CN111747954A - Pyrazine compounds and uses thereof - Google Patents

Pyrazine compounds and uses thereof Download PDF

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CN111747954A
CN111747954A CN202010656947.3A CN202010656947A CN111747954A CN 111747954 A CN111747954 A CN 111747954A CN 202010656947 A CN202010656947 A CN 202010656947A CN 111747954 A CN111747954 A CN 111747954A
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amino
methyl
pyrazine
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carboxamide
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CN111747954B (en
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齐长河
徐汉忠
曾庆北
杨振帆
张小林
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Dizal Jiangsu Pharmaceutical Co Ltd
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

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

Description

Pyrazine compounds and uses thereof
The application is a divisional application of Chinese patent application with the application number of 201980006428.8, the application date of 2019, 8 and 16, and the invention name of pyrazine compound and application thereof. The original application is a national phase application with an international application number of PCT/CN2019/100996, and the international application requires the priority of a PCT patent application with an application number of PCT/CN2018/101006 and an application date of 8-17.2018. All of the above applications are incorporated by reference into this application.
Technical Field
The present disclosure relates to novel pyrazine compounds that target adenosine receptors (particularly a1 and A2, specifically, A2 a). The disclosure also relates to pharmaceutical compositions comprising one or more of the compounds as an active ingredient, and the use of the compounds in the treatment of Adenosine Receptor (AR) related diseases, for example cancer such as non-small cell lung cancer (NSCLC), Renal Cell Carcinoma (RCC), prostate cancer and breast cancer.
Background
Adenosine is a naturally occurring nucleoside that elicits a variety of physiological responses by interacting with a class of adenosine receptors. Based on their biochemical and pharmacological properties, such as ligand binding characteristics, glycosylation and function, four adenosine receptor subtypes have been classified in humans (a1, A2a, A2b and A3).
The inflammatory response helps to eliminate harmful agents from the body, but inflammation is also a non-specific reaction that can harm healthy tissue. There is a wide variety of pathogenic lesions that can trigger inflammatory responses including infections, allergens, autoimmune stimuli, immune responses to transplanted tissue, toxic chemicals and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal trauma, and tumor growth.
Adenosine receptors are reported to play a non-redundant role in down-regulating inflammation in vivo by acting as a physiological "STOP" (termination mechanism) that can limit the immune response and thus protect normal tissues from excessive immune damage during the onset of different diseases. Adenosine receptors such as A2a, A2b, and A3 were shown to down-regulate immune responses during inflammation and protect tissues from immune damage. Inhibition of signaling via adenosine receptors can be used to enhance and prolong immune responses. Adenosine inhibits long-term inflammation acting via the A2a adenosine receptor (Ohta et al, Nature 2001; 414: 916-. The A2b Adenosine receptor is involved in regulating cell growth (see Adenosine A2b receptor (Adenosine A2b Receptors as therapeutic agents), Drug development research (Drug Dev Res)45: 198; Feoktisov et al, Trends in pharmacology sciences (Trends Pharmacol Sci)19: 148-.
Therefore, compounds targeting adenosine receptors are needed as pharmacological tools and are of high interest as drugs for the treatment of adenosine receptor-related diseases, such as cancer (e.g., NSCLC, RCC, prostate or breast cancer), parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive disorders, HIV, ADA-SCID, AHF and chronic heart failure, Chronic Obstructive Pulmonary Disease (COPD) or asthma.
Disclosure of Invention
In one aspect, the present disclosure provides a compound represented by formula (I):
Figure BDA0002577091620000021
or a pharmaceutically acceptable salt thereof, wherein X, Ring A, Ring B, W, V, Y, R1、R2M and n are as defined herein.
In one aspect, the present disclosure provides a compound represented by formula (Ia):
Figure BDA0002577091620000022
or a pharmaceutically acceptable salt thereof, wherein ring a, ring B, Z, Y, R1、R2M and n are as defined herein.
In one aspect, the present disclosure provides a compound represented by formula (Ia-i):
Figure BDA0002577091620000023
or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring Q, R1、R2、R3、R7M, n and i are as defined herein.
In one aspect, the present disclosure provides a compound represented by formula (Ia-ii):
Figure BDA0002577091620000031
or a pharmaceutically acceptable salt thereof, wherein ring A, Z, Y, R1And m is as defined herein.
In one aspect, the present disclosure provides a compound represented by formula (Ib):
Figure BDA0002577091620000032
or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring Q, R1、R2、R3、R7M, n and i are as defined herein.
In another aspect, the present disclosure also relates to a pharmaceutical composition comprising one or more of the compounds or pharmaceutically acceptable salts thereof as an active ingredient, and the use of the compounds or pharmaceutically acceptable salts thereof for the treatment of Adenosine Receptor (AR) related diseases, for example cancer such as NSCLC, RCC, prostate cancer or breast cancer.
Detailed Description
In one aspect, the present disclosure provides compounds of formula (I):
Figure BDA0002577091620000041
or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
x is selected from amino, halogen, hydroxyl, cyano, C1-12Alkoxy, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino group, C1-12An alkanoylamino group;
ring A is a 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group;
ring B is selected from 3-12 membered saturated or unsaturated carbocyclic group or 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group;
w is-C1-12alkylene-or-C (O) -which may be via hydroxyl, C1-12Alkyl radical, C1-12Alkoxy or C1-12alkyl-OH is mono-or independently poly-substituted;
v is-NH-, -NH-C1-12Alkylene-, -NH-C (O) -or N-linked pyrrolidinyl, which may be via hydroxy, C 1-12Alkyl radical, C1-12Alkoxy, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino or C1-12alkyl-OH is mono-or independently poly-substituted;
y is hydrogen, halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbonyl, carbamate, sulfonyl, C1-12Alkyl radical, C1-12Alkoxy radical, C1-12Alkanoyl radical, C1-12alkyl-OH, C1-12Alkyl-cyano, C1-12Haloalkyl, C1-12Haloalkoxy, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C1-12Alkylsulfonyl radical, C1-12Alkanoylamino, 3-12 membered saturated or unsaturated carbocyclic or 3-12 membered saturated or unsaturated heterocyclic, optionally via R3Monosubstituted or independently polysubstituted therewith;
each R1Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C1-12Alkanoylamino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is1Optionally further via R4Mono-substituted or independently poly-substituted therewith;
Each R2Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C1-12Alkanoylamino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is2Optionally further via R5Mono-substituted or independently poly-substituted therewith;
each R3Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)3-12Cycloalkyl) amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl group, (C)1-12Alkyl) sulfonyl, (C)1-12Alkyl) phosphinyl, (C)1-12Alkyl radical)2Phosphinyl, (C)1-12Alkyl) phosphoryl, (C)1-12Alkyl radical)2Phosphoryl, C1-12Alkanoylamino group, N- (C)1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is 3Optionally further via R6Monosubstituted or independently polysubstituted therewith;
wherein each R4、R5Or R6Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, phosphinyl, urea, carbamate, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl group, (C)1-12Alkyl) sulfonyl, (C)1-12Alkyl) phosphinyl, (C)1-12Alkyl radical)2Phosphinyl group, C1-12Alkanoylamino, C1-12Alkylsulfonyl and C1-12A haloalkoxy group;
m is 0, 1, 2, 3 or 4; and is
n is 0, 1, 2, 3 or 4.
In some embodiments, X is selected from amino, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino or C1-12An alkanoylamino group.
In some embodiments, X is amino.
In some embodiments, ring a is a 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2, or 3 heteroatoms selected from N, O or S.
In some embodiments, ring a is a 6-10 membered unsaturated monocyclic or polycyclic heterocyclic group.
In some embodiments, ring a is selected from
Figure BDA0002577091620000061
In some embodiments, ring a is selected from
Figure BDA0002577091620000062
In some embodiments, each R is1Independently selected from hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxacyclo Pentyl, oxetanyl or 1, 1-dioxothietanyl, which may optionally be further substituted by R4Mono-or independently poly-substituted therewith, wherein each R4Independently selected from halogen, hydroxy, cyano, amino, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group.
In some embodiments, each R is1Independently selected from amino, chloro, methyl, difluoromethyl, trifluoromethyl, aminomethyl, ethyl, hydroxyethyl, isopropyl, hydroxypropyl, methoxyethyl, 2-hydroxy-n-propyl, cyclopropyl and oxetanyl. In some embodiments, m is 0.
In some embodiments, m is 1.
In some embodiments, m is 2.
In some embodiments, m is 3.
In some embodiments, m is 4.
In some embodiments, m is 0, 1, or 2.
In some embodiments, ring B is a 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2, or 3 heteroatoms selected from N, O or S.
In some embodiments, ring B is selected from:
Figure BDA0002577091620000071
in some embodiments, ring B is selected from:
Figure BDA0002577091620000072
in some embodiments, each R is2Independently selected from halogen, hydroxy, amino, C1-12Alkyl or C1-12Haloalkyl, wherein each R2Optionally further via R 5Mono-or independently poly-substituted therewith, said R5Selected from halogen, hydroxy, cyano, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group.
In some embodiments, each R is2Independently selected from cyano, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, ethoxy, methoxy, difluoromethoxy, trifluoromethoxy, methylamino, dimethylamino, ethylamino, isopropylamino, hydroxymethyl, or hydroxyethyl.
In some embodiments, each R is2Independently fluorine or methyl.
In some embodiments, n is 0.
In some embodiments, n is 1.
In some embodiments, n is 2.
In some embodiments, n is 3.
In some embodiments, n is 4.
In some embodiments, n is 0, 1, or 2.
In some embodiments, W is methylene or-C (O) -.
In some embodiments, when W is methylene, V is-NH-C (O) -; when W is-C (O) -V is-NH-, -NH-C1-12Alkylene-or N-linked pyrrolidinyl, which may be via hydroxy, C1-12Alkyl radical, C1-12Alkoxy or C1-12alkyl-OH is mono-or independently poly-substituted.
In some embodiments, Y is hydrogen, hydroxy, amino, cyano, carbonyl, carbamoyl, C1-12Alkyl radical, C1-12alkyl-OH, C1-12Alkoxy, sulfonyl, (C)1-12Alkyl) sulfonyl, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl, 3-12 membered saturated or unsaturated carbocyclic or 3-12 membered saturated or unsaturated heterocyclic group, which may optionally be substituted by R3Monosubstituted or, independently, polysubstituted therewith.
In some embodiments, Y is a 3-12 membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl selected from:
Figure BDA0002577091620000081
which may optionally be via R3Monosubstituted or, independently, polysubstituted therewith.
In some embodiments, Y is selected from:
Figure BDA0002577091620000082
which may optionally be via R3Monosubstituted or, independently, polysubstituted therewith.
In some embodiments, Y is hydrogen, halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamato, sulfonyl, C1-12Alkyl radical, C1-12Alkoxy radical, C1-12Alkanoyl radical, C1-12alkyl-OH, C1-12Alkyl-cyano, C1-12Haloalkyl, C1-12Haloalkoxy, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C1-12Alkylsulfonyl, which may optionally be via R 3Monosubstituted or, independently, polysubstituted therewith.
In some embodiments, each R is3Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)3-12Cycloalkyl) amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl group, (C)1-12Alkyl) sulfonyl, (C)1-12Alkyl) phosphinyl, (C)1-12Alkyl radical)2Phosphinyl, (C)1-12Alkyl) phosphorusAcyl, (C)1-12Alkyl radical)2Phosphoryl, C1-12Alkanoylamino group, N- (C)1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is3Optionally further via R6Monosubstituted or, independently, polysubstituted therewith. In some embodiments, each R is3Is independently selected from
Figure BDA0002577091620000091
Which may optionally be further processed by R6Monosubstituted or, independently, polysubstituted therewith.
In some embodiments, each R is6Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, ureido, carbamate, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C 1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl, C1-12Alkanoylamino group, C1-12Alkylsulfonyl radical, C1-12Haloalkoxy or C1-12Alkyl-substituted cycloalkyl groups.
In some embodiments, each R is3Independently selected from: hydroxy, amino, cyano, carbamoyl, sulfonyl, phosphoryl, phosphinyl, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, ethylamino, hydroxyethyl, hydroxymethyl, hydroxyethoxy, sulfonylmethyl, aminomethyl, cyclopropyl, cyclopropylcarbonyl, cyclobutylamino, cyclopropyl, cyclobutyl, cyclohexyl, pyranyl, furyl, phenyl, pyridyl, pyrazinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 1, 4-oxacyclohexylyl, bicyclo [1.1.1]Pentyl, 1, 6-diazaspiro [3.3 ]]Heptylalkyl, 2, 6-diazaspiro [3.3]Heptylalkyl, 2, 6-diazaspiro [3.4 ]]Octyl, 3, 6-diaza-bicyclo [3.1.1]A heptylalkyl group,2, 5-diazabicyclo [2.2.1]Heptylalkyl, and 3, 8-diazabicyclo [3.2.1]Octyl, which may optionally be further mono-or, independently, poly-substituted with fluoro, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, sulfonyl, methylsulfonyl, carbamoyl, N-methylcarbamoyl, N-dimethylcarbamoyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclopropylcarbonyl.
In some embodiments, each R is3Independently selected from: hydroxy, cyano, fluoro, chloro, bromo, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, hydroxyethoxy, methylaminoethoxy, dimethylaminoethoxy, hydroxyethylamino, aminocarbonylmethoxy, 2-hydroxy-ethyl, methoxymethyl, methylsulfonyl, methylsulfonylmethyl, N-methylcarbamoyl, N-dimethylcarbamoyl, dimethylaminomethyl, hydroxymethyl, dimethylphosphoryl, methylaminocarbonyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-methoxy-ethyl, hydroxyethoxy, methylaminoethoxy, cyclopropyl, cyclopropylcarbonyl, 3- (dimethylamino) cyclobutylamino, phenyl, trifluoromethyl, N-dimethylcarbamoyl, N-dimethylcarbamoyl, dimethylaminomethyl, hydroxymethyl, N-dimethylphosphoryl, N-methylcarbonyl, 3- (dimethylamino) cyclobutylamino, methyl, N-dimethylcarbamoyl, pyridin-2-yl, azetidin-1-yl, pyrrolidin-1-yl, N-morpholinyl, 3- (dimethylamino) azetidin-1-yl, 4-methylpiperazin-1-yl, 1, 6-diazaspiro [3.3]Heptane-6-yl, 3-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl, 3, 8-diazabicyclo [3.2.1]Octane-8-yl, 8-methyl-3, 8-diazabicyclo [3.2.1 ]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octane-3-yl, 8-methyl-3, 8-diazabicyclo [3.2.1]Octane-3-yl, 3, 6-diazabicyclo [3.1.1]Heptane-6-yl, 3-methyl-3, 6-diazabicyclo [3.1.1]Heptane-6-yl, 2, 6-diazaspiro [3.4 ]]Oct-2-yl, 6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl, piperidinyl, piperazin-1-yl, 1-methylpiperidin-4-yl, 3- (dimethylamino) pyrrolidine, 3- (dimethylaminomethyl) azetidin-1-yl, 2, 5-diazabicyclo [2.2.1]Heptane-2-yl, 5-methyl-2, 5-diazabicyclo [2.2.1]Heptane-2-yl, 2, 6-diazaspiro [3.3 ]]Heptane-2-yl or 3, 4-dimethylpiperazin-1-yl.
In some embodiments, Y is hydrogen, hydroxy, amino, cyano, carbonyl, carbamoyl, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, sulfonyl, methylamino, dimethylamino, methylcarbamoyl, dimethylcarbamoyl, 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl, which may optionally be substituted with R3Mono-or independently poly-substituted therewith, wherein each R3Independently selected from hydroxy, methyl, fluoro, cyano, dimethylamino, dimethylcarbamoyl, hydroxyethyl, hydroxymethyl, methoxy, trifluoromethyl, trifluoromethoxy, methylsulfonyl, dimethylamino, methoxymethyl, methylcarbamoyl, phenyl, pyridyl, cyclopropyl.
In some embodiments, Y is hydrogen, hydroxy, cyano, carbamoyl, methyl, methoxy, methoxymethyl, 1-methoxy-ethyl, 2-methoxy-ethyl, trifluoromethoxy, trifluoromethoxymethyl, trifluoromethoxyethyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, methoxymethyl, methoxyethyl, methylamino, dimethylamino, methylsulfonyl, methylsulfonylmethyl, methylsulfonylethyl, methylcarbamoyl, dimethylcarbamoyl, dimethylaminomethyl, or piperidin-1-yl-carbonyl.
In another aspect, the present disclosure provides compounds of formula (Ia):
Figure BDA0002577091620000111
or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
ring a is a 6-10 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O or S;
ring B is a 5-6 membered saturated or unsaturated carbocyclic group or a 5-6 membered saturated or unsaturated heterocyclic group;
z is-C1-12Alkylene-or a bond;
y is hydrogen, amino, carbamoyl, carbonyl, sulfonyl, C1-12Alkyl radical, C1-12Alkoxy radical, C1-12alkyl-OH, C1-12Alkyl-cyano, C1-12Haloalkyl, C1-12Haloalkoxy, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C 1-12Alkylsulfonyl radical, C1-12Alkanoylamino, 3-6 membered saturated or unsaturated carbocyclic group or 3-6 membered saturated or unsaturated heterocyclic group, which may optionally be substituted with R3Monosubstituted or independently polysubstituted therewith;
each R1Independently selected from hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxetanyl or 1, 1-dioxothietanyl, which may optionally be further reacted via R4Monosubstituted or independently polysubstituted therewith;
each R2Independently halogen, hydroxy, amino, C1-12Alkyl or C1-12Haloalkyl, wherein each R2Optionally further via R5Monosubstituted or independently polysubstituted therewith;
each R3Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C1-12Alkyl radical, C1-12Haloalkyl, C 1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)3-12Cycloalkyl) amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl group, (C)1-12Alkyl) sulfonyl, (C)1-12Alkyl) phosphinyl, (C)1-12Alkyl radical)2Phosphinyl radical、(C1-12Alkyl) phosphoryl, (C)1-12Alkyl radical)2Phosphoryl, C1-12Alkanoylamino group, N- (C)1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is3Optionally further via R6Monosubstituted or independently polysubstituted therewith;
each R4Independently selected from halogen, hydroxy, cyano, amino, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group;
each R5Independently selected from halogen, hydroxy, cyano, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group;
each R6Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, ureido, carbamate, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C1-12Alkanoylamino group, C1-12Alkylsulfonyl radical, C 1-12Haloalkoxy or C1-12Alkyl-substituted cycloalkyl groups;
m is 0, 1, 2, 3 or 4; and is
n is 0, 1, 2, 3 or 4.
In some embodiments, Z is a bond and Y is C1-12Alkoxy, cyclobutyl optionally mono-substituted with methoxy.
In some embodiments, Z is ethylene and Y is methoxy.
In another aspect, the present disclosure provides compounds of formula (Ia-i):
Figure BDA0002577091620000121
Figure BDA0002577091620000131
or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
ring a is a 6-10 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O or S;
ring B is a 5-6 membered saturated or unsaturated carbocyclic group or a 5-6 membered saturated or unsaturated heterocyclic group;
ring Q is a 3-6 membered saturated or unsaturated carbocyclic group or a 3-6 membered saturated or unsaturated heterocyclic group;
each R1Independently selected from hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxetanyl or 1, 1-dioxothietanyl, which may optionally be further reacted via R 4Monosubstituted or independently polysubstituted therewith;
each R2Independently halogen, hydroxy, amino, C1-12Alkyl or C1-12Haloalkyl, wherein each R2Optionally further via R5Monosubstituted or independently polysubstituted therewith;
each R3Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)3-12Cycloalkyl) amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl group, (C)1-12Alkyl) sulfonyl groupBase, (C)1-12Alkyl) phosphinyl, (C)1-12Alkyl radical)2Phosphinyl, (C)1-12Alkyl) phosphoryl, (C)1-12Alkyl radical)2Phosphoryl, C1-12Alkanoylamino group, N- (C)1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is3Optionally further via R6Monosubstituted or independently polysubstituted therewith;
each R4Independently selected from halogen, hydroxy, cyano, amino, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group;
each R5Independently selected from halogen, hydroxy, cyano, C1-12Alkyl radical, C 1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group;
each R6Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, ureido, carbamate, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C1-12Alkanoylamino group, C1-12Alkylsulfonyl radical, C1-12Haloalkoxy or C1-12Alkyl-substituted cycloalkyl groups;
R7is hydrogen, C1-12Alkyl radical, C1-12Alkoxy or C1-12alkyl-OH;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4; and is
i is 0, 1, 2, 3 or 4.
In some embodiments, R7Is hydrogen, methyl or ethyl.
In some embodiments, ring Q is selected from:
Figure BDA0002577091620000141
in some embodiments, i is 0.
In some embodiments, i is 1.
In some embodiments, i is 2.
In some embodiments, i is 3.
In some embodiments, i is 4.
In some embodiments, i is 0, 1, 2, or 3.
In yet another aspect, the present disclosure provides compounds of formula (Ia-ii):
Figure BDA0002577091620000151
or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
ring a is a 6-10 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O or S;
Z is-C1-12Alkylene-or a bond;
y is hydrogen, C1-12Alkyl radical, C1-12Alkoxy radical, C1-12alkyl-OH, 3-6 membered saturated or unsaturated carbocyclic group or 3-6 membered saturated or unsaturated heterocyclic group, which may optionally be substituted with R3Monosubstituted or independently polysubstituted therewith;
each R1Independently selected from hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxetanyl or 1, 1-dioxothietanyl, which may optionally be further reacted via R4Monosubstituted or independently polysubstituted therewith;
each R3Independently selected from halogen, hydroxy,Cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)3-12Cycloalkyl) amino, N- (C) 1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl group, (C)1-12Alkyl) sulfonyl, (C)1-12Alkyl) phosphinyl, (C)1-12Alkyl radical)2Phosphinyl, (C)1-12Alkyl) phosphoryl, (C)1-12Alkyl radical)2Phosphoryl, C1-12Alkanoylamino group, N- (C)1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is3Optionally further via R6Monosubstituted or independently polysubstituted therewith;
each R4Independently selected from halogen, hydroxy, cyano, amino, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group;
each R6Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, ureido, carbamate, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C1-12Alkanoylamino group, C1-12Alkylsulfonyl radical, C1-12Haloalkoxy or C1-12Alkyl-substituted cycloalkyl groups; and is
m is 0, 1, 2, 3 or 4.
In some embodiments, ring a is pyridonyl (pyridonyl) or azaindolizinyl (azaindolizinyl).
In some embodiments, m is 1 and R1Is C1-12Alkyl, optionally C 1-3Alkyl, optionally methyl.
In some embodiments, Z is a bond and Y is a cyclobutyl group monosubstituted with methoxy.
In some embodiments, Z is ethylene and Y is methoxy.
In some embodiments, Z is methylene, Y is phenyl, pyrrolidinyl, or tetrahydrofuranyl, which may optionally be optionally substituted with R3Monosubstituted or, independently, polysubstituted therewith.
In some embodiments, R3Is halogen or C1-12An alkyl group.
In some embodiments, R3Is fluorine or methyl.
In another aspect, the present disclosure provides a compound of formula (Ib):
Figure BDA0002577091620000161
or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
ring a is a 6-10 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O or S;
ring B is a 5-6 membered saturated or unsaturated carbocyclic group or a 5-6 membered saturated or unsaturated heterocyclic group;
ring Q is a 3-6 membered saturated or unsaturated carbocyclic group or a 3-6 membered saturated or unsaturated heterocyclic group;
R7is hydrogen, C1-12Alkyl radical, C1-12Alkoxy or C1-12alkyl-OH;
each R1Independently selected from hydroxy, fluoro, chloro, bromo, amino, carbamoyl, ureido, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, oxetanyl or 1, 1-dioxothio Heterocycloalkyl which may optionally be further substituted by R4Monosubstituted or independently polysubstituted therewith;
each R2Independently halogen, hydroxy, amino, C1-12Alkyl or C1-12Haloalkyl, wherein each R2Optionally further via R5Monosubstituted or independently polysubstituted therewith;
each R3Independently selected from the group consisting of halogen, hydroxy, cyano, amino, carbamoyl, ureido, carbamate, sulfonyl, phosphate, phosphoryl, phosphinyl, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)3-12Cycloalkyl) amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl group, (C)1-12Alkyl) sulfonyl, (C)1-12Alkyl) phosphinyl, (C)1-12Alkyl radical)2Phosphinyl, (C)1-12Alkyl) phosphoryl, (C)1-12Alkyl radical)2Phosphoryl, C1-12Alkanoylamino group, N- (C)1-12alkyl-OH) amino, 3-10 membered saturated or unsaturated carbocyclic group or 3-10 membered saturated or unsaturated heterocyclic group, wherein each R is3Optionally further via R6Monosubstituted or independently polysubstituted therewith;
each R4Independently selected from halogen, hydroxy, cyano, amino, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group;
each R 5Independently selected from halogen, hydroxy, cyano, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy or C1-12A haloalkoxy group;
each R6Independently selected from halogen, hydroxy, cyano, amino, carbamoyl, sulfonyl, ureido, carbamate, C1-12Alkyl radical, C1-12Haloalkyl, C1-12Alkoxy radical, C1-12Haloalkoxy, C1-12alkyl-OH, N- (C)1-12Alkyl) amino, N- (C)1-12Alkyl radical)2Amino, N- (C)1-12Alkyl) carbamoyl, N- (C)1-12Alkyl radical)2Carbamoyl radical, C1-12Alkanoylamino group, C1-12Alkylsulfonyl radical, C1-12Haloalkoxy or C1-12Alkyl-substituted cycloalkyl groups;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4; and is
i is 0, 1, 2, 3 or 4.
In some embodiments, ring a is selected from
Figure BDA0002577091620000181
In some embodiments, each R is1Independently selected from fluoro, chloro, amino, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxyethyl, hydroxypropyl, methoxyethyl, 2-hydroxypropyl, cyclopropyl or oxetanyl.
In some embodiments, m is 0, 1 or 2.
In some embodiments, ring B is selected from:
Figure BDA0002577091620000182
in some embodiments, R2Is methyl or fluoro.
In some embodiments, n is 0 or 1.
In some embodiments, ring Q is selected from:
Figure BDA0002577091620000183
In some embodiments, each R is3Independently selected from fluoro, chloro, bromo, cyano, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethylOxy, hydroxymethyl, hydroxyethyl, hydroxyethyloxy, methoxyethyloxy, amino, methylamino, dimethylamino, ethylamino, isopropylamino, hydroxyethylamino, methylaminoethyloxy, dimethylaminoethoxy, dimethylphosphino-methyl, carbamoyl, carbamoylmethoxy, azetidinyl, pyrrolidinyl, morpholinyl, pyrazinyl, dimethylaminoazetidinyl, 1-methyl-pyrazin-4-yl, 3-methyl-3, 8-diaza-bicyclo [3.2.1]Octane-8-yl, 3-methyl-3, 6-diaza-bicyclo [3.1.1]Heptylalkyl, 8-methyl-3, 8-diaza-bicyclo [3.2.1]Octane-3-yl, 6-methyl-2, 6-diaza-spiro [3.4]Octane-2-yl or 5-methyl-2, 5-diaza-spiro [3.3]-heptane-2-yl.
In some embodiments, i is 0, 1, 2, or 3.
In one aspect, the present disclosure provides compounds of formula (I) selected from exemplary compounds 1-306 in table 1 below.
TABLE 1 exemplary Compounds 1-306
Figure BDA0002577091620000191
Figure BDA0002577091620000201
Figure BDA0002577091620000211
Figure BDA0002577091620000221
Figure BDA0002577091620000231
Figure BDA0002577091620000241
Figure BDA0002577091620000251
Figure BDA0002577091620000261
Figure BDA0002577091620000271
Figure BDA0002577091620000281
Figure BDA0002577091620000291
Figure BDA0002577091620000301
Figure BDA0002577091620000311
Figure BDA0002577091620000321
Figure BDA0002577091620000331
Figure BDA0002577091620000341
Figure BDA0002577091620000351
Figure BDA0002577091620000361
Figure BDA0002577091620000371
Figure BDA0002577091620000381
Figure BDA0002577091620000391
Figure BDA0002577091620000401
Figure BDA0002577091620000411
Figure BDA0002577091620000421
Figure BDA0002577091620000431
Figure BDA0002577091620000441
Figure BDA0002577091620000451
Figure BDA0002577091620000461
Figure BDA0002577091620000471
Figure BDA0002577091620000481
Figure BDA0002577091620000491
Figure BDA0002577091620000501
Figure BDA0002577091620000511
Figure BDA0002577091620000521
Figure BDA0002577091620000531
Figure BDA0002577091620000541
Figure BDA0002577091620000551
Figure BDA0002577091620000561
Figure BDA0002577091620000571
Figure BDA0002577091620000581
It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
In various places of the present disclosure, linking substituents are described. In the case of structures where a linking group is explicitly required, the markush variables (markush variable) listed in connection with said group are to be understood as linking groups. For example, if a structure requires a linking group and the markush group definition of the variable recites "alkyl," it is understood that the "alkyl" represents a linked alkylene.
As used herein, the term "substituted" when referring to a chemical group means that the chemical group has one or more hydrogen atoms removed and replaced with a substituent. As used herein, the term "substituent" has the ordinary meaning known in the art and refers to a chemical moiety that is covalently attached, or fused as appropriate, to the parent group. As used herein, the term "optionally substituted" or "optionally … … substituted" means that a chemical group may have no substituents (i.e., unsubstituted) or may have one or more substituents (i.e., substituted). It is understood that substitution at a given atom is limited by valence number.
As used herein, the term "Ci-j"indicates a range for the number of carbon atoms, where i and j are integers and the range for the number of carbon atoms includes the endpoints (i.e., i and j) and each integer point in between, and where j is greater than i. E.g. C1-6A range of one to six carbon atoms is indicated, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C" or "C" refers to a compound having a structure that is similar to a structure of a cell1-12"indicates 1 to 12, including 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated or unsaturated hydrocarbon chain, which may be further subdivided into hydrocarbon chains (alkenyl or alkynyl) having at least one double or triple bond. In some embodiments, alkyl refers to a saturated hydrocarbon chain. The above-mentioned hydrocarbon chain may be straight or branched. The term "Ci-jAlkyl "refers to an alkyl group having i to j carbon atoms. Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2, 2-trimethylbutyl and the like. Unsaturated polyester Examples of 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. "C1-12Examples of alkyl groups are methyl, ethyl, propyl, isopropyl and butyl. "C1-3Examples of alkyl groups are methyl, ethyl, propyl and isopropyl.
As used herein, the term "alkylene," whether used as part of another term or independently, refers to a divalent alkyl group. Examples of alkylene groups include, but are not limited to, methylene, 1-ethylene, 1, 2-ethylene, 1-propylene, 1, 2-propylene, 1, 3-propylene, 2-propylene, and the like.
As used herein, the terms "halo" and "halogen" refer to an atom selected from fluorine, chlorine, bromine, and iodine.
As used herein, the term "alkoxy", whether used as part of another term or independently, refers to a group of the formula-O-alkyl. The term "Ci-jAlkoxy "means that the alkyl portion of the alkoxy group has from i to j carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. "C1-12Examples of alkoxy groups are methoxy, ethoxy and propoxy.
As used herein, the term "Ci-jalkyl-OH "means a group of the formula" -Ci-jalkyl-OH ", wherein the alkyl portion of the group has from i to j carbon atoms, and one or more hydroxyl groups may be bonded to any carbon atom in the alkyl portion. In some embodiments, "Ci-jalkyl-OH "has one hydroxyl group. "C1-12Examples of alkyl-OH "are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-hydroxyisopropyl.
As used herein, the term "Ci-jHaloalkyl "refers to halo-substituted (mono-or poly-substituted) Ci-jAn alkyl group. "C1-12Examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl and bromoisopropyl. An example of "difluoroethyl" is 1, 1-difluoroethyl. "trifluoroethyl"Examples of (A) are 2,2, 2-trifluoroethyl and 1,2, 2-trifluoroethyl.
As used herein, the term "Ci-jHaloalkoxy "means halogen-substituted (mono-or poly-substituted) Ci-jAn alkoxy group. "Ci-jExamples of haloalkoxy "are fluoromethoxy, difluoromethoxy or trifluoromethoxy. Examples of "trifluoroethoxy" are 2,2, 2-trifluoroethoxy and 1,2, 2-trifluoroethoxy.
“N-(C1-12Alkyl) amino "are exemplified by methylamino and ethylamino.
“N-(C1-12Haloalkyl) amino "are exemplified by fluoromethylamino, difluoromethylamino, trifluoromethylamino, 2-chloroethylamino and 1-bromoisopropylamino.
“N,N-(C1-12Alkyl radical)2Examples of amino groups are di- (N-methyl) amino, di- (N-ethyl) amino and N-ethyl-N-methylamino.
As used herein, the term "Ci-jAlkanoyl "means Ci-jAn alkylcarbonyl group. "C1-12Examples of alkanoyl "are propionyl and acetyl.
“C1-12Examples of alkanoylamino "are formylamino, acetylamino and propionylamino.
“C1-12An example of alkanoyloxy "is acetoxy.
“C1-12Examples of alkoxycarbonyl "are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl and t-butoxycarbonyl.
As used herein, the term "carbamoyl" refers to aminocarbonyl. "N- (C)1-12Alkyl) carbamoyl "are exemplified by methylaminocarbonyl and ethylaminocarbonyl. "N, N- (C)1-12Alkyl radical)2Examples of carbamoyl "are dimethylaminocarbonyl and methylethylaminocarbonyl.
As used herein, the term "carbocyclyl," whether used as part of another term or independently, refers to any ring, including monocyclic or polycyclic rings (e.g., having 2 or 3 fused, bridged, or spiro rings), wherein all ring atoms are carbon and contain at least three ring-forming carbon atoms. In some cases In embodiments, a carbocyclyl group may contain 3 to 12 ring-forming carbon atoms (i.e., 3-12 membered carbon atoms), 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, or 4 to 8 ring-forming carbon atoms. The carbocyclyl group may be saturated, partially unsaturated, or fully unsaturated. In some embodiments, the carbocyclyl group may be a saturated cyclic alkyl group. In some embodiments, a carbocyclyl group may be an unsaturated cyclic alkyl group containing at least one double bond in its ring system. In some embodiments, an unsaturated carbocyclyl group may contain one or more aromatic rings. In some embodiments, one or more of the saturated or unsaturated carbocyclic groups form a ring-CH2The-group may be replaced by a-C (O) -group.
In some embodiments, carbocyclyl is monocyclic. In some embodiments, the carbocyclyl is a saturated monocyclic alkyl. Examples of monocyclic saturated or unsaturated carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like.
As used herein, the term "spiro" refers to a ring system in which two rings are connected by a single common atom; the term "fused ring" refers to a ring system in which two rings share two adjacent atoms; and the term "bridged ring" refers to a ring system in which two rings share three or more atoms.
A3-12, 3-10, or 5-6 "membered saturated or unsaturated carbocyclyl" is a saturated, partially unsaturated, or fully unsaturated monocyclic or polycyclic ring system having 3 to 12, 3 to 10, or 5 to 6 ring-forming carbon atoms, respectively, wherein one or more is cyclic-CH2The-group may optionally be replaced by a-c (o) -group.
An example of "3-12 membered saturated or unsaturated carbocyclic group" is C3-4Cycloalkyl, cyclohexyl, cyclohexenyl, cyclopentyl, phenyl, naphthyl and bicyclo [1.1.1]Pentane-1-yl. "C3-4Examples of cycloalkyl groups "are cyclopropyl and cyclobutyl. Examples of "5-6 membered saturated or unsaturated carbocyclic group" are cyclopentyl and phenyl.
The term "heterocyclyl" as used herein, refers to a carbocyclic group in which one or more (e.g., 1, 2, or 3) ring atoms are replaced with a heteroatom includingBut are not limited to O, S, N, P, etc. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in the ring system. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl. In some embodiments, heterocyclyl is a fully unsaturated heterocyclyl. In some embodiments, an unsaturated heterocyclyl group may contain one or more aromatic rings. In some embodiments, one or more of the heterocyclic groups form a ring-CH 2The group may optionally be substituted by-C (O) -, -S-, -S (O) -or-S (O)2-group replacement. In some embodiments, where the heterocyclic group contains sulfur in its ring system, the ring-forming sulfur atom may be optionally oxidized to form an S-oxide. In some embodiments, the heterocyclyl is bonded to other moieties of the compound via its ring-forming carbon. In some embodiments, the heterocyclyl is linked to the other moiety of the compound via its ring-forming nitrogen.
In some embodiments, a 3-12 membered saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1, 2, or 3 heteroatoms selected from N, O or S.
"3-12, 3-10, or 5-6 membered saturated or unsaturated heterocyclyl" is a saturated, partially unsaturated, or fully unsaturated monocyclic or polycyclic ring (e.g., having 2 or 3 fused, bridged, or spiro rings) having 3 to 12, 3 to 10, or 5 to 6 ring-forming carbon atoms, respectively, at least one ring-forming atom of which is selected from nitrogen, sulfur, or oxygen, and which may be bonded to other parts of the compound via its ring-forming carbon or nitrogen unless otherwise specified, wherein one or more ring-forming-CH groups of the saturated or unsaturated heterocyclyl are2The group may be substituted by-C (O) -, -S-, -S (O) -or-S (O)2-group replacement, and wherein when the heterocyclyl contains sulfur in its ring system, said ring sulfur atom may be optionally oxidized to form an S-oxide.
Exemplary monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1-dioxothietanylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, and the like,
Figure BDA0002577091620000611
Oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidinonyl, pyrazinonyl (pyrazinonyl), pyrimidinonyl, pyridazinonyl (pyridazinonyl), triazinonyl (triazinonyl), and the like.
Examples of spiro heterocyclic groups include, but are not limited to, spiropyranyl, spiro
Figure BDA0002577091620000612
Oxazine groups, and the like. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolyl, isoquinolyl, quinoxalyl, quinolizyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1,2-a ] phenyl fused rings]Pyridyl, [1,2,4 ] or a salt thereof]Triazolo [4,3-a]Pyridyl, [1,2,3 ] ]Triazolo [4,3-a]Pyridyl, and the like. Examples of bridged heterocyclic groups include, but are not limited to, morphinyl (morphanyl), hexamethylenetetramino, 8-aza-bicyclo [3.2.1]Octane, 1-aza-bicyclo [2.2.2]Octane, 1, 4-diazabicyclo [2.2.2]Octane (DABCO), and the like.
Unless otherwise indicated, the "compounds" of the present disclosure are intended to encompass all stereoisomers, geometric isomers, and tautomers of the depicted structures.
The term "stereoisomer" refers to any of a variety of stereoisomeric configurations (e.g., enantiomers, diastereomers, and racemates) of asymmetric compounds (e.g., compounds having one or more asymmetrically substituted carbon atoms or "asymmetric centers"). Compounds of the present disclosure containing an asymmetric center may be isolated in optically active (enantiomeric or diastereomeric) or optically inactive (racemic) forms. The term "enantiomer" includes a pair of stereoisomers that are not mirror images of each other, which are superimposable. A 1:1 mixture of a pair of enantiomers is a "racemic mixture". The term "diastereomer" or "diastereomer" includes stereoisomers having at least two asymmetric atoms which are not mirror images of each other. Certain compounds containing one or more asymmetric centers may give rise to enantiomers, diastereomers, or other stereoisomeric forms, which may be defined as (R) -or (S) -at each asymmetric center with respect to absolute configuration according to the Cahn-lngold-Prelog R-S system. Resolved compounds with unknown absolute configuration may be indicated using the term "or" at the asymmetric center. Methods for how to prepare optically active forms from racemic mixtures are known in the art, such as by HPLC resolution or stereoselective synthesis.
The term "geometric isomer" or "cis and trans isomers" refers to a compound having the same formula but with its functional groups rotated to different orientations in three-dimensional space.
The term "tautomer" includes proton transfer tautomers in the isomeric protonated state of compounds having the same formula and overall charge. Examples of proton transfer tautomers include, but are not limited to, keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons may occupy two or more positions of a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2, 4-triazole, 2H-1,2, 4-triazole and 4H-1,2, 4-triazole, 1H-isoindole and 2H-isoindole, as well as 1H-pyrazole and 2H-pyrazole. Tautomers can be in equilibrium or sterically locked into a form by appropriate substitution. Unless otherwise specified, a compound of the present disclosure identified by name or structure as one particular tautomeric form is intended to include other tautomeric forms.
The "compounds" of the present disclosure are also intended to encompass all isotopes of atoms in the compounds. Isotopes of atoms include atoms having the same number of atoms but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in a "compound" of the disclosure is intended to also include isotopes thereof, such as, but not limited to 1H、2H、3H、11C、12C、13C、14C、14N、15N、16O、17O、18O、31P、32P、32S、33S、34S、36S、17F、19F、35Cl、37Cl、79Br、81Br、127I and131I. in some embodiments, the hydrogen comprises protium, deuterium, and tritium. In some embodiments, the terms "deuterium substituted" or "deuterium substituted" replace another isoform (e.g., protium) of hydrogen in a chemical group with deuterium. In some embodiments, the carbon comprises12C and13C. in some embodiments, a "compound" of the present disclosure encompasses only isotopes of hydrogen in the compound. In some embodiments, a "compound" of the present disclosure encompasses only isotopes of atoms in natural abundance.
It is also to be understood that the "compounds" of the present disclosure may exist in solvated as well as unsolvated forms such as, for example, hydrated forms, solid forms, and the present disclosure is intended to encompass all such solvated and unsolvated forms.
It is also understood that the "compounds" of the present disclosure may exist in the form of pharmaceutically acceptable salts.
As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, pharmaceutically acceptable compounds, materials, compositions, and/or dosage forms refer to those that are approved or recognized by regulatory agencies such as the united states Food and Drug Administration, the chinese Food and Drug Administration, or the European pharmaceuticals Agency such as those listed in the united states pharmacopeia, the chinese pharmacopeia, or the European pharmacopeia for use in animals, and in particular humans.
As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by conversion of an existing acidic moiety (e.g., carboxy, etc.) or a basic moiety (e.g., amine, alkali metal, etc.) to its salt form. In many cases, the compounds of the present disclosure are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or similar groups. Pharmaceutically acceptable salts are acid and/or base salts that generally do not have a biologically or otherwise undesirable property of the parent compound in order to retain its biological effectiveness and properties. Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts, which can be derived from, for example, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) or organic acids (e.g., formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, trimesic acid, citric acid, lactic acid, phenylacetic acid, benzoic acid, mandelic acid, methanesulfonic acid, naphthalenedisulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, and the like). In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a formate salt. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a TFA salt.
Suitable pharmaceutically acceptable salts of the compounds of the present disclosure also include, for example, base addition salts, which can be derived, for example, from inorganic bases (e.g., sodium, potassium, ammonium salts and hydroxides, carbonates, bicarbonates of metals from columns I-XII of the periodic table, such as calcium, magnesium, iron, silver, zinc, copper, and the like) or organic bases (e.g., primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like). Certain organic amines include, but are not limited to, isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. It will be appreciated by those skilled in the art that addition of an acid or base for forming an acid/base addition salt is possible in addition to that shown in the examples. Other lists of suitable salts can be found, for example, in Remington's pharmaceutical sciences, 20 th edition, Mark Publishing Company (Mack Publishing Company), Iston, Pa. (1985); and Stahl and Wermuth, handbook of pharmaceutically acceptable salts: properties, Selection and Use (handbook of Pharmaceutical Salts: Properties, Selection, and Use) (Wiley-VCH, Weinheim, Germany, 2002). In some embodiments, suitable pharmaceutically acceptable salts of the compounds of the present disclosure are inorganic base salts.
