 15.1%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =445.2. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (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. Preparation of 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]pyrazin-2-carboxamide

Step 1. (2S)-1-(2H-1,2,3-triazol-2-yl)propan-2-amine dihydrochloride

To a stirred mixture of tert-butyl N-[(2S)-1-(2H-1,2,3-triazol-2-yl)propan-2-yl]carbamate (260 mg; 1.15 mmol; 1 eq.) a solution of HCl in 1,4-dioxane (5 ml) was added dropwise to 5 ml of 1,4-dioxane at room temperature. After stirring for 1 hour, the mixture was concentrated to give (2S)-1-(2H-1,2,3-triazol-2-yl)propan-2-amine dihydrochloride (230 mg; 90.0%) as a white solid. substances. LCMS: m/z (ESI), [M+H] ⁺ =127.2.

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]pyrazin-2-carboxamide

To a stirred solution of (2S)-1-(2H-1,2,3-triazol-2-yl)propan-2-amine dihydrochloride (71 mg; 0.357 mmol; 1.50 eq.) and 3-amino-6- [3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (80 mg; 0.238 mmol; 1 eq.), DIE A (184 mg; 1.427 mmol; 6.00 eq.) T ₃ P (454 mg; 0.714 mmol; 3.00 eq.; 50 wt.%) was added dropwise to DMF at 0°C in an air atmosphere. The reaction mixture was purified by preparative HPLC (column: Shiseido CAPCELLCORE C18, 2.1*50 mm, 2.7 μm; mobile phase A: water/0.05% TFA, mobile phase B: ACN/0.05% TFA; flow rate : 1.0 ml/min; gradient: from 5% B to 95% B in 2.0 min, hold for 0.7 min; 254 nm), giving 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)propane -2-yl]pyrazin-2-carboxamide (compound 297) (37 mg; 35.0%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =445.3. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 1.13 (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. Preparation of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)-N-[(2R)-1 -(2H-1,2,3-triazol-2-yl)propan-2-yl]pyrazin-2-carboxamide (compound 298)

Step 1. (2R-1-(2H-1,2,3-triazol-2-yl)propan-2-amine dihydrochloride

To a stirred solution of tert-butyl N-[(2R)-1-(2H-1,2,3-triazol-2-yl)propan-2-yl]carbamate (200 mg; 0.88 mmol; 1 eq.) a 4 M solution of HCl (gas) in 1,4-dioxane (4 ml) was added dropwise at room temperature in an air atmosphere for 1 hour. The solvent was evaporated. The result was (2R)-1-(2H-1,2,3-triazol-2-yl)propan-2-amine dihydrochloride (180 mg; quantitative yield) as a white solid. LCMS: m/z (ESI), [M+H] ⁺ =127.2.

Step 2. 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]pyrazin-2-carboxamide

3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid ( 100 mg; 0.297 mmol; 1 eq.), (2R)-1-(1H-1,2,3-triazol-1-yl)propan-2-amine (56.27 mg; 0.446 mmol; 1.5 eq. .), T ₃ P (283.83 mg; 0.892 mmol; 3 eq.), DIEA (192.15 mg; 1.487 mmol; 5 eq.) and DMF (10 ml) at 0°C. The mixture was then stirred at room temperature under a nitrogen atmosphere for 4 hours. The resulting mixture was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30×150 mm, 5 μm; mobile phase A: water (with NH ₄ HCO ₃ (10 mmol/l)), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 10% B to 50% B in 7 min; 254/220 nm; Rt: 5.48 min), yielding 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]pyrazin-2-carboxamide (compound 298) (20 mg; 15.1%) as a white solid. LCMS: m/z(ESI), [M+H] ⁺ =445.3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.13 (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-oxazol-2-yl)pyrazin-2-carboxamide (compound 301)

Step 1. tert-butyl T-[2-[(2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazole -2-yl)pyrazin-2-yl)formamido]methyl]pyridin-3-yl)oxy]ethyl]-N-methylcarbamate

Tert-butyl N-(2-[[2-(aminomethyl)pyridin-3-yl]oxy]ethyl)-N-methylcarbamate (209.15 mg; 0.743 mmol; 2.50 eq.) was placed in a 6 ml vial. , 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (100 mg; 0.297 mmol ; 1 eq.), DIE A (0.36 ml; 2.805 mmol; 9 eq.), DMF (2.5 ml), T ₃ P (283.83 mg; 0.892 mmol; 3.00 eq.). The resulting solution was stirred for 16 hours at 0°C. The resulting solution was diluted using 20 ml H ₂ O. The resulting solution was extracted with dichloromethane (3x15 ml) and the organic layers were combined. The residue was purified by preparative TLC (DCM: MeOH, 5:1). The result was 60 mg (33.65%) tert-butyl N-[2-[(2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]- 5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]pyridin-3-yl)oxy]ethyl]-N-methylcarbamate as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =600.3.

Step 2. 3-Amino-N-([3-[2-(methylamino)ethoxy]pyridin-2-yl]methyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]- 5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide

Tert-butyl N-[2-[(2-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1) was placed in a 25 ml round bottom flask ,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]pyridin-3-yl)oxy]ethyl]-N-methylcarbamate (60 mg; 0.100 mmol; 1 eq.), DCM (3 ml) , TFA (1 ml; 13.463 mmol; 134.55 eq.). The resulting solution was stirred for 1 hour at 20°C. The resulting mixture was concentrated under vacuum. The pH of the solution was adjusted to 8 with a saturated solution (aq) of sodium bicarbonate. The resulting mixture was concentrated under vacuum. 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: preparative column XBridge C18 OBD, 19×150 mm, 5 µm; mobile phase A:, mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 20% B to 38% B for 8 min; 254/220 nm; Rt: 7.19 min). The result was 10.53 mg (19.59%) of 3-amino-N-([3-[2-(methylamino)ethoxy]pyridin-2-yl]methyl)-6-[3-methylimidazo[1,2 -a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxamide as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =500.4. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 2.30 (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. Preparation of 3-amino-N-((6-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin- 6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 302)

Step 1. 6-(4-(Dimethylamino)piperidin-1-yl)picolinonitrile

6-chloropyridine-2-carbonitrile (500 mg; 3.609 mmol; 1 eq.), N,N-dimethylpiperidin-4-amine (508.99 mg; 3.970 mmol; 1.10 eq.) and K ₂ CO ₃ (1496.27 mg; 10.826 mmol; 3.00 eq.) in DMF (10 ml) at room temperature. The resulting mixture was stirred for 15 hours at 60°C in an air atmosphere. The resulting mixture was diluted with EtOAc (100 ml). The resulting mixture was washed with water (2x100 ml) and saturated brine (2x100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and the solid was filtered 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]pyridin-2-carbonitrile (438 mg; 52.7%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =231.3. 1H-NMR (400 MHz, MeOD-d ₄ ) δ 1.45 (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]pyridin-2-carbonitrile (438 mg; 1.902 mmol; 1 eq.) and Raney Ni (162.93 mg; 1.902 mmol; 1 eq.) were added to a 50 mL round bottom flask. .00 eq.), NH ₃ ⋅H ₂ O (66.65 mg; 1.902 mmol; 1.00 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The solid was filtered and the solvent was evaporated to give 1-[6-(aminomethyl)pyridin-2-yl]-N,N-dimethylpiperidin-4-amine (406 mg; 91.1%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =235.1. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 1.39-1.55 (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-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 302)