The disclosure also includes active intermediates, active metabolites and prodrugs of the compounds of the disclosure. As used herein, "active intermediate" refers to an intermediate compound in the course of synthesis that exhibits the same or substantially the same biological activity as the final synthesized compound.
As used herein, "active metabolite" refers to a breakdown or end product of a compound of the present disclosure, or a salt or prodrug thereof, produced by metabolism or biotransformation in an animal or human body, which exhibits the same or substantially the same biological activity as the specified compound. Such metabolites may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound or salt or prodrug.
As used herein, "prodrug" refers to any compound or conjugate that releases the active parent drug when administered to an animal or human subject. Prodrugs can be prepared by modifying functional groups present in a compound in such a way that the modification is cleavable from the parent compound in routine manipulation or in vivo. Prodrugs include compounds wherein a hydroxy, amino, sulfhydryl, or carboxyl group is bonded to any group such that, when administered to a mammalian subject, it is cleaved to form a free hydroxy, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present disclosure. The preparation and use of prodrugs are discussed in t.higuchi and v.stella, "prodrugs as Novel Delivery Systems (Pro-drugs as Novel Delivery Systems)", "proceedings of the american chemical society of america (a.c.s.symposium Series) volume 14, and" Bioreversible carrier in Drug Design (Drug Design), Edward b.roche eds., american society of pharmacy and bergmann Press (american pharmaceutical Association and Pergamon Press),1987, both of which are hereby incorporated by reference in their entirety.
Synthesis method
The synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, is illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a variety of possible synthetic routes, and thus, these schemes are merely illustrative and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. Moreover, the steps in the described schemes are for better illustration and may be changed as appropriate. The compound examples in the examples were synthesized for the purposes of study and possible submission to regulatory agencies.
The reaction for preparing the disclosed compounds can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, at a temperature in the range of from the freezing temperature of the solvent to the boiling temperature of the solvent. The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for the particular reaction step may be selected by the skilled artisan.
The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The requirements for protection and deprotection, as well as the choice of an appropriate protecting group, can be readily determined by those skilled in the art. The chemical nature of protecting Groups can be found, for example, in t.w.greene and p.g.m.wuts, Protective Groups in organic Synthesis (Protective Groups in organic Synthesis), 3 rd edition, Wiley & Sons, Inc., new york (1999), which is incorporated herein by reference in its entirety.
The reaction may be monitored according to any suitable method known in the art. For example, it can be determined by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.1H or13C) Infrared spectroscopy (IR), spectrophotometry (e.g. UV-visible), mass spectrometry, or by chromatography, e.g. high performance liquid chromatography(HPLC), liquid chromatography-mass spectrometry (LCMS) or Thin Layer Chromatography (TLC) to monitor product formation. One skilled in the art can purify compounds by a variety of methods, including High Performance Liquid Chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound specific Method Optimization", Karl F.Blom, Brian Glass, Richard Sparks, Andrew P.Combs, J.Combo.Chem.chem., 2004,6(6),874-883, incorporated herein by reference in its entirety) and normal phase silica chromatography.
The structures of the compounds in the examples were characterized by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shift () was 10-6(ppm) is given as unit.1H-NMR spectra were obtained on a Bruker AVANCE NMR (300MHz or 400MHz) spectrometer using ICON-NMR (under TopSpin process control) using tetramethylsilane as internal standard and dimethylsulfoxide-d6(DMSO-d6) Or CDCl3Or CD3OD or D2O or acetone _ d6Or CD3CN (from inokay (Innochem) or Sigma-Aldrich (Sigma-Aldrich) or Cambridge Isotope laboratories, Cambridge Isotope lab, Inc.).
MS measurements were performed in positive and negative ion mode using a Shimadzu 2020 mass spectrometer with an electrospray source.
High Performance Liquid Chromatography (HPLC) measurements were performed on a Shimadzu LC-20AD system or a Shimadzu LC-20ADXR system or a Shimadzu LC-30AD system using a homogenously-packed (Shim-pack) XR-ODS C18 column (3.0 x 50mm, 2.2 μm), or an Ascentis Express C18 column (2.1 x 50mm, 2.7 μm), or an Agilent Poroshell HPH-C18 column (3.0 x 50mm, 2.7 μm).
Thin layer chromatography was performed using silica gel plates of national pharmaceutical chemicals Beijing Ltd (Sinopharm Chemical Reagent Beijing co., Ltd.) and Xinnuo Chemical (Xinnuo Chemical). Silica gel plates for Thin Layer Chromatography (TLC) were 175-225 μm. The silica gel plate used for separating and purifying the product by TLC was 1.0 mm.
The purification column uses silica gel as a carrier (100-200, 200-300 or 300-400 mesh, manufactured by Rushanshi shang Xincailiao co., Ltd.) or Rushan Taiyang Desiccant co., Ltd., or the like, or a flash column in the agala Technologies flash system (reverse phase C18 column 20-45 μm, manufactured by agella Technologies). The size of the column is adjusted according to the amount of the compound.
Known starting materials of the present disclosure may be synthesized by using or according to methods known in the art, or may be purchased from Alfa Aesar (Alfa Aesar), echeli (TCI), Sigma-Aldrich (Sigma-Aldrich), bodharma (Bepharm), bibpharma (Bide pharmatech), pharma (PharmaBlock), Enamine, ikano, and jidawei medical technology (JW & Y pharm lab), among others.
Unless otherwise specified, the reactions were all carried out under an argon or nitrogen atmosphere. By argon or nitrogen atmosphere is meant that the reaction flask is connected to a balloon of argon or nitrogen having a volume of about 1L. The hydrogenation is usually carried out under pressure. Unless otherwise specified, the reaction temperature in the examples is ambient temperature, which is from 10 ℃ to 30 ℃.
The reaction progress was monitored by TLC or/and LC-MS. Eluent systems for the reaction include a dichloromethane-methanol system and a petroleum ether-ethyl acetate system. The volume ratio of the solvent is adjusted according to different polarities of the compound.
Elution systems for column chromatography and eluent systems for TLC of purified compounds include dichloromethane-methanol systems and petroleum ether-ethyl acetate systems. The volume ratio of the solvent is adjusted according to different polarities of the compound. Small amounts of basic or acidic reagents (0.1% to 1%), such as formic acid, or acetic acid, or TFA, or ammonia may be added for adjustment.
Abbreviations for the chemicals used in the synthesis of the compounds provided herein are listed below:
Figure BDA0002577091620000661
Figure BDA0002577091620000671
pharmaceutical composition
The present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises more than one compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition comprises one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Generally, the pharmaceutically acceptable carrier is a conventional pharmaceutical carrier in the art, which can be prepared in a manner well known in the pharmaceutical art. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be admixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition.
The form of the pharmaceutical composition depends on various criteria including, but not limited to, the route of administration, the extent of the disease, or the dose to be administered. The pharmaceutical composition may be formulated for oral, nasal, rectal, transdermal, intravenous or intramuscular administration. The pharmaceutical compositions may be formulated as tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants or suppositories, depending on the desired route of administration.
In certain embodiments, the pharmaceutical composition comprises from about 1mg to about 500mg, specifically, from 1mg to about 50mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure, or pharmaceutically acceptable salts thereof, as a first active ingredient, and further comprises a second active ingredient. The second active ingredient can be any immunomodulatory or anti-neoplastic agent known in the art, including, but not limited to, chemotherapeutic agents, immunotherapeutic agents, cell signaling inhibitors, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, anti-hormonal agents, and the like. Examples of such immunomodulators or antineoplastic agents are platinum-based chemotherapeutic agents (e.g., cisplatin (DDP), Carboplatin (CBP), sulfato-1, 2-diaminocyclohexaniplatin (SHP), Nedaplatin (Nedaplatin), Oxaliplatin (OXA), leplatin (Laboplatin)), Docetaxel (Docetaxel), Paclitaxel (Paclitaxel), Doxorubicin (Doxorubicin), Etoposide (Etoposide), Mitoxantrone (Mitoxantrone), CTLA-4 inhibitors, anti-CTLA-4 antibodies, PD-1 inhibitors, PD-L1 inhibitors, anti-PD-1/PD-L1 antibodies, CD39 inhibitors, anti-CD 39 antibodies, CD73 inhibitors, anti-CD 73 antibodies, 2 inhibitors, anti-CCR 2 antibodies, EGFR inhibitors, 4/6 inhibitors, MELK inhibitors, androgen 40 agonists, anti-hormone inhibitors, 4 isotype kinase antibodies, tyrosine kinase inhibitors, CDK inhibitors, DNA methyltransferase inhibitors, Hsp90 inhibitors, FGFR inhibitors, mTOR inhibitors, aromatase inhibitors, VEGF inhibitors, LHRH antagonists, PI3K inhibitors, AKT inhibitors, aurora kinase inhibitors, MEK inhibitors, HDAC inhibitors, BET inhibitors, PIK3CA inhibitors, proteasome inhibitors, other SERDs, farnesyl transferase inhibitors, VEGF-a antibodies, ErbB3(Her3) antibodies, proteasome inhibitors, protein kinase C β inhibitors, anti-IGF-1R antibodies, anti-Her 2 antibodies, SERMs, IGF inhibitors, anti-IgG antibodies, and the like. Representative examples of antineoplastic agents for treating cancer or tumor may include, but are not limited to, cisplatin, carboplatin, SHP, nedaplatin, oxaliplatin, leplatin, docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, vincristine, vinblastine, gemcitabine (gemcitabine), cyclophosphamide, chlorambucil (chlorembecil), carmustine (carmustine), methotrexate, fluorouracil, actinomycin, epirubicin (epirubicin), anthracycline, bleomycin, mitomycin-C, irinotecan (irinotecan), topotecan (topotecan), teniposide (teniposide) interleukin, interferon, tremelimumab (tremelimumab), ipilimumab (ipilimumab), pelizumab (pivalomab), nivolumab (nivolumab), avilluzumab (avavelumab), alutavavalab (ipulatab), ipimab (ipizumab H52), ipravamab (IPzeab), and nivolumab, CPI-006, Protilizumab (plozalizumab), MLN1202, cetuximab (cetuximab), lapatinib (lapatinib), erlotinib (erlotinib), gefitinib (gefitinib), neratinib (neratinib), trastuzumab (trastuzumab), ado-trastuzumab emtansine (ado-trastuzumab emtansine), pertuzumab (pertuzumab), MCLA-128, anastrozole (anaszole), ranioxicenol (raloxifene), G1T38, tamoxifen (tamoxifen), goserelin (goserelin), enzalutamide (enzalutamide), vorinostat, entinostat (pertubatidinit), sunitinib (plozalizumab), bevacizumab (Bpacifib-80), piperacillib (Bpacifib-80), trastuzumab (Kb), trastuzumab (Btrastuzumab), Netzerlotinib (Kd), Netzerlotinib (GDB-80), Netzerlotinib (Btrastuzumab (Kb), Netzerlotinib (Kbab), Netzerlotinib (Btrastuzumab (GDC-80), Netzerlotinib (Btrastuzumab), Netzab (Btrastuzumab), Tab (Tab), Tab-E (Tab), Tab (Tab-E, Tab), Tab-E (Tab), Tab-E (Tab-D-E (Tab), E (, AZD8835, GDC-0941, Taseixib (taselisib), temsirolimus (temsirolimus), everolimus (everolimus), sapacitinib (sapansertinib), AZD5363, MK2206, panitumumab (panitumumab), pemirolizumab (pembrolizumab), sorafenib (sorafenib), palbociclib (palbociclib), Bomaciclib (abemaciclib), Ribocillin (ribociclib), crizotinib (cridinib), doviranib (dovidiib), tyrosine protein kinase inhibitors, azacitidine (azacitidine), CC-HSP, 90 galileotide skin (90 gaesepirib), Debio 1347, Edatinib (erdizatinib), Visergentiticetib (seracitid), AFP-HSP 5857464, Ab (Avertinib), Avertinib (0810, Avertinib), Veertinib (AGisnib), Abetimib (ASetimivir), Ab-K (Avertinib) and Abetimivir, AMG479, and the like.
The treatment of adenosine receptor related diseases as defined hereinafter may be applied as monotherapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy or immunotherapy. Such chemotherapy may include one or more of the following chemotherapeutic agents: cisplatin (DDP), Carboplatin (CBP), sulfato-1, 2-diaminocyclohexaneproplatin (SHP), nedaplatin, Oxaliplatin (OXA), leplatin, docetaxel, paclitaxel, doxorubicin, etoposide, or mitoxantrone. Such immunotherapeutic agents may include one or more of the following antineoplastic agents: (i) anti-CTLA-4 antibodies; (ii) an anti-PD-1 antibody; (iii) anti-PD-L1 antibody; (iv) anti-CD 73 antibodies; (v) anti-CD 39 antibodies; or (vi) an anti-CCR 2 antibody.
Specifically, the anti-CTLA-4 antibody is tremelimumab (as disclosed in US 6,682,736). In another aspect of the invention, specifically, the anti-CTLA-4 antibody is ipilimumab (by Bristol Myers Squib) to
Figure BDA0002577091620000701
Commercially available).
Specifically, the anti-PD-L1 antibody is an antibody as disclosed in US 20130034559 (MedImmune)). In another aspect of the invention, specifically, the anti-PD-L1 antibody is an antibody as disclosed in US 2010/0203056 (gene tex (Genentech)/Roche (Roche)). In another aspect of the invention, specifically, the anti-PD-L1 antibody is an antibody as disclosed in US 20090055944 (Medarex). In another aspect of the invention, specifically, the anti-PD-L1 antibody is an antibody as disclosed in US 20130323249 (sorento therapeutics).
Specifically, the anti-PD-1 antibody is MRK-3475 (Merck). In another aspect of the invention, the anti-PD-1 antibody is, specifically, nivolumab or an anti-PD-1 antibody as disclosed in WO 2006/121168 or US 8,008,449 (Metarex). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody as disclosed in WO2009/101611 (CureTech). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody as disclosed in WO2012/145493 (amplimune). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody (Wyeth)/medical immunization) as disclosed in US 7,488,802. In another aspect of the invention, specifically, the anti-PD-1 antibody is an antibody (the board of the university of Texas (univ.of Texas)) as disclosed in US 20130280275. In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody as disclosed in WO 99/42585(Agonox), WO 95/12673 and WO 95/21915.
Specifically, the anti-CD 39 antibody is IPH52 (innote Pharmaceuticals).
Specifically, anti-CD 73 antibodies are CPI-006(Corvus Pharmaceuticals) or IPH53 (InnatePharmaceutics).
Specifically, the anti-CCR 2 antibody is purolizumab (takeda pharmaceuticals International Co.)) or MLN1202 (millennium pharmaceuticals).
According to this aspect of the present invention there is provided a combination suitable for use in the treatment of an adenosine receptor related disease, particularly cancer, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above; and any one or more of the chemotherapeutic agents listed above and/or any one or more of the immunotherapeutic agents listed under (i) - (vi) above.
For example, the compounds of the present disclosure may be provided in combination with an anti-PD 1/PD-L1 antibody. In some particular embodiments, the compounds of the present disclosure may be provided in combination with an anti-PD 1/PD-L1 antibody and further in combination with an anti-CTLA-4, CD38, CD73, or CCR2 antibody.
According to this aspect of the present disclosure there is provided a combination suitable for use in the treatment of cancer comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof; and any of the immunomodulatory or antineoplastic agents listed above.
Thus, in another aspect of the present disclosure there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulatory or chemotherapeutic agent selected from those listed above.
Herein, when the term "combination" is used, it is understood that this term refers to simultaneous, separate or sequential administration. In some embodiments, "combination" refers to simultaneous administration. In another aspect of the disclosure, "combination" refers to separate administration. In another aspect of the disclosure, "combination" refers to sequential administration. The delay in administering the second component should not be such as to lose the beneficial effect of the combination when administered sequentially or separately.
According to another aspect of the present disclosure there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulatory or antineoplastic agent selected from those listed above, in association with a pharmaceutically acceptable diluent or carrier.
According to another aspect of the present disclosure there is provided a pharmaceutical composition for use in producing an immunomodulatory or anti-cancer effect, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with an immunomodulatory or anti-neoplastic agent selected from the group consisting of the immunomodulatory or anti-neoplastic agents listed above, in association with a pharmaceutically acceptable diluent or carrier.
According to another aspect of the present disclosure there is provided a pharmaceutical composition for use in the treatment of NSCLC, RCC, prostate or breast cancer (etc.) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulatory or antineoplastic agent selected from those listed above, in association with a pharmaceutically acceptable diluent or carrier.
According to another aspect of the present disclosure there is provided a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulatory or antineoplastic agent selected from the immunomodulatory or antineoplastic agents listed above.
According to another aspect of the present disclosure, there is provided a kit comprising:
a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a first unit dosage form;
b) an immunomodulatory or anti-tumor agent selected from the immunomodulatory or anti-neoplastic agents listed above in a second unit dosage form; and
c) a container for holding the first and second dosage forms.
In addition to use in therapeutic medicine, the compounds of formula (I) or pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for assessing the activity or expression of adenosine receptors in experimental animals such as cats, dogs, rabbits, monkeys, rats, and mice, as part of the search for novel therapeutic agents.
In the above other pharmaceutical compositions, processes, methods, uses and medicament manufacturing features, alternative and preferred embodiments of the presently disclosed compounds described herein are also applicable.
Method of treatment
The present disclosure provides a method of treating diseases associated with adenosine receptors, including, for example, a1, A2a, and/or A2b, specifically, A2a, by administering to a subject a therapeutically effective amount of one or more compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the disclosure.
As used herein, the term "adenosine receptor-associated disease" or "AR-associated disease" refers to a disease whose onset or suffering or both are associated with genomic changes, expression, overexpression, decline or activity of AR (including, e.g., a1, A2a and/or A2b, particularly A2a), as the case may be. Examples include, without limitation, inflammatory disorders, cancer, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive disorders, HIV, ADA-SCID, Acute Heart Failure (AHF) and chronic heart failure, Chronic Obstructive Pulmonary Disease (COPD), asthma, and other diseases. In certain embodiments, AR-related diseases refer to diseases that are to be treated by inhibiting the action of adenosine receptors.
In some embodiments, the AR-associated disease is cancer, preferably an AR-expressing cancer or an AR-overexpressing cancer. "AR-expressing cancer" is a cancer involving cancer cells or tumor cells having AR proteins (e.g., A2a, A1, and/or A2b) present on their cell surface. An "AR overexpressing cancer" is a cancer that has significantly higher levels of AR proteins (e.g., A2a, A1, and/or A2b) at the cell surface of the cancer or tumor cell as compared to a noncancerous cell of the same tissue type. Such overexpression may be caused by gene amplification or increased transcription or translation. Adenosine receptor expression or overexpression can be determined in a diagnostic or prognostic assay by assessing the increase in AR protein levels present on the cell surface (e.g., by immunohistochemical analysis; IHC). Alternatively or additionally, the level of nucleic acid encoding AR in a cell may be measured, for example, by fluorescence in situ hybridization (FISH; see WO98/45479 published 10.1998), southern blot or Polymerase Chain Reaction (PCR) techniques, such as real-time quantitative PCR (RT-PCR) (Methods)132:73-80 (1990)). In addition to the above assays, a variety of in vivo assays may be used by those of skill in the art. For example, cells in a patient can be exposed to an antibody, which is optionally labeled with a detectable label (e.g., a radioisotope), and binding of the antibody to the patient's cells can be assessed, e.g., by externally scanning for radioactivity or by analyzing a live tissue examination taken from a patient previously exposed to the antibody.
Specifically, the cancer includes, but is not limited to, lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, lung adenocarcinoma, large cell lung cancer, squamous cell lung cancer), Renal Cell Carcinoma (RCC), prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bone cancer, uterine cancer, colon cancer, leukemia, glioblastoma, melanoma, chondrosarcoma, brain cancer, bile duct cancer, osteosarcoma, lymphoma, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, bladder cancer, liver cancer, gastric cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, nasopharyngeal cancer, or oral cancer. In some embodiments, the cancer is NSCLC, RCC, prostate cancer, or breast cancer. Unless otherwise specified, the cancer as referred to herein may be at any stage. In some embodiments, the cancer is an early stage cancer. In some embodiments, the cancer is a locally advanced cancer. In some embodiments, the cancer is a locally advanced and/or metastatic cancer. In some embodiments, the cancer is an invasive cancer. In some embodiments, the cancer is a cancer that is resistant to an existing therapy.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has efficacy in treating cancer (e.g., NSCLC, RCC, prostate cancer, breast cancer). In addition, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may also be useful in the treatment of other adenosine receptor-related diseases, such as parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive disorders, HIV, ADA-SCID, AHF and chronic heart failure, Chronic Obstructive Pulmonary Disease (COPD), or asthma.
As used herein, the term "treating" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be performed after one or more symptoms have occurred. In other embodiments, treatment may be performed in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, e.g., to prevent or delay their recurrence.
A therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as provided herein will depend on various factors known in the art, such as body weight, age, past medical history, current medications, the health status and likelihood of cross-reactions, allergies, sensitivity, and adverse side effects of the individual, as well as the route of administration and the extent of disease progression. As indicated by these and other circumstances or requirements, one of skill in the art (e.g., a physician or veterinarian) may proportionately decrease or increase the dosage.
Use of compounds
In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a medicament for treating an AR-related disease. Exemplary AR-related diseases include, but are not limited to, cancer (e.g., NSCLC, RCC, prostate cancer, or breast cancer) and other diseases.
In such cases, the present disclosure also provides a method of screening for a patient suitable for treatment with a compound or pharmaceutical composition of the present disclosure, alone or in combination with other ingredients (e.g., a second active ingredient, such as an antineoplastic agent). The method comprises sequencing a tumor sample from a patient and detecting accumulation or activation of AR.
According to another aspect of the present disclosure there is thus provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.
According to a further aspect of the present disclosure there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the modulation of adenosine receptors in a warm-blooded animal such as man.
The term "modulating/modulating" when used in conjunction with an adenosine receptor refers to the effect or result of altering the expression, reduction and/or activity of the adenosine receptor.
According to a further aspect of the present disclosure there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the treatment of an AR-related disease in a warm-blooded animal such as man.
According to this aspect of the present disclosure there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
According to another feature of the present disclosure there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above in the manufacture of a medicament for use in the treatment of NSCLC, RCC, prostate or breast cancer.
According to another feature of the present disclosure there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the treatment of breast cancer.
According to another feature of this aspect of the present disclosure there is provided a method of modulating adenosine receptors in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
According to another feature of this aspect of the present disclosure there is provided a method of treating an AR-related disease in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
According to another feature of this aspect of the present disclosure there is provided a method for producing an anti-cancer effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
According to another feature of this aspect of the present disclosure there is provided a method of producing an anti-cancer effect in a warm-blooded animal, such as a human, in need of such treatment which comprises (1) determining whether or not the warm-blooded animal has an AR-expressing cancer, and (2) administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, if so.
According to a further feature of this aspect of the present disclosure there is provided a method of treating NSCLC, RCC, prostate cancer or breast cancer in a warm-blooded animal, such as a human, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
According to a further aspect of the present disclosure there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in modulating AR in a warm-blooded animal such as a human being.
According to a further aspect of the present disclosure there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of an AR-related disease in a warm-blooded animal such as a human being.
According to this aspect of the present disclosure there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
According to another feature of the present disclosure there is provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of NSCLC, RCC, prostate or breast cancer.
Examples of the invention
The general method of the present disclosure is further illustrated below. The compounds of the present disclosure may be prepared by methods known in the art. Specific methods for preparing preferred compounds of the present disclosure are described below. However, these in no way limit the methods of preparation of the compounds of the present disclosure.
EXAMPLE 01 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- ((3-fluoropyridin-2-yl) methyl) pyrazine-2-carboxamide (Compound 01)
Scheme 01
Figure BDA0002577091620000751
Step 1.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid methyl ester
To a solution of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (200mg, 0.71mmol, 1 eq.) and (2, 6-dimethylpyridin-4-yl) boronic acid (214.4mg, 1.42mmol, 2 eq.) in n-BuOH (25mL) were added xPhos (67.7mg, 0.14mmol, 0.2 eq.) and Pd (OAc) 2(31.9mg, 0.14mmol, 0.2 equiv.), K3PO4(301.4mg, 1.42mmol, 2 equiv.). After stirring at 100 ℃ for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2The residue was purified with MeOH 10:1) to give methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylate (230mg, 36.8%) as a yellow solid. LCMS M/z (ESI), M + ═ 339.2
Step 2.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- [ (3-fluoropyridin-2-yl) Methyl radical]Pyrazine-2-carboxamide (Compound 01)
A solution/mixture of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (215mg, 0.64mmol, 1 eq) and 1- (3-fluoropyridin-2-yl) methylamine (96.2mg, 0.76mmol, 1.20 eq), HATU (483.2mg, 1.3mmol, 2.0 eq), DIEA (246.4mg, 1.9mmol, 3.0 eq) in DMF (10mL) was stirred at 20 ℃ under an air atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)4HCO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 53% B to 62% B within 7 min; 220/254 nm; rt: 6.1min) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- [ (3-fluoropyridin-2-yl) methyl as a pale yellow solid ]Pyrazine-2-carboxamide (Compound 01) (83.3mg, 29.3%). LCMS M/z (ESI), M+＝447.2。1H NMR (400MHz, methanol-d)4):2.4(s,6H),4.8(d, J＝1.7Hz,2H),7.1-7.2(m,4H),7.4(dt,J＝8.6,4.4Hz,1H),7.4-7.5(m,2H),7.6(ddd,J＝9.9,8.4,1.3Hz,1H),8.4(dt,J＝4.8,1.4Hz,1H)。
EXAMPLE 02 preparation of 3-amino-N- [ (2, 6-difluorophenyl) methyl ] -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxamide (Compound 02)
Scheme 02
Figure BDA0002577091620000761
Step 1.6-chloro-3-methyl-5- (5-methylfuran-3-yl) pyrazine-2-carboxylic acid methyl ester
Methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (1g, 4.5mmol, 1 eq.) and (5-methylfuran-2-yl) boronic acid (0.6g, 4.8mmol) and Pd (dppf) Cl2(0.3g, 0.5mmol) and Na2CO3(1.0g, 9.0mmol) in bis
Figure BDA0002577091620000771
alkane/H2Mixture in O (40mL) was stirred at 90 deg.C under nitrogen for 4 hours, the resulting mixture was filtered, the filter cake was washed with DCM: MeOH (1:1) (3 × 10mL), CH2Cl2(3 × 10mL) the filtrate was extracted followed by Na2SO4The organic layer was dried and the solution was concentrated under reduced pressure. By preparative HPLC with the following Conditions (CH)2Cl2EtOAc (1:1)) to purify the crude product, yielding methyl 6-chloro-3-methyl-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (125mg, 7.1%) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝268.2。
Step 2.3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) Pyrazine-2-carboxylic acid methyl ester
Methyl 6-chloro-3-methyl-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (65mg, 0.24mmol, 1 eq.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl) -1, 2-dihydropyridin-2-one (56.4mg, 0.24mmol, 1.00 eq.) and Pd (dppf) Cl2(17.5mg, 0.024mmol, 0.10 eq.) and Na2CO3 (50.88mg, 0.48mmol, 2 equivalents) of beta-cyclodextrin in ethylene glycol
Figure BDA0002577091620000772
alkane/H2The mixture in O (6/1, 3mL) was stirred at 90 ℃ under a nitrogen atmosphere for 10 hours. Filtering the resulting mixture with CH2Cl2MeOH (1:1) (3 × 10mL) washes the filter cake with 20mL H2O washing the filtrate and CH2Cl2(3 × 20mL) extraction over Na2SO4The aqueous layer was dried and concentrated under reduced pressure, then the residue was dissolved in ethyl acetate (10mL), the precipitated solid was collected by filtration and washed with diethyl ether (3 × 3mL), and the resulting solid was dried in vacuo to give methyl 3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (55mg, 63.2%) as a yellow solid, LCMS: M/z (ESI), [ M + H ] pyrazine-2-carboxylic acid methyl ester (55mg, 63.2%), [ M + H ])]+＝341.2。
Step 3.3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) Pyrazine-2-carboxylic acid
Methyl 3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (90 mg, 0.3mmol, 1 eq) was in MeOH (9mL) and 1mL was taken for reaction. LiOH (25.2mg, 1.1mmol, 4.0 equiv.) and H were combined at 0 deg.C2O (1.8mL) was added to the solution and stirred at room temperature for 6 hours. The mixture was basified to pH 6 with HCl (aqueous solution). The solution was concentrated under reduced pressure and 3-methyl-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -5- (5-methylfuran-3-yl) pyrazine-2-carboxylic acid was obtained as a yellow solid (85mg, 96.6%). LCMS M/z (ESI), [ M + H]+＝327.1。
Step 4.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- (1-methyl-6-oxo-1, 6-dihydropyridine-3- Yl) -5- (5-Methylfuran-2-yl) pyrazine-2-carboxamide (Compound 02)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-yl) pyrazine at room temperatureTo a stirred solution of-2-carboxylic acid (80mg, 0.3mmol, 1 equiv) and DIEA (116.1mg, 0.9mmol, 3.00 equiv) in DMSO (4mL) was added HAUT (342mg, 0.9mmol, 3.0 equiv) in portions. The resulting mixture was stirred at room temperature for 10 min. 1- (2, 6-difluorophenyl) methylamine (107.3mg, 0.75mmol, 2.5 equivalents) was then added dropwise and stirred at room temperature for 10 hours. The reaction was quenched by the addition of brine (30mL) at room temperature. The resulting solid was collected by filtration and purified by preparative TLC (CH) 2Cl2EtOAc 1:1) to give 30mg of crude product, which was purified by preparative HPLC (column: XBridgePrep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (10MMOL/L NH)4HCO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 37% B to 37% B within 8 min; 220,254 nm; rt: 7.33min) to yield 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxamide (compound 02) (7.4mg, 6.49%). LCMS M/z (ESI) [ M + H ]]+＝452.3。1H NMR (400MHz, methanol-d)4)2.25(s,3H),3.64(s,3H),4.70(s,2H),6.18(d,J＝3.4Hz,1H),6.55(d,J＝9.2Hz, 1H),6.81(d,J＝3.3Hz,1H),6.98(t,J＝7.9Hz,2H),7.39-7.28(m,1H),7.52(dd,J＝9.2,2.5 Hz,1H),7.92(d,J＝2.5Hz,1H)。
Example 04: preparation of N- ((3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-yl) pyrazin-2-yl) methyl) -2, 6-difluorobenzamide (Compound 04)
Scheme 3
Figure BDA0002577091620000781
Step 1.3-amino-5-chloro-6- (5-methylfuran-2-yl) pyrazine-2-carbonitrile
3-amino-5, 6-dichloropyrazine-2-carbonitrile (250mg, 1.3mmol, 1 eq.) and (5-methylfuran-2-yl) boronic acid (166.6mg, 1.3mmol, 1.00 eq.) and Pd (dppf) Cl2(96.8mg, 0.1mmol, 0.1 equiv.) and Na2CO3(280.4mg, 2.7mmol, 2 equiv.) in II
Figure BDA0002577091620000782
alkane/H2The mixture in O (15mL) was stirred at 70 ℃ under a nitrogen atmosphere for 6 hours.
Filtering the resulting mixture with CH 2Cl2MeOH (1:1) (3 × 10mL) washes the filter cake with 20mL H2O washing the filtrate and CH2Cl2(3 × 20mL) extraction over Na2SO4The organic layer was dried and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column using PE (CH)2Cl2EtOAc (1:1)) (1:1) elution afforded 3-amino-5-chloro-6- (5-methylfuran-2-yl) pyrazine-2-carbonitrile as a yellow solid (130mg, 28.9%). LCMS M/z (ESI), [ M + H]+＝235.1。
Step 2.3- (aminomethyl) -6-chloro-5- (5-methylfuran-2-yl) pyrazin-2-amine
A mixture of 3-amino-5-chloro-6- (5-methylfuran-2-yl) pyrazine-2-carbonitrile (240mg, 1.0mmol, 1 eq) in THF (12mL) was stirred, and DMSB (155.4mg, 2.1mmol, 2.0 eq) was slowly added to the mixed solution at 0 ℃ and stirred at room temperature for 6 hours. By adding H at 0 deg.C2Quench the reaction with O (2mL) and then add Na2CO3The solution was stirred at room temperature for 30min to give 3- (aminomethyl) -6-chloro-5- (5-methylfuran-2-yl) pyrazin-2-amine (240mg, 96.34%) as a yellow liquid. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝239.2。
Step 3.N- [ [ 3-amino-5-chloro-6- (5-methylfuran-3-yl) pyrazin-2-yl ]Methyl radical]Carbamic acid tert-butyl ester Esters
To a solution of 3- (aminomethyl) -6-chloro-5- (5-methylfuran-2-yl) pyrazin-2-amine (238mg, 1.0mmol, 1.0 equivalent) in DCM (10mL) at room temperature was added (BOC)2O (438.9mg, 2.0mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 10 hours. The resulting mixture was quenched with water (20mL) and CH2Cl2(3 × 20mL) extract with H2The combined organic layers were washed with O (3 × 10mL), anhydrous Na2SO4And (5) drying. After filtrationConcentrating the filtrate under reduced pressure and obtaining N- [ [ 3-amino-5-chloro-6- (5-methylfuran-3-yl) pyrazin-2-yl ] as a yellow solid]Methyl radical]Carbamic acid tert-butyl ester (150mg, 41.83%). LCMS M/z (ESI), [ M + H]+＝339.2。
Step 4.N- [ [ 3-amino-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (5-methylfuran-3- Radical) pyrazin-2-yl]Methyl radical]Carbamic acid tert-butyl ester
Reacting N- [ [ 3-amino-5-chloro-6- (5-methylfuran-3-yl) pyrazin-2-yl]Methyl radical]Tert-butyl carbamate (120mg, 0.34 mmol, 1 eq.) was added to the di-tert-butyl carbamate
Figure BDA0002577091620000791
alkane/H2In O (10mL), then in N21-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (124.9mg, 0.5mmol, 1.50 equivalents) and Pd (dppf) Cl were added next 2(25.9mg, 0.1mmol) and Na2CO3(75.1mg, 0.7mmol, 2 equiv.) and stirred at 90 ℃ under nitrogen atmosphere for 10 hours. The reaction solution was concentrated and passed through preparative TLC (CH)2Cl2EtOAc 1:1) purification to yield N- [ [ 3-amino-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (5-methylfuran-3-yl) pyrazin-2-yl) as a yellow solid]Methyl radical]Tert-butyl carbamate (35mg, 23.53%). LCMS M/z (ESI), [ M + H]+＝412.3。
Step 5.5- [ 6-amino-5- (aminomethyl) -3- (5-methylfuran-3-yl) pyrazin-2-yl]-1-methyl-1, 2- Dihydropyridin-2-ones
Reacting N- [ [ 3-amino-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (5-methylfuran-3-yl) pyrazin-2-yl]Methyl radical]Tert-butyl carbamate (120mg, 1 eq) was added to DCM (5mL) and TFA (2.5 mL). The resulting solution was stirred at room temperature under an air atmosphere for 10 hours. With saturated Na2CO3(aqueous solution) the mixture was acidified to pH 7. By CH2Cl2(3 × 30mL) the resulting mixture was extracted with H2The combined organic layers were washed with O (2 × 10mL), anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives a yellowish solid5- [ 6-amino-5- (aminomethyl) -3- (5-methylfuran-3-yl) pyrazin-2-yl in the form of a solid ]-1-methyl-1, 2-dihydropyridin-2-one (80mg, 84.58%). LCMS M/z (ESI), [ M + H]+＝312.2。
Step 6.N- ((3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (5-methylfuran-2-) Yl) pyrazin-2-yl) methyl) -2, 6-difluorobenzamide (compound 04)
To 5- [ 6-amino-5- (aminomethyl) -3- (5-methylfuran-3-yl) pyrazin-2-yl at room temperature under an air atmosphere]To a stirred solution of-1-methyl-1, 2-dihydropyridin-2-one (80mg, 0.26mmol, 1 equiv.) and 2, 6-difluorobenzoic acid (60.9mg, 0.39mmol, 1.5 equiv.) in DMSO (1mL) was added HAUT (197mg, 0.52mmol, 2.0 equiv.) and DIEA (67mg, 0.52mmol, 2.0 equiv.) in portions. The resulting solution was stirred at room temperature for 10 hours. The resulting mixture was quenched with brine (20mL) and CH2Cl2(3 × 10mL) extract the aqueous solution over anhydrous Na2SO4The organic layer was dried, filtered and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC (DCM: MeOH ═ 20:1) to give N- [ [ 3-amino-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (5-methylfuran-3-yl) pyrazin-2-yl) as a light yellow solid]Methyl radical]-2, 6-difluorobenzamide (compound 04) (112mg, 93.7%). LCMS M/z (ESI) [ M + H ] ]+＝452.2。1H NMR (400MHz, methanol-d)4)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＝3.3Hz,1H),7.09(t,J＝8.2Hz,2H),7.41-7.58(m,2H), 7.85(d,J＝2.6Hz,1H)。
Example 05: 3-amino-N- (2, 6-difluorobenzyl) -6- (2, 6-dimethylpyridin-4-yl) -5- (2
Figure BDA0002577091620000802
Preparation of Azol-2-yl) pyrazine-2-carboxamide (Compound 05)
Scheme 4
Figure BDA0002577091620000801
Step 1.3-amino-6-chloro-5-, (
Figure BDA0002577091620000811
Azol-2-yl) pyrazine-2-carboxylic acid methyl ester
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (500mg, 2.25mol, 1 equivalent) and 2- (tributylstannyl) -1,3-
Figure BDA0002577091620000812
Oxazole (806.5mg, 2.25mol, 1.00 eq) in 1, 4-bis
Figure BDA0002577091620000813
To a stirred solution in an alkane (20mL) were added LiCl (190.9mg, 4.50mmol, 2 equiv.), tricyclohexylphosphine (126.3mg, 0.45mmol, 0.2 equiv.) and Pd in portions2(dba)3.CHCl3(466.2mg, 0.45mmol, 0.20 equiv.). The resulting mixture was stirred with microwave stimulation at 140 ℃ under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 20:1) to give 3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000814
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (160mg, 27.9%). LCMS M/z (ESI), [ M + H]+＝255.1。
Step 2.3-amino-6-chloro-5-, (
Figure BDA0002577091620000815
Azol-2-yl) pyrazine-2-carboxylic acid
To 3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000816
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (100mg, 0.4mmol, 1 equivalent) to a stirred solution in MeOH (10mL) and water (1mL) was added lioh 2O (49.4mg, 1.2mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phaseMeOH/water, gradient from 10% to 50% over 35 min; detector, UV 254nm, to give 3-amino-6-chloro-5- (1, 3-) as a yellow solid
Figure BDA0002577091620000817
Oxazol-2-yl) pyrazine-2-carboxylic acid (50mg, 52.9%). LCMS M/z (ESI), [ M + H]+＝241.1，1H NMR(300MHz,DMSO-d6)7.50(d, J＝0.8Hz,1H),8.34(d,J＝0.8Hz,1H)。
Step 3.3-amino-6-chloro-N- (2, 6-difluorobenzyl) -5-, (
Figure BDA0002577091620000818
Azol-2-yl) pyrazine-2-carboxamides
3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000819
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.62mmol, 1 equivalent) and DIEA (241.7mg, 1.87mmol, 3 equivalents) in DMSO (10mL) was added 1- (2, 6-difluorophenyl) methylamine (133.9mg, 0.94mmol, 1.50 equivalents) and HATU (355.6mg, 0.94mmol, 1.5 equivalents) in portions. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2The residue was purified with MeOH 20:1) to give 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] as a yellow solid]-5-(1,3-
Figure BDA00025770916200008110
Oxazol-2-yl) pyrazine-2-carboxamide (compound 05) (140mg, 48.51%). LCMS M/z (ESI), [ M + H ]+＝366.1，1H NMR(300MHz,DMSO-d6)9.10(t,J＝5.7Hz,1H),8.42(s,1H),7.88(s, 2H),7.58(s,1H),7.49-7.28(m,1H),7.10(t,J＝8.0Hz,2H),4.57(d,J＝5.8Hz,2H)。
Step 4.3-amino-N- (2, 6-difluorobenzyl) -6- (2, 6-dimethylpyridin-4-yl) -5-, (
Figure BDA00025770916200008111
Oxazole-2- Yl) pyrazine-2-AAmide (Compound 05)
To (2, 6-dimethylpyridin-4-yl) boronic acid (82.6mg, 550mmol, 2.00 equivalents) and 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl at room temperature under a nitrogen atmosphere]-5-(1,3-
Figure BDA0002577091620000822
Azol-2-yl) pyrazine-2-carboxamide (100mg, 270mmol, 1 eq) in dioxane
Figure BDA0002577091620000823
To a stirred mixture in an alkane (10mL) was added Pd (dppf) Cl in portions2CH2Cl2(44.7mg, 0.05 mmol, 0.2 eq.) and K3PO4(232.2mg, 1.09mmol, 4 equivalents). The resulting mixture was stirred at 90 ℃ overnight under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. By preparative TLC (CH)2Cl2The residue was purified with MeOH 20:1) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- (2, 6-dimethylpyridin-4-yl) -5- (1, 3-)
Figure BDA0002577091620000824
Oxazol-2-yl) pyrazine-2-carboxamide (compound 05) (40mg, 33.2%). LCMS M/z (ESI), [ M + H]+＝437.3；1H NMR(300MHz,DMSO-d6)9.12(t,J＝5.8Hz,1H),8.26(s,1H),7.95(s,2H), 7.46-7.31(m,2H),7.09(t,J＝8.0Hz,2H),7.00(s,2H),4.62(d,J＝5.9Hz,2H),2.40(s,6H)。
The compounds listed in the table below were prepared using the method described for compound 05.