To a stirred mixture of 1-[6-(aminomethyl)pyridin-2-yl]-N,N-dimethylpiperidin-4-amine (55.75 mg; 0.238 mmol; 1.00 eq.) and 3-amino-6-[ 3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-carboxylic acid (80 mg; 0.238 mmol; 1 eq.), DIEA ( 92.23 mg; 0.714 mmol; 3.00 eq.) T ₃ P (151.37 mg; 0.476 mmol; 2.00 eq.) was added dropwise to DMF at 0°C in an air atmosphere. The resulting mixture was stirred for 12 hours at room temperature in an air atmosphere. The resulting mixture was diluted with EtOAc (50 ml). The resulting mixture was washed with water (1x50 ml) and brine (3x50 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give a crude solid. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 12:1) to give a yellow solid. The crude product (50 mg) was purified by preparative HPLC under the following conditions (column: XBridge OBD C18 preparative column, 30x150 mm, 5 μm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 37% B to 50% B in 7 min; 254/220 nm; Rt: 5.52 min), giving 3-amino-N-([6- [4-(dimethylamino)piperidin-1-yl]pyridin-2-yl]methyl)-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol- 2-yl)pyrazin-2-carboxamide (compound 302) (20 mg; 15.21%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =553.4. ^1H NMR (400 MHz, MeOD-d ₄ ) δ 1.21 (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 (1Н, s).

Example 303. Preparation of 3-amino-N-((6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin- 6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (compound 303)

Step 1. Preparation of tert-butyl (1-(6-cyanopyridin-2-yl)azetidin-3-yl)(methyl)carbamate

A mixture of 6-bromopyridin-2-carbonitrile (500 mg; 2.732 mmol; 1 eq.), tert-butyl N-(azetidin-3-yl)-N-methylcarbamate (559.76 mg; 3.005 mmol; 1.1 eq. ) and K ₂ CO ₃ (1132.78 mg; 8.196 mmol; 3.0 eq.) in DMF (20 ml) was stirred for 3 hours at 60°C. The resulting mixture was diluted with water (40 ml). The resulting mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (9:1) to give tert-butyl N-[1-(6-cyanopyridin-2-yl)azetidin-3-yl]-N-methylcarbamate (600 mg ; 76.16%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =289.2. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.38 (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

A mixture of tert-butyl N-[1-(6-cyanopyridin-2-yl)azetidin-3-yl]-N-methylcarbamate (500 mg; 1.734 mmol; 1 eq.), ammonium hydroxide (20.00 ml) and Ni Raney (99.54 mg) in MeOH (20 ml) was stirred for 1 hour at room temperature under H ₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 ml). The filtrate was concentrated under reduced pressure. The result was tert-butyl N-[1-[6-(aminomethyl)pyridin-2-yl]azetidin-3-yl]-N-methylcarbamate (502 mg; 99.02%) as a light yellow oil. LCMS: m/z (ESI), [M+H] ⁺ =293.1. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.38 (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. tert-butyl (1-(6-((3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamido)methyl)pyridin-2-yl)azetidin-3-yl)-(methyl)carbamate

A solution of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2-

yl)pyrazin-2-carboxylic acid (100 mg; 0.297 mmol; 1 eq.), tert-butyl N-[1-[6-(aminomethyl)pyridin-2-yl]azetidin-3-yl]-N-methylcarbamate (173.88 mg; 0.595 mmol; 2.0 eq.), DIEA (192.15 mg; 1.487 mmol; 5.0 eq.) and T ₃ P (189.22 mg; 0.595 mmol; 2.0 eq. ) in DMF (10 ml) was stirred for 2 hours at room temperature. The resulting mixture was diluted with water (20 ml). The resulting mixture was extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a mixture of CH ₂ Cl ₂ /MeOH (10:1), obtaining tert-butyl N-[1-(6-[[(3-amino-6-[3-methylimidazo[1, 2-a]pyridin-6-yl]-5-(1,3-oxazol-2-yl)pyrazin-2-yl)formamido]methyl]pyridin-2-yl)azetidin-3-yl]-N-methylcarbamate (80 mg; 44.06%) as a light yellow oil. 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-(oxazol-2-yl)pyrazin-2-carboxamide

A solution of tert-butyl N-[1-(6-[[(3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(1,3-oxazol-2- yl)pyrazin-2-yl)formamido]methyl]pyridin-2-yl)azetidin-3-yl]-N-methylcarbamate (80 mg; 0.131 mmol; 1 eq.) and TFA (2 ml) in DCM (5 ml ) was stirred for 2 hours at room temperature. The residue was neutralized to pH 7 with saturated (aq) NaHCO ₃ solution. The resulting mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with water (2x30 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD, 5 µm, 19*150 mm; mobile phase A: water (with 0.05% NH ₃ H ₂ O), mobile phase B: ACN; speed flow: 20 ml/min; gradient: from 32% B to 52% B in 8 min; 254/220 nm; Rt: 7.88 min), giving 3-amino-N-([6-[3-(methylamino )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 303) (30 mg; 44.85%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =511.3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.20 (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).

Examples 304/305. Preparation of 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(pyridin-2-yl)-N-((tetrahydrofuran-3-yl)methyl)pyrazin-2 -carboxamide (compounds 304/305)

Step 1. 3-Amino-6-chloro-5-(pyridin-2-yl)pyrazin-2-carboxylate 2-(tributylstannyl)pyridine solution (1658.12 mg; 5.05 mmol; 2.00 eq.), methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (500 mg; 2.525 mmol; 1 eq.), Pd(PPh ₃ ) ₂ Cl ₂ (158.06 mg; 0.226 mmol; 0.1 eq.) and LiCl (190.94 mg; 5.05 mmol; 2 eq.) in 1,4-dioxane (20 ml) was stirred for 16 hours at 90°C under nitrogen atmosphere. This reaction mixture was purified along with another batch of E02189-006. The mixture was flash chromatographed on a silica gel column and eluted with CH ₂ Cl ₂ /MeOH (1:1) to give the crude product. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 30:1) to give methyl 3-amino-6-chloro-5-(pyridin-2-yl)pyrazin-2-carboxylate (180 mg; 30.20%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =265.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.9 (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-yl1-5-(pyridin-2-yl)pyrazin-2-carboxylate

Solution of methyl 3-amino-6-chloro-5-(pyridin-2-yl)pyrazin-2-carboxylate (120 mg; 0.453 mmol; 1 eq.), [3-methylimidazo[1,2-a]pyridine-6 -yl]boronic acid (159.58 mg; 0.907 mmol; 2 eq.), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (37.03 mg; 0.045 mmol; 0.1 eq.) and Cs ₂ CO ₃ (295.45 mg; 0.907 mmol; 2 eq.) in 1,4-dioxane (12.5 ml) and H ₂ O (1.5 ml) was stirred for 4 hours under N ₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 25:1), giving methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(pyridin-2- yl)pyrazine-2-carboxylate (50 mg; 30.60%) as a yellow solid. 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-carboxylic acid

To a stirred solution of methyl 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(pyridin-2-yl)pyrazin-2-carboxylate (1 eq.) in 1, 4-dioxane (10 ml) and H ₂ O (1 ml) were added in portions with LiOH (3 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The mixture was acidified to pH 3 using HCl (aq) solution. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) 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-[(oxolan-3-yl)methyl]-5-(pyridin-2-yl)pyrazine -2-carboxamide

To a stirred solution of 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-5-(pyridin-2-yl)pyrazin-2-carboxylic acid (50 mg; 0.144 mmol; 1 eq.), DMF (5 ml) and 1-(oxolan-3-yl)methanamine (73.01 mg; 0.722 mmol; 5 eq.) to DMF (5 ml) DIPEA (93.29 mg; 0.722 mmol) was added in portions ; 5 eq.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The reaction was quenched by adding water (20 ml) at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 25 ml). The combined organic layers were washed with water (2x20 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 15:1), yielding 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[(oxolan-3- yl)methyl]-5-(pyridin-2-yl)pyrazin-2-carboxamide (30 mg; 48.39%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺ =430.3.

Step 5. rel-3-Amino-6-[3-methylimidazo[1.2-a]pyridin-6-yl]-N-[[(3R-oxolan-3-yl]methyl]-5-(pyridin-2- yl)pyrazine-2-carboxamide

The crude product (30 mg) was purified by preparative chiral HPLC under the following conditions (column: Chiralpak ID-2, 2*25 cm, 5 μm; mobile phase A: MTBE (with 10 mM NH ₃ -MEOH) for HPLC, mobile phase B : MeOH for HPLC; flow rate: 20 ml/min; gradient: from 15 V to 15 V in 20 min; 220/254 nm; Rtl: 12.919; Rt2: 16.74), giving 3-amino-6-[3 -methylimidazo[1,2-a]pyridin-6-yl]-N-[[oxolan-3-yl]methyl]-5-(pyridin-2-yl)pyrazin-2-carboxamide (compound 304) (8 mg ; 26.67%) and 3-amino-6-[3-methylimidazo[1,2-a]pyridin-6-yl]-N-[[oxolan-3-yl]methyl]-5-(pyridin-2 -yl)pyrazin-2-carboxamide (compound 305) as a yellow solid.

(Compound 304) LCMS: m/z (ESI), [M+H] ⁺ =430.3. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 1.7 (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 (400 MHz, DMSO-d ₆ ) δ 1.7 (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 for different adenosine receptors

The binding affinities and specificities of the compounds for the different subtypes of human adenosine receptors (hA1, hA2A, hA2B and hA3) were characterized using cell membrane chromatography binding assays.

Samples of compounds at different concentrations were incubated with hA1 membrane (from PerkinElmer) and [ ³ H]-8-cyclopentyl-1,3-dipropylxanthine (DPCPX) for 50 min at 25°C, meanwhile in the wells of a UNIFILTER-96 filter plate GF/B was added with 100 μl of 0.5% polyethylenimine (PEI) solution and kept for 60 min at 4°C, then the UNIFILTER-96 GF/B filter plate was washed twice using 50 ml of washing buffer into the filter plate. The UNIFILTER-96 GF/B plate was transferred with the membrane mixture and the filter plate was washed 4 times and then incubated at 55°C for 10 minutes. Finally, 40 μl of ULTIMA GOLD was added to each well and the counts per minute (CPM) were measured on a TopCount counter.

Samples of compounds at different concentrations were incubated with hA2a-membrane (from PerkinElmer) and [ ³ H]-CGS21680 for 90 min at 25°C, meanwhile, 100 μl of 0.5% was added to the wells of the UNIFILTER-96 GF/B filter plate. - solution of PEI with incubation for 60 min at 4°C, then the UNIFILTER-96 GF/B filter plate was washed twice using 50 ml of washing buffer, the membrane mixture and filter plate 4 were transferred to the UNIFILTER-96 GF/B filter plate washed twice and then incubated at 55°C for 10 min. Finally, 40 µl of ULTIMA GOLD was added to each well and the CPM was measured on a TopCount counter.

Samples of compounds at various concentrations were incubated with hA2b membrane (from PerkinElmer) and [ ³ H]-DPCPX for 60 min at 27°C and binding reactions were stopped by rapid filtration through coated with 0.5% BSA (bovine whey albumin) UNIFILTER-96 GF/B plates using a cell harvester. The filter plates were then washed three times with ice-cold wash buffer and dried at 37°C for 120 min. Finally, 50 μL of liquid scintillation mixture was added to each well and the CPM was measured on a TopCount counter.

Samples of compounds at different concentrations were incubated with hA3 membrane (from PerkinElmer) and [ ¹²⁵ I]-AB-MECA for 60 min at 27°C and binding reactions were stopped by rapid filtration using 0.5% BSA coated UNIFILTER plates. -96 GF/B using cell harvester. The filter plates were then washed three times with ice-cold wash buffer and dried at 37°C for 120 min. Finally, 50 μL of liquid scintillation mixture was added to each well and the CPM was measured on a TopCount counter.

The binding affinities and specificities of representative compounds for human receptors A1, A2a, A2b and A3 are shown below in Table 3. Blank cells in the tables below indicate that data are not yet available.

Example 308 Inhibition Assay using FLIPR™ and cAMP (cycloadenosine monophosphate) formation inhibition

hADORA1/CHO cells (Chinese hamster ovary expressing human A1) (Genscript) were seeded at a rate of 1x10 ⁴ cells/well in 384-well polystyrene plates one day before the start of the experiment. On the day of the experiment, the supernatant was discarded, replaced with 40 μl of dye solution (FLIPR Calcium Assay Kit 5) per well, and the plates were incubated for 60 min at 37°C and 5% CO ₂ . Test compounds were then added at different concentrations to perform an inhibition assay using FLIPR™. After 400 s of incubation with compound, 10 μM adenosine was added to the cells and the signal was recorded using a fluorescence laser imaging plate reader (FLIPR).

hA2a/CHO, hA2b/CHO, hA3/CHO and mA2a/CHO (mouse A2a-expressing) cells (Genscript) were seeded at 5x10 ³ cells/well in 384-well polystyrene plates on the day of the experiment. The compounds were first incubated with these cells for 30 min at 37°C, 5% CO ₂ . Then, 10 μM adenosine was added to the cells and incubated for 30 min at 37°C, 5% CO ₂ . Detection reagent (CISBIO) was added and the plates were incubated for 60 min at room temperature. The signal was recorded using the En Vision system.

The inhibitory activities of representative compounds using FLIPR™ and cAMP on cell lines overexpressing different adenosine receptors are shown below in Table 4.