Figure BDA0002577091620000821
EXAMPLE 06.3-amino-N- (2, 6-difluorobenzyl) -6- (2, 6-dimethyl (N-morpholinyl)) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 06)
Scheme 5
Figure BDA0002577091620000831
Step 1.3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group ]-5- (4-fluorophenyl) pyrazine-2-carboxamide
A solution/mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (1.2g, 4.48mmol, 1 equiv.) and 1- (2, 6-difluorophenyl) methylamine (1.0g, 6.99mmol, 1.56 equiv.) in DMF (25mL) was stirred at 15 deg.C under an air atmosphere for 2 hours, the resulting mixture was washed with 3 × 10 volumes of water, the precipitated solid was collected by filtration and washed with ethyl ether (3 × 10mL) to give 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] ethyl ether as a tan solid]-5- (4-fluorophenyl) pyrazine-2-carboxamide (1.3g, 73.82%). LCMS M/z (ESI), [ M + H]+＝393.2。
Step 2.N- [ (tert-butoxy) carbonyl]-N- (5-chloro-3- [ [ (2, 6-difluorophenyl) methyl ] methyl]Carbamoyl radical]-6- (4-fluorophenyl) pyrazin-2-yl) carbamic acid tert-butyl ester
N- [ (tert-butoxy) carbonyl group was added to a 40mL sealed tube at room temperature]-N- (3- [ [ (2, 6-difluorophenyl) methyl group]Carbamoyl radical]A solution of tert-butyl-5- (2, 6-dimethylmorpholin-4-yl) -6- (4-methylphenyl) pyrazin-2-yl) carbamate (500mg, 1.27 mmol, 1 eq), DMAP (13mg, 0.127mmol, 0.1 eq) and di-tert-butyl dicarbonate (687mg, 3.18 mmol, 2.5 eq) in DCM (30 mL). The resulting solution was stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:2) to give N- [ (tert-butoxy) carbonyl as a yellow solid ]-N- (5-chloro-3- [ [ (2, 6-difluorophenyl) methyl ] methyl]Carbamoyl radical]Tert-butyl (6- (4-fluorophenyl) pyrazin-2-yl) carbamate (600mg, 79%). LCMS M/z (ESI), [ M + H]+＝593.3
Step 3.N- [ (tert-butoxy) carbonyl]-N- (3- [ [ (2, 6-difluorophenyl) methyl group]Carbamoyl radical]-5-(2,6- Preparation of dimethylmorpholin-4-yl) -6- (4-fluorophenyl) pyrazin-2-yl) carbamic acid tert-butyl ester
N- [ (tert-butoxy) carbonyl group was added to a 10mL sealed test tube at 100 ℃]-N- (5-chloro-3- [ [ (2, 6-difluorophenyl) methyl ] methyl]Carbamoyl radical]-tert-butyl 6- (4-fluorophenyl) pyrazin-2-yl) carbamate (230mg, 0.39mmol, 1 eq), 2, 6-dimethylmorpholine (134.0mg, 1.16mmol,3 equivalents), Cs2CO3(252.7mg, 0.78mmol, 2 equiv.), 2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl (RuPhos) (36.2mg, 0.08mmol, 0.2 equiv.), 3 rd generation methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos-Palladacycle Gen.3) (32.4mg, 0.04mmol, 0.1 equiv.), and toluene (15mL) for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:2) to give N- [ (tert-butoxy) carbonyl as a yellow solid]-N- (3- [ [ (2, 6-difluorophenyl) methyl group ]Carbamoyl radical]Tert-butyl 5- (2, 6-dimethylmorpholin-4-yl) -6- (4-fluorophenyl) pyrazin-2-yl) carbamate (30mg, 11.51%). LCMS M/z (ESI), [ M-Boc + H]+＝572.3。
Step 4.3-amino-N- (2, 6-difluorobenzyl) -6- (2, 6-dimethyl (N-morpholinyl)) -5- (4-fluorobenzene) Yl) pyrazine-2-carboxamide (Compound 06)
N- [ (tert-butoxy) carbonyl was added to a 50mL round-bottom flask at room temperature]-N- (3- [ [ (2, 6-difluorophenyl) methyl group]Carbamoyl radical]A solution of tert-butyl-5- (2, 6-dimethylmorpholin-4-yl) -6- (4-methylphenyl) pyrazin-2-yl) carbamate (50mg, 0.07 mmol, 1 eq) and TFA (2mL) in DCM (10 mL). The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)4HCOO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 78% B to 78% B within 7 min; 220/254 nm; rt: 6.68min) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- (2, 6-dimethylmorpholin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 06) (2mg, 5.6%). LCMS M/z (ESI), [ M + H]+＝472.3。1H(300MHz, DMSO-d6)1.08(6H,s),2.35(2H,t),3.03(2H,d),3.60(2H,d),4.60(2H,d),7.03-7.15(4 H,m),7.29(2H,t),7.39(1H,q),8.07(2H,t),8.57(1H,t)。
Example 07. preparation of N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl ] methyl ] -2-fluoro-6- (trifluoromethyl) benzamide (Compound 07)
Scheme 6
Figure BDA0002577091620000851
Step 1.3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine
To a mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (500mg, 2.0mmol, 1 eq) in MeOH (100mL) was added NH portionwise4OH (2mL) and Raney nickel (10mg, 0.1mmol, 0.1 equiv.). The mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. This gave 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (560mg, 87.1%) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝253.1。
Step 2.N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzene Carboxamides
To a mixture of 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (210mg, 0.8mmol, 1 eq) and 2-fluoro-6- (trifluoromethyl) benzoic acid (259.4mg, 1.3mmol, 1.5 eq) in DCM (5mL) was added HATU (632.0mg, 1.7mmol, 2 eq) and Et in portions3N (252.3mg, 2.5mmol, 3 equiv.). The mixture was stirred at room temperature under an air atmosphere for 4 hours and quenched with water (10 mL). By CH2Cl2(3 × 20mL) the resulting mixture was extracted with H2The combined organic layers were washed with O (3 × 10mL), anhydrous Na 2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subsequently purified by preparative TLC (PE/EtOAc 2:1) to give N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] as a yellow solid]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzamide (457mg, 49.7%). LCMS M/z (ESI), [ M + H]+＝443.1。
Step 3.N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyri dine Oxazin-2-yl]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzamide (compound 07)
To N- [ [ 3-amino-6-chloro-5- (4-fluorobenzene) under nitrogen atmosphereRadical) pyrazin-2-yl]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzamide (90mg, 200mmol, 1 eq) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (167.3mg, 0.7mmol, 3.5 eq) in bis
Figure BDA0002577091620000862
alkane/H2Pd (dppf) Cl was added in portions to a mixture in O (10mL)2(44.6mg, 0.06mmol, 0.30 equiv.) and K3PO4(258.9mg, 1.2mmol, 6.0 equiv.). The mixture was stirred at 110 ℃ under a nitrogen atmosphere for 10 hours and concentrated in vacuo. The resulting residue was purified by preparative TLC (PE/EtOAc 5:4) to give a residue product, followed by preparative HPLC (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH) 4HCOO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 34% B to 54% B within 7 min; 220/254 nm; rt: 7.08min) to give N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl) as a white solid]Methyl radical]-2-fluoro-6- (trifluoromethyl) benzamide (compound 07) (29mg, 27.1%). LCMS M/z (ESI) [ M + H ]]+＝516.1。1H NMR (400MHz, methanol-d)4)3.53 (s,2H),4.71(s,1H),6.37(d,J＝9.4Hz,1H),7.13(t,J＝8.8Hz,2H),7.31(dd,J＝9.4,2.6Hz, 1H),7.53(dt,J＝8.8,6.0Hz,2H),7.63(d,J＝7.6Hz,1H),7.66-7.71(m,1H),7.76(d,J＝2.5Hz,1H)。
Example 08.
Preparation of N- [ [ 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl ] methyl ] pyridine-2-carboxamide (Compound 08)
Scheme 7
Figure BDA0002577091620000861
Step 1.3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine
3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (500mg, 2.0mmol, 1 am)Amount) was added to MeOH (100mL) and NH was added4OH (2mL), followed by slow addition of raney nickel (10mg, 0.1mmol, 0.1 equiv) to the mixture and stirring at room temperature under a hydrogen atmosphere for 10 h. The resulting mixture was concentrated under reduced pressure. This gave 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (560mg, 87.1%) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝253.2。
Step 2.N- [ [ 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl ]Methyl radical] Pyridine-2-carboxamidesA mixture of 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (45mg, 0.2mmol, 1 eq.) and pyridine-2-carboxylic acid (32.9mg, 0.3mmol, 1.5 eq.) and HAUT (135.4mg, 0.4mmol, 2.0 eq.) and TEA (60.9mg, 0.5mmol, 3.0 eq.) in DCM (3mL) was stirred at room temperature under an air atmosphere for 4 hours.
The resulting mixture was quenched with water (10mL) and CH2Cl2(3 × 20mL) extraction with H2The combined organic layers were washed with O (3 × 10mL), anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subsequently purified by preparative TLC (PE/EtOAc 1:2) to give N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] as a yellow solid]Methyl radical]Pyridine-2-carboxamide (53mg, 79.02%). LCMS M/z (ESI), [ M + H]+＝358.2。
Step 3.N- [ [ 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl]Methyl radical] Preparation of pyridine-2-carboxamide (Compound 08)
To N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] under a nitrogen atmosphere]Methyl radical]Pyridine-2-carboxamide (25mg, 0.1mmol, 1 equiv.) and (2, 6-dimethylpyridin-4-yl) boronic acid (16.2mg, 0.1mmol, 1.5 equiv.) in dioxane
Figure BDA0002577091620000871
alkane/H2To the mixture in O (2.0mL) was added Pd (dppf) Cl2(5.1mg, 0.01mmol, 0.1 equiv.) and K3PO4(44.5mg, 0.21mmol, 3 equiv.). The mixture was stirred at 90 ℃ under a nitrogen atmosphere for 10 hours. By means of preparativeThe residue was purified by TLC (PE/EtOAc 1:1) to give the product as a residue, followed by preparative HPLC (column: Xbridge PrepOBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)4HCOO3+0.1％ NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 36% B to 64% B within 7 min; 220/254 nm; rt: 6.97min) to give N- [ [ 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl) -as a white solid]Methyl radical]Pyridine-2-carboxamide (Compound 08) (6.7mg, 9.4%). LCMS M/z (ESI) [ M + H ]]+＝429.2。1H NMR (400MHz, methanol-d)4)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＝7.9Hz,1H),8.18(d,J＝7.8Hz,1H),8.69 (s,1H)。
Example 09.3 preparation of amino-N- [ [6- (dimethylamino) pyridin-2-yl ] methyl ] -6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 09)
Scheme 8
Figure BDA0002577091620000881
Step 1.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid
To a solution of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (1g, 3.55mol, 1 eq) and (2, 6-dimethylpyridin-4-yl) boronic acid (1.1g, 7.3mol, 2.1 eq) in n-BuOH (25mL) under a nitrogen atmosphere was added x-Phos (0.3g, 0.7mmol, 0.2 eq) and Pd (OAc) 2(0.2g, 0.7mmol, 0.2 equiv.), K3PO4(301.4mg, 1.42mmol, 2 equiv.). The mixture was stirred at 100 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2/MeOH 10:1) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid as a yellow solid (400mg, 33.30%). LCMS M/z (ESI), [ M + H]+＝339.0。
Step 2.3-amino-N- [ [6- (dimethylamino) pyridin-2-yl]Methyl radical]-6-(26-dimethylpyridine-4- Yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 09)
To a solution of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (150mg, 0.4mmol, 1 equivalent), 6- (aminomethyl) -N, N-dimethylpyridin-2-amine (134.1mg, 0.9mmol, 2.0 equivalent), HATU (337.1mg, 0.9mmol, 2 equivalents) in DMF (5mL) was added dropwise DIEA (171.9mg, 1.3mmol, 3 equivalents) within 1min at 15 deg.C, the resulting mixture was stirred for a further 2 h at 15 deg.C, the resulting mixture was concentrated under reduced pressure, the mobile phase A water (0.05% NH) was added by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 49% B to 69% B within 7 min; 254/220 nm; rt: 5.8min) to give 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl ] as a pale yellow solid ]Methyl radical]-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-carboxamide (compound 09) (39.0mg, 18.6%). LCMS M/z (ESI), [ M + H]+＝472.3，1H NMR (400MHz,DMSO-d6)2.33(s,6H),2.97(s,6H),4.48(d,J＝5.6Hz,2H),6.52(dd,J＝10.2, 7.9Hz,2H),6.99(s,2H),7.16-7.26(m,2H),7.37-7.51(m,3H),9.20(t,J＝5.7Hz,1H)。
Example 11.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620000882
Preparation of oxazol-2-yl) -N- ((3- (trifluoromethyl) pyridin-2-yl) methyl) pyrazine-2-carboxamide (Compound 11)
Scheme 9
Figure BDA0002577091620000891
Step 1.3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000892
Azol-2-yl) pyrazine-2-carboxylic acid
To 3-amino-6-chloro-5- (1, 3-)
Figure BDA0002577091620000893
To a solution of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (400mg, 1.57mmol, 1 eq) in MeOH (2mL) and THF (8mL) was added lioh2O (131.8mg, 3.14mmol, 2 equivalents). The resulting mixture was stirred at 40 ℃ under a nitrogen atmosphere for 2 hours. With HCl.H2O adjust the mixture to pH 8. The solvent was removed under reduced pressure. The residue was provided with 3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000894
Oxazol-2-yl) pyrazine-2-carboxylic acid (350 mg, 92.6%). LCMS M/z (ESI), [ M + H]+＝241.1，1H NMR:(300MHz,DMSO-d6)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-
Figure BDA0002577091620000895
Azol-2-yl) -N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical] Pyrazine-2-carboxamides
To 3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000896
Azol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.62mmol, 1 eq) in DCM (15mL) was added 1- [3- (trifluoromethyl) pyridin-2-yl in portions ]Methylamine (219.6mg, 1.25mmol, 2 equiv.), HOBT (168.5mg, 1.25mmol, 2 equiv.), and EDC.HCl (239.0mg, 1.25mmol, 2 equiv.) for 5 min. The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000897
Azol-2-yl) -N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (20mg, 8.1%). LCMS M/z (ESI), [ M + H]+＝399.1；1H NMR:(300MHz,MeOD)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-
Figure BDA0002577091620000898
Azol-2-yl) - N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamides (Compound 11)
To 3-amino-6-chloro-5- (1, 3-)
Figure BDA0002577091620000899
Azol-2-yl) -N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (20mg, 0.05mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (23.6mg, 0.10mmol, 2.00 equiv.) in 1, 4-dihydropyridin-2-one
Figure BDA00025770916200008910
Pd (dppf) Cl was added in portions to a mixture in an alkane (5mL)2(7.3mg, 0.01mmol, 0.20 equiv.) and Cs2CO3(32.7mg, 0.10mmol, 2 equivalents). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 min. The resulting mixture was stirred at 90 ℃ under nitrogen for 2 hours and concentrated in vacuo. By preparative HPLC with the following conditions (column: Xbridge Prep C18OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10 MMOL/LNH) 4HCOO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 30% B to 40% B within 7 min; 254,220 nm; rt: 6.55 min) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000902
Azol-2-yl) -N- [ [3- (trifluoromethyl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 11) (2mg, 8.5%). LCMS M/z (ESI), [ M + H]+＝472.3，1H NMR:(300MHz,MeOD)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-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 13)
Scheme 10
Figure BDA0002577091620000901
Step 1.3-amino-N- [ [6- (dimethylamino) pyridin-2-yl]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl- Preparation of 6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide
To a stirred mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (350mg, 1.308mmol, 1 eq) and 6- (aminomethyl) -N, N-dimethylpyridin-2-amine (296.62mg, 1.962mmol, 1.5 eq) in DMF (20mL) was added HATU (994.47mg, 2.615mmol, 2 eq) and DIEA (338.03mg, 2.615mmol, 2 eq) in portions at 15 ℃ under an air atmosphere. The resulting mixture was stirred for 3 hours and quenched with 50mL of water. The resulting solid was collected by filtration and dried under reduced pressure to give 3-amino-6-chloro-N- [ [6- (dimethylamino) pyridin-2-yl ] as a pale yellow solid ]Methyl radical]-5- (4-fluorophenyl) pyrazine-2-carboxamide (300mg, 57.23%). LCMS M/z (ESI), [ M + H]+＝401.2。
Step 2.3-amino-N- [ [6- (dimethylamino) pyridin-2-yl]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl- Preparation of 6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 13)
To 3-amino-6-chloro-N- [ [6- (dimethylamino) pyridin-2-yl ] amine under a nitrogen atmosphere]Methyl radical]-5- (4-fluorophenyl) pyrazine-2-carboxamide (50mg, 0.12mmol, 1 equiv.) and (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) boronic acid (28.6mg, 0.19mmol, 1.50 equiv.) in water (0.2mL) and bis
Figure BDA0002577091620000903
Addition of Cs to a solution in alkane (1.8mL)2CO3(81.3mg, 0.25mmol, 2 equiv.) and Pd (dppf) Cl2(9.1mg, 0.01mmol, 0.1 equiv.) the resulting mixture was stirred at 90 ℃ under nitrogen atmosphere for 2 h and concentrated under reduced pressure. By preparative HPLC with the following conditions (column: XBridge)PrepOBD C18 column 30 × 150mm 5 μm, mobile phase A water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 40% B to 48% B within 7 min; 254/220 nm; rt: 5.37 min) to give 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl ] as a pale yellow solid ]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 13) (12mg, 20.3%).
LCMS:m/z(ESI),[M+H]+＝474.2，1H NMR(400MHz,DMSO-d6)3.0(s,5H),3.4(s,2H),4.5(d,J＝5.9Hz,1H),6.2(d,J＝9.3Hz,1H),6.4-6.5(m,1H),7.3(t,J＝8.8Hz,1H),7.5 (t,J＝7.9Hz,1H),7.5(t,J＝7.1Hz,2H),7.9(d,J＝2.5Hz,1H),9.3(s,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 13.
Figure BDA0002577091620000911
Example 14.3-amino-N- ((3-fluoropyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620000912
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 14)
Scheme 11
Figure BDA0002577091620000921
And (1).3- ((di-tert-butoxycarbonyl) amino) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) - 5-(
Figure BDA0002577091620000922
Azol-2-yl) pyrazine-2-carboxylic acid methyl ester
3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000923
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (80mg, 0.2mmol, 1 eq.) and (Boc)2O (160.0mg, 0.7mmol, 3.0 equivalents) was added DMAP (5.97mg, 0.049mmol, 0.2 equivalents) portionwise to a stirred mixture in DCM (2 mL). The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH20:1) to give 3- [ bis [ (tert-butoxy) carbonyl ] as a pale yellow oil]Amino group]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000924
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (84mg, 65.2%). LCMS M/z (ESI), [ M + H ]+＝528。
And 2. step 2.3- ((di-tert-butoxycarbonyl) amino) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) - 5-(
Figure BDA0002577091620000925
Azol-2-yl) pyrazine-2-carboxylic acid
To 3- [ bis [ (tert-butoxy) carbonyl ] group at room temperature under an air atmosphere]Amino group]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000926
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (84mg, 0.2mmol, 1 eq) in MeOH (5mL) was added LiOH (7.6mg, 0.3mmol, 2 eq) portionwise. The resulting mixture was stirred at 50 ℃ for a further 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH20:1) to give 3- [ bis [ (tert-butoxy) carbonyl ] as a yellow solid]Amino group]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000927
Oxazol-2-yl) pyrazine-2-carboxylic acid (75mg, 91.7%). LCMS M/z (ESI), [ M + H]+＝514.1。
And 3. step 3.(3- (((3-fluoropyridin-2-yl) methyl) carbamoyl) -5- (1-methyl-6-oxo-1, 6-dihydro Pyridin-3-yl) -6-, (
Figure BDA0002577091620000931
Azol-2-yl) pyrazin-2-yl) carbamic acid di-tert-butyl ester
To 3- [ bis [ (tert-butoxy) carbonyl ] group at room temperature under an air atmosphere]Amino group]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000932
Azol-2-yl) pyrazine-2-carboxylic acid (81mg, 0.16mmol, 1 equiv.) and 1- (3-fluoropyridin-2-yl) methylamine (39.8mg, 0.3mmol, 2.0 equiv.) are added in portions to a stirred mixture in DMF (2mL) HATU (120.0 mg, 0.3mmol, 2 equiv.) and DIEA (61.2mg, 0.47mmol, 3 equiv.) the resulting mixture is stirred at room temperature for an additional 6 hours, the resulting mixture is quenched with water (20mL) and extracted with EtOAc (3 × 50mL), the combined organic layers are washed with water (3 × 50mL), anhydrous Na 2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives N- [ (tert-butoxy) carbonyl as a yellow solid]-N- (3- [ [ (3-fluoropyridin-2-yl) methyl)]Carbamoyl radical]-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (1,3-
Figure BDA0002577091620000933
Oxazol-2-yl) pyrazin-2-yl) carbamic acid tert-butyl ester (80mg, 81.6%) which was used directly in the next step without further purification. LCMS M/z (ESI), [ M-Boc + H]+＝522.3。
And 4. step 4.3-amino-N- ((3-fluoropyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (
Figure BDA0002577091620000934
Azol-2-yl) pyrazine-2-carboxamide (Compound 14)
To N- [ (tert-butoxy) carbonyl group at room temperature under an air atmosphere]-N- (3- [ [ (3-fluoropyridin-2-yl) methyl)]Carbamoyl radical]-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (1,3-
Figure BDA0002577091620000935
Oxazol-2-yl) pyrazin-2-yl) carbamic acid tert-butyl ester (70 mg, 0.11mmol, 1 equiv.) and TFA (2mL) were added in portions to a stirred solution/mixture in DCM (2 mL). The resulting mixture was stirred at room temperature for a further 0.5 h. The resulting mixture was concentrated under reduced pressure. The residual water dispersed in MeOH (4mL) NH was added portionwise at room temperature under an air atmosphere3.H2O (4mL). The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (4mL). The residue was purified by preparative TLC (DCM/MeOH 20:1) to give 3-amino-N- [ (3-fluoropyridin-2-yl) methyl) as a yellow solid ]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000936
Oxazol-2-yl) pyrazine-2-carboxamide (compound 14) (22mg, 45.9%). LCMS M/z (ESI), [ M + H]+＝422.2。1H NMR(DMSO-d6,400MHz)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 15.3-amino-N- [ [6- (dimethylamino) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000937
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 15)
Scheme 12
Figure BDA0002577091620000941
Step 1.6- (dimethylamino) pyridine-2-carbonitrile
To a solution of 6-bromopyridine-2-carbonitrile (2g, 10.9mmol, 1 eq) in THF (25mL) was added dimethylamine (3.0g, 65.6mmol, 6 eq). The solution was stirred at 80 ℃ for 12 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (5:1) to give 6- (dimethylamino) pyridine-2-carbonitrile as a pale yellow solid (1.1g, 68.4%). LCMS M/z (ESI), [ M + H]+＝148.2
Step 2.6- (aminomethyl) -N, N-dimethylpyridin-2-amine
To a solution of 6- (dimethylamino) pyridine-2-carbonitrile (1.1g, 7.5mmol, 1 eq) in MeOH (50mL), NH at room temperature3.H2Raney nickel (64.03mg, 0.747mmol, 0.10 equiv.) was added to a mixture of O (0.3g, 7.5mmol, 1 equiv.). The mixture was stirred at 20 ℃ under a hydrogen atmosphere for 30 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 6- (aminomethyl) -N, N-dimethylpyridin-2-amine (1g, 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 radical]-6- (1-methyl-6-oxo-1, 6-di Hydropyrid-3-yl) -5- (1,3-
Figure BDA0002577091620000942
Azol-2-yl) pyrazine-2-carboxamide (Compound 15)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000943
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.32mmol, 1 equiv.) and 6- (aminomethyl) -N, N-dimethylpyridin-2-amine (72.4mg, 0.48mmol, 1.5 equiv.) to a mixture in DMF (3mL) was added HATU (243mg, 0.64mmol, 2 equiv.) and DIEA (118mg, 0.96mmol, 3 equiv.) in portions the mixture was stirred at 15 ℃ under air atmosphere for 10min, the precipitated solid was collected by filtration and washed with water (3 × 10 mL.) the resulting solid was dried under infrared light to give 3-amino-N- [ [6- (dimethylamino) pyridin-2-yl as a pale yellow solid]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000944
Oxazol-2-yl) pyrazine-2-carboxamide (compound 15) (66.1mg, 46.4%).
LCMS:m/z(ESI),[M+H]+＝447.2。1H NMR(400MHz,DMSO-d6)2.9(s,5H),3.3(s,2H),4.4(d,J＝5.7Hz,2H),6.3(d,J＝9.3Hz,1H),6.5(dd,J＝9.2,7.9Hz,2H),7.3-7.4(m,2H),7.46(dd,J＝8.5,7.3Hz,1H),7.8(s,1H),8.0(d,J＝2.6Hz,1H),8.3(d,J＝0.8Hz,1H),9.3(t,J＝5.7Hz,1H)。
Example 16.3-amino-N- ((3- (dimethylamino) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620000952
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 16)
Scheme 13
Figure BDA0002577091620000951
Step 1.2- (aminomethyl) -N, N-dimethylpyridin-4-amine
To a solution of 4- (dimethylamino) pyridine-2-carbonitrile (200mg, 1.4mmol, 1 eq) in MeOH (5mL) was added NH3.H2O (0.1mL, 2.6mmol, 1.9 equiv.). The resulting mixture was stirred at 15 ℃ under a hydrogen atmosphere for 30 min. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2- (aminomethyl) -N, N-dimethylpyridin-4-amine (190mg, 92.5%) as a brown solid. LCMS M/z (ESI), [ M + H]+＝152.2。
Step 2.3-amino-N- ((3- (dimethylamino) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-di Hydropyridin-3-yl) -5-, (
Figure BDA0002577091620000953
Azol-2-yl) pyrazine-2-carboxamide (Compound 16)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000954
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.32mmol, 1 eq) and 2- (aminomethyl) -N, N-dimethylpyridin-3-amine (72.4mg, 0.48mmol, 1.5 eq) were added to a mixture in DMF (5mL) in portions HATU (242.7mg, 0.64mmol, 2 eq) and DIEA (165.12mg, 1.28mmol, 4 eq). The mixture was stirred at 15 ℃ for 60min under an air atmosphere and water was added(15 mL) quench the precipitated solid was collected by filtration and washed with water (3 × 100mL) 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- (3-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (as a yellow solid
Figure BDA0002577091620000955
Oxazol-2-yl) pyrazine-2-carboxamide (compound 16) (50.6mg, 35.5%). LCMS M/z (ESI), [ M + H]+＝447.2，1H NMR (400MHz, methanol-d)4)-0.05(s,1H),1.2(s,1H),2.7(s,6H),3.3(s,3H),4.7 (d,J＝5.5Hz,2H),6.3(d,J＝9.4Hz,1H),7.3(dd,J＝8.1,4.7Hz,1H),7.3-7.4(m,2H),7.5 (dd,J＝8.1,1.5Hz,1H),7.8(s,1H),8.0(d,J＝2.6Hz,1H),8.2(dd,J＝4.7,1.4Hz,1H),8.3(d, J＝0.7Hz,1H),9.3(t,J＝5.5Hz,1H)。
Example 17.3-amino-N- ((6-methoxypyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620000962
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 17)
Scheme 14
Figure BDA0002577091620000961
Step 1.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000963
Azol-2-yl) pyrile Oxazine-2-carboxylic acid esters
3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000964
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1g, 3.93 mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (1.8g, 7.85mmol, 2 equiv.) in 1, 4-bis
Figure BDA0002577091620000965
Cs was added in portions to a stirred mixture in an alkane (50mL)2CO3(2.6g, 7.85mmol, 2 equiv.) and Pd (dppf) Cl2CH2Cl2(0.5g, 0.59mmol, 0.15 equiv.). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 3 hours. Filtering the resulting mixture with CH2Cl2(1 × 200mL) washing the filter cake, the filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography eluting with DCM/PE (0-100%) after EA/DCM (0-10%) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000966
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1.1g, 85.58%). LCMS M/z (ESI), [ M + H]+＝328.0。1H NMR(300MHz,DMSO-d6)3.47(s,3H),3.91(s,3H),6.36(d,J＝9.4Hz,1H),7.35(dd,J＝9.3,2.6Hz,1H),7.43(d,J＝0.8Hz,1H),7.63(s,2H),7.85(d,J＝2.6Hz,1H),8.32(d,J＝0.8Hz,1H)
Step 2.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000967
Azol-2-yl) pyrile 2-oxazinecarboxylic acid
3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000968
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (7g, 21.39mmol, 1 eq) to a stirred mixture in THF (500mL) and methanol (100mL) was added portionwise a solution of LiOH (1024.4mg, 42.77mmol, 2 eq) in water (20 mL). The resulting mixture was stirred at 35 ℃ under an air atmosphere for 3 hours. The mixture was neutralized to pH 6 with HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000969
Oxazol-2-yl) pyrazine-2-carboxylic acid (6.3g, 94.03%). 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-dihydropyrazine Pyridin-3-yl) -5- (1,3-
Figure BDA00025770916200009610
Azol-2-yl) pyrazine-2-carboxamide (Compound 17)
To HATU (24.3mg, 0.06mmol, 2 equiv.) and 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000972
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (10mg, 0.03mmol, 1 eq) in DMF (5mL) was added DIEA (10.3mg, 0.08mmol, 2.5 eq) portionwise. The resulting mixture was stirred at room temperature for 5 min. 1- (6-methoxypyridin-2-yl) methylamine (6.6mg, 0.05mmol, 1.5 eq) was added portionwise. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and passed through preparative TLC (CH) 2Cl2MeOH 3:1) to give 3-amino-N- [ (6-methoxypyridin-2-yl) methyl as a yellow solid]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000973
Oxazol-2-yl) pyrazine-2-carboxamide (compound 17) (30mg, 27.10%). LCMS M/z (ESI), [ M + H]+＝434.0，1H NMR(300MHz,DMSO-d6)9.36 (t,J＝6.1Hz,1H),8.29(d,J＝0.8Hz,1H),8.02(d,J＝2.6Hz,1H),7.79(s,2H),7.65(t,J＝7.8Hz,1H),7.48-7.32(m,2H),6.90(d,J＝7.3Hz,1H),6.68(d,J＝8.2Hz,1H),6.31(d,J＝9.4Hz,1H),4.53(d,J＝6.0Hz,2H),3.81(s,3H),3.45(s,3H)。
Example 18.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (6-methylpyridin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620000974
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 18)
Scheme 15
Figure BDA0002577091620000971
Step 1.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000975
Azol-2-yl) pyrile Oxazine-2-carboxylic acid methyl ester
3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620000976
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1.1g, 4.32 mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (2.0g, 8.64mmol, 2 equiv.) in 1, 4-bis
Figure BDA0002577091620000977
Pd (dppf) Cl was added to a mixture in an alkane (40mL)2(0.3 g, 0.43mmol, 0.1 equiv.) and Cs2CO3(2.8g, 8.64mmol, 2 equiv.). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 2 hours and concentrated in vacuo. Purifying the residue by silica gel column chromatography using CH2Cl2MeOH (4%) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000978
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1g, 70.72%). LCMS M/z (ESI), [ M + H]+＝328.0。1HNMR:(400 MHz,DMSO-d6)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-
Figure BDA0002577091620000979
Azol-2-yl) pyrile 2-oxazinecarboxylic acid
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000982
To a solution of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1g, 3.06mmol, 1 eq) in MeOH (30mL) THF (10mL) was added LiOH (0.1g, 6.11mmol, 2.00 eq). The resulting mixture was stirred at 40 ℃ under an air atmosphere for 2 hours. The mixture was adjusted to pH 5 with HCl. The solvent was removed under reduced pressure to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000983
Oxazol-2-yl) pyrazine-2-carboxylic acid (800mg, 83.58%). LCMS M/z (ESI), [ M + H]+＝314.0。1H NMR:(400MHz,DMSO-d6)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- Radical) methyl]-5-(1,3-
Figure BDA0002577091620000984
Azol-2-yl) pyrazine-2-carboxamide (Compound 18)
3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000985
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.32mmol, 1 eq) and HATU (242.7mg, 0.64mmol, 2 eq) and DIEA (123.8mg, 0.96mmol, 3 eq) in DMF (5mL) was added 1- (6-methylpyridin-2-yl) methylamine (58.5mg, 0.48mmol, 1.5 eq) in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The mixture was poured into water, filtered, the solid collected by filtration and washed with MeOH (10mL) Vacuum drying to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (6-methylpyridin-2-yl) methyl ] amide as a yellow solid]-5-(1,3-
Figure BDA0002577091620000986
Oxazol-2-yl) pyrazine-2-carboxamide (compound 18) (24mg, 18.01%). LCMS M/z (ESI), [ M + H]+＝418.3。1H NMR(400MHz,DMSO-d6)3.48(s,3H),4.58(d,J＝6.1Hz, 2H),6.33(d,J＝9.4Hz,1H),7.15(d,J＝7.7Hz,2H),7.36～7.47(m,2H),7.65(t,J＝7.7Hz,1H),7.81(s,2H),8.06(d,J＝2.6Hz,1H),31(d,J＝0.8Hz,1H),82.47(s,3H),9.45(t,J＝6.1 Hz,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 18.
Figure BDA0002577091620000981
Figure BDA0002577091620000991
Example 19.3-amino-N- [ [3- (difluoromethoxy) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620000993
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 19)
Scheme 16
Figure BDA0002577091620000992
Step 1.1- [3- (difluoromethoxy) pyridin-2-yl]Methylamine
To a stirred mixture of 3- (difluoromethoxy) pyridine-2-carbonitrile (70mg, 0.41mmol, 1 eq) and Raney nickel (7.1mg, 0.1mmol, 0.2 eq) in MeOH (5mL) was added NH portionwise at room temperature3.H2O (1mL), the resulting mixture was stirred at room temperature under an atmosphere of hydrogen for an additional 3 hours, the resulting mixture was filtered, washed with MeOH (3 × 10mL)And washing the filter cake. The filtrate was concentrated under reduced pressure. This gives 1- [3- (difluoromethoxy) pyridin-2-yl as a purple oil]Methylamine (50mg, 69.7%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H ]+＝175.2。
Step 2.3-amino-N- [ [3- (difluoromethoxy) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6- Dihydropyridin-3-yl) -5- (1, 3-)
Figure BDA0002577091620001002
Azol-2-yl) pyrazine-2-carboxamide (Compound 19)
Reaction of 1- [3- (difluoromethoxy) pyridin-2-yl at room temperature under an air atmosphere]Methylamine (41.7mg, 0.24mmol, 1.5 equiv.) and 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001003
Azol-2-yl) pyrazine-2-carboxylic acid (50mg, 0.16mmol, 1 equiv.) to a stirred solution/mixture in DMF (4mL) was added HATU (242.7mg, 0.64mmol, 4 equiv.) and DIEA (82.5mg, 0.64mmol, 4 equiv.) dropwise, the resulting mixture was stirred at room temperature for a further 0.5 h, the resulting mixture was added dropwise to water (200mL), the resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10mL), which gave 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001004
Azol-2-yl) pyrazine-2-carboxylic acid [3- (difluoromethoxy) pyridin-2-yl]Methyl ester (compound 19) (18mg, 23.7%). LCMS M/z (ESI), [ M + H]+＝470.2。1H NMR(DMSO,400MHz)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)
Scheme 17
Figure BDA0002577091620001001
Step 1.N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl]Methyl radical]-3- (difluoromethoxy) pyridine- 2-carboxamides
To a mixture of 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (40mg, 0.16mmol, 1 eq) and 3- (difluoromethoxy) pyridine-2-carboxylic acid (59.9mg, 0.32mmol, 2.0 eq) in DCM (2.5mL) were added HATU (120.4mg, 0.32mmol, 2 eq) and TEA (48.1mg, 0.5mmol, 3 eq) and stirred at room temperature under an air atmosphere for 6 hours. The resulting mixture was quenched with water (20mL) and CH2Cl2extract (3 × 20mL) with H2the combined organic layers were washed with O (3 × 310 mL) and anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc1:1) to give N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] as a yellow solid]Methyl radical]-3- (difluoromethoxy) pyridine-2-carboxamide (30mg, 42.5%). LCMS M/z (ESI), [ M + H]+＝424.1。
Step 2.N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyri dine Oxazin-2-yl]Methyl radical]-3- (difluoromethoxy) pyridine-2-carboxamide (Compound 21)
To N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl group ]Methyl radical]-3- (difluoromethoxy) pyridine-2-carboxamide (30mg, 0.07mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (33.3mg, 0.14mmol, 2.0 equiv.) in dioxane
Figure BDA0002577091620001012
alkane/H2To the mixture in O (1mL) was added Pd (dppf) Cl2(10.4mg, 0.01mmol, 0.2 eq.) and K3PO4(45.1mg, 0.21mmol, 3 equiv.) and stirred at 90 ℃ under nitrogen atmosphere for 10 h. The residue was purified by preparative TLC (PE/EtOAc 1:1) followed by preparative HPLC (column: Xbridge Prep C18OBD column, 5 μm, 19 x 150 mm; mobile phase A: water (10 MMOL/LNH)4HCOO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 25% B to 27% B within 8 min; 254,220 nm; rt: 7.32min) to give N- [ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl) as a white solid]Methyl radical]-3- (difluoromethoxy) pyridine-2-carboxamide (Compound 21) (2.7mg, 7.61%). LCMS M/z (ESI) [ M + H ]]+＝497.2。1H NMR (400MHz, methanol-d)4)3.52(s,2H),4.70(s,1H),7.08-7.23(m,1H),7.33(dd,J＝9.4, 2.6Hz,1H),7.45-7.55(m,1H),7.65(dd,J＝8.4,4.6Hz,1H),7.74-7.84(m,1H),8.56(dd,J ＝4.6,1.3Hz,1H)。
Example 23.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ [6- (methylamino) pyridin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620001013
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 23)
Scheme 18
Figure BDA0002577091620001011
Step 1.6- (methylamino) pyridine-2-carbonitrile
To a solution of 6-bromopyridine-2-carbonitrile (500mg, 2.7mmol, 1 eq) in THF (10mL) was added methylamine (424.3mg, 13.6mmol, 5.0 eq) at room temperature and stirred at 80 ℃ under an air atmosphere for 6 h. The residue was purified by preparative TLC (PE/EtOAc 5:1) to give 6- (methylamino) pyridine-2-carbonitrile as a white solid (80mg, 21.9%). LCMS M/z (ESI), [ M + H]+＝134.3。
Step 2.6- (aminomethyl) -N-methylpyridin-2-amine
To a stirred mixture of 6- (methylamino) pyridine-2-carbonitrile (80mg, 0.6mmol, 1 eq) and Raney nickel (51.5mg, 0.6mmol, 1.0 eq) in MeOH (5mL) was added NH portionwise at room temperature3.H2O (21.1mg, 0.60mmol, 1 equiv.). Stirring the obtained mixture at 15 deg.C under hydrogen atmosphere for 30min and concentrating under reduced pressure to obtain6- (aminomethyl) -N-methylpyridin-2-amine as a white solid (60mg, 72.8%). LCMS M/z (ESI), [ M + H]+＝ 137.1。
Step 3.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ [6- (methylamino) pyridine- 2-radical]Methyl radical]-5-(1,3-
Figure BDA0002577091620001021
Azol-2-yl) pyrazine-2-carboxamide (Compound 23)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001022
Oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.22mmol, 1 eq) and 6- (aminomethyl) -N-methylpyridin-2-amine (46.0mg, 0.3mmol, 1.5 eq) were added to a stirred solution/mixture in DMF (3mL) dropwise/portionwise HATU (169.9mg, 0.5mmol, 2 eq) and DIEA (86.6mg, 0.6mmol, 3 eq) and stirred at 15 ℃ under an air atmosphere for 10 min. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 x 150mm 5 μm; mobile phase A: water (0.05% NH) 3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 20% B to 28% B within 7 min; 254/220 nm; rt: 6.5min) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ [6- (methylamino) pyridin-2-yl ] -as a yellow solid]Methyl radical]-5-(1,3-
Figure BDA0002577091620001023
Oxazol-2-yl) pyrazine-2-carboxamide (compound 23) (8mg, 8.3%). LCMS M/z (ESI), [ M + H]+＝433.2。1H NMR (400MHz, methanol-d)4)2.8(s,2H),3.6(s,2H),4.5(s,1H),6.4(d,J＝8.2Hz,1H),6.4-6.6(m,1H),7.3-7.4(m, 1H),7.5(dd,J＝9.3,2.6Hz,1H),8.0(d,J＝2.5Hz,1H),8.0(d,J＝0.8Hz,1H)。
Example 24.3-amino-N- [ (6-aminopyridin-2-yl) methyl]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001024
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 24)
Scheme 19
Figure BDA0002577091620001031
Step 1.6- (aminomethyl) pyridin-2-amine
To a solution of 6-aminopyridinecarbonitrile (100mg, 0.84mmol, 1 eq) in 20mL MeOH in a 50mL round bottom flask under a nitrogen atmosphere was added Raney nickel (10mg, 0.12mmol, 0.14 eq). The mixture was hydrogenated using a hydrogen balloon under a hydrogen atmosphere at room temperature for 1.5 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give 6- (aminomethyl) pyridin-2-amine (100mg, 96.73%) as a brown oil. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝124.0。
Step 2.3-amino-N- [ (6-aminopyridin-2-yl) methyl ]-6- (1-methyl-6-oxo-1, 6-dihydropyrazine Pyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001032
Azol-2-yl) pyrazine-2-carboxamide (Compound 24)
3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001033
Oxazol-2-yl) pyrazine-2-carboxylic acid (381.5mg, 1.22mmol, 1.5 equiv.) and HATU (617.5mg, 1.62mmol, 2 equiv.) are added portionwise to a stirred mixture in DMF (15.0mL) with DIEA (314.8mg, 2.44mmol, 3 equivalents) and 6- (aminomethyl) pyridin-2-amine (100mg, 0.81mmol, 1 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography on CH2Cl2MeOH (20:1) to give 3-amino-N- [ (6-aminopyridin-2-yl) methyl as a yellow solid]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001034
Oxazol-2-yl) pyrazine-2-carboxamide (compound 24) (57mg, 16.43%). LCMS M/z (ESI), [ M + H]+＝419.0。1H NMR(400MHz,DMSO-d6)3.48(s,3H), 4.39(d,J＝6.2Hz,2H),5.92(s,2H),6.32(dd,J＝8.8,3.8Hz,2H),6.42(d,J＝7.3Hz,1H), 7.28～7.40(m,2H),7.42(s,1H),7.83(s,2H),8.07(d,J＝2.6Hz,1H),8.31(s,1H),9.26(t,J＝6.2Hz,1H)。
Example 25.3-amino-N- ((4- (dimethylamino) pyrimidin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001035
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 25)
Scheme 20
Figure BDA0002577091620001041
Step 1.4- (dimethylamino) pyrimidine-2-carbonitrile
4-bromopyrimidine-2-carbonitrile (980mg, 5.3mmol, 1 equiv.) and NHMe were added at 80 deg.C in a 40mL sealed tube 2A solution of (15mL, 30.00mmol, 5.6 equiv.) in THF (10mg) was maintained for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexanes/EtOAc (1:1) to give 4- (dimethylamino) pyrimidine-2-carbonitrile as a white solid (700mg, 88.7%). LCMS M/z (ESI), [ M + H]+＝149.2。
Step 2.2- (aminomethyl) -N, N-dimethylpyrimidin-4-amine
To a stirred mixture of 4- (dimethylamino) pyrimidine-2-carbonitrile (80mg, 0.5mmol, 1 eq) and raney nickel (9.3mg, 0.1mmol, 0.2 eq) in MeOH (5mL) was added NH dropwise at room temperature4OH (1 mL.) the resulting mixture was stirred at room temperature under an atmosphere of hydrogen for an additional 1 h, the resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10mL), the filtrate was concentrated under reduced pressure to give 70mg of a brown oil, the crude product was used directly in the next step without further purification, LCMS: m/z: (R) ((R))ESI),[M+H]+＝153.2。
Step 3.3-amino-N- [ [4- (dimethylamino) pyrimidin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-di Hydropyrid-3-yl) -5- (1,3-
Figure BDA0002577091620001042
Azol-2-yl) pyrazine-2-carboxamide (Compound 25)
3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001043
Azol-2-yl) pyrazine-2-carboxylic acid (50mg, 0.16mmol, 1 equiv.) and 2- (aminomethyl) -N, N-dimethylpyrimidin-4-amine (36.4mg, 0.2mmol, 1.5 equiv.) are added in portions to a stirred mixture in DMF (5mL) DIEA (82.5mg, 0.64mmol, 4 equiv.) and HATU (242.7mg, 0.6mmol, 4 equiv.) the resulting mixture is stirred at room temperature for a further 30min, the resulting mixture is added to water and filtered, the filter cake is washed with EtOAc (3 × 5mL) and MeOH (2 × 5mL) the crude product is recrystallized from water/DMF (5:1mL) to give 3-amino-N- [ [4- (dimethylamino) pyrimidin-2-yl) as a yellow solid ]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001044
Oxazol-2-yl) pyrazine-2-carboxamide (compound 25) (14mg, 19.41%). LCMS M/z (ESI), [ M + H]+＝448.3。1H NMR(DMSO,400MHz)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 26.3-amino-N- [ [6- (azetidin-1-yl) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001052
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 26)
Scheme 21
Figure BDA0002577091620001051
Step 1.6- (azetidin-1-yl) pyridine-2-carbonitrile
6-bromopyridine-2-carbonitrile (500mg, 2.732mmol, 1 equiv.), azetidine (202.79mg, 3.552mmol, 1.30 equiv.) and K were added at room temperature to a 40mL sealed tube2CO3(755.19mg, 5.464mmol, 2.00 equiv.) in DMF (20 mL). The mixture was stirred at 80 ℃ for 2 hours and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with PE/EtOAc (1:1) to give 6- (azetidin-1-yl) pyridine-2-carbonitrile as a white solid (400mg, 91.97%). LCMS M/z (ESI), [ M + H]+＝160.2。
Step 2.1- [6- (azetidin-1-yl) pyridin-2-yl]Methylamine
A50 mL round bottom flask was charged with Raney nickel (40mg, 0.47mmol, 0.32 equiv.) and 6- (azetidin-1-yl) pyridine-2-carbonitrile (230mg, 1.44mmol, 1 equiv.) in MeOH (20mL) at room temperature. Mixing the mixture with H 2Stirred under atmosphere for 2 hours. Raney nickel is removed by filtration. The filtrate was concentrated under reduced pressure to give 1- [6- (azetidin-1-yl) pyridin-2-yl as a yellow oil]Methylamine (200mg, 84.81%), which was used in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝164.2。
Step 3.3-amino-N- [ [6- (azetidin-1-yl) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo Substituted-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001053
Azol-2-yl) pyrazine-2-carboxamide (Compound 26)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001054
Azol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.26mmol, 1 eq.) and 1- [6- (azetidin-1-yl) pyridin-2-yl]Methylamine (62.9mg, 0.39mmol, 1.5 equiv.) in DMF (5mL) was added to HATU (R) (N-dimethylformamide)195.4mg, 0.51mmol, 2 equivalents) and DIEA (99.6mg, 0.77mmol, 3 equivalents). The resulting mixture was stirred for 60min and concentrated in vacuo. By preparative HPLC with the following conditions (column: Xbridge Prep C18OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10 MMOL/LNH)4HCO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 25% B to 43% B within 7 min; 254,220 nm; rt: 6.68min) to give 3-amino-N- [ [6- (azetidin-1-yl) pyridin-2-yl ] as a yellow solid ]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001062
Oxazol-2-yl) pyrazine-2-carboxamide (compound 26) (11mg, 9.40%). LCMS M/z (ESI), [ M + H]+＝459.3。1HNMR(300MHz,DMSO-d6)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 27.3-amino-N- (5- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001063
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 27)
Scheme 22
Figure BDA0002577091620001061
Step 1.5 preparation of (dimethylamino) -2-fluorocyclohexane-1, 3-diene-1-carbonitrile
To a solution of 5-amino-2-fluorobenzonitrile (2g, 14.69mmol, 1 eq) in DMF (40mL) at 0 deg.C was added NaH (1057.7mg, 44.08mmol, 3 eq). After stirring for 5min, MeI (8341.4mg, 58.77mmol, 4 equiv.) was added dropwise at 0 ℃. The resulting solution was stirred at 0 ℃ for 2 hours and treated with NH4quenched with saturated aqueous Cl (50mL) the resulting solution was extracted with 3 × 50mL ethyl acetate, dried over anhydrous sodium sulfate and evaporatedAnd (5) performing empty concentration. The residue was applied to a silica gel column together with dichloromethane/methanol (40: 1). This gave 1.2g (49.75%) of 5- (dimethylamino) -2-fluorocyclohexane-1, 3-diene-1-carbonitrile as a light yellow solid. LCMS M/z (ESI), [ M + H]+＝ 165.2。1HNMR(400MHz,DMSO-d6)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 nickel (52.18mg, 0.609mmol, 0.20 equiv.) and 5- (dimethylamino) -2-fluorobenzonitrile (500mg, 3.045mmol, 1 equiv.) in MeOH (50mL) in a 250mL round bottom flask was added NH4OH (2mL, 51.361mmol, 16.87 equiv.). The resulting solution was stirred at room temperature under a hydrogen atmosphere for 2 hours. The raney nickel is filtered off. The filtrate was concentrated to give 400mg (78.08%) of 3- (aminomethyl) -4-fluoro-N, N-dimethylbenzylamine as a solid. LCMS M/z (ESI), [ M-NH ]2]+＝152.3。1HNMR(400MHz,DMSO-d6)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-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyrazine Pyridin-3-yl) -5-, (
Figure BDA0002577091620001072
Azol-2-yl) pyrazine-2-carboxamide (Compound 27)
To a 25mL round bottom flask 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001073
To a mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (50mg, 0.16mmol, 1 eq) and 3- (aminomethyl) -4-fluoro-N, N-dimethylaniline (32.2mg, 0.19mmol, 1.20 eq) in DMF (10mL) was added TEA (48.5mg, 0.48mmol, 3.0 eq) and HATU (66.8mg, 0.18mmol, 1.1 eq). The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched with 50mL of water. The resulting solid was collected by filtration and dried in vacuo to give 17.2 mg (23.25%) of 3-amino-N- [ [5- (dimethylamino) -2-fluorophenyl ] group as a yellow solid ]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001074
Oxazol-2-yl) pyrazine-2-carboxamide (compound 27). LCMS M/z (ESI), [ M + H]+＝464.2。1HNMR (300MHz,DMSO-d6)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 28.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001075
Preparation of oxazol-2-yl) -N- ((6- (pyrrolidin-1-yl) pyridin-2-yl) methyl) pyrazine-2-carboxamide (Compound 28)
Scheme 23
Figure BDA0002577091620001071
Step 1.1- [6- (pyrrolidin-1-yl) pyridin-2-yl]Methylamine
To a mixture of 6- (pyrrolidin-1-yl) pyridine-2-carbonitrile (200mg, 1.1mmol, 1 equiv.) and Raney nickel (98.9mg, 1.1mmol, 1.0 equiv.) in MeOH (10mL) was added NH3.H2O (40.5mg, 1.1mmol, 1 equiv.) and stirred at 15 ℃ under a hydrogen atmosphere for 30 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 1- [6- (pyrrolidin-1-yl) pyridin-2-yl as a white solid]Methylamine (120mg, 58.6%). LCMS M/z (ESI), [ M + H]+＝178.3。
Step 2.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001082
Azol-2-yl) - N- [ [6- (pyrrolidin-1-yl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamides (Compound 28)
To 1- [6- (pyrrolidin-1-yl) pyridin-2-yl at room temperature]Methylamine (100mg, 0.5)6mmol, 1 equiv.) and 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001083
Oxazol-2-yl) pyrazine-2-carboxylic acid (176.7mg, 0.56 mmol, 1.00 equiv.) to a mixture in DMF (3mL) was added HATU (429.0mg, 1.13mmol, 2 equiv.) and DIEA (218.7mg, 1.69mmol, 3 equiv.). The mixture was stirred at 15 ℃ for 60min under an air atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)4HCOO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 39% B to 40% B within 9 min; 254,220 nm; rt: 8.3min) to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001084
Azol-2-yl) -N- [ [6- (pyrrolidin-1-yl) pyridin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 28) (36.7mg, 13.17%). LCMS M/z (ESI), [ M + H]+＝473.3，1H NMR (400MHz, methanol-d)4) 1.8-1.9(m,4H),3.3(d,J＝6.6Hz,4H),4.5(d,J＝5.5Hz,2H),6.3(dd,J＝13.3,8.9Hz, 2H),6.5(d,J＝7.3Hz,1H),7.4-7.5(m,3H),7.8(s,1H),7.9(d,J＝2.6Hz,1H),8.3(d,J＝0.8 Hz,1H),9.3(t,J＝5.6Hz,1H)。
Example 29: preparation of 3-amino-N- [ (2, 6-difluorophenyl) methyl ] -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 29)
Scheme 24
Figure BDA0002577091620001081
Step 1.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, preparation of 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 29)
Under nitrogen atmosphere at room temperatureTo 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group]-5- (4-fluorophenyl) pyrazine-2-carboxamide (100mg, 0.25mmol, 1 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (119.7mg, 0.5mmol, 2.0 equiv.) in dioxane
Figure BDA0002577091620001092
alkane/H2Pd (dppf) Cl was added to a mixture of O (2mL)2(37.3mg, 0.1mmol, 0.2 eq.) and K3PO4(162.1mg, 0.8mmol, 3 equiv.) the mixture is stirred at 90 ℃ for 10 h under nitrogen atmosphere the residue is purified by preparative TLC (PE/EtOAc 1:2) followed by preparative HPLC (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 39% B to 49% B within 7 min; 254/220 nm; rt: 6.18min) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 29) (7mg, 5.85%). LCMS M/z (ESI) [ M + H ]]+＝466.2。1H NMR (400MHz, methanol-d)4)3.55(s,2H),4.73(s,2H),6.38(d,J＝9.2Hz,1H),6.93-7.05(m,2H),7.10-7.19(m, 2H),7.30(dd,J＝9.4,2.6Hz,1H),7.32-7.42(m,1H),7.50-7.61(m,2H),7.88(d,J＝2.5Hz, 1H)。
Example 30.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001093
Azol-2-yl) -N- [ [3- (trifluoromethoxy) pyridin-2-yl]Methyl radical]Preparation of pyrazine-2-carboxamide (Compound 30)
Scheme 25
Figure BDA0002577091620001091
Step 1.3- (trifluoromethoxy) pyridine-2-carbonitrile.