Claims (409)

1. Compound of formula (I) or a pharmaceutically acceptable salt thereof, where X represents amino; ring A is selected from ring B is selected from a 3-12 membered unsaturated carbocyclyl or a 3-12 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from O and N, where one of the ring-forming groups -CH ₂ - is optionally substituted by a -C group (ABOUT)-; W represents -C _1-12 alkylene- or -C(O)-; V represents -NH-, -NH-C _1-12 alkylene-, -NH-C(O)- or N-attached pyrrolidinyl, each of which may be substituted singly or independently multiple times with hydroxyl, C _1-12 alkyl, C _1-12 alkoxyl, N-(C _1-12 alkyl)amino group, N,N-(C _1-12 alkyl) ₂ amino or C _1-12 alkyl-OH; Y represents hydroxyl, cyano, amino, carbamoyl, carbonyl, sulfonyl, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 alkyl-OH, C _1-12 alkyl-cyano, C _1-12 haloalkoxy, N -(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkylsulfonyl, C _1-12 alkanoylamino, 3-12 membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, where one of the constituents the ring of -CH ₂ - groups is optionally substituted by a -C(O)- group, each of which may possibly be substituted once or independently multiple times by an R ₃ group; each R ₁ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkyl-OH groups, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, 3-10 membered saturated carbocyclyl or 3-10 membered saturated heterocyclyl containing 1 heteroatom O, wherein each R ₁ can optionally be additionally substituted once or independently multiple times with an R ₄ group; each R ₂ is independently selected from halogen, C _1-12 alkyl, C _1-12 haloalkyl; each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-(C _1-12 alkyl) carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl )phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl containing 1-2 heteroatoms independently selected from N and O, each R ₃ possibly being additionally substituted once or independently multiple times by an R ₆ group; wherein each R ₄ or R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C groups _1-12 alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _{1 -12} alkyl) ₂ carbamoyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, C _1-12 alkanoylamino, C _1-12 alkylsulfonyl, C _1-12 alkyl-substituted cycloalkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4. 2. The compound according to claim 1, where each R ₁ is independently selected from fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methylamino, dimethylamino ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl or oxetanyl, each of which may optionally be further substituted once or independently multiple times with an R ₄ group, each R ₄ group being independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl , C _1-12 haloalkyl, C _1-12 alkoxy or C _1-12 haloalkoxy. 3. Connection according to claim 1, where m is 0, 1 or 2. 4. The connection according to claim 1, where ring B is selected from: 5. The compound of claim 1, wherein each R ₂ is independently selected from halogen, C _1-12 alkyl, or C _1-12 haloalkyl. 6. The compound of claim 5, wherein each R ₂ is independently selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or trifluoroethyl. 7. Connection according to claim 1, where n is 0, 1 or 2. 8. The compound according to claim 1, where W represents methylene or -C(O)-. 9. A compound according to claim 8, wherein when W is methylene, V is -NH-C(O)-; or, when W is -C(O)-, V is -NH-, -NH-C _1-12 alkylene- or N-attached pyrrolidinyl, each of which may be substituted singly or independently multiple times with hydroxyl, C _{1- 12} alkyl, C _1-12 alkoxyl or C _1-12 alkyl-OH group. 10. A compound according to claim 1, where Y is a 3-12 membered saturated or unsaturated carbocyclyl or a 3-12 membered saturated or unsaturated heterocyclyl selected from: which may optionally be substituted once or independently multiple times by the group R ₃ . 11. A compound according to claim 1, where Y represents hydroxyl, amino, cyano, carbonyl, carbamoyl, C _1-12 alkyl, C _1-12 alkyl-OH, C _1-12 alkoxyl, sulfonyl, (C _1-12 alkyl )sulfonyl, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl, each of which may optionally be substituted once or independently multiple times with R ₃ . 12. The compound according to claim 1, where each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, groups C _1-12 alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl) phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl-OH) amino, C _1-12 haloalkoxyl, 3-10 -membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl, each R ₃ optionally being further substituted once or independently multiple times by an R ₆ group. 13. The compound according to claim 1, where each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy , groups C _1-12 alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N- (C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino or C _1-12 alkyl-substituted cycloalkyl. 14. A compound according to claim 1, having the structure of formula (Ia) or a pharmaceutically acceptable salt thereof, where ring A is chosen from ring B is a 5-6 membered unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from O and N, where one of the ring-forming groups -CH ₂ - is optionally substituted by a -C group (ABOUT)-; Z represents a -C _1-12 alkylene- or bond; Y is amino, carbamoyl, carbonyl, sulfonyl, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 alkyl-OH, C _1-12 alkyl-cyano, C _1-12 haloalkoxy, N-(C _{1 -12} alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkylsulfonyl , C _1-12 alkanoylamino, 3-6 membered saturated or unsaturated carbocyclyl or 3-6 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, where one of the ring-forming groups is -CH ₂ - optionally substituted by the group -C(O)-, each of which may possibly be substituted once or independently multiple times by the group R ₃ ; each R ₁ is independently selected from fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methylamino, dimethylamino ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl or oxetanyl, each of which may optionally be further substituted once or independently multiple times with an R ₄ group; each R ₂ independently represents halogen, C _1-12 alkyl or C _1-12 haloalkyl; each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-(C _1-12 alkyl) carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl )phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl containing 1-2 heteroatoms independently selected from N and O, each R ₃ possibly being additionally substituted once or independently multiple times by an R ₆ group; each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy; each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH groups , N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl , C _1-12 alkanoylamino or C _1-12 alkyl-substituted cycloalkyl; m is 0, 1, 2, 3 or 4; And n is 0, 1, 2, 3 or 4. 15. A compound according to claim 14, where Z represents a bond, Y represents a cyclobutyl monosubstituted with C _1-12 alkoxy, possibly methoxy. 16. The compound according to claim 14, where Z represents ethylene, Y represents methoxyl. 17. A compound according to claim 1, having the structure of formula (Ia-i) or a pharmaceutically acceptable salt thereof, where ring A is chosen from ring B is a 5-6 membered unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from O and N, where one of the ring-forming groups -CH ₂ - is optionally substituted by a -C group (ABOUT)-; ring Q is a 3-6 membered saturated or unsaturated carbocyclyl or a 3-6 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, where one of the ring-forming CH ₂ groups is optionally substituted group -C(O)-; R ₇ represents hydrogen, C _1-12 alkyl, C _1-12 alkoxy or C _1-12 alkyl-OH; each R ₁ is independently selected from fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl or oxetanyl, each of which may optionally be further substituted once or independently multiple times with an R ₄ group; each R ₂ independently represents halogen, C _1-12 alkyl or C _1-12 haloalkyl; each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-(C _1-12 alkyl) carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl )phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl containing 1-2 heteroatoms independently selected from N and O, each R ₃ possibly being additionally substituted once or independently multiple times by an R ₆ group; each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy; each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH groups , N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl , C _1-12 alkanoylamino or C _1-12 alkyl-substituted cycloalkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; And i is 0, 1, 2, 3 or 4. 18. A compound according to claim 1, having the structure of formula (Ib) or a pharmaceutically acceptable salt thereof, where ring A is chosen from ring B is a 5-6 membered unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from O and N, where one of the ring-forming groups -CH ₂ - is optionally substituted by a -C group (ABOUT)-; ring Q is a 3-6 membered saturated or unsaturated carbocyclyl or a 3-6 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, where one of the ring-forming groups is -CH ₂ -possibly substituted by the group -C(O)-; R ₇ represents hydrogen; each R ₁ is independently selected from fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methylamino, dimethylamino ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl or oxetanyl, each of which may optionally be further substituted once or independently multiple times with an R ₄ group; each R ₂ independently represents halogen, C _1-12 alkyl or C _1-12 haloalkyl; each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-(C _1-12 alkyl) carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl )phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl containing 1-2 heteroatoms independently selected from N and O, each R ₃ possibly being additionally substituted once or independently multiple times by an R ₆ group; each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy; each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH groups , N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl , C _1-12 alkanoylamino or C _1-12 alkyl-substituted cycloalkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; And i is 0, 1, 2, 3 or 4. 19. The connection according to claim 14, 17 or 18, where ring A is selected from 20. The compound according to claim 14, 17 or 18, where each R ₁ is independently selected from fluorine, chlorine, amino, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxyethyl, hydroxypropyl, methoxyethyl, 2-hydroxypropyl, cyclopropyl or oxetanyl . 21. Connection according to paragraph 14, 17 or 18, where m is 0, 1 or 2. 22. The connection according to claim 14, 17 or 18, where ring B is selected from: 23. The compound according to claim 14, 17 or 18, where R ₂ represents methyl or fluorine. 24. Connection according to paragraph 14, 17 or 18, where n is 0 or 1. 25. The connection according to claim 17 or 18, where the ring Q is selected from: 26. The compound according to claim 14, 17 or 18, where each R ₃ is independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxyl, ethoxyl, difluoromethoxyl, trifluoromethoxyl, trifluoroethoxyl, hydroxymethyl, hydroxyethyl , hydroxyethyloxyl, methoxyethyloxyl, amino, methylamino, dimethylamino, ethylamino, isopropylamino, hydroxyethylamino, methylaminoethyloxyl, dimethylaminoethyloxyl, dimethylphosphinylmethyl, carbamoyl, carbamoylmethoxyl, azetidinyl, pyrrolidyl, morpholinyl, pyrazinyl, dimethylaminoazetidinyl, 1 -methyl-pyrazin-4-yl, 3 -methyl-3,8-diaza-bicyclo[3.2.1]octan-8-yl, 3-methyl-3,6-diaza-bicyclo[3.1.1]heptanyl, 8-methyl-3,8-diaza-bicyclo [3.2.1]octan-3-yl, 6-methyl-2,6-diaza-spiro[3.4]octan-2-yl or 5-methyl-2,5-diaza-spiro[3.3]-heptan-2- silt. 27. The connection according to claim 17 or 18, where i is 0, 1, 2 or 3. 28. A compound according to claim 1, having the structure of formula (Ia-ii) or a pharmaceutically acceptable salt thereof, where ring A is chosen from Z represents a -C _1-12 alkylene- or bond; Y represents a C _1-12 alkyl, a C _1-12 alkoxyl, a C _1-12 alkyl-OH, a 3-6 membered saturated or unsaturated carbocyclyl, or a 3-6 membered saturated or unsaturated heterocyclyl containing 1-3 heteroatoms, regardless selected from N, O and S, wherein one of the ring-forming groups -CH ₂ - is optionally substituted by a -C(O)- group, each of which may optionally be substituted once or independently multiple times by an R ₃ group; each R ₁ is independently selected from fluorine, chlorine, bromine, amino, cyano, C _1-12 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methylamino, dimethylamino, ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclopentanyl or oxetanyl, each of which may optionally be further substituted once or independently multiple times with an R ₄ group; each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, phosphoryl, phosphinyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1- groups ₁₂ alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _3-12 cycloalkyl)amino, N-(C _1-12 alkyl) carbamoyl, N,N-(C ₁ - ₁₂ alkyl) ₂ carbamoyl, (C _1-12 alkyl)sulfonyl, (C _1-12 alkyl)phosphinyl, (C _1-12 alkyl) ₂ phosphinyl, (C _1-12 alkyl )phosphoryl, (C _1-12 alkyl) ₂ phosphoryl, C _1-12 alkanoylamino, N-(C _1-12 alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl containing 1-2 heteroatoms independently selected from N and O, each R ₃ possibly being additionally substituted once or independently multiple times by an R ₆ group; each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy; each R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, sulfonyl, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH groups , N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl , C _1-12 alkanoylamino or C _1-12 alkyl-substituted cycloalkyl; m is 0, 1, 2, 3 or 4; And n is 0, 1, 2, 3 or 4. 29. The compound according to claim 28, wherein ring A is azaindolizinyl. 30. A compound according to claim 28, where m is 1 and R ₁ is C _1-12 alkyl, preferably C _1-3 alkyl, more preferably methyl. 31. The compound according to claim 28, where Z represents a bond, Y represents cyclobutyl monosubstituted with methoxyl. 32. The compound according to claim 28, where Z is ethylene, Y is methoxyl. 33. The compound of claim 28, wherein Z is methylene, Y is phenyl, pyrrolidyl or tetrahydrofuryl, each of which may optionally be substituted once or independently multiple times with R ₃ . 34. The compound according to claim 33, where R ₃ represents halogen or C _1-12 alkyl. 35. The compound according to claim 33, where R ₃ represents fluorine or methyl. 36. A compound selected from the group consisting of: 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-((3-fluoropyridin-2-yl)methyl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)pyrazin-2 -carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide ; 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; 3-amino-N-(2,6-difluorobenzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(2,6-dimethylmorpholino)-5-(4-fluorophenyl)pyrazine-2-carboxamide; 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; N-((3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-yl)methyl)picolinamide; 3-amino-N-((6-(dimethylamino)pyridin-2-yl)methyl)-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(2-methylpyridin-4-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)-N-((3-(trifluoromethyl)pyridin-2-yl )methyl)pyrazine-2-carboxamide; 3-amino-N-((6-(dimethylamino)pyridin-2-yl)methyl)-5-(4-fluorophenyl)-6-(2-methylpyridin-4-yl)pyrazin-2-carboxamide; 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; 3-amino-N-((3-fluoropyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; 3-amino-N-((6-(dimethylamino)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-((6-(dimethylamino)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-((6-methoxypyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((6-methylpyridin-2-yl)methyl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; 3-amino-N-((3-(difluoromethoxy)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-(1-(2,6-difluorophenyl)ethyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; N-((3-amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-yl)methyl)-3-(difluoromethoxy )picolinamide; 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((5-methylthiazol-4-yl)methyl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((6-(methylamino)pyridin-2-yl)methyl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-((6-aminopyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; 3-amino-N-((4-(dimethylamino)pyrimidin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-((6-(azetidin-1-yl)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5- (oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(5-(dimethylamino)-2-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)-N-((6-(pyrrolidin-1-yl)pyridine -2-yl)methyl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-carboxamide; 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)-N-((3-(trifluoromethoxy)pyridin-2-yl )methyl)pyrazine-2-carboxamide; 3-amino-6-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)-5-(oxazol-2- yl)pyrazine-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(imidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(3-(dimethylamino)-2-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 6-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-amino-N-(2,6-difluorobenzyl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(2H-1,2,3-triazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-((3-(hydroxymethyl)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide ; 3-amino-6-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(2,6-difluorobenzyl)-5-(oxazol-2-yl)pyrazin-2-carboxamide ; 3-amino-N-(2-fluoro-6-morpholinobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamide; 3-amino-N-(1-(2,6-difluorophenyl)ethyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide (isomers); 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-5-(oxazol-2-yl)-6-(1-(oxetan-3-yl)-6-oxo-1,6-dihydropyridin-3-yl )pyrazine-2-carboxamide; 3-amino-N-((3-fluoropyridin-2-yl)methyl)-6-(imidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2- carboxamide; 3-amino-6-(imidazo[1,2-a]pyridin-6-yl)-N-((2-methylthiazol-4-yl)methyl)-5-(oxazol-2-yl)pyrazin-2- carboxamide; 3-amino-6-(imidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(thiazol-4-ylmethyl)pyrazin-2-carboxamide; 3-amino-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((3-(methylamino)pyridin-2-yl)methyl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-6-(1H-benzo[d]imidazol-5-yl)-N-((3-fluoropyridin-2-yl)methyl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-aminopyridin-2-yl)methyl)-6-(imidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2- carboxamide; 3-amino-N-((6-amino-3-fluoropyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol- 2-yl)pyrazin-2-carboxamide; 3-amino-N-((3-fluoro-6-(methylamino)pyridin-2-yl)methyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5- (oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((3-fluoropyridin-2-yl)methyl)-6-(3-methyl-3H-benzo[d]imidazol-5-yl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(4-fluoro-2-methoxybenzyl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(3-fluoro-2-methoxybenzyl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; 3-amino-N-(2-(difluoromethyl)benzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(1H-pyrazol-1-yl)pyrazin-2-carboxamide; 3-amino-N-((3-(difluoromethoxy)pyridin-2-yl)methyl)-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; 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; 3-amino-N-(2-(difluoromethoxy)phenyl)-5-(3-methyl-1H-pyrazol-1-yl)-6-(1-methyl-6-oxo-1,6-dihydropyridine-3- yl)pyrazine-2-carboxamide; 3-amino-6-(2-amino-6-methylpyridin-4-yl)-N-(2-(difluoromethoxy)phenyl)-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2- carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(5-methylfuran-2-yl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(5-methylfuran-2-yl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-(2-(trifluoromethoxy)benzyl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-((2-methoxypyridin-3-yl)methyl)pyrazin-2-carboxamide; 3-amino-5-(4-fluorophenyl)-N-(2-methoxybenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-carboxamide; 3-amino-6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazin-2-carboxamide; 3-amino-6-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazin-2-carboxamide; 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(2-methoxybenzyl)pyrazine-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-((3-methoxypyridin-2-yl)methyl)pyrazin-2-carboxamide; 3-amino-N-(2-(difluoromethoxy)benzyl)-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-carboxamide; 3-amino-N-(2-(difluoromethoxy)-6-fluorobenzyl)-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2 -carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(5-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-(3-methyl-1H-pyrazol-1-yl)pyrazin-2-carboxamide; 3-amino-6-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazine-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-5-(4-fluorophenyl)-6-(1-(oxetan-3-yl)-6-oxo-1,6-dihydropyridin-3-yl)pyrazine -2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-fluorobenzyl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; 3-amino-N-(2-chlorobenzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxamide; 3-amino-N-(2-bromobenzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-(2-methylbenzyl)pyrazin-2-carboxamide; 3-amino-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazine-2-carboxamide; 3-amino-6-(2-amino-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-ethylbenzyl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; 3-amino-N-(2-(difluoromethoxy)-6-fluorobenzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; N-((3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazin-2-yl)methyl)-2-methoxybenzamide; 3-amino-6-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(2,6-difluorobenzyl)-5-(4-fluorophenyl)pyrazine-2-carboxamide; N-((3-amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-yl)methyl)-2,6- difluorobenzamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-N-(2-methoxybenzyl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-fluoro-6-methoxybenzyl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; 3-amino-N-(2-(difluoromethoxy)benzyl)-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(5-fluoro-2-methoxybenzyl)-5-(4-fluorophenyl)pyrazin-2-carboxamide; 3-amino-6-(2,6-dimethylpyridin-4-yl)-N-(2-methoxybenzyl)-5-phenylpyrazine-2-carboxamide; 3-amino-6-(imidazo[1,2-a]pyridin-6-yl)-N-((5-methylthiazol-4-yl)methyl)-5-(oxazol-2-yl)pyrazin-2- carboxamide; 3-amino-N-((4-aminopyrimidin-2-yl)methyl)-6-(imidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2- carboxamide; 3-amino-N-(2-(dimethylphosphoryl)-6-fluorobenzyl)-6-(imidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide ; 3-amino-N-(2-(dimethylphosphoryl)-6-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 3-amino-N-(1-(2,6-difluorophenyl)-2-hydroxyethyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-6-(imidazo[1,2-a]pyridin-6-yl)-N-((6-(methylamino)pyridin-2-yl)methyl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 6-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-amino-N-((3-fluoropyridin-2-yl)methyl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-((3-fluoropyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(1-(3-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 3-amino-N-((3-fluoropyridin-2-yl)methyl)-6-(imidazo[1,2-a]pyridin-6-yl)-5-(2H-1,2,3-triazol- 2-yl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-5-(oxazol-2-yl)-6-(6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide (isomers); 3-amino-N-(2-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(2-chloro-6-fluorobenzyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamide; 3-amino-N-((6-(3-(dimethylamino)azetidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl) -5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-5- (oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-5-(4-fluorophenyl)-N-((3-(2-hydroxyethoxy)pyridin-2-yl)methyl)-6-(3-methyl-3H-benzo[d]imidazol-5-yl )pyrazine-2-carboxamide; 3-amino-5-(4-fluorophenyl)-N-((3-(2-methoxyethoxy)pyridin-2-yl)methyl)-6-(3-methyl-3H-benzo[d]imidazol-5-yl )pyrazine-2-carboxamide; 3-amino-5-(4-fluorophenyl)-6-(3-methyl-3H-benzo[d]imidazol-5-yl)-N-((3-(2-(methylamino)ethoxy)pyridin-2- yl)methyl)pyrazine-2-carboxamide; 3-amino-N-((3-(2-(dimethylamino)ethoxy)pyridin-2-yl)methyl)-5-(4-fluorophenyl)-6-(3-methyl-3H-benzo[d]imidazol- 5-yl)pyrazin-2-carboxamide; 3-amino-5-(4-fluorophenyl)-N-((3-(2-hydroxyethylamino)pyridin-2-yl)methyl)-6-(3-methyl-3H-benzo[d]imidazol-5-yl )pyrazine-2-carboxamide; 3-amino-N-((4-(dimethylamino)pyridin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl )pyrazine-2-carboxamide; 3-amino-N-((3-(2-amino-2-oxoethoxy)pyridin-2-yl)methyl)-5-(4-fluorophenyl)-6-(3-methyl-3H-benzo[d]imidazole -5-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide (isomers); (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(pyrrolidin-2-ylmethyl)pyrazin-2 -carboxamide; (S)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(pyrrolidin-2-ylmethyl)pyrazin-2 -carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpiperidin-2-yl)methyl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide (isomers); (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydrofuran-2-yl)methyl) pyrazine-2-carboxamide; (S)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydrofuran-2-yl)methyl) pyrazine-2-carboxamide; (R)-3-amino-6-(3-ethylpyrazolo[1,5-a]pyridin-5-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2- yl)pyrazine-2-carboxamide; (S)-3-amino-6-(3-ethylpyrazolo[1,5-a]pyridin-5-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2- yl)pyrazine-2-carboxamide; (S)-3-amino-6-(3-methyl-3H-benzo[d]imidazol-5-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(2H-1, 2,3-triazol-2-yl)pyrazin-2-carboxamide; (R)-3-amino-6-(3-methyl-3H-benzo[d]imidazol-5-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(2H-1, 2,3-triazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-ethyl-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-isopropyl-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(oxetan-2-ylmethyl)pyrazin-2-carboxamide (isomers ); (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydrofuran-3-yl)methyl) pyrazine-2-carboxamide; (S)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydrofuran-3-yl)methyl) pyrazine-2-carboxamide; (R)-3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl) pyrazine-2-carboxamide; (S)-3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl) pyrazine-2-carboxamide; 3-amino-N-(2-cyanoethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(3-(dimethylamino)-3-oxopropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamide; (R)-3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-(1-methylpyrrolidin-3-yl)pyrazin-2 -carboxamide; (R)-3-amino-N-(2-hydroxypropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide ; (S)-3-amino-N-(2-hydroxypropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide ; 3-amino-N-(2-methoxyethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(2-(trifluoromethoxy)ethyl)pyrazin-2-carboxamide; 3-amino-N-(3-methoxypropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-(2-(methylsulfonyl)ethyl)pyrazine-2-carboxamide; 3-amino-N-((1r,3r)-3-methoxycyclobutyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamide; 3-amino-N-((1s,3s)-3-methoxycyclobutyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamide; 3-amino-N-(2-(dimethylamino)ethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((1-(dimethylamino)cyclopropyl)methyl)-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide ; 3-amino-N-(cyclopropylmethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (S)-N-((3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)-1- methylpyrrolidine-2-carboxamide; (R)-N-((3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)-1- methylpyrrolidine-2-carboxamide; N-(2-(1H-pyrazol-1-yl)ethyl)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; (R)-3-amino-N-(1-methoxypropan-2-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; (S)-3-amino-N-(1-methoxypropan-2-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; (S)-3-amino-N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5 -(oxazol-2-yl)pyrazin-2-carboxamide; (R)-3-amino-N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5 -(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(tetrahydro-2H-pyran-3-yl)pyrazin-2 -carboxamide (isomers); 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydro-2H-pyran-2-yl)methyl) pyrazine-2-carboxamide (isomers); 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydro-2H-pyran-3-yl)methyl) pyrazine-2-carboxamide (isomers); (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((tetrahydrofuran-2-yl)methyl)-5-(2H-1,2, 3-triazol-2-yl)pyrazin-2-carboxamide; (S)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((tetrahydrofuran-2-yl)methyl)-5-(2H-1,2, 3-triazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a ]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-6-(3 -methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-6-(3 -methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2 -a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a ]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((6-(1-methylpiperidin-4-yl)pyridin-2-yl)methyl)-5- (oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(1-(2,6-difluorophenyl)ethyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(pyrrolidin-2-ylmethyl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpiperidin-2-yl)methyl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydrofuran-2-yl)methyl)pyrazin-2- carboxamide; 3-amino-6-(3-ethylpyrazolo[1,5-a]pyridin-5-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide; 3-amino-6-(3-methyl-3H-benzo[d]imidazol-5-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(2H-1,2,3- triazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(oxetan-2-ylmethyl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydrofuran-3-yl)methyl)pyrazin-2- carboxamide; 3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)pyrazin-2- carboxamide; 3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-(1-methylpyrrolidin-3-yl)pyrazin-2-carboxamide; 3-amino-N-(2-hydroxypropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((1r,3r)-3-methoxycyclobutyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamide; N-((3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)-1-methylpyrrolidin-2- carboxamide; 3-amino-N-(1-methoxypropan-2-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide ; 3-amino-N-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol- 2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(tetrahydro-2H-pyran-3-yl)pyrazin-2 -carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydro-2H-pyran-2-yl)methyl) pyrazine-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydro-2H-pyran-3-yl)methyl) pyrazine-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((tetrahydrofuran-2-yl)methyl)-5-(2H-1,2,3-triazol- 2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluoropyridin-2-yl)methyl)-5-(oxazol-2-yl )pyrazine-2-carboxamide; 3-amino-5-(4-fluorophenyl)-N-((3-(2-(methylamino)ethoxy)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin- 6-yl)pyrazin-2-carboxamide 2,2,2-trifluoroacetate; (R)-3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-(1-methylpyrrolidin-3-yl)pyrazin-2 -carboxamide; (S)-3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-(1-methylpyrrolidin-3-yl)pyrazin-2 -carboxamide; (S)-3-amino-5-(3-methyl-1H-pyrazol-1-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1- methylpyrrolidin-2-yl)methyl)pyrazine-2-carboxamide; (R)-3-amino-5-(3-methyl-1H-pyrazol-1-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1- methylpyrrolidin-2-yl)methyl)pyrazin-2-carboxamide; 3-amino-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2-yl)-6-(3-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl )pyrazine-2-carboxamide (isomers); (R)-(3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)(3-(dimethylamino)pyrrolidin- 1-yl)methanone; (S)-(3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)(3-(dimethylamino)pyrrolidin- 1-yl)methanone; (R)-(3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)(2-(methoxymethyl)pyrrolidin- 1-yl)methanone; (S)-(3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)(2-(methoxymethyl)pyrrolidin- 1-yl)methanone; 3-amino-N-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol- 2-yl)pyrazin-2-carboxamide; rac-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(2-(2-oxopyrrolidin-1-yl)ethyl) pyrazine-2-carboxamide; (R)-3-amino-6-(3-chloroimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2- yl)pyrazine-2-carboxamide; (S)-3-amino-6-(3-chloroimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-(oxazol-2- yl)pyrazine-2-carboxamide; 3-amino-N-((1-methyl-5-oxopyrrolidin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide (isomers); rac-N-((1,4-dioxan-2-yl)methyl)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide; rac-3-amino-N-((1-methyl-5-oxopyrrolidin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol- 2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(3-oxo-3-(piperidin-1-yl) propyl)pyrazine-2-carboxamide; 3-amino-N-((1-methyl-2-oxopyrrolidin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide (isomers); 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(3-oxo-3-(pyrrolidin-1-yl) propyl)pyrazine-2-carboxamide; 3-amino-N-cyclobutyl-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (R)-3-amino-N-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazole -2-yl)pyrazin-2-carboxamide; (S)-3-amino-N-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazole -2-yl)pyrazin-2-carboxamide; 3-amino-N-(bicyclo[1.1.1]pentan-1-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 3-amino-N-((3-fluoropyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-morpholinopyrazin-2-carboxamide; cis-3-amino-N-((6-(3-(dimethylamino)cyclobutylamino)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5 -(oxazol-2-yl)pyrazin-2-carboxamide; trans-3-amino-N-((6-(3-(dimethylamino)cyclobutylamino)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5 -(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(3-(methylamino)-3-oxopropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2 -carboxamide; (S)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((tetrahydrofuran-2-yl)methyl)-5-(2H-1,2, 3-triazol-2-yl)pyrazin-2-carboxamide; (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((tetrahydrofuran-2-yl)methyl)-5-(2H-1,2, 3-triazol-2-yl)pyrazin-2-carboxamide; rac-3-amino-N-(2-methoxypropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(2-methoxypropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide (isomers); 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 (isomers); (R)-3-amino-5-(3-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl) pyrazine-2-carboxamide; 