Under nitrogen atmosphere at room temperature to produce 2-bromo-3- (trifluoromethoxy)) Pyridine (300mg, 1.24mmol, 1 equiv.) and Zn (CN)2(291.2mg, 2.48mmol, 2 equiv.) in THF (15mL) and H2t-BuXantPhos-Pd-G3(197.0mg, 0.25mmol, 0.2 equiv.) and t-BuXantPhos (171.3mg, 0.25mmol, 0.2 equiv.) were in a stirred mixture in O (3 mL). The resulting mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure. By preparative TLC (CH)2Cl2/MeOH 20:1) to give 3- (trifluoromethoxy) pyridine-2-carbonitrile as a white solid (200mg, 85.76%). LCMS M/z (ESI), [ M + H]+＝188.9。
Step 2.1- [3- (trifluoromethoxy) pyridin-2-yl]Methylamine.
To 3- (trifluoromethoxy) pyridine-2-carbonitrile (100mg, 0.53mmol, 1 eq) and NH under a nitrogen atmosphere3.H2O (1.0mL, 28.54mmol, 48.31 equiv.) in MeOH (10mL) was added Raney nickel (22.8mg, 0.27mmol, 0.5 equiv.) the resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 2 h, the resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10mL), the filtrate was concentrated under reduced pressure, this gave 1- [3- (trifluoromethoxy) pyridin-2-yl ] oil as a purple oil ]Methylamine (80mg, 78.32%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝193.2。
Step 3.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001101
Azol-2-yl) - N- [ [3- (trifluoromethoxy) pyridin-2-yl ] amino acids]Methyl radical]Pyrazine-2-carboxamide (Compound 30)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001103
Azol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.26mmol, 1 eq.) and 1- [3- (trifluoromethoxy) pyridin-2-yl]Methylamine (98.1mg, 0.51mmol, 2 equiv.) in DMF (10mL) was added HATU (194.2mg, 0.51mmol, 2 equiv.) and DIEA (66.0mg, 0.51mmol, 2 equiv.). Subjecting the obtained product toThe mixture was stirred at room temperature under an air atmosphere for 30 min. The solvent was removed under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep C18OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10MMOL/L NH)4HCOO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 25% B to 46% B within 7 min; 254/220 nm; rt: 6.83min) to purify the crude product (80mg) to obtain 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1, 3-) as a yellow solid
Figure BDA0002577091620001104
Azol-2-yl) -N- [ [3- (trifluoromethoxy) pyridin-2-yl ]Methyl radical]Pyrazine-2-carboxamide (compound 30) (10 mg, 8.03%). LCMS M/z (ESI), [ M + H]+＝488.2。1H NMR:(400MHz,MeOD)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 31.3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620001105
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 31)
Scheme 26
Figure BDA0002577091620001102
Step 1.3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001106
Azole- 2-Yl) pyrazine-2-carboxylic acid methyl ester
To a stirred solution of 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (340.1mg, 1.34mmol, 2 equivalents) and 5-bromo-1- (difluoromethyl) -1, 2-dihydropyridin-2-one (150mg, 0.67mmol, 1 equivalent) in THF (20mL) at room temperature under a nitrogen atmosphere was added portionwiseKOAc (197.2mg, 2.01mmol, 3.00 equiv.) and Pd (dppf) Cl2CH2Cl2(82.0mg, 0.10mmol, 0.15 equiv.). The resulting mixture was stirred at 75 ℃ for 3 hours under a nitrogen atmosphere. To this resulting mixture of 1- (difluoromethyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one in THF (20mL) at room temperature under a nitrogen atmosphere was added 3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620001111
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (84.5mg, 0.33mmol, 0.50 equiv.), Cs 2CO3(432.7mg, 1.33mmol, 2 equiv.) and Pd (dppf) Cl2CH2Cl2(70.5 mg, 0.09mmol, 0.13 equiv.). The resulting mixture was stirred at 75 ℃ for 4 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH2Cl2(2 × 20mL) the filter cake was washed, the filtrate was concentrated under reduced pressure, by preparative TLC (CH)2Cl2MeOH 30:1) to give 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl as a yellow solid]-5-(1,3-
Figure BDA0002577091620001112
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (100mg, 18.65%). LCMS M/z (ESI), [ M + H]+＝364.1。1H NMR(300MHz,DMSO-d6)3.87(s,3H),6.51(d,J＝9.7Hz,1H),7.41(s,1H),7.59(dd,J ＝9.6,2.5Hz,1H),7.69(s,1H),7.80(d,J＝2.5Hz,1H),7.90(d,J＝8.8Hz,1H),8.32(d,J＝ 0.8Hz,1H)。
Step 2.3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001113
Azole- 2-yl) pyrazine-2-carboxylic acid
To 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl group at room temperature]-5-(1,3-
Figure BDA0002577091620001114
Azole-2-yl)To a stirred solution of pyrazine-2-carboxylic acid methyl ester (90mg, 0.25mmol, 1 equiv) in THF (15mL) was added dropwise a solution of LiOH (11.9mg, 0.50mmol, 2.01 equiv) in water (1 mL). The resulting mixture was stirred at room temperature under an air atmosphere for 3 hours. The mixture was neutralized to pH 6 with 1N aqueous HCl and concentrated in vacuo to give crude 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl as a yellow solid ]-5-(1,3-
Figure BDA0002577091620001115
Oxazol-2-yl) pyrazine-2-carboxylic acid (85 mg, 98.24%) which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝350.0。
Step 3.3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-N- [ (3-fluoropyridine-) 2-yl) methyl]-5-(1,3-
Figure BDA0002577091620001116
Azol-2-yl) pyrazine-2-carboxamide (Compound 31)
To 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl under an air atmosphere at room temperature]-5-(1,3-
Figure RE-GDA0002600337970001117
Oxazol-2-yl) pyrazine-2-carboxylic acid (10mg, 0.03mmol, 1 equivalent), DIEA (11.1mg, 0.09mmol, 3.00 equivalents), and HATU (21.8mg, 0.06mmol, 2.00 equivalents) were added drop-wise to a stirred mixture in DMF (8mL) 1- (3-fluoropyridin-2-yl) methylamine (5.4mg, 0.04mmol, 1.50 equivalents). The resulting mixture was stirred at room temperature under an air atmosphere for 3 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and passed through preparative TLC (CH)2Cl2MeOH 20:1) to give 3-amino-6- [1- (difluoromethyl) -6-oxo-1, 6-dihydropyridin-3-yl as a yellow solid]-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-
Figure RE-GDA0002600337970001121
Oxazol-2-yl) pyrazine-2-carboxamide (compound 31) (30 mg, 28.64%). LCMS M/z (ESI), [ M + H]+＝458.2，1H NMR(300MHz,DMSO-d6)9.30(t,J＝5.9Hz,1H),8.35(dd,J＝4.0,2.3Hz,1H),8.30(d,J＝0.8Hz,1H),8.10(s,0H),7.97(d,J＝ 2.5Hz,1H),7.87(d,J＝13.8Hz,2H),7.75，7.64(m,2H),7.41(q,J＝4.3Hz,2H),6.50(d,J＝ 9.7Hz,1H),4.68(dd,J＝5.7,1.5Hz,2H)。
Example 32.3-amino-N- [ (2, 6-difluorophenyl) methyl]-6- [ imidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001123
Preparation of Azol-2-yl) pyrazine-2-carboxamides (Compound 32)
Scheme 27
Figure BDA0002577091620001121
Step 1.3-amino-6- (imidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001124
Azol-2-yl) pyrazine-2-carboxylic acid methyl ester
3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620001125
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (300mg, 1.18 mmol, 1 equiv.) and 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a]Pyridine (431.4mg, 1.77mmol, 1.5 equiv.) in bis
Figure BDA0002577091620001126
Alkane (18mL) and H2To a stirred mixture in O (2mL) was added Cs portion by portion2CO3(767.7mg, 2.36mmol, 2 equiv.) and Pd (dppf) Cl2(172.4mg, 0.24mmol, 0.2 equiv.) the resulting mixture is stirred at 90 ℃ overnight, the mixture is allowed to cool to room temperature, the resulting mixture is filtered, the filter cake is washed with DCM (3 × 10mL), the filtrate is concentrated under reduced pressure, the residue is purified by preparative TLC (DCM/MeOH 20:1) to give 3-amino-6- [ imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001127
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (165mg, 41.6%). LCMS M/z (ESI), [ M + H]+＝337.2。1H NMR(DMSO-d6,400MHz)3.9(3H,s),7.1 (1H,dd,J＝9.4,1.8Hz),7.4(1H,s),7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.2Hz),7.7(1H,d, J＝19.0Hz),8.0(1H,d,J＝1.1Hz),8.3(1H,s),8.7(1H,t,J＝1.4Hz)
Step 2.3-amino-6- (imidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001128
Azol-2-yl) pyrazine-2-carboxylic acid
To 3-amino-6- [ imidazo [1,2-a ] at room temperature ]Pyridin-7-yl]-5-(1,3-
Figure BDA0002577091620001129
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (160 mg, 0.48mmol, 1 equiv.) to a stirred solution in THF (20mL) and water (2mL) was added LiOH (13.7mg, 0.57mmol, 1.2 equiv.) portionwise. The resulting mixture was stirred at room temperature for 4 hours and adjusted to PH 5 with 1N aqueous HCl. The resulting mixture was concentrated in vacuo and used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝323.2。
Step 3.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001132
Azol-2-yl) pyrazine-2-carboxamide (Compound 32)
3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001133
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.25mmol, 1 equiv.) and 1- (2, 6-difluorophenyl) methylamine (71.1mg, 0.50mmol, 2 equiv.) in DMF (5mL) was added HATU (377.5mg, 1mmol, 4 equiv.) and DIEA (128.3mg, 1mmol, 4 equiv.) in portions. Subjecting the obtained product toThe mixture was stirred at room temperature for 0.5 hour. The resulting mixture was quenched with water, and the resulting solid was collected by filtration and slurried with MeOH (5 mL). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid ]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001135
Oxazol-2-yl) pyrazine-2-carboxamide (compound 32) (30mg, 25.8%). LCMS M/z (ESI), [ M + H]+＝448.2。1H NMR(DMSO-d6,400MHz)4.6(2H,d,J＝5.8Hz),7.1(2H,t,J＝7.9Hz),7.2(1H,dd,J ＝9.4,1.8Hz),7.3-7.4(2H,m),7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.3Hz),7.9(3H,d,J＝ 23.3Hz),8.3(1H,s),8.7(1H,t,J＝1.3Hz),9.2(1H,t,J＝5.9Hz)。
Example 33.3-amino-N- (3- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001134
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 33)
Scheme 28
Figure BDA0002577091620001131
Step 1.3- (dimethylamino) -2-fluorobenzonitrile
to a stirred mixture of 3-amino-2-fluorobenzonitrile (300mg, 2.20mmol, 1 equiv.) and NaH (158.7mg, 6.61mmol, 3.00 equiv.) in DMF (10mL) was added iodomethane (938.4mg, 6.61mmol, 3.00 equiv.) portionwise at room temperature under an air atmosphere, the resulting mixture was stirred at room temperature for 4 hours, the resulting mixture was quenched with water (30mL) and extracted with EtOAc (3 × 50mL), the combined organic layers were washed with water (3 × 10mL), over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and purified by preparative TLC (PE/EtOAc 5:1) to give 3- (dimethylamino) -2-fluorobenzonitrile (160mg, 44.2%) as a light yellow crude solid. LCMS M/z (ESI), [ M + H]+＝165.2。1H NMR (chloroform-d, 400MHz)2.9(6H, d, J ═ 1.3Hz),7.1-7.1(3H, m).
Step 2.3- (aminomethyl) -2-fluoro-N, N-dimethylaniline
To a stirred mixture of 3- (dimethylamino) -2-fluorobenzonitrile (160mg, 0.97mmol, 1 eq) and raney nickel (16.7mg, 0.19mmol, 0.20 eq) in MeOH (20mL) was added NH portionwise at room temperature4OH (2 mL.) the resulting mixture was stirred at room temperature under an atmosphere of hydrogen for an additional 1H, the resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10mL), the filtrate was concentrated under reduced pressure, the crude product was used in the next step without further purification, LCMS: M/z (ESI), [ M + H ] M]+＝169.0。
Step 3.3-amino-N- (3- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyrazine Pyridin-3-yl) -5-, (
Figure BDA0002577091620001141
Azol-2-yl) pyrazine-2-carboxamide (Compound 33)
3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001142
Oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.26mmol, 1 equiv.) and 3- (aminomethyl) -2-fluoro-N, N-dimethylaniline (85.9mg, 0.5mmol, 2.0 equiv.) were added to a stirred mixture in DMF (5mL) in portions HATU (194.2mg, 0.51 mmol, 2.00 equiv.) and DIEA (132.0mL, 1.02mmol, 4.00 equiv.). The resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 20:1) to give the crude product 3-amino-N- (3- (dimethylamino) -2-fluorophenylmethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (3-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001143
Oxazol-2-yl) pyrazine-2-carboxamide (100 mg). By preparative HPLC with the following conditions (column: XSelectCSH OBD column 30 x 150mm 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient:16% B to 27% B within 7 min; 254; 220 nm; rt: 4.40min) to give 3-amino-N- (3- (dimethylamino) -2-fluorobenzyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (3- (dimethylamino) -2-fluorobenzyl) -5- (5-dihydropyridin-3-yl) as a brown yellow solid
Figure BDA0002577091620001144
Oxazol-2-yl) pyrazine-2-carboxamide (compound 33) (44mg, 37.06%). LCMS M/z (ESI), [ M + H]+＝464.2。1H NMR(DMSO-d6,400MHz)2.8(5H,s),4.6(2H,d,J＝6.3 Hz),6.3(1H,d,J＝9.4Hz),6.9-7.0(2H,m),7.1(1H,t,J＝7.8Hz),7.4-7.4(2H,m),7.8(1H, s),8.0(1H,d,J＝2.6Hz),8.3(1H,d,J＝0.8Hz),9.3(1H,t,J＝6.4Hz)。
EXAMPLE 35 preparation of 3-amino-N- (2, 6-difluorobenzyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 35)
Scheme 29
Figure BDA0002577091620001151
Step 1.3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid methyl ester
To a stirred solution of methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (2.5g, 11.26mmol, 1 eq) and 2H-1,2, 3-tris (1555.4mg, 22.52mmol, 2 eq) in DMSO (50mL) was added t-BuONa (1082.1mg, 11.26mmol, 1 eq) portionwise at room temperature. The resulting mixture was stirred in an oil bath for 3 hours at 60 ℃, cooled to room temperature and quenched with water (200 mL). The resulting solid was collected by filtration, dried in vacuo and purified by a silica gel column (DCM: EA 0-20%) to give 1.6g of crude product. The crude product was further purified by preparative TLC (DCM: EA 6:1) to give methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (800mg, 29%). 1H NMR (300 MHz, chloroform-d) 4.06(s,3H),8.03(s, 2H).
Step 2.3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid
To 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine at room temperatureTo a stirred mixture of methyl-2-carboxylate (200mg, 0.79mmol, 1 equiv) in THF (50mL) was added dropwise a solution of LiOH (38.0mg, 1.59mmol, 2.02 equiv) in water (2 mL). The resulting mixture was stirred at 40 ℃ for 3 hours. The resulting mixture was concentrated to 10mL in vacuo. The mixture was acidified to pH 6 with HCl (aq). The precipitated solid was collected by filtration and dried in vacuo to give 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (120mg, 52.91%) as a yellow solid, which was used in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝240.9。
Step 3.3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group]-5- (2H-1,2, 3-triazol-2-yl) pyrazin- 2-carboxamides
To a stirred solution of 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (130mg, 0.54mmol, 1 equivalent), DIEA (209.5mg, 1.62mmol, 3.00 equivalents), and 1- (2, 6-difluorophenyl) methylamine (116.0mg, 0.81 mmol, 1.50 equivalents) in DMF (10mL) was added dropwise 50% W T at room temperature 3P (687mg, 1.08mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and passed through preparative TLC (CH)2Cl2Purification in MeOH 20:1) to give 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] p-toluenesulfonate as a yellow solid]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (110mg, 55.67%). LCMS M/z (ESI), [ M + H]+＝366.0。1H NMR (300MHz, chloroform-d) 8.00(s,3H),7.38-7.30(m,1H), 6.98(t, J ═ 7.8Hz,2H),4.77(d, J ═ 6.0Hz, 2H).
Step 4.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- (1-methyl-6-oxo-1, 6-dihydropyridine-3- Yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 35)
To 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group at room temperature under a nitrogen atmosphere]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (100mg, 0.27mmol, 1 eq), Cs2CO3(267.3mg, 0.82mmol, 3 equiv.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (128.6mg, 0.55mmol, 2.00 equiv.) in 1,4-two
Figure BDA0002577091620001162
To a stirred mixture in an alkane (20mL) was added Pd (dppf) Cl in portions2CH2Cl2(44.7mg, 0.05mmol, 0.2 equiv.). The resulting mixture was stirred at 90 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. By preparative TLC (CH) 2Cl2The residue was purified with MeOH 20:1) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 35) (40mg, 33.04%). LCMS M/z (ESI), [ M + H]+＝439.2，1H NMR(300MHz,DMSO-d6)9.18(t,J＝5.9Hz,1H),8.13(s,2H),7.93(s, 2H),7.76(d,J＝2.6Hz,1H),7.48-7.25(m,1H),7.08(t,J＝8.0Hz,2H),6.73(dd,J＝9.5,2.7 Hz,1H),6.20(d,J＝9.5Hz,1H),4.61(d,J＝5.9Hz,2H),3.39(s,3H)。
Example 36.3-amino-N- ((3- (hydroxymethyl) pyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001163
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 36)
Scheme 30
Figure BDA0002577091620001161
Step 1.2- (((tert-butoxycarbonyl) amino) methyl) nicotinic acid methyl ester
To a mixture of methyl 2- (aminomethyl) pyridine-3-carboxylate (1g, 6.02mmol, 1 equiv.) and TEA (1826.8mg, 18.05mmol, 3.0 equiv.) in DCM (30mL) in a 250mL round bottom flask was added Boc portion by portion at room temperature2O (1379.0mg, 6.32mmol, 1.05 equiv.) the resulting solution was stirred at room temperature for 16 h, the resulting solution was diluted with 50mL of water, the resulting solution was extracted with 3 × 50mL of dichloromethane, dried over anhydrous sodium sulfate and concentrated, which yielded 1.5g (93.61%) of 2- ([ [ (tert-butoxy) carbonyl) as a solid]Amino group]Methyl) pyridine-3-carboxylic acid methyl ester. LCMS M/z (ESI), [ M + H]+＝267.1。
Step 2.((3- (hydroxymethyl) pyridin-2-yl) methyl) carbamic acid tert-butyl ester
Place 2- ([ [ (tert-butoxy) carbonyl) in a 50-mL round-bottom flask]Amino group]Methyl) pyridine-3-carboxylic acid methyl ester (100mg, 0.38mmol, 1 eq) in THF (5 mL). After this LiAlH was added portionwise at 0 ℃4(42.8mg, 1.13mmol, 3 equiv.). The resulting solution was stirred at 0 ℃ for 1 hour in a water/ice bath. The reaction was then quenched by the addition of 0.043mL of water and 0.172mL of NaOH (15% in water). The resulting solid was filtered off. The filtrate was concentrated and 85mg (94.9%) of N- [ [3- (hydroxymethyl) pyridin-2-yl ] as a solid were produced]Methyl radical](iii) carbamic acid tert-butyl ester. LCMS M/z (ESI), [ M + H]+＝239.2。1H NMR(300MHz,DMSO-d6)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
Placing N- [ [3- (hydroxymethyl) pyridin-2-yl ] in a 10-mL round bottom flask]Methyl radical]A solution of tert-butyl carbamate (50mg, 0.21 mmol, 1 eq), TFA (1mL) in DCM (3 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated and yielded 28mg (96.6%) of [2- (aminomethyl) pyridin-3-yl as a solid]Methanol TFA salt. LCMS M/z (ESI), [ M + H]+＝139.3。1H NMR(300MHz,DMSO-d6)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-dihydro Pyridin-3-yl) -5-, (
Figure BDA0002577091620001171
Azol-2-yl) pyrazine-2-carboxamide (Compound 36)
[2- (aminomethyl) pyridin-3-yl ] into a 50-mL round-bottomed flask at room temperature ]Methanol (52.9mg, 0.38mmol, 2.0 equiv.), 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001172
Azol-2-yl) pyrazine-2-carboxylic acid (60mg, 0.19MMOL, 1 equiv.) to a mixture of HATU (87.4mg, 0.23MMOL, 1.2 equiv.) and DIEA (74.3mg, 0.57MMOL, 3.0 equiv.) in DMF (15 mL.) the resulting solution was stirred at room temperature for 1 hour then the reaction was quenched by addition of 20mL water, the resulting solution was extracted with 3 × 25mL ethyl acetate and the organic layers were combined, the resulting mixture was washed with 1 × 10mL saturated brine, the resulting mixture was concentrated, and the resulting mixture was subjected to preparative HPLC with the following conditions (column: Xbridge PrepC18OBD column, 5 μm, 19. 150 mm; mobile phase A: water (10MMOL/L NH)4HCOO3+ 0.1％NH3.H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 30% B to 30% B within 7 min; 254,220 nm; rt: 6.35min) to purify the crude product. This gives 20mg (24.09%) of 3-amino-N- [ [3- (hydroxymethyl) pyridin-2-yl ] as a yellow solid]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001183
Oxazol-2-yl) pyrazine-2-carboxamide (compound 36). LCMS M/z (ESI), [ M + H]+＝434.2。1HNMR(300MHz, DMSO-d6)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 listed in the table below were prepared using the procedure described for compound 36.
Figure BDA0002577091620001181
Example 38.3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (2, 6-difluorophenyl) methyl]-5-(1,3-
Figure BDA0002577091620001184
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 38)
Scheme 31
Figure BDA0002577091620001182
Step 1.5-bromo-1-cyclopropyl-1, 2-dihydropyridin-2-one.
To 5-bromo-1, 2-dihydropyridin-2-one (2g, 11.49mmol, 1 eq), cyclopropylboronic acid (2.0g, 23.28mmol, 2.03 eq) and CU (AcO) at room temperature under a nitrogen atmosphere2(2.1g, 0.01mmol, 1 eq.) in CH2ClCH2To the mixture in Cl (50mL) was added Na2CO3(2.4g, 0.02mmol, 2 equiv.) and 44-di-tert-butyl-22-bipyridine (3.1g, 0.01mmol, 1 equiv.). The resulting mixture was stirred at 70 ℃ for 12 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography using CH2Cl2MeOH (20:1) gave 5-bromo-1-cyclopropyl-1, 2-dihydropyridin-2-one (600mg, 24.39%) as a white solid. LCMS M/z (ESI), [ M + H]+＝ 213.9,215.9。1HNMR:(300MHz,CDCl3)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 group]-5-(1,3-
Figure BDA0002577091620001191
Azol-2-yl) pyrazine-2-carboxylic acid esters An amide.
To 3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620001192
To a solution of oxazol-2-yl) pyrazine-2-carboxylic acid (50mg, 0.21mmol, 1 equiv.) and 1- (2, 6-difluorophenyl) methylamine (44.6mg, 0.31mmol, 1.5 equiv.) in DMF (5mL) was added T 3P (132.2mg, 0.42mmol, 2.00 equiv.) and DIEA (80.6mg, 0.62mmol, 3 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours and concentrated in vacuo. By preparative TLC (CH)2Cl2The residue was purified with MeOH 20:1) to give 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] as a yellow solid]-5-(1,3-
Figure BDA0002577091620001193
Oxazol-2-yl) pyrazine-2-carboxamide (120mg, 39.47%). LCMS M/z (ESI), [ M + H]+＝366.0。1H NMR:(300 MHz,DMSO-d6)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-di Hydropyridin-2-ones.
To a solution of 5-bromo-1-cyclopropyl-1, 2-dihydropyridin-2-one (100mg, 0.47mmol, 1 equivalent) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (177.9mg, 0.70mmol, 1.50 equivalents) in THF (10mL) at room temperature under an atmosphere was added KOAc (137.5mg, 1.40mmol, 3.00 equivalents) and Pd (dppf) Cl2CH2Cl2(38.1mg, 0.05mmol, 0.1 equiv.). The mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. This resulting solution of 1-cyclopropyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one in THF (10mL) was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H ]+＝262.1。
Step 4.3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (2, 6-difluorophenyl) Methyl radical]-5-(1,3-
Figure BDA0002577091620001194
Oxazol-2-yl) pyrazine-2-carboxamide (compound 38).
To a solution of 1-cyclopropyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (100mg, 0.38mmol, 1 eq) in THF (10mL) under a nitrogen atmosphere was added 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] methyl]-5-(1,3-
Figure BDA0002577091620001195
Oxazol-2-yl) pyrazine-2-carboxamide (280.1mg, 0.77mmol, 2 equiv.), Cs2CO3(249.5mg, 0.77mmol, 2.00 equiv.) and Pd (dppf) Cl2CH2Cl2(31.3mg, 0.04mmol, 0.1 equiv.). The mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours and concentrated in vacuo. By preparative TLC (CH)2Cl2/MeOH 20:1) to give 3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ (2, 6-difluorophenyl) methyl ] p-rin as a yellow solid]-5-(1,3-
Figure BDA0002577091620001202
Oxazol-2-yl) pyrazine-2-carboxamide (compound 38) (20mg, 11.25%).
LCMS:m/z(ESI),[M+H]+＝465.2。1H NMR:(300MHz,MeOD)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 39.3-amino-N- [ [ 2-fluoro-6- (morpholin-4-yl) phenyl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001203
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 39)
Scheme 32
Figure BDA0002577091620001201
Step 1.2-fluoro-6- (morpholin-4-yl) benzonitrile
To a stirred mixture of 2, 6-difluorobenzonitrile (1000mg, 7.19mmol, 1 equiv.) and morpholine (939.5mg, 10.78mmol, 1.5 equiv.) in DMSO (10mL) was added DIEA (1858.2mg, 14.38 mmol, 2.00 equiv.) in portions at room temperature, the resulting mixture was stirred at 80 ℃ under an air atmosphere for 2.5 hours, the resulting mixture was diluted with water (200mL), the resulting mixture was extracted with EtOAc (2 × 300mL), the combined organic layer was washed with water (2 × 100mL), anhydrous Na 2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2-fluoro-6- (morpholin-4-yl) benzonitrile (637mg, 42.97%) as a white solid. LCMS M/z (ESI), [ M + H]+＝207.0。1H NMR (400MHz, chloroform-d) 3.21-3.28(m,4H),3.85-3.92(m,4H),6.78 (m,4H)dt,J＝8.4,4.2Hz,2H),7.47(td,J＝ 8.4,6.6Hz,1H)。
Step 2.1- [ 2-fluoro-6- (morpholin-4-yl) phenyl]Methylamine
To a solution of 2-fluoro-6- (morpholin-4-yl) benzonitrile (200mg, 0.97mmol, 1 eq) in MeOH at room temperature was added raney nickel (166.2mg, 1.94mmol, 2 eq.) the resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 1.5 h, the resulting mixture was filtered, the filter cake was washed with MeOH (2 × 10mL), the filtrate was concentrated under reduced pressure to give 1- [ 2-fluoro-6- (morpholin-4-yl) phenyl ] carbonitrile as a white oil]Methylamine (150mg, 73.56%), which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝211.2。
Step 3.3-amino-N- [ [ 2-fluoro-6- (morpholin-4-yl) phenyl]Methyl radical]-6- (1-methyl-6-oxo-1, 6- Dihydropyridin-3-yl) -5- (1, 3-)
Figure BDA0002577091620001204
Azol-2-yl) pyrazine-2-carboxamide (Compound 39)
3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001212
Azol-2-yl) pyrazine-2-carboxylic acid (200mg, 0.64mmol, 1 eq.) and 1- [ 2-fluoro-6- (morpholin-4-yl) phenyl ]Methylamine (134.2mg, 0.64mmol, 1 equiv.) in a stirred mixture of DMF (10mL) was added T in portions3P (812.5mg, 2.55mmol, 4 equiv.) and DIEA (247.5mg, 1.92mmol, 3 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The resulting mixture was poured into water (30 mL). The resulting solid was collected by filtration and slurried with MeOH (10 mL). The resulting solid was collected by filtration and dried under reduced pressure to give 3-amino-N- [ [ 2-fluoro-6- (morpholin-4-yl) phenyl ] as a yellow solid]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001213
Oxazol-2-yl) pyrazine-2-carboxamide (compound 39) (120mg, 37.18%). LCMS m/z (E)SI),[M+H]+＝506.1。1H NMR(400MHz,DMSO-d6)2.88(t,J＝4.5Hz,4H),3.34(s,3H),3.64(t,J＝4.5Hz,4H),4.72(d,J＝5.8Hz,2H),6.32(d,J＝9.4Hz,1H),7.00(dd,J＝9.8,8.4Hz,1H),7.07(d,J＝8.1Hz,1H),7.29～7.43 (m,3H),7.83(s,2H),7.97(d,J＝2.6Hz,1H),8.30(d,J＝0.8Hz,1H),9.14(t,J＝5.8Hz,1H)。
Example 40.3-amino-N- (1- (2, 6-difluorophenyl) ethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001214
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 40)
Scheme 33
Figure BDA0002577091620001211
Step 1.3-amino-N- [1- (2, 6-difluorophenyl) ethyl]-6- (1-methyl-6-oxo-1, 6-dihydropyridine- 3-yl) -5- (1,3-
Figure BDA0002577091620001215
Oxazol-2-yl) pyrazine-2-carboxamide.
3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001216
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.32mmol, 1 equiv.), T3To a stirred mixture of P (242.7mg, 0.76mmol, 2.39 equiv.) and DIEA (123.8mg, 0.96mmol, 3 equiv.) in DMF (10mL) was added 1- (2, 6-difluorophenyl) ethan-1-amine (75.3mg, 0.48mmol, 1.5 equiv.) in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was poured into water (30 mL). The resulting solid was collected by filtration and slurried with MeOH (10 mL). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-N- [1- (2, 6-difluorophenyl) ethyl as a yellow solid ]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001222
Oxazol-2-yl) pyrazine-2-carboxamide (40mg, 27.42%). LCMS M/z (ESI), [ M + H]+＝453.0。
Step 2.3-amino-N- (1- (2, 6-difluorophenyl) ethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (
Figure BDA0002577091620001223
Azol-2-yl) pyrazine-2-carboxamide (Compound 40-1 and Compound 40-2)
The racemate product (60mg) was purified by preparative chiral HPLC on eluent. Column: CHIRALPAKIG, 20 × 250mm, 5 μm; mobile phase A: hex: DCM ═ 5:1(10mm NH)3-MEOH) -HPLC, mobile phase B: EtOH- -HPLC; flow rate: 16 mL/min; gradient: 50B to 50B within 16 min; 220/254 nm; RT 1: 10.8 of the total weight of the mixture; RT 2: 12.8. this gave 3-amino-N- (1- (2, 6-difluorophenyl) ethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (2, 6-dihydropyridin-3-yl) as a yellow solid
Figure BDA0002577091620001224
Oxazol-2-yl) pyrazine-2-carboxamide (isomer 1) (compound 40-1) (15 mg). LCMS M/z (ESI), [ M + H]+＝453。1H NMR (400MHz, MeOD)1.62(d,3H),3.64(s, 3H),5.68(q,1H),6.53(m,1H),7.00(m,2H),7.32(m,2H),7.49(dd,1H),7.93(d,1H),8.03(d, 1H). Chirality: tR 1.967 min. And 3-amino-N- (1- (2, 6-difluorophenyl) ethyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (b) as a yellow solid
Figure BDA0002577091620001225
Oxazol-2-yl) pyrazine-2-carboxamide (isomer 2) (compound 40-2) (15 mg). LCMS M/z (ESI), [ M + H]+＝453.2。1H NMR (400MHz, MeOD)1.62(d,3H),3.64(s,3H), 5.68(q,1H),6.53(dd,1H),6.99(m,2H),7.32(m,2H),7.50(dd,1H),7.93(d,1H),8.03(d, 1H). Chirality: tR 2.500min, mixed chirality: tR is 1.981min,2.480 min.