3-amino-N-((6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl) -5-(oxazol-2-yl)pyrazin-2-carboxamide (isomers); rac-3-amino-N-(2-(methyl(tetrahydrofuran-3-yl)amino)ethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol- 2-yl)pyrazin-2-carboxamide; (S)-3-amino-N-(4-(dimethylamino)-4-oxobutan-2-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazole -2-yl)pyrazin-2-carboxamide; (R)-3-amino-N-(4-(dimethylamino)-4-oxobutan-2-yl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazole -2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(2-(2-oxopyridin-1(2H)-yl )ethyl)pyrazine-2-carboxamide; 3-amino-N-(2,6-difluorobenzyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-morpholinopyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl) pyrazine-2-carboxamide; 3-amino-N-(2-(methyl(pyridin-2-yl)amino)ethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide; (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((tetrahydrofuran-3-yl)methyl)-5-(2H-1,2, 3-triazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(2-methoxyethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(2H-1,2,3-triazol-2-yl)pyrazine -2-carboxamide; 3-amino-N-(2-(methyl(phenyl)amino)ethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide; 3-amino-N-cyclopropyl-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((4-methylmorpholin-2-yl)methyl)pyrazin-2- carboxamide (isomers); 3-amino-N-((1,2-dimethylpyrrolidin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide (isomers); 3-amino-N-(4-methoxycyclohexyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((3-methyltetrahydrofuran-3-yl)methyl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide (isomers); 3-amino-N-(2-cyclopropyl-2-(dimethylamino)ethyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide (isomers); 3-amino-N-((1-methyl-2-oxopiperidin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2- yl)pyrazine-2-carboxamide; (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(tetrahydrofuran-3-yl)pyrazin-2 -carboxamide; (S)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(tetrahydrofuran-3-yl)pyrazin-2 -carboxamide; 3-amino-5-(4-fluorophenyl)-N-((1-methyl-2-oxopyrrolidin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl) pyrazine-2-carboxamide; (R)-N-((3-amino-5-(3,4-difluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)- 1-methylpyrrolidine-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)-N-(1-(tetrahydrofuran-2-yl)ethyl)pyrazin- 2-carboxamide; (R)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)-5-phenylpyrazin-2-carboxamide ; 3-amino-N-((4,4-dimethyloxetan-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; 3-amino-N-((6-(3-((dimethylamino)methyl)azetidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6 -yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (S)-N-((3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)tetrahydrofuran-3 -carboxamide; (R)-N-((3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)tetrahydrofuran-3 -carboxamide; (S)-N-((3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)tetrahydrofuran-2 -carboxamide; (R)-N-((3-amino-5-(4-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)tetrahydrofuran-2 -carboxamide; cis-3-amino-N-(3-(dimethylamino)cyclobutyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2- carboxamide; trans-3-amino-N-(3-(dimethylamino)cyclobutyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2- carboxamide; (R)-3-amino-5-(3,4-difluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((1-methylpyrrolidin-2-yl) methyl)pyrazine-2-carboxamide; (S)-3-amino-N-((1-(dimethylcarbamoyl)pyrrolidin-3-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazole -2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-N-((6-morpholinopyridin-2-yl)methyl)-5-(oxazol-2-yl)pyrazin- 2-carboxamide; (R)-N-((3-amino-5-(3-fluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)-1- methylpyrrolidine-2-carboxamide; 3-amino-N-((-3-methoxytetrahydrofuran-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazine -2-carboxamide; 3-amino-N-(3-(dimethylamino)-2,2-dimethyl-3-oxopropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-((6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-6-(3 -methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-6-(3 -methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a ]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (R)-3-amino-N-((6-(3,4-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6 -yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (S)-3-amino-N-((6-(3,4-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6 -yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (S)-3-amino-N-((6-(2,4-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6 -yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((3,3-dimethyloxetan-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl) pyrazine-2-carboxamide; (R)-N-((3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(2H-1,2,3-triazol-2-yl)pyrazine -2-yl)methyl)-1-methylpyrrolidin-2-carboxamide; (R)-N-((3-amino-5-(3,5-difluorophenyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-yl)methyl)- 1-methylpyrrolidine-2-carboxamide; 3-amino-N-(3-methoxycyclohexyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (S)-N-(1-(1H-1,2,3-triazol-1-yl)propan-2-yl)-3-amino-6-(3-methylimidazo[1,2-a]pyridin- 6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (S)-N-(1-(2H-1,2,3-triazol-2-yl)propan-2-yl)-3-amino-6-(3-methylimidazo[1,2-a]pyridin- 6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; (R)-N-(1-(2H-1,2,3-triazol-2-yl)propan-2-yl)-3-amino-6-(3-methylimidazo[1,2-a]pyridin- 6-yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-(3-methoxypropyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(2H-1,2,3-triazol-2-yl)pyrazine -2-carboxamide; 3-amino-N-((3-(2-hydroxyethoxy)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(oxazol-2 -yl)pyrazin-2-carboxamide; 3-amino-N-((3-(2-(methylamino)ethoxy)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-( oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl) -5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-N-((6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)-6-(3-methylimidazo[1,2-a]pyridin-6-yl) -5-(oxazol-2-yl)pyrazin-2-carboxamide; 3-amino-6-(3-methylimidazo[1,2-a]pyridin-6-yl)-5-(pyridin-2-yl)-N-((tetrahydrofuran-3-yl)methyl)pyrazin-2- carboxamide; rac-N-(1-(1H-1,2,4-triazol-1-yl)propan-2-yl)-3-amino-6-(3-methylimidazo[1,2-a]pyridin-6- yl)-5-(oxazol-2-yl)pyrazin-2-carboxamide, or a pharmaceutically acceptable salt thereof. 37. A pharmaceutical composition capable of inhibiting adenosine receptors, which contains an effective amount of one or more compounds according to any one of paragraphs. 1-36 and a pharmaceutically acceptable carrier. 38. The use of one or more compounds according to any one of paragraphs. 1-36 in the manufacture of a medicament for the treatment of a disease associated with adenosine receptors. 39. Use according to claim 38, wherein the adenosine receptor-associated disease is cancer, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, human immunodeficiency virus (HIV) infection, adenosine deaminase deficiency severe combined immunodeficiency (ADA- SCID), acute heart failure and chronic heart failure, chronic obstructive pulmonary disease (COPD) or asthma. 40. Use according to claim 39, wherein the cancer is NSCLC (non-small cell lung cancer), RCC (renal cell carcinoma), prostate cancer or breast cancer. 41. Use according to claim 39, where the drug is used in combination with radiation therapy, chemotherapy or immunotherapy. 42. A method of inhibiting adenosine receptors, comprising administering to a subject an effective amount of one or more compounds according to any one of claims. 1-36 or the pharmaceutical composition according to claim 37. 43. The method of claim 42, further comprising administering one or more than one immunotherapeutic agent or chemotherapeutic agent to the subject. 44. The method of claim 42, further comprising administering radiation therapy to the subject. 45. A combination capable of inhibiting adenosine receptors, containing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-36 and immunotherapeutic agents or chemotherapeutic agents. 46. The combination according to claim 45, wherein said immunotherapeutic agents are selected from the group consisting of an antibody to PD-1/PD-L1 (programmed cell death protein 1/PD-1 ligand), an antibody to CTLA-4 (cytotoxic T -lymphocyte antigen 4), antibodies to CD73 (cluster of differentiation 73), antibodies to CD39, antibodies to CCR2 (C-C family chemokine receptor 2) and any combination thereof. 47. The combination of claim 46, wherein said chemotherapeutic agents are selected from the group consisting of platinum-based chemotherapeutic agents (cisplatin, oxaliplatione), docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, and any combination thereof.