Example 41.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-yl) -5- (C)
Figure BDA0002577091620001226
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 41)
Scheme 34
Figure BDA0002577091620001221
Step 1.5-bromo-1- (2-hydroxyethyl) pyridin-2 (1H) -one
To a mixture of 5-bromo-1, 2-dihydropyridin-2-one (2g, 11.49mmol, 1 eq.) and 2-iodoethan-1-ol (4.0g, 22.98mmol, 1.999 eq.) in DMSO (30mL) in a 50-mL round bottom at room temperature was added K2CO3(4.8g, 34.47mmol, 2.999 equiv.) the resulting mixture is stirred at room temperature for 16H, then the reaction is quenched by the addition of 50mL water, the resulting solution is extracted with 3 × 50mL ethyl acetate and the organic layers are combined, the resulting organic layer is washed with 3 × 50mL saturated NaCl, the combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue is applied to a silica gel column with ethyl acetate/petroleum ether (1:2) to give 330mg (12%) of 5-bromo-1- (2-hydroxyethyl) -1, 2-dihydropyridin-2-one as a white solid, LCMS: M/z (ESI), [ M + H ] as a white solid, LCMS: M/z (ESI) ]+＝218.1。1HNMR (400MHz, chloroform-d) 3.93(2H, s),4.08(2H, s),4.41-4.53(1H, m),6.49(1H, d),7.66-7.69(2H, m)
Step 2.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (
Figure BDA0002577091620001231
Azol-2-yl) pyrazine-2-carboxamide (Compound 41)
In a 50-mL round bottom flask was placed 5-bromo-1- (2-hydroxyethyl) -1, 2-dihydropyridin-2-one (298.1mg, 1.37mmol, 5 equivalents), 4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (416.6mg, 1.64mmol, 6 equivalents), Pd (dppf) Cl2(120.0mg, 0.16mmol, 0.60 equiv.), KOAc (80.5mg, 0.82mmol, 3 equiv.), bis
Figure BDA0002577091620001232
Alkane (15 mL). The resulting solution was stirred in an oil bath for 2 hours at 80 ℃. The resulting mixture was used directly in the next step. To this mixture was added 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group]-5-(1,3-
Figure BDA0002577091620001233
Oxazol-2-yl) pyrazine-2-carboxamide (100mg, 0.27mmol, 1 equiv.), Pd (dppf) Cl2(100.0mg, 0.14mmol, 0.5 equiv.), K3PO4(348.2mg, 1.64mmol, 6.00 equiv.), bis
Figure BDA0002577091620001234
Alkane (15mL) and water (10 mL). The resulting solution was stirred under N2reaction in an oil bath for a further 16 hours at 80 ℃ under an atmosphere, concentration of the resulting mixture, extraction of the resulting solution with 3 × 30mL of ethyl acetate, concentration of the organic layer, by preparative HPLC with the following conditions (column: Xbridge Prep C18OBD column, 5 μm, 30 × 150 mm; mobile phase A: water (10MMOL/L NH) 4HCO3) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 18% B to 42% B within 7 min; 254,220 nm; rt: 6.42min) to purify the crude product. This gave 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- [1- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001235
Oxazol-2-yl) pyrazine-2-carboxamide (compound 41) (20mg, 15.3%). LCMS M/z (ESI), [ M + H]+＝469.2。1HNMR(300MHz,DMSO-d6) 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 42.3-amino-N- [ (2, 6-difluorophenyl) methyl]-5-(1,3-
Figure BDA0002577091620001236
Azol-2-yl) -6- [1- (Oxetan-3-yl) -6-oxo-1, 6-dihydropyridin-3-yl]Preparation of pyrazine-2-carboxamide (Compound 42)
Scheme 35
Figure BDA0002577091620001241
Step 1.5-bromo-1- (oxetan-3-yl) -1, 2-dihydropyridin-2-one
To a stirred mixture of 5-bromo-1, 2-dihydropyridin-2-one (200mg, 1.15mmol, 1 equiv.) and 3-bromooxetane (629.8mg, 4.60mmol, 4 equiv.) in DMF (10mL) at room temperature under an air atmosphere was added K in portions2CO3(476.6mg, 3.45mmol, 3 equiv.). The resulting mixture was stirred at 100 ℃ for 3 hours under an air atmosphere. The resulting mixture was poured into water. By CH2Cl2the resulting mixture was extracted (2 × 100mL), the combined organic layers were washed with water (1 × 30mL), dried over anhydrous Na 2SO4And (5) drying. 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 (120mg, 45.38%) as a white solid. LCMS M/z (ESI), [ M + H]+＝230.0。1H NMR (400MHz, chloroform-d) 4.66-4.74(m,2H),4.96(ddd, J ═ 7.3,6.2,1.0Hz,2H),5.55(tt, J ═ 6.3, 5.3Hz,1H),6.71(dd, J ═ 8.8,0.7Hz,1H),7.67(dd, J ═ 8.7,2.5Hz,1H),8.11(dd, J ═ 2.6,0.7 Hz, 1H).
Step 2.1- (Oxetan-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan- 2-yl) pyridin-2 (1H) -ones
To a stirred mixture of 5-bromo-1- (oxetan-3-yl) -1, 2-dihydropyridin-2-one (230mg, 1.00 mmol, 1 equivalent) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (507.7mg, 2.00mmol, 2 equivalents) in THF (7mL) was added KOAc (294.3mg, 3.00mmol, 3 equivalents) and Pd (dppf) Cl in portions at room temperature under a nitrogen atmosphere2(146.3mg, 0.20mmol, 0.2 equiv.). The resulting mixture was stirred at 80 ℃ for 3 hours under a nitrogen atmosphere.The resulting mixture was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H ]+＝278.2。
Step 3.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-5-(1,3-
Figure BDA0002577091620001242
Azol-2-yl) -6- [1- (Oxetanyl) Alk-3-yl) -6-oxo-1, 6-dihydropyridin-3-yl]Pyrazine-2-carboxamide (Compound 42)
To 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group at room temperature under a nitrogen atmosphere]-5-(1,3-
Figure BDA0002577091620001243
Azol-2-yl) pyrazine-2-carboxamide (200mg, 0.55mmol, 1 equiv.) and 1- (oxetan-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (151.6mg, 0.55mmol, 1 equiv.) to a stirred solution/mixture in THF (20mL) was added Pd (dppf) Cl in portions2(80.0mg, 0.11mmol, 0.20 equiv.) and Cs2CO3(534.5mg, 1.64mmol, 3.00 equiv.). The resulting mixture was stirred at 80 ℃ for 3 hours under a nitrogen atmosphere. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30-150 mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 25% B to 50% B within 7 min; 254/220 nm; rt: 5.20min) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-5-(1,3-
Figure BDA0002577091620001252
Azol-2-yl) -6- [1- (oxetan-3-yl) -6-oxo-1, 6-dihydropyridin-3-yl]Pyrazine-2-carboxamide (5mg, 1.90%) (compound 42). LCMS M/z (ESI), [ M + H ]+＝481.2。1H NMR(300MHz,DMSO-d6)4.58(d,J＝5.8Hz,2H),4.66(t,J＝7.0Hz,2H),4.83(t,J＝7.4Hz,2H),5.56(p,J＝7.3Hz,1H),6.37(d,J＝9.4Hz,1H),7.07(t,J＝8.0Hz,2H),7.28～7.45(m,2H),7.60(dd,J ＝9.4,2.5Hz,1H),7.75(s,2H),7.96(d,J＝2.5Hz,1H),8.29(d,J＝0.8Hz,1H),9.11(t,J＝5.9 Hz,1H)。
Example 45.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001253
Oxazol-2-yl) -N- [ (1, 3-thiazol-4-yl) methyl]Preparation of pyrazin-2-carboxamides (Compound 45)
Scheme 36
Figure BDA0002577091620001251
Step 1.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001254
Azol-2-yl) pyrazine-2-carboxylic acid methyl ester Esters
3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620001255
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1200mg, 4.71mmol, 1 eq.) and 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a]Pyridine (1725.6mg, 7.07mmol, 1.50 equiv.) in bis
Figure BDA0002577091620001256
To a stirred mixture of alkane (20mL) and water (2mL) was added Pd (dppf) Cl in portions2(689.7mg, 0.94mmol, 0.2 equiv.) and Cs2CO3(3071.0mg, 9.43mmol, 2 equiv.) the resulting mixture is stirred at 90 ℃ overnight, the mixture is allowed to cool to room temperature, the resulting mixture is filtered, the filter cake is washed with DCM (3 × 10mL), the filtrate is concentrated under reduced pressure, the residue is purified by chromatography on a silica gel column with CH2Cl2MeOH (50:1) elution gave 3-amino-6- [ imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001257
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1200mg, 75.71%). LCMS M/z (ESI), [ M + H]+＝337。1H NMR(DMSO-d6,400 MHz)3.9(3H,s),7.1(1H,dd,J＝9.4,1.8Hz),7.4(1H,s),7.5(1H,d,J＝9.3Hz),7.6(1H,d, J＝1.2Hz),7.7(2H,s),8.0(1H,s),8.3(1H,s),8.7(1H,t,J＝1.4Hz)
Step 2.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl ]-5-(1,3-
Figure BDA0002577091620001262
Azol-2-yl) pyrazine-2-carboxylic acid
3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001263
Azol-2-yl) pyrazine-2-carboxylic acid methyl ester (2.5g, 7.4mmol, 1 equiv.) to a stirred solution in THF (30mL) was added LiOH (0.2 g, 8.4mmol, 1.12 equiv.) and H in portions2O (5 mL). The resulting mixture was stirred at room temperature for 4 hours and acidified with 1N aqueous HCl to PH 6, the resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ imidazole [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001264
Oxazol-2-yl) pyrazine-2-carboxylic acid (2g, 83.5%). LCMS M/z (ESI), [ M + H]+＝323.2。1H NMR(DMSO-d6,400MHz)3.9(3H,s),7.1(1H,dd,J＝9.4,1.8Hz),7.4(1H,s), 7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.2Hz),7.7(2H,s),8.0(1H,s),8.3(1H,s),8.7(1H,t,J ＝1.4Hz)。
Step 3.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001265
Azol-2-yl) -N- [ (1, 3-thia-zole Oxazol-4-yl) methyl]Pyrazine-2-carboxamide (Compound 45)
3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001266
Azol-2-yl) pyrazine-2-carboxylic acid (100)mg, 0.31mmol, 1 eq) and 1- (1, 3-thiazol-4-yl) methylamine (70.9mg, 0.6mmol, 2.0 eq) in DMF (3mL) was added HATU (471.9mg, 1.2mmol, 4.0 eq) and DIEA (160.4mg, 1.2mmol, 4.0 eq) in portions. The resulting mixture was stirred at room temperature for a further 60 min. The resulting mixture was poured into water (30mL), the resulting solid was collected by filtration and slurried with MeOH (16mL), the resulting solid was collected by filtration and dried under vacuum to give 3-amino-6- [ imidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001267
Oxazol-2-yl) -N- [ (1, 3-thiazol-4-yl) methyl]Pyrazine-2-carboxamide (compound 45) (43mg, 32.8%). LCMS M/z (ESI), [ M + H]+＝419.2。1H NMR(DMSO-d6,400MHz)2.6(3H,s),4.6(2H,d,J＝6.2Hz), 7.2(1H,s),7.3-7.4(2H,m),7.6(1H,d,J＝9.3Hz),7.8(1H,s),8.0(1H,s),8.0(1H,s),8.3(1H,s),8.9(1H,s),9.3(1H,t,J＝6.1Hz)。
The compounds listed in the table below were prepared using the procedure described for compound 45.
Figure BDA0002577091620001261
Figure BDA0002577091620001271
Example 46.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- ((3- (methylamino) pyridin-2-yl) methyl) -5-, (
Figure BDA0002577091620001273
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 46)
Scheme 37
Figure BDA0002577091620001272
Step 1.2-cyano-3- (methylamino) pyridine (3- (methyiamino) picolinatotrile)
To a solution of 3-fluoropyridine-2-carbonitrile (500mg, 4.09mmol, 1 eq) in THF (20mL) was added methylamine (190.8mg, 6.14mmol, 1.50 eq) at room temperature. The resulting mixture was stirred at 50 ℃ for 3 hours. The reaction was quenched by the addition of water (10mL) at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to give 3- (methylamino) pyridine-2-carbonitrile (300mg, 55.02%) as a white solid. LCMS M/z (ESI), [ M + H]+＝134.0。
Step 2.2- (aminomethyl) -N-methylpyridin-3-amine
To a stirred solution of 3- (methylamino) pyridine-2-carbonitrile (100mg, 0.75mmol, 1 eq) in THF (15mL) at room temperature under a nitrogen atmosphere was added raney nickel (128.7mg, 1.50mmol, 2.00 eq) in portions. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to give 2- (aminomethyl) -N-methylpyridin-3-amine (90mg, 87.35%) as a brown semi-solid. LCMS M/z (ESI), [ M + H ]+＝138.0。
Step 3.3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- ((3- (methylamino) pyridine- 2-yl) methyl) -5- (C
Figure BDA0002577091620001282
Azol-2-yl) pyrazine-2-carboxamide (Compound 46)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001283
Azol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.22mmol, 1 eq) and 2- (aminomethyl) -N-methylpyridin-3-amine (36.8mg, 0.27mmol, 1.20 eq) were added portionwise to a stirred mixture in DMF (10mL) DIEA (86.6mg, 0.67mmol, 3 eq) and T3P (142.2mg, 0.45mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (40mL) at room temperature. The precipitated solid was collected by filtration and washed with water (10 mL). The product was poorly soluble and purified by wet milling with DMF (5 mL). The resulting yellow solid was collected by filtration and washed with waterAlcohol (10mL) was washed and dried under infrared light to give 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- [ [3- (methylamino) pyridin-2-yl ] as a yellow solid]Methyl radical]-5-(1,3-
Figure BDA0002577091620001284
Oxazol-2-yl) pyrazine-2-carboxamide (compound 46) (20mg, 19.46%). LCMS M/z (ESI), [ M + H]+＝433.2，1H NMR(300MHz,DMSO-d6)2.74(d,J＝4.5 Hz,3H),3.47(s,3H),4.46(d,J＝5.3Hz,2H),5.68(d,J＝5.0Hz,1H),6.33(d,J＝9.4Hz,1H), 6.88(d,J＝7.9Hz,1H),7.13(dd,J＝8.0,4.8Hz,1H),7.30-7.47(m,2H),7.69-7.90(m,3H), 8.01(d,J＝2.6Hz,1H),8.29(s,1H),9.40(d,J＝5.4Hz,1H)。
Example 47.3-amino-6- (1H-1, 3-benzodiazol-5-yl) -N- [ (3-fluoropyridin-2-yl) methyl ]-5-(1,3-
Figure BDA0002577091620001285
Preparation of Azol-2-yl) pyrazine-2-carboxamide (Compound 47)
Scheme 38
Figure BDA0002577091620001281
Step 1.3-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620001286
Azol-2-yl) pyrazine-2-carboxylic acid esters Amides of carboxylic acids
3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620001287
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (2000mg, 8.31 mmol, 1 eq) and 1- (3-fluoropyridin-2-yl) methylamine (1572.7mg, 12.47mmol, 1.5 eq) in DMF (20 mL) was added DIEA (4297.4mg, 33.25mmol, 4 eq) and T3P (10579.6mg, 33.25mmol, 4 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was poured into water. Tong (Chinese character of 'tong')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 group as a yellowish green solid]-5-(1,3-
Figure BDA0002577091620001292
Oxazol-2-yl) pyrazine-2-carboxamide (2.2g, 75.89%). LCMS M/z (ESI), [ M + H]+＝349.1。1H NMR(400MHz,DMSO-d6)4.68(dd,J＝5.7,1.7Hz,2H),7.43(dt, J＝8.6,4.4Hz,1H),7.59(s,1H),7.73(ddd,J＝10.0,8.4,1.3Hz,1H),7.92(s,2H),8.38～8.46 (m,2H),9.17(t,J＝5.7Hz,1H)。
Step 2.3-amino-6- (1H-1, 3-benzodiazol-5-yl) -N- [ (3-fluoropyridin-2-yl) methyl]-5-(1, 3-
Figure BDA0002577091620001293
Oxazol-2-yl) pyrazine-2-carboxamide (compound 47).
In N23-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620001294
Azol-2-yl) pyrazine-2-carboxamide (100 mg, 0.29mmol, 1 equiv.) and 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-1, 3-benzodiazole (140.0mg, 0.57mmol, 2 equiv.) in 1, 4-bis
Figure BDA0002577091620001295
Alkane (10mL) and H2Addition of Cs to O (1mL) solution2CO3(186.9mg, 0.57mmol, 2 equiv.) and Pd (dppf) Cl2(21.0mg, 0.03mmol, 0.1 equiv.) the resulting mixture is stirred at 90 ℃ for 24 h under nitrogen and concentrated in vacuo and subjected to preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 21% B to 31% B within 7 min; 254/220 nm; rt: 6.45min) to give 3-amino-6- (1H-1, 3-benzooxadiazol-5-yl) -N- [ (3-fluoropyridin-2-yl) methyl as a yellow solid]-5-(1,3-
Figure BDA0002577091620001296
Oxazol-2-yl) pyrazine-2-carboxamide (compound 47) (12mg, 16.20%). LCMS M/z (ESI), [ M + H]+＝431.1。1H NMR:(300MHz,DMSO-d6)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 listed in the table below were prepared using the procedure described for compound 47.
Figure BDA0002577091620001291
EXAMPLE 48 preparation of 5- (2, 6-Dimethylpyridin-4-yl) -6- (4-fluorophenyl) -N4- (2- ((3-fluoropyridin-2-yl) amino) ethyl) pyrimidine-2, 4-diamine (Compound 48)
Scheme 39
Figure BDA0002577091620001301
Step 1.6- (aminomethyl) pyridin-2-amine
To a mixture of 6-aminopyridine-2-carbonitrile (100mg, 0.8mmol, 1 eq) and Raney nickel (21.6mg, 0.3mmol, 0.3 eq) in THF (10mL) was added NH dropwise at room temperature 4OH (1 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for another 40 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 6- (aminomethyl) pyridin-2-amine (80mg, 77.4%) as a light brown oil which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝124.3。
Step 2.3-amino-N- [ (6-aminopyridin-2-yl) methyl]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5- (1,3-
Figure BDA0002577091620001302
Azol-2-yl) pyrazine-2-carboxamide (Compound 48)
3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001303
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.3mmol, 1 equiv.) and 6- (aminomethyl) pyridin-2-amine (76.4mg, 0.6mmol, 2.0 equiv.) were added dropwise/portionwise to a stirred solution/mixture in DMF (3mL) HATU (471.9mg, 1.2mmol, 4.0 equiv.) and DIEA (160.4mg, 1.2mmol, 4.0 equiv.) the resulting mixture was stirred at room temperature for a further 30 min. the resulting mixture was added dropwise to water, the resulting mixture was filtered, the filter cake was washed with water (3 × 10mL) the crude product was recrystallized from DCM/MeOH (5: 16 mL) to give 3-amino-N- [ (6-aminopyridin-2-yl) methyl ] ate as a yellow solid]-6- [ imidazole [1,2-a ]]Pyridin-6-yl ]-5-(1,3-
Figure BDA0002577091620001304
Oxazol-2-yl) pyrazine-2-carboxamide (compound 48) (89mg, 66.1%). LCMS M/z (ESI), [ M + H]+＝428.1。1H NMR(DMSO-d6,400MHz)4.4(2H,d,J＝6.1Hz),5.9(2H, d,J＝6.0Hz),6.3(1H,d,J＝8.1Hz),6.4(1H,d,J＝7.2Hz),7.2(1H,dd,J＝9.4,1.8Hz),7.3 (1H,t,J＝7.8Hz),7.4(1H,s),7.5(1H,d,J＝9.4Hz),7.6(1H,d,J＝1.3Hz),7.9(3H,s),8.3(1H,s),8.8(1H,t,J＝1.4Hz),9.3(1H,t,J＝6.2Hz)
Example 49.3-amino-N- ((6-amino-3-fluoropyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001312
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 49)
Scheme 40
Figure BDA0002577091620001311
Step 1. (6-amino-3-fluoropyridin-2-yl) methylcarbamic acid tert-butyl ester
To 6-bromo-5-fluoropyridin-2-amine (19mg, 0.10mmol, 1 eq) and Na at room temperature under a nitrogen atmosphere2CO3(42.2mg, 0.40mmol, 4 equiv.) and tert-butyl N- [ (trifluoromethylboryl) methyl]To a stirred mixture of potassium carbamate (70.7mg, 0.30mmol, 3 equiv.) in toluene (20mL) and water (3mL) were added 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (S-Phos) (12.3mg, 0.03mmol, 0.3 equiv.) and Pd (AcO)2(6.7mg, 0.03mmol, 0.3 equiv.). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 30:1) to give N- [ (6-amino-3-fluoropyridin-2-yl) methyl as a brown solid]Tert-butyl carbamate (130mg, 41.17%). LCMS M/z (ESI), [ M + H]+＝242.1。
Step 2.6- (aminomethyl) -5-fluoropyridin-2-amine
To N- [ (6-amino-3-fluoropyridin-2-yl) methyl at room temperature]Tert-butyl carbamate (120mg, 0.50mmol, 1 eq) was added dropwise to a stirred solution in DCM (5mL) to 1, 4-bis
Figure BDA0002577091620001313
HCl (gas) in alkane (362.7mg, 9.95mmol, 20 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 3 hours. The resulting mixture was concentrated to give 6- (aminomethyl) -5-fluoropyridin-2-amine (100mg, 142.44%) as an off-white solid, which was used in the next step without purification.1H NMR(300MHz,DMSO-d6)3.98(d,J＝5.8Hz,2H),6.64(dd,J＝9.1, 3.3Hz,1H),7.53(t,J＝9.1Hz,1H)。
Step 3.3-amino-N- ((6-amino-3-fluoropyridin-2-yl) methyl) -6- (1-methyl-6-oxo-1, 6-di Hydropyridin-3-yl) -5-, (
Figure BDA0002577091620001314
Azol-2-yl) pyrazine-2-carboxamide (Compound 49)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001315
Oxazol-2-yl) pyrazine-2-carboxylic acid (90mg, 0.29mmol, 1 eq), 6- (aminomethyl) -5-fluoropyridin-2-amine (61.2mg, 0.43mmol, 1.51 mAmount) and DIEA (149.3mg, 1.15mmol, 4.02 equiv.) in DMF (10mL) A stirred mixture was added T dropwise3P (182.8mg, 0.57mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of water (40mL) at room temperature. The precipitated solid was collected by filtration and washed with methanol (20mL) to give 3-amino-N- [ (6-amino-3-fluoropyridin-2-yl) methyl ] as a yellow solid ]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001322
Oxazol-2-yl) pyrazine-2-carboxamide (compound 49) (30mg, 15.95%). LCMS M/z (ESI), [ M + H]+＝437.2。1H NMR(300MHz,DMSO-d6)3.48(s,3H),4.50(dd,J＝5.8,2.1Hz,2H),5.85(s, 2H),6.20-6.47(m,2H),7.20-7.49(m,3H),7.81(s,2H),8.05(d,J＝2.6Hz,1H),8.31(d,J＝ 0.8Hz,1H),9.09(t,J＝5.8Hz,1H)。
Example 50.3-amino-N- [ [ 3-fluoro-6- (methylamino) pyridin-2-yl]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001323
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 50)
Scheme 41
Figure BDA0002577091620001321
Step 1.6-bromo-5-fluoro-N-methylpyridin-2-amine
To copper (acetoxy) acetate (1.64g, 9.03mmol, 2.5 equiv.) and methylboronic acid (540.6mg, 9.03mmol, 2.5 equiv.) in bis (N-acetyl) at room temperature under an air atmosphere
Figure BDA0002577091620001324
To a stirred mixture in an alkane (30mL) was added pyridine (1g, 12.64mmol, 3.5 equivalents) and 6-bromo-5-fluoropyridin-2-amine (690mg, 3.61mmol, 1 equivalent) in portions, the resulting mixture was stirred at 100 ℃ under an air atmosphere for 3 hours, the resulting mixture was filtered, and the filter cake was washed with DCM (2 × 30mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 4:1) to give 6-bromo-5-fluoro-N-methylpyridin-2-amine (120mg, 16.20%) as a brown solid. LCMS M/z (ESI), [ M + H]+＝ 205.1,207.1。
Step 2. (3-fluoro-6- (methylamino) pyridin-2-yl) methylcarbamic acid tert-butyl ester
Tert-butyl N- [ (trifluoroboranyl) methyl group at room temperature under nitrogen atmosphere]To a stirred mixture of potassium carbamate (346.9mg, 1.46 mmol, 3 equivalents) and 6-bromo-5-fluoro-N-methylpyridin-2-amine (100mg, 0.49mmol, 1 equivalent) in toluene (20mL) and water (3mL) was added S-Phos (60.1mg, 0.15mmol, 0.3 equivalents), Pd (AcO)2(32.9mg, 0.15mmol, 0.3 equiv.) and Na2CO3(206.8mg, 1.95mmol, 4.00 equiv.). The resulting mixture was stirred at 95 ℃ for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2/MeOH 30:1) to give N- [ [ 3-fluoro-6- (methylamino) pyridin-2-yl ] as a brown solid]Methyl radical]Tert-butyl carbamate (90mg, 72.28%). LCMS M/z (ESI), [ M + H]+＝256.3。
Step 3.6- (aminomethyl) -5-fluoro-N-methylpyridin-2-amine
To N- [ [ 3-fluoro-6- (methylamino) pyridin-2-yl group at room temperature]Methyl radical]To a stirred solution of tert-butyl carbamate (80mg, 0.31mmol, 1 eq) in DCM (5mL) was added HCl (6m) (228.9mg, 6.28mmol, 20.03 eq) dropwise. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure to give 6- (aminomethyl) -5-fluoro-N-methylpyridin-2-amine (45mg, 98.71%) as an off-white solid. 1H NMR(300MHz,DMSO-d6),2.82(d,J＝2.5Hz,3H),4.02(dd,J＝5.9,2.2Hz,2H),6.49(d,J＝9.6Hz,1H),7.40(t,J＝8.3 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- (b 1)
Figure BDA0002577091620001331
Azol-2-yl) pyrazine-2-carboxamide (Compound 5)0)
To 3-amino-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001332
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.22mmol, 1 eq) and 6- (aminomethyl) -5-fluoro-N-methylpyridin-2-amine (38.1mg, 0.25mmol, 1.10 eq) in DMF (10mL) was added DIEA (86.6mg, 0.67mmol, 3 eq) and (3H3) phosphine (17.9mg, 0.45mmol, 2.00 eq) 50% EA solution dropwise. The resulting mixture was stirred at room temperature under an air atmosphere for 3 hours. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and washed with MeOH (20mL) to give 3-amino-N- [ [ 3-fluoro-6- (methylamino) pyridin-2-yl ] as a yellow solid]Methyl radical]-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (1,3-
Figure BDA0002577091620001333
Oxazol-2-yl) pyrazine-2-carboxamide (compound 50) (25mg, 24.59%). LCMS M/z (ESI), [ M + H]+＝451.2。1H NMR(300MHz,DMSO-d6)2.63(d,J＝4.7Hz,3H), 3.43(s,3H),4.51(dd,J＝5.3,2.1Hz,2H),6.21-6.42(m,2H),6.49(p,J＝4.5,4.0Hz,1H), 7.22-7.46(m,3H),7.82(s,2H),7.95(d,J＝2.6Hz,1H),8.28(d,J＝0.8Hz,1H),9.21(t,J＝ 5.2Hz,1H)。
EXAMPLE 52 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (4-fluoro-2-methoxybenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 52)
Scheme 42
Figure BDA0002577091620001341
Step 1.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (4-fluoro-2-methoxybenzyl) -5- (4-fluoro Preparation of phenyl) pyrazine-2-carboxamide (Compound 52)
To 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (0.05g, 0.15mmol), (4-fluoro-2-methoxyphenyl) methylamine (0.03g, 0.22mmol) in DMF (5mL) at 20 deg.CDIEA (0.06g, 0.44mmol) and HATU (0.06g, 0.15mmol) were added to the mixture then the mixture was stirred at this temperature for 1 hour LCMS showed the reaction was complete then the mixture was concentrated and the residue was poured into water and then extracted with EA (2 × 25mL) then the organic solution was purified with rp-c18 and concentrated to give the product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (4-fluoro-2-methoxybenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 52) (0.04g, yield: 56.9%) as a white solid LCMS M/z (ESI), [ M + H ] M/z (ESI), [ M + H ] M]+＝476.1。1H NMR(500MHz,DMSO-d6) ppm2.3(s,6H),3.9(s,3H),4.5(d,J＝6.3Hz,2H),6.7(td,J＝8.4,2.4Hz,1H),6.9(d,J＝11.2Hz,1H),7.0(s,2H),7.2-7.2(m,3H),7.4(dd,J＝8.8,5.7Hz,2H),9.1(t,J＝6.3Hz,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 52.
Figure BDA0002577091620001342
Figure BDA0002577091620001351
EXAMPLE 56 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide (Compound 56)
Scheme 43
Figure BDA0002577091620001352
Step 1.3 preparation of amino-5, 6-dichloropyrazine-2-carboxylic acid
To a stirred solution of methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (3.6g, 16.29mmol) in MeOH (20mL) at 25 deg.C was added NaOH (1.3g, 32.58 mmol.) then the mixture was stirred at this temperature for 16 h LCMS showed the reaction complete then the mixture was concentrated and the residue poured into water and then extracted with EA (2 × 25 mL.) then the organic solution was concentrated to give the crude 3-amino-5, 6-dichloropyrazine-2-methyl ester as a yellow solid Acid (2.6g, yield: 77.1%). LCMS M/z (ESI), [ M + H]+＝208.1。
Step 2.5- ((3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yl) oxy) -3-amino-6-chloro-N- (2-methyl) oxy Preparation of oxybenzyl) pyrazine-2-carboxamides
To a mixture of 3-amino-5, 6-dichloropyrazine-2-carboxylic acid (2.5g, 12.08mmol), (2-methoxyphenyl) methylamine (1.99 g, 14.5mmol) in DMF (20mL) was added DIEA (4.67g, 36.24mmol) and HATU (4.59g, 12.08mmol) at 20 deg.C, then the mixture was stirred at this temperature for 1 hour LCMS shows completion of the reaction, then the mixture was concentrated and the residue was poured into water and then extracted with EA (2 × 25mL), then the organic solution was chromatographed on silica gel and concentrated to give the product 5- ((3H- [1,2, 3) as a white solid]Triazolo [4,5-b]Pyridin-3-yl) oxy) -3-amino-6-chloro-N- (2-methoxybenzyl) pyrazine-2-carboxamide (5g, yield: 97.1%). LCMS M/z (ESI), [ M + H]+＝427.2。
Step 3.3-amino-6-chloro-N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamidePreparation of
At 110 deg.C 5- ((3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yl) oxy) -3-amino-6-chloro-N- (2-methoxybenzyl) pyrazine-2-carboxamide (0.2g, 0.47mmol) to a stirred solution in DMF (5mL) was added 1H-pyrazole (0.05 g, 0.7mmol) and K 2CO3(0.33g, 2.35 mmol.) the mixture was then stirred at 110 ℃ for 3H LCMS showed completion, the mixture was then concentrated and the residue was poured into water and then extracted with EA (2 × 25 mL.) the organic solution was then chromatographed on silica gel and concentrated to give the product 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide (0.14g, yield: 83.3%) as a white solid, LCMS: M/z (ESI), [ M + H ], [ M + H-pyrazol-1-yl) pyrazine-2-carboxamide (0.14g, yield: 83.3%). LCMS]+＝359.1。
Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1H-pyrazole- Preparation of 1-yl) pyrazine-2-carboxamide (Compound 56)
To a solution of 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide (0.07g,0.2mmol), (2-methoxyphenyl) methylamine (0.07g, 0.29mmol) in bis
Figure BDA0002577091620001361
To a mixture of alkanes (10mL) was added K3PO4(0.12g, 0.59mmol) and Pd2dba3(0.02g, 0.02 mmol.) the mixture was then stirred at this temperature for 0.5 h.LCMS showed reaction completion then the mixture was concentrated and the residue was poured into water and then extracted with EA (2 × 25 mL.) then the organic solution was concentrated and purified with rp-c18 to give the product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide (compound 56) (0.017g, yield: 20.3%) as a white solid lcMS M/z (ESI), [ M + H + pyrazole-1-yl) pyrazine-2-carboxamide (compound 56) (0.017g, 20.3%). LCMS ]+＝429.5。1H NMR(500MHz, DMSO-d6)ppm 2.3(s,6H),2.7-2.8(m,2H),3.5(br d,J＝6.0Hz,2H),3.7(s,3H),5.6-5.7 (m,1H),6.3(br s,2H),6.6(s,2H)6.7-6.9(m,3H),7.0(br t,J＝8.7Hz,2H),7.2(br t,J＝7.1 Hz,3H)。
EXAMPLE 57.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1H-pyrazol-1-yl) pyrazine-2-carboxamide (Compound 57) preparation
Scheme 44
Figure BDA0002577091620001371
Step 1.2 preparation of cyano-3- (difluoromethoxy) pyridine
To a stirred solution of 2-cyano-3-hydroxypyridine (2.2g, 18.33mmol) in ACN (10mL) and water at-78 deg.C was added dimethyl (bromodifluoromethyl) phosphonate (8.72g, 36.66mmol) and KOH (3.08g, 54.99 mmol). The mixture was then stirred at-78 ℃ for 16 hours. LCMS showed reaction completion. Water was added and extracted with EA, and concentrated to give 2-cyano-3- (difluoromethoxy) pyridine as a dark oil. LCMS M/z (ESI), [ M + H]+＝171.4。
Step 2 preparation of (3- (difluoromethoxy) pyridin-2-yl) methylamine
To a solution of 2-cyano-3- (difluoromethoxy) pyridine (1.5g,8.82mmol) in THF (20mL) was added LiAlH4(0.5g, 13.23 mmol). The mixture was then stirred at 0 ℃ for 1 hour. LCMS showed the desired product. Water was added and extracted with EA. Concentration gave a yellow oil. LCMS M/z (ESI), [ M + H]+＝175.1。
Step 3.3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -6- (2, 6-dimethylpyridine-4- Preparation of yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 57)
Adding 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (0.03g, 0.09mmol) at 20℃,(3- (difluoromethoxy) pyridin-2-yl) methylamine(0.02g, 0.13mmol) to a mixture in DMF (5mL) was added DIEA (0.03g, 0.27mmol) and HATU (0.03g, 0.09mmol) and the mixture was stirred at this temperature for 1H LCMS showed the reaction complete, then the mixture was concentrated and the residue was poured into water and then extracted with EA (2 × 25mL), then the organic solution was purified with rp-c18 and concentrated to give the product 3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 57) (0.03g, yield: 68.4%) as a white solid, LCMS: M/z (ESI), [ M + H ] LCMS]+＝495.6。1H NMR(500MHz,DMSO-d6)ppm 2.3(s,6H),4.7(d,J＝6.0Hz,2H),7.0(s,2H),7.2-7.3(m,3H),7.3-7.5(m,4H),7.7(d,J＝8.5Hz,1H),8.4(d,J＝3.5Hz,1H),9.2(t,J＝5.7Hz,1H)。
EXAMPLE 58 preparation of 3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 58)
Scheme 45
Figure BDA0002577091620001381
Step 1.3-amino-6-chloro-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) pyri-dine Preparation of oxazine-2-carboxamides
To 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (0.12g, 0.45mmol), (3- (bis) ethyl acetate) at 20 deg.C Fluoromethoxy) pyridin-2-yl) methylamine (0.08g, 0.45mmol) was added to a mixture of DIEA (0.17g, 1.35mmol) and HATU (0.17g, 0.45mmol) in DMF (5mL) and the mixture was then stirred at this temperature for 1 hour LCMS showed the reaction was complete LCMS then the mixture was concentrated and the residue was poured into water and then extracted with EA (2 × 25mL) then the organic solution was purified with rp-c18 and concentrated to give the product 3-amino-6-chloro-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (0.07g, yield: 36.8%) as a white solid LCMS M/z (esi), [ M + H esi ], [ M + H ] LCMS]+＝424.2。
Step 2.3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) -6- (1-methyl) Preparation of 1, 6-dihydropyridin-3-yl-6-oxo-2-pyrazinecarboxamide (Compound 58)
To 3-amino-6-chloro-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (0.06g, 0.14mmol), 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.05g, 0.21mmol) in bis (N, N-ethyl-N, N-propyl) -2-carboxylic acid amide at 120 deg.C
Figure BDA0002577091620001382
To the mixture in alkane (3mL) was added K3PO4(0.09g, 0.43mmol) and Pd2dba3(0.01g, 0.01 mmol.) the mixture is then stirred at this temperature for 0.5 h.LCMS shows completion.the mixture is then concentrated and the residue is poured into water and then extracted with EA (2 × 25 mL.) the organic solution is then concentrated and purified with RP-C18 to give the product 3-amino-N- ((3- (difluoromethoxy) pyridin-2-yl) methyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 58) (0.025g, yield: 35.5%) as a white solid ]+＝497.2。1H NMR(500MHz,DMSO-d6) ppm 3.4(s,3H),4.7(d,J＝5.7Hz,2H),6.2(d,J＝9.5Hz,1H),7.1(dd,J＝9.5,2.5Hz,1H), 7.2-7.3(m,3H),7.4(s,1H),7.4(dd,J＝8.5,4.7Hz,1H),7.5-7.6(m,3H),7.7(d,J＝8.2Hz, 1H),8.0(d,J＝2.5Hz,1H),8.4(d,J＝4.4Hz,1H),9.2(t,J＝6.0Hz,1H)。
EXAMPLE 59 preparation of 3-amino-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 59)
Scheme 46
Figure BDA0002577091620001391
Step 1.3-amino-6-chloro-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) pyridine Preparation of oxazine-2-carboxamides
To a mixture of 3-amino-6-chloro-5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxylic acid (0.1g, 0.4mmol), 2- (difluoromethoxy) aniline (0.1g, 0.59mmol) in DMF (5mL) was added DIEA (0.15g, 1.19 mmol) and HATU (0.15g, 0.4mmol) at 20 deg.C, then the mixture was stirred at this temperature for 1 hour LCMS showed the reaction to be complete, then the mixture was concentrated and the residue was poured into water, and then extracted with EA (2 × 25mL), then the organic solution was purified with rp-c18, concentrated to give the product 3-amino-6-chloro-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (0.05g, yield: 30.7%) as a white solid, and LCM + ESI [ M ] M + M (0.05 g)]+＝413.4。
Step 2.3-amino-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) -6- (1-methyl) Preparation of 1, 6-dihydropyridin-3-yl-6-oxo-2-pyrazinecarboxamide (Compound 59)
To 3-amino-6-chloro-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (0.03g, 0.07mmol), 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.03g, 0.11mmol) in bis (N, N-dimethylformamide) at 120 deg.C
Figure BDA0002577091620001392
To the mixture in alkane (3mL) was added K3PO4(0.05g, 0.22 mmol) and Pd2dba3(0.01g, 0.01 mmol). The mixture was then stirred at this temperature for 0.5 h. LCMS showed reaction completion. The mixture is then concentrated and the residue is taken upThe material was poured into water and then extracted with EA (2 × 25 mL.) the organic solution was concentrated and purified with rp-c18 to give the product 3-amino-N- (2- (difluoromethoxy) phenyl) -5- (3-methyl-1H-pyrazol-1-yl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 59) as a white solid (0.02g, yield: 56.6%). LCMS: M/z (ESI), [ M + H ], (ESI) ]]+＝486.1。1H NMR(500MHz,DMSO-d6) ppm 2.2(s,3H),3.5(s,3H),6.3(d,J＝9.5Hz,1H),6.4(d,J＝2.5Hz,1H),7.0(dd,J＝9.5, 2.5Hz,1H),7.1-7.5(m,5H),7.8-7.9(m,2H),8.1(d,J＝2.2Hz,1H),8.3-8.3(m,1H),10.3 (s,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 59.
Figure BDA0002577091620001401
EXAMPLE 61.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (5-methylfuran-3-yl) pyrazine-2-carboxamide (Compound 61) preparation
Scheme 47
Figure BDA0002577091620001402
Step 1.3 preparation of methyl 3-amino-6-chloro-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (0.5g, 2.26mmol), 4,5, 5-tetramethyl-2- (5-methylfuran-2-yl) -1,3, 2-dioxaborolane (0.71g, 3.39mmol) in bis (N-methyl-ethyl-L-methyl-2-oxolane at 100 deg.C
Figure BDA0002577091620001404
Na was added to the mixture in an alkane (20mL)2CO3(0.94g, 4.53mmol) and Pd (dppf) Cl2(0.83g, 1.13 mmol). The mixture was then stirred at this temperature for 2 hours. LCMS showed the reaction was complete and purified by silica gel chromatography to afford the desired product methyl 3-amino-6-chloro-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate. LCMS M/z (ESI), [ M + H]+＝268.4。
Step 2.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid Preparation of methyl esters
To methyl 3-amino-6-chloro-5- (5-methylfuran-3-yl) pyrazine-2-carboxylate (0.26g, 1mmol), 2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.23g, 1mmol) in bis (N-ethyl-N-methyl-2-oxolane-2-yl) at 100 deg.C
Figure BDA0002577091620001411
To the mixture in alkane (20mL) was added Na2CO3(0.94g, 4.53mmol) and Pd (dppf) Cl2(0.073g, 0.1 mmol). The mixture was then stirred at this temperature for 2 hours. LCMS showed the reaction was complete and purified by silica gel chromatography to afford the desired product methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylate. LCMS M/z (ESI), [ M + H ]+＝339.5。
Step 3.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid Preparation of
To a stirred solution of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylate (0.4 g, 1.18mmol) in MeOH (20mL) at 25 deg.C was added NaOH (0.09g, 2.37 mmol.) then the mixture was stirred at this temperature for 16H LCMS showed completion then the mixture was concentrated and the residue poured into water and then extracted with EA (2 × 10mL) then the organic solution was concentrated to give the crude product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid as a yellow solid (0.3g, yield: 78.2%). LCMS M/z (ESI), [ M + H ], [ M + ESI ], [ M]+＝325.2。
Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (5-methylfuran Preparation of pyran-2-yl) pyrazine-2-carboxamide (Compound 61)
To a mixture of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxylic acid (0.05g, 0.15mmol), (2-methoxyphenyl) methylamine (0.021g, 0.15mmol) in DMF (5mL) at 20 deg.C was added DIEA (0.058g, 0.45mmol) and HA TU (0.057g, 0.15mmol) then the mixture was stirred at this temperature for 1 hour LCMS shows reaction completion then the mixture was concentrated and the residue poured into water and then extracted with EA (2 × 25mL) then the organic solution was purified with rp-c18 and concentrated to give the product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (5-methylfuran-2-yl) pyrazine-2-carboxamide (compound 61) (0.021g, yield: 32%) as a white solid]+＝444.1。1H NMR(500MHz, DMSO-d6)ppm 2.2(s,3H),2.4(s,6H),3.8(s,3H),4.5(d,J＝6.3Hz,2H),6.2(d,J＝3.2Hz, 1H),6.5(d,J＝3.2Hz,1H),6.9(t,J＝7.4Hz,1H),7.0(d,J＝8.2Hz,1H),7.1-7.2(m,3H), 7.2(t,J＝7.1Hz,1H),8.9(t,J＝6.3Hz,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 61.
Figure BDA0002577091620001421
EXAMPLE 63.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxamide (Compound 63) preparation
Scheme 48
Figure BDA0002577091620001422
Step 1.3 preparation of methyl 3-amino-6-chloro-5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (0.5g, 2.26mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid (0.43g, 3.39mmol) in bis (hydroxymethyl) phosphonium bromide at 100 deg.C
Figure BDA0002577091620001423
To the mixture in alkane (20mL) was added Na2CO3(0.57g, 4.53mmol) and Pd (dppf) Cl2(0.83g, 1.13 mmol). The mixture was then stirred at this temperature for 2 hours. LCMS shows the reaction is complete and purification by silica gel chromatography to afford the desired product 3-amino-6-chloro-5- (1-methyl-1H) -pyrazol-4-yl) pyrazine-2-carboxylic acid methyl ester. LCMS M/z (ESI), [ M + H]+＝268.6。
Step 2.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazin-2- Preparation of methyl formate
To methyl 3-amino-6-chloro-5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate (0.4g, 1.5mmol), (2, 6-dimethylpyridin-4-yl) boronic acid (0.34g, 2.25mmol) in dipyridyl-bis (hydroxymethyl) borate at 100 deg.C
Figure BDA0002577091620001431
To the mixture in alkane (20mL) was added Na2CO3(0.45g, 3mmol) and Pd (dppf) Cl2(0.55g, 0.75 mmol). The mixture was then stirred at this temperature for 2 hours. LCMS showed the reaction was complete and purified by silica gel chromatography to afford the desired product methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate. LCMS M/z (ESI), [ M + H]+＝339.2。
Step 3.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazin-2- Preparation of formic acid
to a stirred solution of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylate (0.4g, 1.18mmol) in MeOH (20mL) at 25 deg.C was added NaOH (0.09g, 2.37mmol) then the mixture was stirred at this temperature for 16H LCMS shows completion then the mixture was concentrated and the residue poured into water and then extracted with EA (2 × 10mL) then the organic solution was concentrated to give the crude product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylic acid as a yellow solid (0.3g, yield: 78.2%). LCMS M/z (ESI), [ M + H-pyrazol-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylic acid (0.3g, 78.2%). M ]+＝325.5。
Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1-methyl- Preparation of 1H-pyrazol-4-yl) pyrazine-2-carboxamide (Compound 63)
To 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxylic acid (0.05 g, 0.15mmol), (2-methoxyphenyl) at 20 ℃) methylamine (0.021g, 0.15mmol) in DMF (5mL) was added DIEA (0.058g, 0.45mmol) and HATU (0.057g, 0.15 mmol.) the mixture was then stirred at this temperature for 1H LCMS showed the reaction complete then the mixture was concentrated and the residue poured into water and then extracted with EA (2 × 25mL) then the organic solution was purified with rp-c18 and concentrated to give the product 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (1-methyl-1H-pyrazol-4-yl) pyrazine-2-carboxamide (compound 63) (0.004g, yield: 6%) as a white solid, LCMS M/z (ESI), [ M + H ] M]+＝444.2。1H NMR(500 MHz,DMSO-d6)ppm 2.2(s,3H),2.4(s,6H),3.8(s,3H),4.5(d,J＝6.3Hz,2H),6.2(d,J＝ 3.2Hz,1H),6.5(d,J＝3.2Hz,1H),6.9(t,J＝7.4Hz,1H),7.0(d,J＝8.2Hz,1H),7.1-7.2(m, 3H),7.2(t,J＝7.1Hz,1H),8.9(t,J＝6.3Hz,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 63.
Figure BDA0002577091620001441
EXAMPLE 72 preparation of 3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 72)
Scheme 49
Figure BDA0002577091620001442
Step 1.3 preparation of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (4.4g, 19.91mmol), 2- (4-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (3.07g, 21.9mmol) in bis (ethyl acetate)
Figure BDA0002577091620001443
Na was added to a mixture of an alkane (50mL) and water (5mL)2CO3(4.22g, 39.82mmol) and dppfPdCl2(2.84g, 3.98 mmol). The mixture was then brought to 100 deg.CUnder N2after stirring under atmosphere for 1H, the mixture was concentrated and the residue was poured into water (100mL), and then extracted with EA (100mL × 3) the organic solution was concentrated to give the crude product as a yellow solid (5.5g, 98% yield) which was used in the next step without further purification MS M/z (ESI) [ M + H) ]]+＝282.2。
Step 2.3 preparation of amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid
To a mixture of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (1.1g, 3.9mmol) in methanol (5mL) and water (3mL) was added LiOH (0.3g, 12 mmol). The mixture was then stirred at 20 ℃ for 3 hours. The mixture was then diluted by citric acid solution (2N, 50mL) and then filtered. The solid was dried to give 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid as a yellow solid (0.95g, 91% yield). MS M/z (ESI) [ M + H ] ]+＝ 268.2。
Step 3.3-amino-6-chloro-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide Preparation of
To a mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (100mg, 0.37mmol), (2- (difluoromethoxy) phenyl) methylamine (80mg, 0.46mmol), and DIEA (100mg, 0.78mmol) in DMF (3mL) was added HATU (200mg, 0.53mmol) at 20 ℃. The resulting mixture was stirred at 20 ℃ for 10 min. The mixture was purified by C18-40g (MeCN/water ═ 5% to 80%) to give 3-amino-6-chloro-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide as a yellow solid (120mg, 76% yield). MS M/z (ESI) [ M + H ]]+＝ 423.3。
Step 4.3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo- Preparation of 1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 72)
To 3-amino-6-chloro-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (90mg, 0.21 mmol), 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (50mg, 0.21 mmol), Pd2(dba)3(8mg, 0.0087mmol), tricyclohexylPhenylphosphine (11mg, 0.039mmol) and K3PO4(75 mg, 0.35mmol) in bis
Figure BDA0002577091620001452
To the mixture in alkane (3mL) was added water (1 mL). The resulting mixture was sealed and heated in a microwave at 120 ℃ for 15 min. The mixture was filtered and the filtrate was purified by C18-40g (MeCN/water ═ 5% -80%) to give 3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 72) as a yellow solid (82mg, 78% yield). LCMS M/z (ESI), [ M + H ]+＝496.3。1H NMR(500MHz,DMSO-d6)ppm 3.42(s,3H),4.57(d,J＝6.31Hz,2H),6.20(d,J＝9.46Hz,1H),7.10(dd,J＝9.30,2.68Hz,1H),7.16-7.30(m,5H),7.30-7.36(m,2H),7.44-7.83(m,3H),7.64(br d,J＝16.08Hz,1H),7.99(d,J＝2.52Hz,1H),9.23(t,J＝6.31Hz,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 72.
Figure BDA0002577091620001451
EXAMPLE 75.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (Compound 75) preparation
Scheme 50
Figure BDA0002577091620001461
Step 1.3-amino-6-chloro-N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2- Preparation of carboxamides
To 5- ((3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yl) oxy) -3-amino-6-chloro-N- (2-methoxybenzyl) pyrazine-2-carboxamide (500mg, 1.2mmol) to a mixture in DMF (5mL) was added 3-methyl-1H-pyrazole (120mg, 1.5mmol) and K2CO3(350mg, 2.5 mmol). The resulting mixture was heated at 120 ℃ for 1 hour. By C18-40 g (MeCN/water 5% -80%)The mixture was purified to give 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (200mg, 46% yield) and 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (5-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (40mg, 7% yield) as a yellow solid. LCMS M/z (ESI) [ M + H ]]+＝373.2。
Step 2.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (3-methyl- Preparation of 1H-pyrazol-1-yl) pyrazine-2-carboxamide (Compound 75)
To 3-amino-6-chloro-N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (45mg, 0.12mmol), (2, 6-dimethylpyridin-4-yl) boronic acid (20mg, 0.13mmol), Pd2(dba)3(7mg, 0.0076mmol), tricyclohexylphosphine (13mg, 0.046mmol) and K3PO4(45mg, 0.21mmol) in bis
Figure BDA0002577091620001462
To the mixture in alkane (3mL) was added water (1 mL). The resulting mixture was sealed and heated in a microwave at 120 ℃ for 15 min. The mixture was filtered and the filtrate was purified by C18-40g (MeCN/water ═ 5% -80%) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazine-2-carboxamide (compound 75) as a white solid (36mg, 67% yield). LCMS M/z (ESI), [ M + H]+＝444.3。1H NMR(500MHz,DMSO-d6)ppm2.10(s,3H),2.34(s,6H),3.84(s,3H),4.50(d,J＝6.31Hz,2H),6.34(d,J＝2.52Hz,1H),6.86(s,2H),6.89(t,J＝7.41Hz,1H),7.00(d,J＝8.20Hz,1H),7.15(d,J＝7.25Hz,1H),7.23(t,J＝7.90Hz,1H),7.98(d,J＝2.21Hz,3H),9.04(t,J＝6.42Hz,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 75.
Figure BDA0002577091620001471
EXAMPLE 77 preparation of 3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 77)
Scheme 51
Figure BDA0002577091620001472
Step 1.5 preparation of bromo-1- (oxetan-3-yl) pyridin-2 (1H) -one
To a mixture of 5-bromopyridin-2 (1H) -one (1.2g, 6.9mmol) in DMF (10mL) was added 3-iodooxetane (1.3g, 7.1mmol) and Cs 2CO3(2.7g, 8.3 mmol). The resulting mixture was heated at 100 ℃ for 4 hours. The mixture was filtered and the filtrate was purified by C18-40g (MeCN/water 5% -40%) to give 5-bromo-1- (oxetan-3-yl) pyridin-2 (1H) -one (310mg, 20% yield) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝230.1。
Step 2.1- (Oxetan-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan- Preparation of 2-yl) pyridin-2 (1H) -ones
To 5-bromo-1- (oxetan-3-yl) pyridin-2 (1H) -one (260mg, 1.1mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (300mg, 1.2mmol) and PdCl2(dppf) (30mg, 0.041mmol) in bis
Figure BDA0002577091620001473
KOAc (250mg, 2.6mmol) was added to the mixture in an alkane (5 mL). The mixture was then heated in a microwave at 90 ℃ for 30 min. The mixture was then diluted with water (50mL) and extracted with EA (50 mL). By means of brine and anhydrous Na2SO4To dry the organic layer, followed by concentration, the crude product was obtained as a brown solid (250mg, 80% yield). MS M/z (ESI)278.3[ M + H ]]+。
Step 3.3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo- Preparation of 1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (Compound 77)
To 1- (oxetan-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2(1H) -one (20mg, 0.072mmol), 3-amino-6-chloro-N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (35mg, 0.89mmol), Pd2(dba)3(7mg, 0.0076mmol), tricyclohexylphosphine (13mg, 0.046mmol) and K3PO4(45mg, 0.21mmol) in bis
Figure BDA0002577091620001482
To the mixture in alkane (3mL) was added water (1 mL). The resulting mixture was sealed and heated in a microwave at 120 ℃ for 15 min. The mixture was filtered and the filtrate was purified by C18-40g (MeCN/water ═ 5% -80%) to give 3-amino-N- (2- (difluoromethoxy) benzyl) -5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carboxamide (compound 77) as a yellow solid (21mg, 57% yield). LCMS M/z (ESI), [ M + H]+＝508.3。1H NMR(500MHz,DMSO-d6)ppm 4.30(s,2H),4.64(t,J＝6.94Hz,2H), 4.94(t,J＝7.41Hz,2H),5.62(quin,J＝7.01Hz,1H),6.40(d,J＝9.14Hz,1H),6.99(br t,J＝ 7.72Hz,2H),7.10(br t,J＝8.67Hz,2H),7.24(dd,J＝9.46,2.21Hz,1H),7.30-7.37(m,1 H),7.54(br dd,J＝8.51,5.36Hz,2H),7.86(d,J＝2.21Hz,1H)。
EXAMPLE 78 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-fluorophenylmethyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 78)
Scheme 52
Figure BDA0002577091620001481
3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-fluorophenylmethyl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid Preparation of the amine (Compound 78)
To a stirred mixture of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (20mg, 0.059mmol), (2-fluorophenyl) methylamine (7.4mg, 0.059mmol) and DIPEA (15mg, 0.118mmol) was added HATU (25mg, 0.065mmol) in one portion at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solution was purified by C18-40g (MeCN/water 0% -80%) to give 3-ammonia as an off-white solid Yl-6- (2, 6-dimethylpyridin-4-yl) -N- (2-fluorophenylmethyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 78) (16.3 mg, 61.94% yield). LCMS M/z (ESI), [ M + H]+＝446.4。1H NMR(500MHz,CDCl3)ppm 1.9(brs,2H),2.5(s,6H),4.7(d,J＝6.3Hz,2H),6.9(s,2H),7.0(t,J＝8.7Hz,2H),7.1-7.2(m,2H),7.25-7.30(m,1H),7.3-7.4(m,3H),8.3(brt,J＝6.1Hz,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 78.
Figure BDA0002577091620001491
Figure BDA0002577091620001501
EXAMPLE 82 preparation of 3-amino-6- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (Compound 82)
Scheme 53
Figure BDA0002577091620001502
3-amino-6-chloro-5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (30mg, 0.078mmol), 1, 3-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (23mg, 0.093 mmol) and K3PO4(28mg, 0.132mmol) in bis
Figure BDA0002577091620001503
Suspension in alkane (1.50 mL)/water (0.375mL) with N2Purged and degassed 3 times, then added Pcy3(6.5mg, 0.023mmol) and Pd2(dba)3(7mg, 0.008 mmol). The resulting mixture was again treated with N2Purge and degas 3 times. The reaction mixture was sealed and heated at 120 ℃ for 1 hour through a microwave reactor. The solution was filtered and evaporated under reduced pressure. Elution gradient 0% to 60% MeCN/water (0.05% ammonium hydroxide) by C18-40g flash chromatography) The residue was purified to give 3-amino-6- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (compound 82) as a yellow solid (25mg, 68.08% yield). LCMS M/z (ESI), [ M + H ]+＝474.4。1H NMR(500MHz,CDCl3)ppm1.7(s,2H),2.1 (s,3H),3.5(s,3H),3.9(s,3H),4.7(d,J＝6.3Hz,2H),6.9(d,J＝8.2Hz,1H),6.9(t,J＝7.4 Hz,1H),7.1(t,J＝8.7Hz,2H),7.1(d,J＝2.2Hz,1H),7.2(s,1H),7.3-7.3(m,1H),7.3-7.4 (m,1H)7.5(dd,J＝8.8,5.4Hz,2H),8.4(brt,J＝6.0Hz,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 82. .
Figure BDA0002577091620001511
EXAMPLE 83.3-amino-6- (2-amino-6-methylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (Compound 83)
Scheme 54
Figure BDA0002577091620001521
(2-amino-6-methylpyridin-4-yl) boronic acidPreparation of
4-bromo-6-methylpyridin-2-amine (80mg, 0.428mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (130mg, 0.513mmol) and KOAc (50mg, 0.51mmol) in bis
Figure BDA0002577091620001522
Suspension in alkane (4mL) with N2Purged and degassed 3 times, followed by addition of PdCl2(dppf) (16mg, 0.021 mmol). The resulting mixture was again treated with N2Purge and degas 3 times. The reaction mixture was sealed and heated at 100 ℃ for 16 hours. The solution was filtered and evaporated under reduced pressure to give (2-amino-6-methylpyridin-4-yl) boronic acid (96mg, crude material), which was used in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝153.3
Step 2.3-amino-6- (2-amino-6-methylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) Yl) pyrazine-2-carboxamide (Compound 83)
3-amino-6-chloro-5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (30mg, 0.078mmol), (2-amino-6-methylpyridin-4-yl) boronic acid (48mg, 0.093mmol) and K 3PO4(48mg, 0.244mmol) in Ethans
Figure BDA0002577091620001523
Suspension in alkane (1.50 mL)/water (0.37mL) with N2Purged and degassed 3 times, then added Pcy3(6.5mg, 0.023mmol) and Pd2(dba)3(7mg, 0.008 mmol). The resulting mixture was again treated with N2Purge and degas 3 times. The reaction mixture was sealed and heated at 120 ℃ for 1 hour by means of a microwave reactor. The solution was filtered and evaporated under reduced pressure. The residue was purified by C18-40g flash chromatography, elution gradient 0% to 100% MeCN/water (0.05% ammonia hydroxide) to give 3-amino-6- (2-amino-6-methylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (compound 83) as an off-white solid (7.6mg, 21.3% yield). LCMS M/z (ESI), [ M + H]+＝495.3。1HNMR(500MHz,CDCl3)ppm 1.9(brs,2H),2.3(s,3H),3.9(s,3H),4.7(d,J＝6.3Hz,2H), 4.7(brs,2H),6.3(s,1H),6.5(s,1H),6.9(d,J＝8.2Hz,1H),6.9-7.0(m,1H),7.0(t,J＝8.5Hz,2H),7.3-7.4(m,2H),7.4-7.5(m,2H),8.4(brt,J＝6.1Hz,1H)。
EXAMPLE 86. preparation of N- ((3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl) methyl) -2-methoxybenzamide (Compound 86)
Scheme 55
Figure BDA0002577091620001531
Step 1.3 preparation of amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile
To 3-amino-5, 6-dichloropyrazine-2-carbonitrile (300mg, 1.5mmol) and (4-fluorophenyl) boronic acid (233mg, 1.6mmol) in bis
Figure BDA0002577091620001532
2M Na was added to a solution in alkane (14mL)2CO3(1.6mL) in the reaction. The obtained mixture is mixed with N2Purged and degassed 3 times, followed by addition of PdCl 2(dppf) (58mg, 0.079 mmol). The resulting mixture was again treated with N2purge and degas 3 times the resulting mixture is heated at 80 ℃ under a nitrogen balloon atmosphere for 6 hours, the reaction is diluted with water (20mL) and extracted with EtOAc (3 × 20mL), the combined organics are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated under reduced pressure to give 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (395mg, crude material) as a brown solid, LCMS: M/z (ESI), [ M + H (ESI) ]]+＝249.2。
Step 2.3 preparation of amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carbonitrile
3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (395mg, 1.5mmol) and (2, 6-dimethylpyridin-4-yl) boronic acid (288mg, 1.9mmol) in Di
Figure BDA0002577091620001533
Solution in alkane (14 mL). Followed by addition of 2M Na2CO3(1.6mL) was added to the reaction. The mixture obtained is treated with N2Purged and degassed 3 times, followed by addition of PdCl2(dppf) (58mg, 0.079 mmol). The resulting mixture was again treated with N2purge and degas 3 times the resulting mixture was heated at 90 ℃ under a nitrogen balloon atmosphere for 16H, dilute the reaction with EtOAc (20mL), extract with EtOAc (3 × 20mL), dry the combined organics over anhydrous sodium sulfate, filter and evaporate the filtrate under reduced pressure and purify by silica gel column chromatography (petroleum ether/EtOAc ═ 10/1-3/1 (v/v)) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carbonitrile (311mg, 61% yield) as a brown solid, LCMS: M/z (ESI), [ M + H/-H ] pyrazine-2-carbonitrile (311mg, 61% yield) ]+＝320.3。
Step 3.3 preparation of 3- (aminomethyl) -5- (2, 6-dimethylpyridin-4-yl) -6- (4-fluorophenyl) pyrazin-2-amine
3-amino-6- (2,6-Dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carbonitrile (60 mg, 0.188mmol) in dry THF (0.5mL) was added dropwise to LiAlH4(14mg, 0.376mmol) in dry THF (1.5mL) with stirring. The reaction was slowly warmed to room temperature and stirred at room temperature for 16 hours. The reaction was diluted with anhydrous THF (10mL) and cooled by an ice/water bath at 0 ℃ with stirring. Sodium sulphate decahydrate (500mg, three portions) was then added and the resulting mixture was stirred at this temperature for 30min, then filtered and the filtrate was concentrated in vacuo to give 3- (aminomethyl) -5- (2, 6-dimethylpyridin-4-yl) -6- (4-fluorophenyl) pyrazin-2-amine (50mg, 82% yield) as a brown oil. LCMS M/z (ESI), [ M + H]+＝324.4
Step 4.N- ((3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl) methyl) - Preparation of 2-methoxybenzamide (Compound 86)
A solution of 3- (aminomethyl) -5- (2, 6-dimethylpyridin-4-yl) -6- (4-fluorophenyl) pyrazin-2-amine (50mg, 0.15mmol) and TEA (47mg, 0.46mmol) in NMP (1mL) was cooled at 0 ℃ by an ice/water bath and a solution of 2-methoxybenzoyl chloride (26mg, 0.155mmol) in NMP (1.0mL) was subsequently added dropwise to the reaction. The resulting mixture was stirred and slowly warmed to room temperature for 2 hours. The solution was purified by C18-40g flash chromatography, elution gradient 0% to 50% MeCN/water (0.05% ammonium hydroxide) to give N- ((3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazin-2-yl) methyl) -2-methoxybenzamide (compound 86) as an off-white solid (15mg, 46% yield). LCMS M/z (ESI), [ M + H ]+＝458.3。1H NMR(500MHz,CDCl3)ppm 2.5(s,6H),3.9(s,3H), 4.8(d,J＝6.3Hz,2H),6.0(brs,2H),6.9(s,2H),7.0-7.0(m,3H),7.1-7.1(m,1H),7.3-7.4 (m,2H),7.5-7.5(m,1H),8.3(dd,J＝7.9,1.6Hz,1H),8.7(brt,J＝6.0Hz,1H)
EXAMPLE 87 preparation of 3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 87)
Scheme 56
Figure BDA0002577091620001541
Step 1.3 preparation of amino-6-chloro-N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide
To a stirred mixture of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (200mg, 0.74mmol), (2, 6-difluorophenyl) methylamine (107mg, 0.74mmol), and DIPEA (93mg, 1.49mmol) was added HATU (313mg, 0.82mmol) in one portion at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solution was purified by C18-40g (MeCN/water 0% -60%) to give 3-amino-6-chloro-N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide as a yellow solid (290mg, 99% yield). LCMS M/z (ESI), [ M + H]+＝ 393.2。
Step 2.3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- (2, 6-difluorobenzyl) Preparation of yl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (Compound 87)
3-amino-6-chloro-N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (50mg, 0.12mmol), 1-cyclopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (40mg, 0.15 mmol) and K 3PO4(46mg, 0.21mmol) in bis
Figure BDA0002577091620001551
Suspension in alkane (2.0 mL)/water (0.4mL) with N2Purged and degassed 3 times, then added Pcy3(11mg, 0.039mmol) and Pd2(dba)3(12mg, 0.013 mmol). The resulting mixture was again treated with N2Purge and degas 3 times. The reaction mixture was sealed and heated at 120 ℃ for 15min through a microwave reactor. The solution was filtered and evaporated under reduced pressure. The residue was purified by C18-40g flash chromatography, eluting with a gradient of 0% to 70% MeCN/water (0.05% ammonia hydroxide) to give 3-amino-6- (1-cyclopropyl-6-oxo-1, 6-dihydropyridin-3-yl) -N- (2, 6-difluorobenzyl) -5- (4-fluorophenyl) pyrazine-2-carboxamide (compound 87) as a yellow solid (40mg, 64% yield). LCMS M/z (ESI), [ M + H]+＝492.31H NMR(500MHz,CDCl3)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＝6.3Hz,2H),6.5(d,J＝9.1Hz,1H), 6.9(t,J＝7.9Hz,2H),7.1(t,J＝8.5Hz,2H),7.2-7.3(m,1H),7.3-7.3(m,2H),7.4-7.5(m, 2H),8.2(brt,J＝6.3Hz,1H)。
EXAMPLE 88. preparation of N- ((3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl) methyl) -2, 6-difluorobenzamide (Compound 88)
Scheme 57
Figure BDA0002577091620001561
Step 1.3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2- Preparation of carbonitrile
To 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (395mg, 1.587mmol) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (448mg, 1.905mmol) in bis
Figure BDA0002577091620001562
2M Na was added to a solution in alkane (14mL)2CO3(336mg, 1.6mL) was in the reaction. The mixture obtained is treated with N2Purged and degassed 3 times, followed by addition of PdCl2(dppf) (58mg, 0.079 mmol). The resulting mixture was again treated with N2purge and degas 3 times the resulting mixture was heated at 90 ℃ under a nitrogen balloon atmosphere for 16H, dilute the reaction with water (20mL) and extract with EtOAc (3 × 20mL), dry the combined organics over anhydrous sodium sulfate, filter and evaporate the filtrate under reduced pressure and purify by silica gel column chromatography (petroleum ether/EtOAc ═ 10/1-3/1(v/v)) to give 3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carbonitrile (235mg, 46% yield) as a brown solid, LCMS: M/z (ESI), [ M + H (ESI) ]]+＝322.3。
Step 2.5- (5-amino-6- (aminomethyl) -3- (4-fluorophenyl) pyrazin-2-yl) -1-methylpyridine-2 (1H) - Preparation of ketones
3-amino-5- (4-fluorobenzene) was washed at 0 ℃ with ice/water bathA solution of yl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazine-2-carbonitrile (51mg, 0.159mmol) in anhydrous THF (0.5mL) was added dropwise to LiAlH4(12mg, 0.317mmol) in dry THF (1.5mL) with stirring. The reaction was slowly warmed to room temperature and stirred at room temperature for 16 hours. The reaction was diluted with anhydrous THF (10mL) and cooled by an ice/water bath at 0 ℃ with stirring. Sodium sulfate decahydrate (500mg, triplicate) was then added and the resulting mixture was stirred at this temperature for 30min, then filtered and the filtrate concentrated in vacuo to give 5- (5-amino-6- (aminomethyl) -3- (4-fluorophenyl) pyrazin-2-yl) -1-methylpyridin-2 (1H) -one (52mg, 100% yield) as a brown oil. LCMS M/z (ESI), [ M + H ]+＝326.5
Step 3.N- ((3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyridine Preparation of oxazin-2-yl) methyl) -2, 6-difluorobenzamide (Compound 88)
A solution of 5- (5-amino-6- (aminomethyl) -3- (4-fluorophenyl) pyrazin-2-yl) -1-methylpyridin-2 (1H) -one (52mg, 0.16mmol) and TEA (49mg, 0.48mmol) in NMP (1mL) was cooled at 0 ℃ by an ice/water bath, and a solution of 2, 6-difluorobenzoyl chloride (34mg, 0.19mmol) in NMP (1.0mL) was subsequently added dropwise to the reaction. The resulting mixture was stirred and slowly warmed to room temperature for 2 hours. The solution was purified by C18-40g flash chromatography, eluting with a gradient of 0% to 60% MeCN/water (0.05% ammonia hydroxide) to give N- ((3-amino-5- (4-fluorophenyl) -6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrazin-2-yl) methyl) -2, 6-difluorobenzamide (compound 88) as an off white solid (8mg, 11% yield). LCMS M/z (ESI), [ M + H]+＝466.3。1H NMR(500MHz,CDCl3)ppm 3.5(s,3H),4.8(d,J＝6.3Hz,2H),5.5(brs,2H),6.4(d,J＝9.5Hz,1H),7.0-7.0(m,3H),7.1 (t,J＝8.7Hz,2H),7.1(dd,J＝9.5,2.5Hz,1H),7.4-7.5(m,4H)。
EXAMPLE 89 preparation of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (Compound 89)
Scheme 58
Figure BDA0002577091620001571
Step 1.3 preparation of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (4.4g, 19.91mmol), 2- (4-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (3.07g, 21.9mmol) in bis (ethyl acetate)
Figure BDA0002577091620001572
Na was added to a mixture of an alkane (50mL) and water (5mL)2CO3(4.22g, 39.82mmol) and DppfPdCl2(2.84g, 3.98 mmol). The mixture was then heated at 100 ℃ under N2after stirring under atmosphere for 1H, the mixture was concentrated and the residue was poured into water (100mL), and then extracted with EA (100mL × 3) the organic solution was concentrated to give the crude product as a yellow solid (5.5g, 98% yield) which was used in the next step without further purification MS M/z (ESI) [ M + H) ]]+＝282.2。
Step 2.3 preparation of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylate Prepare for
To methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (2.8g, 9.96mmol), 2, 6-dimethylpyridin-4-yl) boronic acid (1.51g, 9.96mmol) in bis
Figure BDA0002577091620001581
Mixture of alkane (50mL) and water (5mL) Na was added2CO3(3.01g, 19.93mmol) and Pd (PPh)3)4(1.42g, 1.99 mmol). The mixture was then heated at 80 ℃ under N2after stirring for 8H under atmosphere, the mixture was concentrated and the residue was poured into water (100mL), and then extracted with EA (100mL × 3) then the organic solution was concentrated to give the crude product, which was further purified by flash column to give the desired methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylate (2.5g, 71% yield) as a yellow solid MS M/z (ESI) [ M + H ] M ]+＝353.4。1H NMR(500MHz,DMSO-d6)ppm 2.33(s,6H),3.89(s,3 H),6.89(s,2H),7.22(t,J＝8.29Hz,2H),7.43(t,J＝6.58Hz,2H),7.61(br s,2H)。
Step 3.3 preparation of amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid
To a stirred solution of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylate (2.3g, 6.53mmol) in methanol (25mL) and water (5mL) was added sodium hydroxide (1.3g, 32.66 mmol). The mixture was then stirred at 45 ℃ for 2 hours. The solution was then concentrated and the residue was suspended in 25mL of water. The solution was washed twice with 15mL DCM. The inorganic layer was then acidified to pH 3 with 0.5N HCl. The solid formed was collected and dried to give the desired product as a white solid (1.70g, 77% yield). MS M/z (ESI) [ M + H ]]+＝339.4。1H NMR(500MHz,DMSO-d6)ppm 2.31-2.38(m,6H),6.94(s,2H),7.22(t,J＝8.41Hz,2 H),7.43(t,J＝6.73Hz,2H),7.64(br s,2H),12.56-13.99(m,1H)。
Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) Preparation of pyrazine-2-carboxamide (Compound 89)
To a stirred solution of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) pyrazine-2-carboxylic acid (25mg, 0.07 mmol), (2-methoxyphenyl) methylamine (20mg, 0.15mmol), and DIEA (15mg, 0.118mmol) in DMF (2mL) was added HATU (40mg, 0.11mmol) at room temperature in one portion. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The solution was purified by C18-40g (MeCN/water ═ 5% -60%) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5- (4-fluorophenyl) -N- (2-methoxybenzyl) pyrazine-2-carboxamide (compound 89) as an off white solid (19.8mg, 59.2% yield). MS M/z (ESI) [ M + H ] ]+＝458.4。1H NMR(500MHz, CDCl3)ppm 2.33(s,6H),3.86(s,3H),4.46-4.57(m,2H),6.87-6.95(m,1H),7.02(s,3 H),7.13-7.30(m,4H),7.38-7.48(m,2H),7.51-8.20(m,2H),9.02-9.13(m,1H)。
The compounds listed in the table below were prepared using the procedure described for compound 89.
Figure BDA0002577091620001591
Example 93.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5-phenylpyrazine- Preparation of 2-carboxamide (Compound 93)
Scheme 59
Figure BDA0002577091620001592
Step 1.3 preparation of methyl amino-6-chloro-5-phenylpyrazine-2-carboxylate
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (0.22g, 1.0mmol), phenylboronic acid (0.13g, 1.05mmol) in dioxane
Figure BDA0002577091620001593
A mixture of alkane (3mL) and water (0.3mL) was added Na2CO3(0.21g, 1.99mmol) and Pd (dppf) Cl2(0.14g, 0.20 mmol). The mixture is subsequently heated at 100 ℃ under N2after stirring under atmosphere for 1H, the mixture was concentrated and the residue was poured into water (100mL) and then extracted with EA (10mL × 3) the organic solution was concentrated to give the crude product as a yellow solid (0.24g, 91% yield) which was used in the next step without further purification MS M/z (ESI) [ M + H) ]]+＝263.3。
Step 2.3 preparation of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylate
To methyl 3-amino-6-chloro-5-phenylpyrazine-2-carboxylate (0.24g, 0.91mmol) and (2, 6-dimethylpyridin-4-yl) boronic acid (0.14g, 0.96mmol) in bis
Figure BDA0002577091620001601
Na was added to a mixture of an alkane (5mL) and water (0.5mL) 2CO3(0.19 g, 1.82mmol) and Pd (PPh)3)4(0.14g, 0.20 mmol). The mixture was then heated at 80 ℃ under N2stirring under atmosphere for 8 h, then concentrating the mixture and pouring the residue into water (10mL) and then extracting with EA (10 mL. times.3.) then concentrating the organic solution to give a crudeThe product was further purified by flash column to give the desired methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylate as a yellow solid (0.30g, 98% yield). MS M/z (ESI) [ M + H ]]+＝335.4。
Step 3.3 preparation of amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylic acid
to a stirred solution of methyl 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylate (0.30g, 0.90mmol) in methanol (10mL) and water (2mL) was added sodium hydroxide (0.18g, 4.49 mmol.) the mixture was then stirred at 45 ℃ for 2 hours then the solution was concentrated and the residue suspended in 5mL water the solution was washed with DCM (2 × 5mL) then the inorganic layer was acidified to pH 3 with 0.5N HCl the solid formed was collected and dried to give the desired product as a white solid (0.14g, 49% yield). MS M/z (ESI) [ M + H ] M ]+＝321.4。
Step 4.3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5-phenylpyrazine- Preparation of 2-carboxamide (Compound 93)
To a stirred solution of 3-amino-6- (2, 6-dimethylpyridin-4-yl) -5-phenylpyrazine-2-carboxylic acid (35mg, 0.11mmol), (2-methoxyphenyl) methylamine (22mg, 0.16mmol), and DIEA (28mg, 0.22mmol) in DMF (2mL) was added HATU (50mg, 0.13mmol) at room temperature in one portion. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The solution was purified by C18-40g (MeCN/water ═ 5% to 60%) to give 3-amino-6- (2, 6-dimethylpyridin-4-yl) -N- (2-methoxybenzyl) -5-phenylpyrazine-2-carboxamide (compound 93) as an off white solid (23.0mg, 48% yield). MS M/z (ESI) [ M + H ]]+＝440.4。1H NMR(500MHz,CDCl3)ppm 2.30 (s,6H),3.86(s,3H),4.52(d,J＝6.31Hz,2H),6.91(t,J＝7.36Hz,1H),6.99-7.04(m,3H),7.18(d,J＝7.57Hz,1H),7.25(t,J＝7.87Hz,1H),7.35-7.45(m,5H),7.82(br s,2H),9.06(t, J＝6.31Hz,1H)。
Example 94.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-N- [ (5-methyl-1, 3-thiazol-4-yl) methyl]-5-(1,3-
Figure BDA0002577091620001612
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 94)
Scheme 60
Figure BDA0002577091620001611
And (1).N- [ (5-methyl-1, 3-thiazol-4-yl) methyl]Carbamic acid tert-butyl ester
To 4-bromo-5-methyl-1, 3-thiazole (400mg, 2.3mmol, 1 eq) and tert-butyl N- [ (trifluoro-lambda 4-boryl) methyl at room temperature under a nitrogen atmosphere]To a stirred mixture of potassium carbamate (639.11mg, 2.7mmol, 1.2 equiv.) in toluene (16mL) was added Na in portions 2CO3(714.3mg, 6.7mmol, 3.0 equiv.), S-Phos (368.9mg, 0.9mmol, 0.4 equiv.), Water (2mL) and Pd (AcO)2(100.9mg, 0.45mmol, 0.2 eq.) the resulting mixture was stirred at 90 ℃ overnight, the mixture was allowed to cool to room temperature, the resulting mixture was filtered, the filter cake was washed with EtOAc (3 × 10mL), the filtrate was concentrated under reduced pressure, the residue was purified by preparative TLC (PE/EtOAc 5:1) to give N- [ (5-methyl-1, 3-thiazol-4-yl) methyl) as a yellow crude solid]Tert-butyl carbamate (280mg, 54.6%). LCMS M/z (ESI), [ M + H]+＝229.2。
Step 2.1- (5-methyl-1, 3-thiazol-4-yl) methylamine
To N- [ (5-methyl-1, 3-thiazol-4-yl) methyl group at room temperature under an air atmosphere]To a stirred solution of tert-butyl carbamate (270mg, 1.2mmol, 1 eq) in DCM (5mL) was added 4N HCl bis (N-HCl) dropwise
Figure BDA0002577091620001613
Alkane (5mL) solution. The resulting mixture was stirred at room temperature for another 3 hours. The resulting mixture was concentrated under reduced pressure. This gave 1- (5-methyl-1, 3-thiazol-4-yl) methylamine as a brown crude solid (150mg, 91.0%) which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝129.3。
Step 3.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl ]-N- [ (5-methyl-1, 3-thiazol-4-yl) methyl Base of]-5-(1,3-
Figure BDA0002577091620001614
Azol-2-yl) pyrazine-2-carboxamide (Compound 94)
3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001615
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.3mmol, 1 eq) and 1- (5-methyl-1, 3-thiazol-4-yl) methylamine (79.6mg, 0.6mmol, 2.0 eq) in DMF (5mL) was added HATU (471.9mg, 1.24mmol, 4.0 eq) and DIEA (160.4mg, 1.2mmol, 4.0 eq) in portions. The resulting mixture was stirred at room temperature for a further 60 min. The resulting mixture was poured into water (20mL), and the resulting solid was collected by filtration and washed with water (10 mL). The crude material was slurried with MeOH (5mL) to give 3-amino-6- [ imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ (5-methyl-1, 3-thiazol-4-yl) methyl]-5-(1,3-
Figure BDA0002577091620001622
Oxazol-2-yl) pyrazine-2-carboxamide (compound 94) (106mg, 77.9%). LCMS M/z (ESI), [ M + H]+＝433.2。1H NMR (methanol-d)4,400MHz)2.6(3H,s),4.7(2H,s),7.2 (1H,dd,J＝9.3,1.8Hz),7.3(1H,s),7.5(1H,d,J＝9.3Hz),7.6(1H,d,J＝1.3Hz),7.9(1H, s),8.0(1H,s),8.7(1H,d,J＝1.5Hz),8.8(1H,s)。
Example 95.3-amino-N- [ (4-aminopyrimidin-2-yl) methyl]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001623
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 95)
Scheme 61
Figure BDA0002577091620001621
Step 1.2- (aminomethyl) pyrimidin-4-amine
To a stirred mixture of 4-aminopyrimidine-2-carbonitrile (200mg, 1.67mmol, 1 eq) in THF (10mL) was added Raney nickel (71.3mg, 0.83mmol, 0.5 eq) at room temperature under a nitrogen atmosphere, the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1.5H, the resulting mixture was filtered, the filter cake was washed with THF (2 × 5mL), the filtrate was concentrated under reduced pressure to give 2- (aminomethyl) pyrimidin-4-amine (200mg, 96.75%) as a pale yellow solid which was used directly in the next step without further purification ]+＝125.1。
Step 2.3-amino-N- [ (4-aminopyrimidin-2-yl) methyl]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5- (1,3-
Figure BDA0002577091620001624
Azol-2-yl) pyrazine-2-carboxamide (Compound 95)
3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001625
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.31mmol, 1 eq) and 2- (aminomethyl) pyrimidin-4-amine (77.0mg, 0.62mmol, 2 eq) in DMF (10mL) was added T in portions3P (394.9mg, 1.24mmol, 4 equivalents) and DIEA (120.3mg, 0.93mmol, 3 equivalents). the resulting mixture was stirred at room temperature under an air atmosphere overnight, the resulting mixture was concentrated under reduced pressure, and subjected to preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30 × 150 mm 5 μm; mobile phase a: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 25% B within 7 min; 254/220 nm; rt: 5.77min) to yield 3-amino-N- [ (4-aminopyrimidin-2-yl) methyl ] methyl as a yellow solid]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001632
Oxazol-2-yl) pyrazine-2-carboxamide (compound 95) (13mg, 9.78%). LCMS M/z (ESI), [ M + H]+＝429.2，1H NMR(400MHz,DMSO-d6)4.33～4.77(m,2H),6.29(d,J＝5.9Hz,1H),7.18(dd,J＝9.3, 1.8Hz,2H),7.37(d,J＝0.8Hz,1H),7.52(d,J＝9.3Hz,1H),7.61(d,J＝1.2Hz,1H),7.96(d,J ＝1.1Hz,1H),8.00(d,J＝5.9Hz,4H),8.28(d,J＝0.8Hz,1H),8.80(t,J＝1.4Hz,1H),9.18(t, J＝5.8Hz,1H)。
Example 96.3-amino-N- [ [2- (dimethylphosphoryl) -6-fluorophenyl ] group ]Methyl radical]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001633
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 96)
Scheme 62
Figure BDA0002577091620001631
Step 1.2- (dimethylphosphoryl) -6-fluorobenzonitrile
To 2-bromo-6-fluorobenzonitrile (1g, 5.00mmol, 1 equiv.) and (methylphosphoryl) methane (0.4 g, 1.00 equiv.) in 1, 4-bis (methylene chloride) under a nitrogen atmosphere
Figure BDA0002577091620001634
To the mixture in alkane (15mL) was added Pd (AcO)2(0.1g, 0.1 equiv.), XantPhos (0.6g, 0.2 equiv.), and K3PO4(2.1g, 0.01mmol, 2.00 equiv.). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2/MeOH 20:1) to give 2- (dimethylphosphoryl) -6-fluorobenzonitrile (620mg, 62.90%) as a white solid. LCMS M/z (ESI), [ M + H]+＝198.0。1H NMR:(300MHz,DMSO-d6)1.83(s,3H),1.87(s, 3H),7.80(m,2H),7.95(m,1H)。
Step 2.1- [2- (dimethylphosphoryl) -6-fluorophenyl]Methylamine.
To 2- (dimethylphosphoryl) -6-fluorobenzonitrile (600mg, 3.04mmol, 1 eq) and NH at room temperature under a nitrogen atmosphere3.H2O (0.1mL, 3.82mmol, 1.13 equiv.) in MeOH (10mL) is addedRaney nickel (130.4mg, 1.52mmol, 0.5 equiv.) the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours the resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10mL) and the filtrate was concentrated under reduced pressure to give 1- [2- (dimethylphosphoryl) -6-fluorophenyl ] as a purple oil ]Methylamine (550mg, 89.83%), which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝202.2，1H NMR:(300MHz,DMSO-d6)1.82(m,6H),3.17(s, 3H),4.02(d,2H),7.45(s,3H)。
Step 3.3-amino-N- [ [2- (dimethylphosphoryl) -6-fluorophenyl ] group]Methyl radical]-6- [ imidazo [1,2-a ]]Pyridine- 6-yl]-5-(1,3-
Figure BDA0002577091620001642
Oxazol-2-yl) pyrazine-2-carboxamide (compound 96).
To 1- [2- (dimethylphosphoryl) -6-fluorophenyl at room temperature]Methylamine (10mg, 0.05mmol, 1 eq) and 3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001643
To a solution of oxazol-2-yl) pyrazine-2-carboxylic acid (16.0mg, 0.05mmol, 1.00 equiv.) in DMF (5mL) was added T3P (31.6mg, 0.10mmol, 2 equiv.) and DIEA (19.3mg, 0.15mmol, 3 equiv.). The resulting solution was stirred at room temperature under an air atmosphere for 60 min. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Shield RP18OBD column, 5 μm, 19X 150 mm; mobile phase A: water (10MMOL/L NH)4HCO3) And the mobile phase B: ACN; flow rate: 20 mL/min; gradient: 25% B to 35% B within 8 min; 254/220 nm; rt: 6.27min) to give 3-amino-N- [ [2- (dimethylphosphoryl) -6-fluorophenyl ] group as a yellow solid]Methyl radical]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001644
Oxazol-2-yl) pyrazine-2-carboxamide (compound 96) (95mg, 37.81%). LCMS M/z (ESI), [ M + H ]+＝506.2。1H NMR:(300MHz,DMSO-d6)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 101.3-amino-N- ((3-fluoropyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001645
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 101)
Scheme 63
Figure BDA0002577091620001641
Step 1.3-Methylimidazo [1,2-a ]]Pyridin-6-ylboronic acids
A mixture of 2-bromo-1, 1-dimethoxypropane (500mg, 2.73mmol, 1 eq.) in 2.5mL of 1N aqueous HCl was stirred at 80 ℃ for 1 hour. The mixture was cooled to room temperature and NaHCO was used3(solid) neutralized to pH 7. With CHCl3(3 × 5mL) the aqueous layer was extracted and the resulting CHCl was added at room temperature3To the solution was added 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (180.3mg, 0.82mmol, 0.30 equiv) in portions. The resulting mixture was stirred at 80 ℃ overnight. The resulting mixture was concentrated under reduced pressure to give the crude product as a crude oil, which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝177.0。
Step 2.3-amino-N- ((3-fluoropyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridine-6- Base) -5-, (
Figure BDA0002577091620001652
Azol-2-yl) pyrazine-2-carboxamide (Compound 101)
To 3-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl at room temperature under a nitrogen atmosphere]-5-(1,3-
Figure BDA0002577091620001653
Oxazol-2-yl) pyrazine-2-carboxamide (100mg, 0.29mmol, 1 eq.) and [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]Boric acid (100.9mg, 0.57mmol, 2.00 equiv.) in 1, 4-bis
Figure BDA0002577091620001654
Cs was added in portions to a stirred mixture in an alkane (20mL)2CO3(467.2 mg, 1.43mmol, 5 equiv.) and Pd (dppf) Cl2CH2Cl2(70.3mg, 0.09mmol, 0.3 equiv.). The resulting mixture was stirred at 105 ℃ overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2The residue was purified with MeOH 20:1) to give 3-amino-N- [ (3-fluoropyridin-2-yl) methyl ] p]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001655
Oxazol-2-yl) pyrazine-2-carboxamide (compound 101) (23mg, 18.05%). LCMS M/z (ESI), [ M + H]+＝445.2。1H NMR(400MHz,DMSO-d6)2.44(d,J＝0.9 Hz,3H),4.72(dd,J＝5.8,1.7Hz,2H),7.25(dd,J＝9.4,1.8Hz,1H),7.31-7.47(m,3H),7.50 (dd,J＝9.4,1.0Hz,1H),7.72(ddd,J＝10.0,8.3,1.3Hz,1H),7.90(s,2H),8.29(d,J＝0.8Hz, 1H),8.33-8.42(m,2H),9.36(t,J＝5.9Hz,1H)。
Example 102.3-amino-N- [ (2, 6-difluorophenyl) methyl]-6- [1- (3-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001656
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (example 102)
Scheme 64
Figure BDA0002577091620001651
Step 1.5-bromo-1- (3-hydroxypropyl) -1, 2-dihydropyridin-2-one.
To a solution of 5-bromo-1, 2-dihydropyridin-2-one (1g, 5.75mmol, 1 eq.) and 3-iodopropan-1-ol (2.1g, 11.49mmol, 2 eq.) in DMF (15mL) at room temperature was added K2CO3(1.6g, 11.49mmol, 2 equivalents). Will be provided withThe mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CHCl) 3MeOH 20:1) to give 5-bromo-1- (3-hydroxypropyl) -1, 2-dihydropyridin-2-one as a yellow solid (300mg, 22.49%). LCMS M/z (ESI), [ M + H]+＝232.1,234.1。1H NMR:(300 MHz,DMSO-d6)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 (200mg, 0.86mmol, 1 eq.) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (437.7mg, 1.72mmol, 2 eq.) in THF (15mL) at room temperature under a nitrogen atmosphere was added KOAc (137.5 mg, 1.40mmol, 3.00 eq.) and Pd (dppf) Cl2(63.1mg, 0.09mmol, 0.1 equiv.). The mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The mixture was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝280.3。
Step 3.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- [1- (3-hydroxypropyl) -6-oxo-1, 6-dihydro Pyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001661
Oxazol-2-yl) pyrazine-2-carboxamide (compound 102).
To a solution of 1- (3-hydroxypropyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (305.3mg, 1.09mmol, 2.00 equiv.) in THF (15mL) at room temperature under a nitrogen atmosphere was added 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl ] methyl ]-5-(1,3-
Figure BDA0002577091620001662
Oxazol-2-yl) pyrazine-2-carboxamide (200mg, 0.55 mmol, 1 equiv.), Cs2CO3(356.4mg, 1.09mmol, 2.00 equiv.) and Pd (dppf) Cl2(40.0mg, 0.05 mmol, 0.10 equiv.). The mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours and passed through preparative TLC (CH)2Cl2The residue was purified with MeOH 20:1) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl group as a yellow solid]-6- [1- (3-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001663
Oxazol-2-yl) pyrazine-2-carboxamide (compound 102) (60mg, 22.74%). LCMS M/z (ESI), [ M + H]+＝483.3。1H NMR:(300MHz,DMSO-d6)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 103.3-amino-N- [ (2, 6-difluorophenyl) methyl]-6- [1- (2-methoxyethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001664
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 103)
Scheme 65
Figure BDA0002577091620001671
Step 1.5-bromo-1- (2-methoxyethyl) -1, 2-dihydropyridin-2-one
To a stirred mixture of 5-bromo-1, 2-dihydropyridin-2-one (500mg, 2.87mmol, 1 equiv.) and 1-bromo-2-methoxyethane (1597.6mg, 11.49mmol, 4 equiv.) in DMF (15mL) at 80 ℃ under an air atmosphere was added K in portions2CO3(1191.4mg, 8.62mmol, 3 equiv.) the resulting mixture was stirred at 80 ℃ under an atmosphere of air for 5 h, the resulting mixture was poured into water, the resulting mixture was extracted with EtOAc (2 × 100mL), the combined organic layers were washed with water (1 × 40mL), over anhydrous Na 2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give 5-bromo-1- (2-methoxyethyl) -1, 2-propanoic acid as a white solidDihydropyridin-2-one (200mg, 29.99%). LCMS M/z (ESI), [ M + H]+＝231.9。1H NMR(400 MHz,DMSO-d6)3.24(s,3H),3.56(t,J＝5.3Hz,2H),4.04(t,J＝5.3Hz,2H),6.38(d,J＝9.6 Hz,1H),7.53(dd,J＝9.7,2.8Hz,1H),7.91(d,J＝2.8Hz,1H)。
Step 2.1- (2-methoxyethyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-) Yl) pyridin-2 (1H) -ones
To a stirred mixture of 5-bromo-1- (2-methoxyethyl) -1, 2-dihydropyridin-2-one (150mg, 0.65 mmol, 1 eq.) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (328.3mg, 1.29mmol, 2 eq.) in THF (5mL) at 80 deg.C under a nitrogen atmosphere was added Pd (dppf) Cl2(94.6mg, 0.13mmol, 0.2 equiv.) and KOAc (190.3mg, 1.94mmol, 3 equivalents). The resulting mixture was stirred at 80 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝280.3。
Step 3.3-amino-N- [ (2, 6-difluorophenyl) methyl group]-6- [1- (2-methoxyethyl) -6-oxo-1, 6- Dihydropyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001673
Azol-2-yl) pyrazine-2-carboxamide (Compound 103)
To 3-amino-6-chloro-N- [ (2, 6-difluorophenyl) methyl group at 100 ℃ under a nitrogen atmosphere]-5-(1,3-
Figure BDA0002577091620001674
Azol-2-yl) pyrazine-2-carboxamide (100mg, 0.27mmol, 1 equiv.) and 1- (2-methoxyethyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (152.7mg, 0.55mmol, 2.00 equiv.) were added in portions to a stirred mixture in THF (8mL) Pd (dppf) Cl2(40.0mg, 0.05mmol, 0.2 equiv.) and Cs2CO3(356.4 mg, 1.09mmol, 4 equiv.). The resulting mixture was stirred at 100 ℃ overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH2Cl2MeOH (20:1) to give 3-amino-N- [ (2, 6-difluorophenyl) methyl as a yellowish green solid]-6- [1- (2-methoxyethyl) -6-oxo-1, 6-dihydropyridin-3-yl]-5-(1,3-
Figure BDA0002577091620001682
Oxazol-2-yl) pyrazine-2-carboxamide (compound 103) (33mg, 24.77%). LCMS M/z (ESI), [ M + H]+＝483.2。1H NMR(400MHz,DMSO-d6)3.22(s,3H),3.57(t,J＝5.4Hz,2H),4.04(t, J＝5.5Hz,2H),4.61(d,J＝5.9Hz,2H),6.35(d,J＝9.4Hz,1H),7.10(t,J＝8.0Hz,2H),7.34 ～7.46(m,2H),7.47(dd,J＝9.4,2.6Hz,1H),7.75～7.80(m,2H),7.88(d,J＝2.6Hz,1H),8.30 (d,J＝0.8Hz,1H),9.07(t,J＝5.9Hz,1H)。
EXAMPLE 104 preparation of 3-amino-N- [ (3-fluoropyridin-2-yl) methyl ] -6- [ imidazo [1,2-a ] pyridin-6-yl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 104)
Scheme 66
Figure BDA0002577091620001681
Step 1.3-amino-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2- Formic acid
To methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (300 mg, 1.178mmol, 1 eq) and 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] imidazole at room temperature under a nitrogen atmosphere ]Pyridine (431.39mg, 1.767mmol, 1.5 equiv.) in dioxane
Figure BDA0002577091620001683
To a stirred mixture in an alkane (20mL) was added Pd (dppf) Cl in portions2(172.41mg, 0.236mmol, 0.2 equiv.), water (2mL) and Cs2CO3(1151.62mg, 3.535mmol, 3 eq.) the resulting mixture was stirred at 90 ℃ overnight, the resulting mixture was filtered, the filter cake was washed with DCM (3 × 10mL), the filtrate was acidified to PH with 2N aqueous HCl5. The resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ imidazo [1,2-a ] as a brown crude solid]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (290mg, 76.37%) which was used directly 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) pyrazine-2-carboxamide (Compound 104)
3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.31mmol, 1 equivalent) and 1- (3-fluoropyridin-2-yl) methylamine (67.1mg, 0.62mmol, 2 equivalents) to a stirred mixture in DMF (3mL) was added portionwise HATU (471.9mg, 1.24mmol, 4 equivalents) and DIEA (160.4mg, 1.24mmol, 4 equivalents). the resulting mixture was stirred at room temperature for 2 hours the resulting mixture was quenched by water (10mL), the resulting solid was collected by filtration and washed with water (3 × 10mL), the crude product was slurried with MeOH (6mL), the resulting solid was collected by filtration and dried in vacuo to give 3-amino-N- [ (3-fluoropyridin-2-yl) methyl as a yellow solid ]-6- [ imidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 104) (48mg, 35.5%). LCMS M/z (ESI), [ M + H]+＝431.2。1H NMR(DMSO-d6,400MHz) 4.7(2H,d,J＝5.9Hz),6.7(1H,dd,J＝9.4,1.8Hz),7.4(2H,dd,J＝8.8,4.4Hz),7.6(1H,d,J ＝1.2Hz),7.7(1H,ddd,J＝10.0,8.3,1.3Hz),7.9(1H,s),8.1(3H,s),8.4(1H,dt,J＝4.7,1.5Hz),8.6-8.7(1H,m),9.4(1H,t,J＝6.0Hz)。
Example 107.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001692
Preparation of oxazol-2-yl) pyrazine-2-carboxamides
Example 108.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5-, (
Figure BDA0002577091620001693
Preparation of oxazol-2-yl) pyrazine-2-carboxamides
Figure BDA0002577091620001691
Step 1.5-bromo-1- (2-hydroxypropyl) -1, 2-dihydropyridin-2-one.
5-bromo-1, 2-dihydropyridin-2-one (1g, 5.75mmol, 1 equiv.) and 1-bromopropan-2-ol (1.6g, 0.01mmol, 2.00 equiv.), K at 80 deg.C under an air atmosphere2CO3A solution of (1.6g, 0.01mmol, 2.00 equiv.) in DMF (15mL) was stirred for 4 h. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 20:1) to give 5-bromo-1- (2-hydroxypropyl) -1, 2-dihydropyridin-2-one (0.9g, 67.48%) as a white solid. LCMS M/z (ESI), [ M + H]+＝232.1,234.1。1H NMR:(300MHz,DMSO-d6)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- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one.
To a solution of 5-bromo-1- (2-hydroxypropyl) -1, 2-dihydropyridin-2-one (300mg, 1.29mmol, 1 equivalent) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (656.5mg, 2.59 mmol, 2 equivalents) in THF (15mL) was added KOAc (137.5mg, 1.40mmol, 3.00 equivalents) and Pd (dppf) Cl 2(94.6mg, 0.13mmol, 0.10 equiv.). The mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝280.1。
Step 3.3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridine- 3-yl) -5-, (
Figure BDA0002577091620001701
Azol-2-yl) pyrazine-2-carboxamides
To a solution of methyl 3-amino-6-bromo-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (200mg, 0.67mmol, 1 eq.) and 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (314.4mg, 1.34mmol, 2.00 eq.) in THF (15mL) was added Cs2CO3(435.8mg, 1.34mmol, 2 equiv.) and Pd (dppf) Cl2(48.9mg, 0.07mmol, 0.1 equiv.). After stirring at 80 ℃ for 2 hours under nitrogen atmosphere, by preparative TLC (CH)2Cl2/MeOH 20:1) to give 3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5- (2-ethyl-phenyl) -5- (d-tert-butyl-ethyl) -ethyl acetate as a yellow solid
Figure BDA0002577091620001702
Oxazol-2-yl) pyrazine-2-carboxamide (racemate, 10mg, 4.77%). LCMS M/z (ESI), [ M + H]+＝483.3。1H NMR:(300MHz, DMSO-d6)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-dihydropyridine- 3-yl) -5-, (
Figure BDA0002577091620001703
Oxazol-2-yl) pyrazine-2-carboxamide (unknown absolute, Peak 1, Compound 107) and 3-amino-N- (2, 6-Difluoro) Benzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5- (2-hydroxy-propyl) -methyl-benzyl ester
Figure BDA0002577091620001704
Azol-2-yl) pyrazine-2-carboxamides (unknown absolute, peak 2, compound 108).
The racemate product (100mg) was purified by preparative chiral HPLC on eluent. Column: column: (R, R) Whelk-O1, 21.1 x 250mm, 5 μm; mobile phase A: hex (8mmol/L NH)3MeOH) - — HPLC, mobile phase B: EtOH- -HPLC; flow rate: 20 mL/min; gradient: 50B to 50B within 26 min; 254/220 nm; RT 1: 16.649, respectively; RT 2:19.223. this gave 3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5- (2-hydroxy-ethyl) -5-methyl (tert-butyl) acetate as a yellow solid
Figure BDA0002577091620001712
Azol-2-yl) pyrazine-2-carboxamide (isomer 1) (Compound 107) (30mg, 30%) LCMS M/z (ESI), [ M + H]+＝483.3。1H NMR:(300MHz,DMSO-d6)1.05 (d,3H),3.62(m,1H),3.93(m,2H),4.60(s,2H),4.83(d,1H),6.35(d,1H),7.08(t,2H),7.38 (m,2H),7.49(dd,1H),7.74(s,2H),7.80(d,1H),8.27(d,1H),9.05(t, 1H). Chirality: tR 2.59 min. And 3-amino-N- (2, 6-difluorobenzyl) -6- (1- (2-hydroxypropyl) -6-oxo-1, 6-dihydropyridin-3-yl) -5- (2-hydroxy-phenyl) -5- (b-hydroxy-phenyl) as a yellow solid
Figure BDA0002577091620001713
Oxazol-2-yl) pyrazine-2-carboxamide (isomer 2) (compound 108) (30mg, 30%). LCMS M/z (ESI), [ M + H]+＝483.3。1H NMR:(300MHz,DMSO-d6)1.05(d,3H),3.62(m,1H),3.93(m,2H), 4.60(s,2H),4.83(d,1H),6.35(d,1H),7.08(t,2H),7.38(m,2H),7.49(dd,1H),7.74(s,2H), 7.80(d,1H),8.27(d,1H),9.05(t, 1H). Chirality: tR ═ 3.03min, mixed chirality: tR 2.59min,3.03 min.
Example 111.3-amino-N- ((6- (3- (dimethylamino) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001714
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 111)
Scheme 67
Figure BDA0002577091620001711
Step 1.2-cyano-6- (3- (dimethylamino) azetidin-1-yl) pyridine
In a 50-mL round bottom flask was placed 6-chloropyridine-2-carbonitrile (1.5g, 10.826mmol, 1 eq.), N-dimethylazetidin-3-amine-dihydrochloride (1.87g, 10.826mmol, 1 equiv.), DMF (10mL, 129.218mmol, 11.94 equiv.), K2CO3(4.49g, 32.479mmol, 3 equiv.) the resulting solution was stirred at 80 ℃ for 16 h, the resulting solution was extracted with 3 × 20mL of dichloromethane, the residue was applied to a silica gel column with dichloromethane/methanol (50:1), this gave 6- [3- (dimethylamino) azetidin-1-yl ] as a light brown solid (475mg, 21.69%) ]Pyridine-2-carbonitrile (Compound 111).1H NMR (400MHz, chloroform-d) 3.96(1H, s),6.20(6H, s),7.22-7.33 (6H, m),7.83(2H, dd),8.05-8.14(2H, m),8.81(6H, s),10.62(1H, dd),11.02(1H, dd),11.57 (1H, dd)
Step 2.1- (6- (aminomethyl) pyridin-2-yl) -N, N-Dimethylazetidin-3-amine
In a 25mL round bottom flask was placed 2-cyano-6- (3- (dimethylamino) azetidin-1-yl) pyridine. After this time MeOH (10mL, 246.989mmol, 111.01 equiv.), NH were added at room temperature4OH (2mL, 51.361mmol, 23.09 eq.) and Raney nickel. The resulting mixture was stirred at room temperature for 1 hour. The solid was filtered off. The resulting mixture was concentrated. This gave 290mg (63.18%) of 1- [6- (aminomethyl) pyridin-2-yl as a solid]-N, N-dimethylazetidin-3-amine. LCMS M/z (ESI), [ M + H]+＝207.11H NMR (300MHz, methanol-d4,)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-, (
Figure BDA0002577091620001722
Azol-2-yl) pyrazine-2-carboxamide (Compound 111)
Placing 3-amino-6- [ 3-methylimidazo [1,2-a ] in a 25-mL round-bottom flask]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001723
Oxazol-2-yl) pyrazine-2-carboxylic acid (130mg), DMF (5mL), T3P (750mg), DIEA (530mg), 1- [6- (aminomethyl) pyridin-2-yl ]-N, N-dimethyl azacycloButane-3-amine (130mg), the resulting solution was stirred at room temperature for 16 hours, the resulting solution was extracted with 3 × 10mL of ethyl acetate, the organic layers were combined and concentrated, the residue was applied to a silica gel column together with methylene chloride/methanol (8:1), preparative HPLC was carried out with the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm5 μm; mobile phase a: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 41% B within 7 min; 254/220 nm; rt: 5.10min) to purify the crude product and obtain the product. This gave (51.6mg) 3-amino-N- ([6- [3- (dimethylamino) azetidin-1-yl) as a yellow solid]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001724
Oxazol-2-yl) pyrazine-2-carboxamide (compound 111). LCMS M/z (ESI), [ M + H]+＝525.31H-NMR (300MHz, methanol-d)4)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 112.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -N- ((6- (4-methylpiperazin-1-yl) pyridin-2-yl) methyl) -5-, (
Figure BDA0002577091620001725
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 112)
Scheme 68
Figure BDA0002577091620001721
Step 1.2-cyano-6- (4-methylpiperazin-1-yl) pyridine.
6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 equiv.), 1-methylpiperazine (615.25mg, 6.142mmol, 1.5 equiv.), K2CO3(1131.89mg, 8.190mmol, 2 equiv.) was dissolved in 3mL of DMF. The mixture was stirred at 50 ℃ for 8 hours. LCMS showed no problem for the reaction. Passing through silica gel column with DCM: CH3OH(15:1) to purify the crude product, which was further purified by preparative HPLC to give 2-cyano-6- (4-methylpiperazin-1-yl) pyridine (158mg, 19.08%) as a brown oil. LCMS M/z (ESI), [ M + H]+＝203.3。
(6- (4-methylpiperazin-1-yl) pyridin-2-yl) methylamine.
6- (4-Methylpiperazin-1-yl) pyridine-2-carbonitrile (140mg, 0.692mmol, 1 equiv.), Raney's nickel (118.60mg, 1.384mmol, 2.00 equiv.) were dissolved in 3mL NH4OH and MeOH. The mixture is left at room temperature in H2Stirred for 3 hours. LCMS showed no problem for the reaction. The crude product was purified by column on silica gel with DCM: CH3OH (15:1) was eluted and the product was further purified by preparative HPLC to give (6- (4-methylpiperazin-1-yl) pyridin-2-yl) methylamine as a grey oil (40mg, 28.01%). LCMS M/z (ESI), [ M + H]+＝207.3。
Step 3.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -N- ((6- (4-methylpiperazin-1-) Yl) pyridin-2-yl) methyl) -5-, (
Figure BDA0002577091620001731
Azol-2-yl) pyrazine-2-carboxamide (Compound 112)
1- [6- (4-methylpiperazin-1-yl) pyridin-2-yl]Methylamine (29.44mg, 0.143mmol, 1.20 equivalents), 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001732
Oxazol-2-yl) pyrazine-2-carboxylic acid (40mg, 0.119mmol, 1 equivalent), EDCI (45.60mg, 0.238mmol, 2.00 equivalents), HOBT (32.14mg, 0.238mmol, 2.00 equivalents), DIEA (92.23mg, 0.714mmol, 6.00 equivalents) were dissolved in 3mL DMF. The mixture was stirred at room temperature for 2 hours. LCMS showed no problem for the reaction. Passing through silica gel column with DCM: CH3OH (15:1) and further purification by preparative HPLC to give 3-amino-6- (3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl) -N- ((6- (4-methylpiperazin-1-yl) pyridin-2-yl) methyl) -5-, (
Figure BDA0002577091620001733
Oxazol-2-yl) pyrazine-2-carboxamide (26.5mg, 42.47%). LCMS M/z (ESI), [ M + H]+＝525.3。1H-NMR (300MHz, methanol-d)4):1.29 (s,6H),2.29(1H,d),2.49(3H,d),3.31-3.48(4H,m),4.58(2H,s),6.67(2H,dd),7.24-7.33(2H,m),7.42(1H,d),7.46-7.58(2H,m),7.99(1H,d),8.39(1H,t)。
EXAMPLE 113 preparation of 3-amino-5- (4-fluorophenyl) -N- [ [3- (2-hydroxyethoxy) pyridin-2-yl ] methyl ] -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 113)
Scheme 69
Figure BDA0002577091620001741
Step 1.3- (2-Hydroxyethoxy) pyridine-2-carbonitrile
To 3-fluoropyridine-2-carbonitrile (1.5g, 12.3mmol, 1 equiv.) and ethane-1, 2-diol (1.5g, 24.5mmol, 2 equiv.) in 1, 4-bis
Figure BDA0002577091620001742
Addition of Cs to a mixture in an alkane (25mL)2CO3(8.0g, 24.5mmol, 2 equiv.). The mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (5:1) to give 3- (2-hydroxyethoxy) pyridine-2-carbonitrile as a yellow oil (1g, 49.6%). LCMS M/z (ESI), [ M + H]+＝166.1。1H-NMR(300MHz,DMSO-d6)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 radical]Ethan-1-ol
To 3- (2-hydroxyethoxy) pyridine-2-carbonitrile (200mg, 1.2mmol, 1 eq) in MeOH (5mL) and NH3H2To a solution in O (1mL) was added Raney nickel (469.7mg, 5.5mmol, 3 equiv.) the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours, the resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10mL), and the filtrate was reducedThe filtrate was concentrated under pressure. This gives 2- [ [2- (aminomethyl) pyridin-3-yl ] as a violet oil]Oxy radical]Ethan-1-ol (200 mg). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝169.3。
Step 3.3-amino-5- (4-fluorophenyl) -N- [ [3- (2-hydroxyethoxy) pyridin-2-yl]Methyl radical]-6-(1- methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 113)
To 2- [ [2- (aminomethyl) pyridin-3-yl group ]Oxy radical]Ethyl-1-ol (200mg, 1.2mmol, 1 equiv.) and a solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxylic acid (302.4mg, 0.8mmol, 0.7 equiv.) in DMF (15mL) were added T in portions3P (756.7mg, 2.4mmol, 2 equiv.), DIEA (307.4mg, 2.4mmol, 2 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product (60mg) was purified by preparative HPLC with the following conditions (column: XSelect CSH OBD column 30 x 150mm 5um N; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 45% B over 7 min; 254; 220 nm; Rt: 7.02min) to give 3-amino-5- (4-fluorophenyl) -N- [ [3- (2-hydroxyethoxy) pyridin-2-yl as a yellow solid]Methyl radical]-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (compound 113) (20mg, 6.55%). LCMS M/z (ESI), [ M + H]+＝514.3。1H NMR (300MHz,DMSO-d6)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)。19F NMR(282MHz,DMSO-d6)-74.48,-112.25。
The compounds listed in the table below were prepared using the procedure described for compound 113.
Figure BDA0002577091620001751
EXAMPLE 114.preparation of 3-amino-5- (4-fluorophenyl) -N- [ [3- (2-methoxyethoxy) pyridin-2-yl ] methyl ] -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxamide (Compound 114)
Scheme 70
Figure BDA0002577091620001752
Step 1.N- [2- [ (2-cyanopyridin-3-yl) oxy group]Ethyl radical]-N-methylcarbamate
To 3-fluoropyridine-2-carbonitrile (1.5g, 12.2mmol, 1 equiv.) and tert-butyl N- (2-hydroxyethyl) -N-methylcarbamate (4.3g, 24.5mmol, 2 equiv.) in 1, 4-bis-formamide at room temperature
Figure BDA0002577091620001753
Addition of Cs to a mixture in an alkane (25mL)2CO3(8.01g, 24.6mmol, 2.0 equiv.). The mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (10:1) to give N- [2- [ (2-cyanopyridin-3-yl) oxy) as a yellow solid]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester (1.8g, 52.8%). LCMS M/z (ESI), [ M + H]+＝179.0。1H-NMR(300MHz,DMSO-d6)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]Methylamine
To 3- (2-methoxyethoxy) pyridine-2-carbonitrile (300mg, 1.7mmol, 1 eq) in MeOH (5mL) and NH at room temperature3H2Raney nickel (288.4mg, 3.3mmol, 2 equiv.) is added portionwise to a solution in O (1mL), the resulting mixture is stirred at room temperature under a hydrogen atmosphere for 2 hours, the resulting mixture is filtered, the filter cake is washed with MeOH (3 × 10mL), the filtrate is concentrated under reduced pressure, this gives 1- [3- (2-methoxyethoxy) pyridin-2-yl as a purple oil ]Methylamine (200 mg, 65.2%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝ 183.1。
Step 3.3-amino-5- (4-fluorophenyl) -N- [ [3- (2-methoxyethoxy) pyridin-2-yl ] amino]Methyl radical]-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 1)14)
To 1- [3- (2-methoxyethoxy) pyridin-2-yl group at room temperature]Methylamine (180mg, 1mmol, 1 equiv.) and a solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzoxadiazol-6-yl) pyrazine-2-carboxylic acid (251.2mg, 0.7mmol, 0.7 equiv.) in DMF (15mL) were added T in portions3P (628.6mg, 2mmol, 2 equiv.) and DIEA (255.3mg, 2mmol, 2 equiv.) the resulting mixture was stirred at room temperature under an air atmosphere for 1 hour, the resulting mixture was concentrated under reduced pressure, preparative HPLC was carried out with the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase a: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 45% B within 7 min; 254/220 nm; rt: 6.83min) to give 3-amino-5- (4-fluorophenyl) -N- [ [3- (2-methoxyethoxy) pyridin-2-yl ] as a yellow solid ]Methyl radical]-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (compound 114) (48.1mg, 9.2%). LCMS M/z (ESI), [ M + H]+＝528.3。1HNMR(300MHz,DMSO-d6)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 115.3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -N- ([3- [2- (methylamino) ethoxy ] pyridin-2-yl ] methyl) pyrazine-2-carboxamide (Compound 115) preparation
Scheme 71
Figure BDA0002577091620001771
Step 1.N- [2- [ (2-cyanopyridin-3-yl) oxy group]Ethyl radical]-N-methylcarbamic acid tert-butyl ester
To 3-fluoropyridine-2-carbonitrile (1.5g, 12.2mmol, 1 equiv.) and tert-butyl N- (2-hydroxyethyl) -N-methylcarbamate (4.3g, 24.5mmol, 2 equiv.) in 1, 4-bis-formamide at room temperature
Figure BDA0002577091620001772
The mixture in an alkane (25mL) was added portionwiseAdding Cs2CO3(8.01g, 24.5mmol, 2 equiv.). The resulting mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (10:1) to give N- [2- [ (2-cyanopyridin-3-yl) oxy) as a yellow solid]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester (1.8g, 52.8%). LCMS M/z (ESI), [ M + H]+＝278.0。1H-NMR(300MHz,DMSO-d6)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.N- (2- [ [2- (aminomethyl) pyridin-3-yl)]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester
To N- [2- [ (2-cyanopyridin-3-yl) oxy group at room temperature ]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester (300mg, 1.08 mmol, 1 equiv.) in MeOH (5mL) and NH3H2Addition of Raney Nickel (185.3mg, 2.1mmol, 2 equiv.) to a solution in O (1mL), stirring the resulting mixture at room temperature under an atmosphere of hydrogen for 2 hours, filtering the resulting mixture, washing the filter cake with MeOH (3 × 10mL), concentrating the filtrate under reduced pressure, this gives N- (2- [ [2- (aminomethyl) pyridin-3-yl) as a purple oil]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester (200mg, 65.7%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝282.3。
Step 3.N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) Pyrazin-2-yl radicals]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Ethyl) -N-methylcarbamate
To N- (2- [ [2- (aminomethyl) pyridin-3-yl) at room temperature]Oxy radical]Tert-butyl ethyl) -N-methylcarbamate (200mg, 0.7mmol, 1 equiv.) and a solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxylic acid (180.8mg, 0.5mmol, 0.7 equiv.) in DMF (15mL) were added T in portions3P (452.3mg, 1.4mmol, 2 equiv.) and DIEA (183.7mg, 1.4mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH) 2Cl2MeOH 20:1) for purificationThe residue was taken up as a yellow solid to give N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazin-2-yl)]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Tert-butyl ethyl) -N-methylcarbamate (150mg, 33.6%). LCMS M/z (ESI), [ M + H]+＝627.4。
Step 4.3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -N- ([3- [2- (methylamino) ethoxy]Pyridin-2-yl]Methyl) pyrazine-2-carboxamide (Compound 115)
At room temperature to 4N.HCl (gas) in 1, 4-bis
Figure BDA0002577091620001782
To the solution in an alkane (10mL) was added N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazin-2-yl) in portions]Carboxamido radical]Methyl) pyridin-3-yl]Oxygen radical]Ethyl) -N-methylcarbamic acid tert-butyl ester (150mg, 0.2mmol, 1 equivalent.) the resulting mixture was stirred at room temperature under an air atmosphere for 1 hour by preparative HPLC with the following conditions (column: XBridge PrepOBD C18 column 30 × 150mm 5 μm; mobile phase a: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 43% B within 7 min; 254/220 nm; rt: 5.8min) to give 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) -N- ([3- [2- (methylamino) ethoxy ] ethoxy) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) as a yellow solid ]Pyridin-2-yl]Methyl) pyrazine-2-carboxamide (compound 115) (51mg, 40.5%). LCMS M/z (ESI), [ M + H]+＝527.3。1H NMR(300MHz,DMSO-d6)2.31(3H,s),2.85(2H,t),3.79(3H,s),4.11 (2H,t),4.66(2H,d),7.09(3H,m),7.28(1H,dd),7.44(5H,m),7.69(2H,d),8.08(1H,dd),8.20 (1H,s),9.18(1H,t)。
EXAMPLE 116 preparation of 3-amino-N- ([3- [2- (dimethylamino) ethoxy ] pyridin-2-yl ] methyl) -5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxamide (Compound 116)
Scheme 72
Figure BDA0002577091620001781
Step 1.3- [2- (dimethylamino) ethoxy group]Pyridine-2-carbonitriles
To 3-fluoropyridine-2-carbonitrile (1g, 8.1mmol, 1 equiv.) and 2- (dimethylamino) ethan-1-ol (1.4g, 0.02mmol, 2.0 equiv.) in 1, 4-bis (methanol) at room temperature
Figure BDA0002577091620001791
Addition of Cs to a mixture in an alkane (25mL)2CO3(5.3g, 0.02mmol, 2 equiv.). The resulting mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (2:3) to give 3- [2- (dimethylamino) ethoxy ] ethanol as a yellow oil]Pyridine-2-carbonitrile (1.2g, 76.6%). LCMS M/z (ESI), [ M + H]+＝192.1。1H-NMR(300MHz, DMSO-d6)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]Methylamine
To 3- [2- (dimethylamino) ethoxy group at room temperature]Pyridine-2-carbonitrile (300mg, 1.5mmol, 1 eq) in MeOH (5mL) and NH3H2Raney nickel (403.2mg, 4.7mmol, 3 equiv.) is added to a solution in O (1mL), the resulting mixture is stirred at room temperature under an atmosphere of hydrogen for 2 hours, the resulting mixture is filtered, the filter cake is washed with MeOH (3 × 10mL), the filtrate is concentrated under reduced pressure, this gives 1- [3- [2- (dimethylamino) ethoxy ] as a purple oil ]Pyridin-2-yl]Methylamine (200mg, 65.3%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝ 196.1。
Step 3.3-amino-N- ([3- [2- (dimethylamino) ethoxy)]Pyridin-2-yl]Methyl) -5- (4-fluorophenyl) 6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 116)
To 1- [3- [2- (dimethylamino) ethoxy group at room temperature]Pyridin-2-yl]Methylamine (200mg, 1.02mmol, 1 equiv.) and 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxylic acid (260.5mg, 0.7 mmo)l, 0.7 eq) in DMF (15mL) T was added portionwise3P (651.8mg, 2.04mmol, 2 equiv.) and DIEA (264.7mg, 2.04mmol, 2 equiv.) the resulting mixture was stirred at room temperature under an air atmosphere for 1 hour, the resulting mixture was concentrated under reduced pressure, by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase a: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 43% B within 7 min; 254/220 nm; rt: 7.08min) to give 3-amino-N- ([3- [2- (dimethylamino) ethoxy) ethanol) as a yellow solid ]Pyridin-2-yl]Methyl) -5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxamide (compound 116) (46.5mg, 8.40%). LCMS M/z (ESI), [ M + H]+＝541.4。1H NMR(300MHz,DMSO-d6)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 117.3-amino-5- (4-fluorophenyl) -N- ([3- [ (2-hydroxyethyl) amino ] pyridin-2-yl ] methyl) -6- (1-methyl-1H-1, 3-benzoxadiazol-6-yl) pyrazine-2-carboxamide preparation (Compound 117)
Scheme 73
Figure BDA0002577091620001801
Step 1.3- [ (2-hydroxyethyl) amino group]Pyridine-2-carbonitriles
To a mixture of 3-fluoropyridine-2-carbonitrile (1.5g, 12.3mmol, 1 equiv.) and 2-aminoethan-1-ol (1.5g, 24.5mmol, 2 equiv.) in DMSO (25mL) was added Cs portion by portion at room temperature2CO3(8.01g, 24.5mmol, 2 equiv.). The resulting mixture was stirred at 80 ℃ for 4 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (1:1) to give 3- [ (2-hydroxyethyl) amino group as a yellow oil]Pyridine-2-carbonitrile (1g, 49.8%). LCMS M/z (ESI), [ M + H]+＝164.2。1H-NMR(300MHz, DMSO-d6)3.25(2H,q),3.54(2H,t),4.83(1H,s),6.18(1H,t),7.29(1H,dd),7.39(1H,ddd), 7.86(1H,dd)。
Step 2.2- [ [2- (aminomethyl) pyridin-3-yl]Amino group]Ethan-1-ol
To 3- [ (2-hydroxyethyl) amino group at room temperature]Pyridine-2-carbonitrile (300mg, 1.8mmol, 1 eq) in MeOH (5mL) and NH3H2Addition of Raney Nickel (472.5mg, 5.5mmol, 3 equiv.) to a solution in O (1mL), stirring the resulting mixture at room temperature under an atmosphere of hydrogen for 2 hours, filtering the resulting mixture, washing the filter cake with MeOH (3 × 10mL), concentrating the filtrate under reduced pressure, which yields 2- [ [2- (aminomethyl) pyridin-3-yl ] as a purple oil ]Amino group]Ethan-1-ol (230mg, 74.8%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝168.1。
Step 3.3-amino-5- (4-fluorophenyl) -N- ([3- [ (2-hydroxyethyl) amino group]Pyridin-2-yl]Methyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 117)
To 2- [ [2- (aminomethyl) pyridin-3-yl group]Amino group]Ethyl-1-ol (200mg, 1.2mmol, 1 equiv.) and a solution of 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxylic acid (304.2mg, 0.8mmol, 0.7 equiv.) in DMF (15mL) were added T in portions3P (761.1mg, 2.3mmol, 2 equiv.) and DIEA (309.1mg, 2.4mmol, 2 equiv.) the resulting mixture was stirred at room temperature under an air atmosphere for 1 hour, the resulting mixture was concentrated under reduced pressure, preparative HPLC was performed with the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase a: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 36% B within 7 min; 254/220 nm; rt: 5.57min) to obtain 3-amino-5- (4-fluorophenyl) -N- ([3- [ (2-hydroxyethyl) amino) as a yellow solid ]Pyridin-2-yl]Methyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (compound 117) (33.3mg, 5.4%). LCMS M/z (ESI), [ M + H]+＝ 513.4。1H NMR(300MHz,DMSO-d6)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 118.3-amino-N- ((4- (dimethylamino) pyridin-3-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001812
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 118)
Scheme 74
Figure BDA0002577091620001811
Step 1.4- (dimethylamino) nicotinonitrile
In a 20mL vial at room temperature was added dimethylamine (295.63mg, 6.557mmol, 2.00 equiv.), 4-bromopyridine-3-carbonitrile (600mg, 3.279mmol, 1 equiv.), and K2CO3(1.36g, 9.836mmol, 3.00 equiv.) the resulting mixture was stirred at 40 ℃ for 2 h, the resulting mixture was filtered, the filter cake was washed with DCM (2 × 20mL), the filtrate was concentrated under reduced pressure, the residue was purified by preparative TLC (EtOAc) to give 4- (dimethylamino) pyridine-3-carbonitrile (470mg, 97.40%) as an off-white solid (crude material).1H-NMR(400MHz,CDCl3)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
4- (dimethylamino) pyridine-3-carbonitrile (470mg, 3.193mmol, 1 eq) and Raney nickel (957.56mg, 11.177mmol, 3.50 eq), NH were reacted at room temperature under a hydrogen atmosphere3H2A solution of O (1.12g, 31.958mmol, 10.01 eq) in MeOH is stirred for 7H, the resulting mixture is filtered, the filter cake is washed with DCM (2 × 10mL), the filtrate is concentrated under reduced pressure, this gives 3- (aminomethyl) -N, N-dimethylpyridin-4-amine (467mg, 96.71%) as a green oil, LCMS M/z (ESI), [ M + H ] M ]+＝152.3。1H-NMR(300MHz,MeOD-d4)2.75-3.05(6H,m),3.93 (2H,s),6.95(1H,s),7.90-8.51(2H,m)。
Step 3.3-amino-N- ((4- (dimethylamino) pyridin-3-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (
Figure BDA0002577091620001822
Azol-2-yl) pyrazine-2-carboxamide (Compound 118)
To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001823
Oxazol-2-yl) pyrazine-2-carboxylic acid (70 mg, 0.208mmol, 1 eq.) and DIEA (80.70mg, 0.624mmol, 3.00 eq.), T3To a stirred solution of P (132.45mg, 0.416mmol, 2.00 equiv) in DMF was added 3- (aminomethyl) -N, N-dimethylpyridin-4-amine (62.95mg, 0.416mmol, 2.00 equiv) dropwise. The resulting mixture was stirred at room temperature for 1 hour. By preparative TLC (CH)2Cl2The residue was purified by MeOH 20:1) to give a yellow solid preparative HPLC was carried out with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (10MMOL/L NH)4HCO3) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 50% B within 7 min; 254/220 nm; rt: 5.82min) to give 3-amino-N- [ [4- (dimethylamino) pyridin-3-yl ] as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001824
Oxazol-2-yl) pyrazine-2-carboxamide (compound 118) (45mg, 46.05%). LCMS M/z (ESI), [ M + H ]+＝470.3。1H-NMR(400MHz,DMSO-d6)2.42 (3H,d),2.80(6H,s),4.57(2H,d),6.89(1H,d),7.26(1H,dd),7.38(2H,dd),7.48(1H,dd),7.89(2H,s),8.19-8.30(3H,m),8.34(1H,dd),9.39(1H,t)。
Example 119.preparation of 3-amino-N- [ [3- (carbamoylmethoxy) pyridin-2-yl ] methyl ] -5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 119)
Scheme 75
Figure BDA0002577091620001821
Step 1.2- [ (2-cyanopyridin-3-yl) oxy]Acetamide
Reacting K at 80 ℃ in an air atmosphere2CO3A mixture of (448.75mg, 3.247mmol, 3 equivalents), 2-chloroacetamide (121.45 mg, 1.299mmol, 1.2 equivalents), and 3-hydroxypyridine-2-carbonitrile (130mg, 1.082mmol, 1 equivalent) in DMF (6mL) was stirred for 16 h, the resulting mixture was diluted with water (30mL) and extracted with EtOAc (3 × 20mL), the combined organic layers were washed with brine (3 × 30mL), and dried over Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 12:1) to give 2- [ (2-cyanopyridin-3-yl) oxy) as a white solid]Acetamide (100mg, 52.15%). LCMS M/z (ESI), [ M + H]+＝178.0。1H-NMR(300MHz,CDCl3):4.78(2H,s),7.47(1H,d),7.61(2H,d),7.70(1H,d),8.32(1H,d)
Step 2.2- [ [2- (aminomethyl) pyridin-3-yl]Oxy radical]Acetamide
Raney nickel (26.98mg, 0.315mmol, 0.62 equiv.) and 2- [ (2-cyanopyridin-3-yl) oxy were reacted at room temperature under a hydrogen atmosphere]A mixture of acetamide (90mg, 0.508mmol, 1 equiv.) in MeOH (5mL) was stirred for 1 hour, the precipitated solid was collected by filtration and washed with MeOH (3 × 10mL), and the resulting mixture was concentrated under reduced pressure to give 2- [ [2- (aminomethyl) pyridin-3-yl ] as a purple solid ]Oxy radical]Acetamide (60mg, 65.18%). LCMS M/z (ESI), [ M + H]+＝182.1
Step 3.3-amino-N- [ [3- (carbamoylmethoxy) pyridin-2-yl]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxamide (Compound 119)
Reacting T at room temperature in an air atmosphere3P (100mg, 1.344mmol, 4 equiv.), DIEA (470.5mg, 1.344mmol, 4.00 equiv.), 3-amino-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) pyrazine-2-carboxylic acid (120 mg, 0.336mmol, 1.00 equiv.), and 2- [ [2- (aminomethyl) pyridin-3-yl ] pyrazine-2-carboxylic acid]Oxy radical]A mixture of acetamide (59.8mg, 0.336mmol, 1 eq.) in DMF (0.2mL) was stirred for 4 hours. By preparative HPLCWith the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 31% B to 45% B within 8 min; 254/220 nm; rt: 7.30min) to give 3-amino-N- [ [3- (carbamoylmethoxy) pyridin-2-yl ] as a yellow solid]Methyl radical]-5- (4-fluorophenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) pyrazine-2-carboxamide (compound 119) (20mg, 12.14%). LCMS M/z (ESI), [ M + H]+＝527.3。1H-NMR(300MHz,DMSO-d6)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)。19F NMR(282MHz,DMSO-d6):-112.591
Example 120/121 (R/S) -3-amino-6- (3-methylimidazo [1,2-a ] ]Pyridin-6-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5-, (
Figure BDA0002577091620001831
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 120/121)
Scheme 76
Figure BDA0002577091620001841
Step 1.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -N- ((1-methylpyrrolidin-2-yl) Methyl) -5-, (
Figure BDA0002577091620001843
Azol-2-yl) pyrazine-2-carboxamides
To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001844
Oxazol-2-yl) pyrazine-2-carboxylic acid (300mg, 0.892mmol, 1 eq), Et3N (270.79mg, 2.676mmol, 3.00 equiv.) and T3To a stirred solution of P (851.48 mg, 2.676mmol, 3.00 equiv.) in DMF was added 1- (1-methylpyridine) dropwisePyrrolidin-2-yl) methylamine (203.73mg, 1.784mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. By preparative TLC (CH)2Cl2The residue was purified by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 23% B to 38% B within 7 min; 254/220 nm; rt: 6.33min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-N- [ (1-methylpyrrolidin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620001845
Oxazol-2-yl) pyrazine-2-carboxamide (120mg, 31.10%). LCMS M/z (ESI), [ M + H]+＝433.3。1H-NMR(400MHz,DMSO-d6)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-methylpyrrolidine- 2-yl) methyl) -5- (C
Figure BDA0002577091620001846
Azol-2-yl) pyrazine-2-carboxamide (Compound 120/121)
By preparative HPLC with the following conditions (column: CHIRALPAK IG,20 × 250mM, 5 μm; mobile phase a: Hex: DCM ═ 3:1(10mM NH)3-MEOH) -HPLC, mobile phase B: EtOH-HPLC; flow rate: 18 mL/min; gradient: 50B to 50B within 25 min; 220/254 nm; RT 1: 13.303, respectively; RT 2: 19.802) to obtain 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620001847
Azol-2-yl) pyrazine-2-carboxamide (isomer 1) (Compound 120) (42mg, 42.00%), LCMS: m/z (ESI)), [M+H]+＝433.2。1H-NMR(400MHz,DMSO-d6)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 ] as yellow solid]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620001852
Oxazol-2-yl) pyrazine-2-carboxamide (isomer 2) (compound 121) (40mg, 40%). LCMS M/z (ESI), [ M + H]+＝433.2。1H-NMR(400MHz,DMSO-d6)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 (R) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001853
Preparation of oxazol-2-yl) -N- (pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (Compound 122)
Scheme 77
Figure BDA0002577091620001851
Step 1.(R) -2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001854
Azol-2-yl) pyrile Oxazine-2-carboxamido) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001855
Oxazol-2-yl) pyrazine-2-carboxylic acid (140mg, 0.416mmol, 1 eq) and (2R) -2- (aminomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester ((2R) -2- (aminomethyl)125.06mg, 0.624 mmol, 1.50 equiv.), DIEA (161.40mg, 1.249mmol, 3.00 equiv.) in DMF was added T dropwise3P (264.91mg, 0.833mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (100 mL). By CH2Cl2(4 × 100mL) the resulting mixture was extracted over anhydrous Na2SO4The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 20:1) to give (2R) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001856
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (156mg, 72.26%). LCMS M/z (ESI), [ M + H]+＝519.2。
Step 2.(R) -3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001857
Azol-2-yl) -N- (pyri-dine Pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (Compound 122)
(2R) -2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] was added to a 50mL round bottom flask at room temperature]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001858
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (140mg, 0.270mmol, 1 equiv.) and TFA (2.00mL, 17.541mmol, 99.74 equiv.). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 mL). Saturated NaHCO at room temperature3The reaction was quenched. By CH2Cl2(3 × 100mL) the resulting mixture was extracted over anhydrous Na2SO4The combined organic layers were dried after filtration, the filtrate was concentrated under reduced pressure, by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (10MMOL/L NH)4HCO3+0.1％NH3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 10% B to 30% B within 7 min; 254/220 nm; rt: 6.82 min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001862
Azol-2-yl) -N- [ [ (2R) -pyrrolidin-2-yl ]Methyl radical]Pyrazine-2-carboxamide (compound 122) (60mg, 53.11%). LCMS M/z (ESI), [ M + H]+＝419.2。1H-NMR(400MHz,DMSO-d6)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 (S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001863
Preparation of oxazol-2-yl) -N- (pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (Compound 123)
Scheme 78
Figure BDA0002577091620001861
Step 1.(S) -2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001864
Azol-2-yl) pyrile Oxazine-2-carboxamido) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3-amino-6- [ 3-methylimidazo [1,2-a ] was added at room temperature in an 8mL vial]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001865
Oxazol-2-yl) pyrazine-2-carboxylic acid (140mg, 0.416mmol, 1 equiv.) and tert-butyl (2S) -2- (aminomethyl) pyrrolidine-1-carboxylate (125.06 mg, 0.624mmol, 1.50 equiv.) and DIEA (161.40mg, 1.249mmol, 3.00 equiv.), T3P (264.91 mg, 0.833mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (100 mL). By CH2Cl2(4 × 100mL) the resulting mixture was extracted over anhydrous Na2SO4The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 20:1) to give (2S) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001866
Azole-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (170mg, 78.75%). LCMS M/z (ESI), [ M + H]+＝519.4。
Step 2.(S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001872
Azol-2-yl) -N- (pyri-dine Pyrrolidin-2-ylmethyl) pyrazine-2-carboxamide (Compound 123)
(2S) -2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] was added to a 50mL round bottom flask at room temperature]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001873
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (170mg, 0.328mmol, 1 equiv.) and TFA (3mL, 40.389mmol, 123.21 equiv.). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 mL). Saturated NaHCO at room temperature3Quench the reaction and use CH2Cl2(3 × 100mL) extraction over anhydrous Na2SO4The combined organic layers were dried, after filtration, the filtrate was concentrated under reduced pressure, by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 37% B within 7 min; 254/220 nm; rt: 5.73min) to pure The crude product (100mg) was purified to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001874
Azol-2-yl) -N- [ [ (2S) -pyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 123) (60mg, Y ═ 43.74%). LCMS M/z (ESI), [ M + H]+＝419.2。1H-NMR(400MHz,DMSO-d6)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 (R) -3-amino-6- (3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5- (C
Figure BDA0002577091620001875
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 128)
Scheme 79
Figure BDA0002577091620001871
Step 1.1- [ 5-Bromopyrazolo [1,5-a ]]Pyridin-3-yl]Ethan-1-ol
To 5-bromopyrazolo [1,5-a ] at-50 ℃ under a nitrogen atmosphere]Pyridine-3-carbaldehyde (1g, 4.444mmol, 1 eq.) and CH3MgBr (2.12g, 17.8mmol, 4.00 equiv.) in a stirred solution of THF (20 mL). At 0 ℃ by addition of saturated NH4The reaction was quenched with Cl (aq) (5 mL). By CH2Cl2(3 × 30mL) the aqueous layer was extracted the residue was purified by column chromatography on silica eluting with PE/EtOAc (5:1) to give 1- [ 5-bromopyrazoio [1,5-a ] as a white solid]Pyridin-3-yl]Ethan-1-ol (600mg, 56.01%). LCMS M/z (ESI), [ M + H]+＝241.2。
Step 2.5-bromo-3-ethylpyrazolo [1,5-a ]]Pyridine compound
1- [ 5-Bromopyrazolo [1,5-a ] at room temperature in an air atmosphere ]Pyridin-3-yl]Ethan-1-ol (640mg, 2.65mmol, 1 equiv.) and triethylsilane (1852.03mg, 15.93mmol, 6.0 equivalents)Amount) in a stirred solution of TFA (10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 5:1) to give 5-bromo-3-ethylpyrazolo [1,5-a ] as a white solid]Pyridine (490mg, 82.0%). LCMS M/z (ESI), [ M + H]+＝225.1。
Step 3.3-Ethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1, 5-a]pyridine compound
To 5-bromo-3-ethylpyrazolo [1,5-a ]]Pyridine (430mg, 1.9mmol, 1 equiv.) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (970.2mg, 3.81 mmol, 2.0 equiv.) in dioxane
Figure BDA0002577091620001881
To a solution in alkane (10mL) was added K3PO4(1216.5mg, 5.73mmol, 3.0 equiv.) and Pd (dppf) Cl2(279.6mg, 0.38mmol, 0.2 equiv.). After stirring at 90 ℃ for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 12:1) to give 3-ethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] as a white solid]Pyridine (420mg, 80.78%). LCMS M/z (ESI), [ M + H ]+＝273.2。
Step 4.3-amino-6- [ 3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl]-5-(1,3-
Figure BDA0002577091620001882
Azol-2-yl) pyrazine- 2-Carboxylic acid methyl ester
To 3-amino-6-chloro-5- (1, 3-)
Figure BDA0002577091620001883
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (400mg, 1.571mmol, 1 equiv.) and 3-ethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ]]Pyridine (641.31mg, 2.356 mmol, 1.50 equiv.) in bis
Figure BDA0002577091620001884
K was added to a solution of alkane (10mL) and water (1mL)3PO4(1000.35mg, 4.713mmol, 3 equiv.) and Pd (dppf) Cl2(229.89mg, 0.314mmol, 0.2 equiv.). After stirring at 85 ℃ under a nitrogen atmosphere for 2 hours, by preparative TLC (CH)2Cl2MeOH 15:1) to give 3-amino-6- [ 3-ethylpyrazolo [1,5-a ] as a brown-yellow solid]Pyridin-5-yl]-5-(1,3-
Figure BDA0002577091620001885
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (300mg, 52.4%). LCMS M/z (ESI), [ M + H]+＝365.3。
Step 5.3-amino-6- (3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl) -5-, (
Figure BDA0002577091620001886
Azol-2-yl) pyrazine-2-carboxylic acid esters Acid(s)
3-amino-6- [ 3-ethylpyrazolo [1,5-a ] at room temperature in an air atmosphere]Pyridin-5-yl]-5-(1,3-
Figure BDA0002577091620001887
A solution of oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (280mg, 0.77mmol, 1 equiv.) and LiOH (36.8mg, 1.54mmol, 2.0 equiv.) in THF (20mL) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified to pH 5 with HCl (1 aq). The precipitated solid was collected by filtration and concentrated in vacuo to give 3-amino-6- [ 3-ethylpyrazolo [1,5-a ] as a tan solid ]Pyridin-5-yl]-5-(1,3-
Figure BDA0002577091620001892
Oxazol-2-yl) pyrazine-2-carboxylic acid (240mg, 89.15%). LCMS M/z (ESI), [ M + H]+＝351.3。
Step 6.3-amino-6- [ 3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl]-N- [ [ (2R) -1-methylpyrrolidine- 2-radical]Methyl radical]-5-(1,3-
Figure BDA0002577091620001893
Azol-2-yl) pyrazine-2-carboxamide (Compound 128)
3-amino-6- [ 3-ethylpyrazolo [1,5-a ] at room temperature in an air atmosphere]Pyridin-5-yl]-5-(1,3-
Figure BDA0002577091620001894
Oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.2mmol, 1 equiv.), 1- [ (2R) -1-methylpyrrolidin-2-yl]A solution of methylamine (34.22mg, 0.3 mmol, 1.5 equiv.), HATU (151.95mg, 0.4mmol, 2 equiv.), DIEA (77.5mg, 0.6mmol, 3 equiv.) in DMF (2mL) was stirred for 30 min. By preparative HPLC with the following conditions (column: Xbridge PrepOBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 40% B to 50% B within 8 min; 254/220 nm; rt: 7.25min) to give 3-amino-6- [ 3-ethylpyrazolo [1,5-a ] as a yellow solid]Pyridin-5-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620001895
Oxazol-2-yl) pyrazine-2-carboxamide (compound 128) (20.1 mg, 22.42%). LCMS M/z (ESI), [ M + H]+＝447.3。1H NMR(400MHz,DMSO-d6)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 (S) -3-amino-6- (3-ethylpyrazolo [1,5-a ] ]Pyridin-5-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5- (C
Figure BDA0002577091620001896
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 129)
Scheme 80
Figure BDA0002577091620001891
Step 1.3-amino-6- [ 3-ethylpyrazolo [1,5-a ]]Pyridin-5-yl]-N- [ [ (2R) -1-methylpyrrolidine- 2-radical]Methyl radical]-5-(1,3-
Figure BDA0002577091620001897
Azol-2-yl) pyrazine-2-carboxamide (Compound 129)
3-amino-6- [ 3-ethylpyrazolo [1,5-a ] at room temperature in an air atmosphere]Pyridin-5-yl]-5-(1,3-
Figure BDA0002577091620001902
Oxazol-2-yl) pyrazine-2-carboxylic acid (70mg, 0.200mmol, 1 equiv.), 1- [ (2S) -1-methylpyrrolidin-2-yl]A solution of methylamine (34.22mg, 0.300mmol, 1.5 equiv.), HATU (151.95mg, 0.400mmol, 2.00 equiv.), DIEA (77.47mg, 0.599mmol, 3 equiv.) in DMF (2mL) was stirred for 30 min. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 39% B to 51% B within 8 min; 254/220 nm; rt: 7.67min) to give 3-amino-6- [ 3-ethylpyrazolo [1,5-a ] as a yellow solid]Pyridin-5-yl]-N- [ [ (2S) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620001903
Oxazol-2-yl) pyrazine-2-carboxamide (compound 129) (29.8mg, 22.42%). LCMS M/z (ESI), [ M + H ]+＝447.3。1H NMR(400MHz,DMSO-d6)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) pyrazine-2-carboxamide (Compound 130)
Scheme 81
Figure BDA0002577091620001901
Step 1.3-amino-6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) -5- (1, 3-)
Figure BDA0002577091620001904
Oxazol-2-yl) -N- [ (1, 3-thiazol-4-yl) methyl]Pyrazine-2-carboxamide (Compound 130)
To 3-amino-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (300mg, 0.892mmol, 1 eq.) and 1- [ (2S) -1-methylpyrrolidin-2-yl) was added under an air atmosphere at room temperature]Methylamine (101.86 mg, 0.892mmol, 1 equivalent) in a stirred solution in DMF T was added dropwise/portion by portion3P (851.47mg, 2.676 mmol, 3 equiv.) and DIEA (576.44mg, 4.460mmol, 5 equiv.) the resulting mixture was stirred at room temperature under an air atmosphere for 4 h, the resulting mixture was extracted with EtOAc (3 × 20mL), the combined organic layers were washed with brine (3 × 10mL), anhydrous Na2SO4Drying, after filtration, the filtrate was concentrated under reduced pressure by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH) 3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 18% B to 35% B within 7 min; 254/220 nm; rt: 7.08min) to give 3-amino-6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) -N- [ [ (2S) -1-methylpyrrolidin-2-yl ] as a yellow solid]Methyl radical]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 130) (20mg, 5.18%). LCMS M/z (ESI) [ M + H ]]+＝433.2；1H-NMR(400MHz,MeOD-d4) 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) pyrazine-2-carboxamide (Compound 131)
Scheme 82
Figure BDA0002577091620001911
Step 1.3-amino-6- (1-methyl-1H-benzo [ D ]]Imidazol-6-yl) -5- (2H-1,2, 3-triazol-2-yl) pyri dine 2-oxazinecarboxylic acid
3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid methyl ester (500 mg, 1.964mmol, 1 eq), 1-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-1, 3-benzodiazole (608.25mg, 2.356mmol, 1.20 eq), Pd (dppf) Cl at 100 ℃ under a nitrogen atmosphere2(287.36mg, 0.393mmol, 0.2 equiv.) and Cs2CO3(2559.16mg, 7.855mmol, 4.0 equiv.) in bis
Figure BDA0002577091620001912
A solution in alkane (40mL), water (5mL) was stirred for 16H, the resulting mixture was extracted with EtOAc (3 × 40mL), the aqueous solution was acidified to pH6 with HCl (1M), the precipitated solid was collected by filtration and washed with water (2 × 10mL), which afforded 3-amino-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (240mg, 36.34%) as a light yellow solid, LCMS M/z (ESI), [ M + H-2-yl) pyrazine-2-carboxylic acid (240mg, 36.34%), [ LCMS M/z (ESI), [ M + H-1, 3-triazol-2 ]+＝337.1。1H-NMR(300MHz,MeOD-d4)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-methylpyrrolidine-2-) Yl) methyl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 131)
3-amino-6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq), 1- [ (2R) -1-methylpyrrolidin-2-yl) was reacted at room temperature]A mixture of methylamine (67.91mg, 0.595mmol, 2.0 equiv.), T3P (473.04mg, 1.487mmol, 5 equiv.), and DIEA (384.29mg, 2.973mmol, 10 equiv.) in DMF (5mL) was stirred for 2 hours, the resulting mixture was extracted with EtOAc (3 × 20mL), the combined organic layers were washed with brine (20mL), over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Kinetex EVO C1)8 columns 30 x 150, 5 μm; mobile phase A: water (10 MMOL/LNH)4HCO3) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 20% B to 35% B within 7 min; 254/220 nm; rt: 5.73min) to give 3-amino-6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) -N- [ [ (2R) -1-methylpyrrolidin-2-yl ] as a yellow solid]Methyl radical]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 131) (20mg, 15.55%). LCMS M/z (ESI), [ M + H ]+＝433.3。1H-NMR(300MHz,DMSO-d6)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,m)。
The compounds listed in the table below were prepared using the procedure described for compound 131.
Figure BDA0002577091620001921
Example 134/135.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001932
Azol-2-yl) -N- [ [ (2R/2S) -oxetan-2-yl]Methyl radical]Preparation of pyrazine-2-carboxamide (Compound 134/135)
Scheme 83
Figure BDA0002577091620001931
Step 1.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001934
Oxazol-2-yl) -N- [ (Oxetan-2-yl) methyl]Pyrazine-2-carboxamides
At 25 ℃ under nitrogen atmosphere towards T3A mixture of P (946.09mg, 2.973mmol, 5.00 equiv.) and 1- (oxetan-2-yl) methylamine (77.72mg, 0.892mmol, 1.50 equiv.) in DMF (5mL)Adding 3-amino-6- [ 3-methylimidazo [1,2-a ] dropwise into the stirred mixture]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001933
Oxazol-2-yl) pyrazine-2-carboxylic acid (200mg, 0.595mmol, 1 equiv.) and DIEA (307.44mg, 2.379mmol, 4.00 equiv.) the resulting mixture was stirred at 25 ℃ under nitrogen atmosphere for 6 h the reaction was quenched by addition of water (50mL) at 25 ℃, the aqueous layer was extracted with EtOAc (3 × 50mL), the aqueous layer was evaporated, the mobile phase a: water (0.05% NH; preparative HPLC was followed by the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase a: water (0.05% NH) 3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 19% B to 29% B within 7 min; 254/220 nm; rt: 6.45min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001935
Azol-2-yl) -N- [ (oxetan-2-yl) methyl]Pyrazine-2-carboxamide (90mg, 37.33%). LCMS M/z (ESI), [ M + H]+＝406.2。
Step 2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001936
Oxazol-2-yl) -N- [ [ (2R/2S) -oxetan-2-yl]Methyl radical]Preparation of pyrazine-2-carboxamide (Compound 134/135)
The crude product (150mg) was purified by preparative HPLC accompanied by the following conditions (column: CHIRALPAK IE, 2X 25cm, 5 μm; mobile phase A: MTBE (10mM NH3-MEOH) - - -HPLC- -, mobile phase B: EtOH- - -HPLC; flow rate: 20 mL/min; gradient: 20B to 20B over 18 min; 220/254 nm; RT 1: 12.678; RT 2: 14.094) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001937
Azol-2-yl) -N- [ [ (2R) -oxetan-2-yl]Methyl radical]Pyrazine-2-carboxamides (isomer 1)(Compound 134) (60mg, 40%). LCMS M/z (ESI), [ M + H]+＝406.1。1H NMR(300MHz,MeOD-d4)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 ] in the form of a yellow solid ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001942
Azol-2-yl) -N- [ [ (2R) -oxetan-2-yl]Methyl radical]Pyrazine-2-carboxamide (isomer 2) (compound 135) (60mg, 40%). LCMS M/z (ESI), [ M + H]+＝406.1。1H NMR(300MHz,MeOD-d4)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 (R) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001943
Preparation of oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 136)
Scheme 84
Figure BDA0002577091620001941
(R) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001944
Oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 136)
Placing 3-amino-6- [ 3-methylimidazo [1,2-a ] in a 25mL round-bottomed flask]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001945
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq.), DIEA (384.30mg, 2)973mmol, 10 equivalents) and (R) - (tetrahydrofuran-3-yl) methylamine (90.23mg, 0.892mmol, 3 equivalents) in DMF (4 mL). At 0 ℃ C3P (378.44mg, 1.189MMOL, 4 equiv.) is added to the above solution the resulting solution is stirred at room temperature for 1 hour by preparative HPLC with conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (10MMOL/L NH H)4HCO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 37% B within 7 min; 254/220 nm; rt: 5.85min) to purify the reaction mixture. This gave 67mg (53.72%) of (R) -3-amino-6- (3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001946
Oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (compound 136). LCMS M/z (ESI), [ M + H]+＝420.2。1H-NMR(400MHz,MeOD-d4)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 (S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001947
Preparation of oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 137)
Scheme 85
Figure BDA0002577091620001951
Step 1.(S) -3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001953
Oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 137)
At room temperature in air atmosphere3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001954
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 equiv.) and (S) - (tetrahydrofuran-3-yl) methylamine (130mg, 1.285mmol, 4.32 equiv.) in DMF were added DIEA (1.04mL, 5.946mmol, 20 equiv.) and T3P (473.05mg, 1.487MMOL, 5 equivalents), dilution of the reaction mixture with water (25mL), extraction of the aqueous layer with EtOAc (2 × 25mL), concentration of the combined organic layers under reduced pressure, preparative HPLC with the following conditions (column: Xbridge PrepOBD C18 column 30 × 150mm 5 μm; mobile phase A: water (10MMOL/L NH) 4HCO3+0.1％NH3.H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 35% B within 7 min; 254/220 nm; rt: 6.48min) to give (S) -3-amino-6- (3-methylimidazo [1, 2-a) as a yellow solid]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001955
Oxazol-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (compound 137) (70mg, 56.00%). LCMS M/z (ESI), [ M + H]+＝420.3；1H-NMR(400MHz,MeOD-d4)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 listed in the table below were prepared using the procedure described for compound 137.
Figure BDA0002577091620001952
Figure BDA0002577091620001961
Figure BDA0002577091620001971
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
Figure BDA0002577091620001981
Step 1.3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]pyrazine-2-A Acid(s)
In a 100mL round bottom flask purged and maintained with an inert nitrogen atmosphere were placed 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid (1g, 3.736mmol, 1 eq), [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (1.12g, 6.364 mmol, 1.70 equiv.), Cs2CO3(3.04g, 9.330mmol, 2.50 equiv.), bis
Figure BDA0002577091620001982
Alkane (25mL), Pd (dppf) Cl2(273.39mg, 0.374mmol, 0.10 equiv.). The resulting solution was stirred at 100 ℃ for 16 hours. Using 20mL of H 2The resulting solution was diluted O, the resulting solution was extracted with 3 × 20mL ethyl acetate and the aqueous layer was combined, the pH of the solution was adjusted to 4 with HCl (1mol/L) the solid was collected by filtration, this gave 500mg (36.83%) of 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a brown solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid. LCMS M/z (ESI), [ M + H]+＝ 364。1H NMR(400MHz,DMSO-d6)2.37(3H,s),6.97(1H,d),7.21(2H,t),7.38(2H,t),7.51 (2H,d),7.62(2H,s),8.26(1H,s)
Step 2.3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N-[[(2R)- 1-Methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamides (Compound 138)
Place 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] in a 20-mL vial]Pyridin-6-yl]Pyrazine-2-carboxylic acid (130mg, 0.358mmol, 1 equiv.), 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (81.71mg, 0.716mmol, 2.00 equiv.), DMF (6mL), DIEA (0.31mL, 2.39 mL)6mmol, 3.42 equivalents), T3P (569.19mg, 1.789mmol, 5.00 equiv.) the resulting solution is stirred at 20 ℃ for 16 h, the resulting mixture is concentrated in vacuo, the mixture is purified by preparative HPLC (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 34% B to 49% B within 7 min; 254/220 nm; rt: 6.52min) to purify the crude product. This gave 54.29mg (33.02%) of 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (Compound 138). LCMS M/z (ESI), [ M + H]+＝460。1H-NMR(400MHz,DMSO-d6) 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)。19F NMR(400MHz,DMSO-d6,) -112.225(1F)
Example 147.3-amino-N- (2-methoxyethyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001992
Preparation of Azol-2-yl) pyrazine-2-carboxamides (Compound 147)
Scheme 87
Figure BDA0002577091620001991
Step 1.3-amino-N- (2-methoxyethyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620001993
Azol-2-yl) pyrazine-2-carboxamide (Compound 147)
3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001994
Azol-2-yl) pyrazine-2-carboxylic acid (90mg, 0.268mmol, 1 equivalent) And 2-methoxyethyl-1-amine (60.30mg, 0.803mmol, 3 equiv.) to a stirred mixture of DMF DIEA (164.08mg, 1.270mmol, 5 equiv.) and T3P (323.16mg, 1.016mmol, 4 eq.) the resulting solution was stirred at room temperature for 1 h water (25mL) was added to the reaction mixture, the resulting mixture was extracted with EtOAc (3 × 25mL), the combined organic layers were washed with brine (1 × 15mL), anhydrous Na2SO4Drying, after filtration, the filtrate was concentrated under reduced pressure by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH) 3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 18% B to 32% B within 7 min; 254 nm; rt: 6.83min) to give 3-amino-N- (2-methoxyethyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620001995
Oxazol-2-yl) pyrazine-2-carboxamide (compound 147) (50mg, 49.78%). LCMS M/z (ESI), [ M + H]+＝394.2。1H-NMR(400MHz,MeOD-d4)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 listed in the table below were prepared using the procedure described for compound 147.
Figure BDA0002577091620002001
Figure BDA0002577091620002011
Figure BDA0002577091620002021
Figure BDA0002577091620002031
Figure BDA0002577091620002041
Figure BDA0002577091620002051
Figure BDA0002577091620002061
Figure BDA0002577091620002071
Figure BDA0002577091620002081
Figure BDA0002577091620002091
Example 149: 3-amino-N- (3-methoxypropyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002093
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 149)
Scheme 88
Figure BDA0002577091620002092
Step 1.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002094
Azol-2-yl) pyrazine- 2-Carboxylic acid methyl ester
3-amino-6-chloro-5- (1,3-
Figure BDA0002577091620002095
Methyl oxazol-2-yl) pyrazine-2-carboxylate (3000mg, 11.8mmol, 1 equivalent) and [ 2 ], [ solution of3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (4146.7mg, 23.6mmol, 2 equivalents) in bis
Figure BDA0002577091620002096
Cs was added in portions to a stirred mixture in an alkane (300mL)2CO3(11516.2mg, 35.3mmol, 3 equiv.) and Pd (dppf) Cl2(1724.1mg, 2.4mmol, 0.2 equiv.). The resulting mixture was stirred at 95 ℃ for 1.5 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH 2Cl2EtOAc (1:4) elution affording 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002097
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (1500mg, 36.3%). LCMS M/z (ESI), [ M + H]+＝351.3。1H-NMR (400MHz,DMSO-d6)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-
Figure BDA0002577091620002101
Azol-2-yl) pyrazine- 2-carboxylic acid
Reacting 3-amino-6- [ 3-methylimidazo [1,2-a ] at 45 DEG C]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002102
A mixture of methyl oxazol-2-yl) pyrazine-2-carboxylate (1500mg, 4.3mmol, 1 eq) and LiOH (205.1mg, 8.6mmol, 2 eq) in THF (100mL) and MeOH (20mL) was stirred for 1.5 h. The resulting mixture was stirred at 45 ℃ under an air atmosphere for 2.5 hours. The mixture was acidified to pH 5 with HCl (aq). The resulting mixture was concentrated in vacuo to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002103
Oxazol-2-yl) pyrazine-2-carboxylic acid (1200mg, 83.3%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝337.3。
Step 3.3-amino-N- (3-methoxypropyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1, 3-
Figure BDA0002577091620002104
Azol-2-yl) pyrazine-2-carboxamide (Compound 149)
3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002105
Azol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.3mmol, 1 equiv.) and 3-methoxypropan-1-amine (53mg, 0.6mmol, 2 equiv.) were added in portions to a stirred mixture of DMF (8mL) HATU (226.1mg, 0.6mmol, 2 equiv.) and DIEA (115.3mg, 0.9mmol, 3 equiv.) the resulting mixture was stirred at room temperature under an air atmosphere for 2.5 hours, the resulting mixture was concentrated under reduced pressure, by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH) 3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 21% B to 34% B within 7 min; 254/220 nm; rt: 6.67min) to give 3-amino-N- (3-methoxypropyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow-green solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002106
Oxazol-2-yl) pyrazine-2-carboxamide (compound 149) (10mg, 8.3%). LCMS M/z (ESI), [ M + H]+＝408.3。1H-NMR(400MHz,DMSO-d6)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
Figure BDA0002577091620002111
Step 1.[ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid
5- (3,3,4, 4-tetramethylborane-1-yl) pyridin-2-amine (20.0g, 92.5mmol, 1.0 eq.) was added to HCl (1.0mol/L) and stirred at 80 ℃ for 1 hour under an air atmosphere. With NaHCO3The mixture was basified to pH 7. With CHCl3The resulting mixture was extracted (5 × 40mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, 2-bromo-1, 1-dimethoxypropane (49.9g, 272.9mmol, 2.9 equiv.) was added to the above mixture. The resulting mixture was stirred at 100 ℃ for 10 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. Recrystallization of the crude product from EtOAc/MeOH (20: 150 mL) afforded [ 3-methylimidazo [1,2-a ] as a white solid ]Pyridin-6-yl]Boric acid (14.6g, 87.8%). LCMS M/z (ESI), [ M + H]+＝177.2。
Step 2.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid methyl ester
3-amino-5, 6-dichloropyrazine-2-carboxylic acid methyl ester (20g, 90.1mmol, 1.0 equivalent) and (4-fluorophenyl) boronic acid (13.9g, 99.1mmol, 1.1 equivalent) and Pd (dppf) Cl were reacted at 90 ℃ under a nitrogen atmosphere2(6.6g, 9.0mmol, 0.1 equiv.) and Na2CO3(19.1g, 180.2mmol, 2.0 equiv.) in 1, 4-bis
Figure BDA0002577091620002112
alkane/H2The mixture in O (300mL) was stirred for 2H, the resulting mixture was extracted with EtOAc (3 × 200mL), H2The combined organic layers were washed with O (3 × 80mL), anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was recrystallized from MeOH (100mL) to give methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (19.2g, 74.2%) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝282.2。
Step 3.3-amino-5- (4-fluorophenyl) -6- [ 3-methylImidazo [1,2-a ]]Pyridin-6-yl]pyrazine-2-A Acid methyl ester
3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid methyl ester (9.2g, 32.6mmol, 1.0 equiv.) and [ 3-methylimidazo [1,2-a ] at 90 ℃ under a nitrogen atmosphere ]Pyridin-6-yl]Boric acid (11.5g, 65.3mmol, 2.0 equiv.) and Pd (dppf) Cl2(2.4g, 3.3mmol, 0.1 eq.) and K3PO4(13.9g, 65.3mmol, 2.0 equiv.) in 1, 4-bis
Figure BDA0002577091620002113
alkane/H2The mixture in O (200mL) was stirred for 2H, the resulting mixture was extracted with EtOAc (4 × 80mL), H2The combined organic layers were washed with O (3 × 30mL), anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH2Cl2EtOAc (2:1) elution gave 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a tan solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (9.5g, 76.1%). LCMS M/z (ESI), [ M + H]+＝378.3。
And 4. step 4. 3-amino-5- (4-fluorophenyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) pyrazin-2-yl Acid(s)
To the 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (3.0g, 7.9 mmol, 1.0 equiv.) and lithium alcohol (380.8mg, 15.9mmol, 2.0 equiv.) in THF/H2O ═ 20:1(82mL) in a stirred solution. The resulting mixture was stirred at room temperature under an air atmosphere for 4.0 hours. The desired product can be detected by LCMS. With HCl (in II)
Figure BDA0002577091620002121
In an alkane) to pH 3 the precipitated solid was collected by filtration and washed with water (2 × 10mL) to give 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a light yellow solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid (2.1g, 72.7%). LCMS M/z (ESI), [ M + H]+＝364.2。1H-NMR(400MHz,DMSO-d6)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 radical]-5- (4-fluorophenyl) -6- [ 3-methylimidazole And [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 154)
3-amino-5- (4-fluorophenyl) -6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]A mixture of pyrazine-2-carboxylic acid (100.0mg, 0.3mmol, 1.0 equiv.) and 1- (aminomethyl) -N, N-dimethylcycloprop-1-amine (49.0mg, 0.4mmol, 1.5 equiv.) and HATU (217.6mg, 0.6mmol, 2.0 equiv.) and DIEA (111.0mg, 0.9mmol, 3.0 equiv.) in DMF (2.5mL) was stirred for 1 h. The reaction was quenched with water at room temperature. The solid was isolated and the crude product was subsequently recrystallized from EtOH (4mL) to give 3-amino-N- [ [1- (dimethylamino) cyclopropyl ] as a yellow solid]Methyl radical]-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (compound 154) (25mg, 18.6%). LCMS M/z (ESI), [ M + H ]+＝460.3。1H NMR(400MHz,DMSO-d6)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 listed in the table below were prepared using the procedure described for compound 154.
Figure BDA0002577091620002131
Figure BDA0002577091620002141
Figure BDA0002577091620002151
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
Figure BDA0002577091620002161
Step 1.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide
3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylic acid methyl ester (2.0g, 7.10mmol, 1 eq) and NH were added at room temperature in a 50mL sealed tube3(g) In MeOH (30mL, 7.0mmol/L), heated at 50 deg.C for 5 hours, and concentrated to give 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide as a pale yellow solid (1.5g, 79%). LCMS M/z (ESI), [ M + H]+＝267.1。
Step 2.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile
3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide (1.5g, 5.63 mmol, 1 equiv.) and POCl were added at room temperature to a 25mL round bottom flask3(10mL, 107.28mmol, 19.07 equiv.) and heated at 90 ℃ for 3 hours. Cooling to room temperature, pouring NaHCO3(aq., 200ml), filtered and dried to give 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile as a yellow solid (1.2g, 86%). LCMS M/z (ESI), [ M + H ]+＝249.2。
Step 3.3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine
A500 mL round bottom flask was charged with a solution of 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (1.4g, 5.63 mmol, 1 eq) and Raney nickel (0.3g, 3.50mmol, 0.62 eq) in methanol (150mL) at room temperature in H2Stirring under conditions (about 1.5atm) for 15 h, filtration and concentration gave 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (1.1g, crude material) as a light brown solid. LCMS M/z (ESI), [ M-NH ]2]+＝236.2。
Step 4.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]-1-methylpyrrolidine-2-carboxamide
To (2S) -1-methylpyrrolidine-2-carboxylic acid (168.68mg, 1.31mmol, 1.10 equiv.) and 3- (aminomethyl) -5-chloro-6- (4-fluorophenyl) pyrazin-2-amine (300mg, 1.19mmol, 1 Dang et al., 1 am.) at 0 deg.C under a nitrogen atmosphereAmount) and HATU (496.58mg, 1.31mmol, 1.1 equiv.) to a stirred mixture in DMF (3.0mL) DIEA (306.89mg, 2.38mmol, 2.0 equiv.) was added dropwise, stirred at room temperature for 3 hours, water (15mL) was added, filtered and dried to give (2S) -N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl as a pale yellow solid]Methyl radical]-1-methylpyrrolidine-2-carboxamide (250 mg, 57.88%). LCMS M/z (ESI), [ M + H ]+＝364.2。
Step 5.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 156)
Reacting (2S) -N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] at 90 ℃ under a nitrogen atmosphere]Methyl radical]-1-methylpyrrolidine-2-carboxamide (180.0mg, 0.5mmol, 1.0 equiv.) and [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (174.1 mg, 0.9mmol, 2.0 equiv.) and Pd (dppf) Cl2(36.2mg, 0.1mmol, 0.1 equiv.) and K3PO4(315.1 mg, 1.5mmol, 3.0 equiv.) in 1, 4-bis
Figure BDA0002577091620002172
alkane/H2The mixture in O (4.0mL) was stirred for 10 hours. By preparative TLC (CH)2Cl2The residue was purified by preparative HPLC with the following conditions (column: xbridge Prep OBD C18Column 30 × 150mm 5 μm, mobile phase A water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 43% B within 7 min; 254/220 nm; rt: 6.70min) to give (2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a pale yellow solid]Pyridin-6-yl]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (compound 157) (20.0mg, 8.6%). LCMS M/z (ESI), [ M + H ]+＝460.3。1H-NMR(400MHz,DMSO-d6)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
Figure BDA0002577091620002171
Step 1.(2R) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 157)
Reacting (2R) -N- [ [ 3-amino-6-chloro-5- (4-fluorophenyl) pyrazin-2-yl ] at 90 ℃ under a nitrogen atmosphere]Methyl radical]-1-methylpyrrolidine-2-carboxamide (180.0mg, 0.5mmol, 1.0 equiv.) and [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (174.1 mg, 0.9mmol, 2.0 equiv.) and Pd (dppf) Cl2(36.2mg, 0.1mmol, 0.2 equiv.) and K3PO4(315.1 mg, 1.5mmol, 3.0 equiv.) in 1, 4-bis
Figure BDA0002577091620002182
alkane/H2The mixture in O (4.0mL) was stirred for 10 hours. By preparative TLC (CH)2Cl2/MeOH 40:1) followed by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 43% B within 7 min; 254/220 nm; rt: 6.70min) to give (2R) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a pale yellow solid ]Pyridin-6-yl]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (compound 157) (20.0mg, 8.6%). LCMS M/z (ESI), [ M + H]+＝460.3。1H-NMR(400MHz,DMSO-d6)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 listed in the table below were prepared using the procedure described for compound 157.
Figure BDA0002577091620002181
Example 161 (S) -3-amino-N- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5- (C)
Figure BDA0002577091620002183
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 161)
Scheme 92
Figure BDA0002577091620002191
Step 1.(S) -2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002192
Azol-2-yl) pyrile Oxazine-2-carboxamido) methyl) -4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester
3-amino-6- [ 3-methylimidazo [1,2-a ] at 0 ℃ in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002193
To a stirred solution of (150mg, 0.446mmol, 1 equivalent) oxazol-2-yl) pyrazine-2-carboxylic acid and (2S) -tert-butyl 2- (aminomethyl) -4, 4-difluoropyrrolidine-1-carboxylate (210.75mg, 0.892mmol, 2.00 equivalents), DIEA (172.93mg, 1.338mmol, 3.00 equivalents) in DMF was added T dropwise3P (283.83mg, 0.892mmol, 2.00 equiv.) the resulting mixture was stirred at room temperature under an air atmosphere for 1 hour, the resulting mixture was diluted with EtOAc (40mL), the resulting mixture was washed with 2 × 40mL of water, the resulting mixture was washed with anhydrous Na 2SO4The organic layer was dried and the solid was filtered off and concentrated in vacuo. By preparative TLC (CH)2Cl2MeOH200:15) to give (2S) -2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002194
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (220mg, 88.95%). LCMS M/z (ESI), [ M + H]+＝555.2。
Step 2.(S) -3-amino-N- ((4, 4-difluoropyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (
Figure BDA0002577091620002195
Azol-2-yl) pyrazine-2-carboxamides
(2S) -2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] was added to a 50mL round bottom flask at room temperature]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002196
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (220mg, 0.397mmol, 1 equiv.) and TFA ((2mL, 26.926mmol, 67.87 equiv.) the resulting mixture was stirred at room temperature under air atmosphere for 1 hour the solvent and TFA were evaporated off to give 3-amino-N- [ (4, 4-difluoropyrrolidin-2-yl) methyl as a yellow solid]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002197
Oxazol-2-yl) pyrazine-2-carboxamide (180 mg, 99.84%) (crude material). LCMS M/z (ESI), [ M + H]+＝455.2。
Step 3.(S) -3-amino-N- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo) [1,2-a]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002198
Azol-2-yl) pyrazine-2-carboxamide (Compound 161)
3-amino-N- [ [ (2S) -4, 4-difluoropyrrolidin-2-yl ester at room temperature in an air atmosphere]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002199
Azol-2-yl) pyrazine-2-carboxamide (180mg, 0.396mmol, 1 equiv.) and HCHO (118.93mg, 3.961mmol, 10.00 equiv.), DIEA (510.9mg, 3.961mmol, 10.00 equiv.) in CH2Cl2To a stirred mixture in MeOH (6mL) and NaBH (3mL) was added portionwise3CN (149.35mg, 2.377 mmol, 6.00 equiv.) the reaction mixture was stirred at room temperature for 2 hours, quenched by water (50mL) and extracted by DCM (2 × 50mL), the organic layers were combined and extracted over anhydrous Na2SO4Dry, filter off the solid and evaporate the solvent. The residue was purified by preparative TLC (DCM: MeOH ═ 20:1) to give a yellow solid. By preparative HPLC with the following conditions (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A: water (10MMOL/L NH)4HCO3) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 27% B to 40% B within 7 min; 254/220 nm; rt: 6.05min) to give 3-amino-N- [ [ (2S) -4, 4-difluoro-1-methylpyrrolidin-2-yl ] as a yellow solid ]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002202
Oxazol-2-yl) pyrazine-2-carboxamide (compound 161) (60mg, 32.34%). LCMS M/z (ESI), [ M + H]+＝469.2。1H NMR(400MHz, DMSO-d6)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 (R) -3-amino-N- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5- (C)
Figure BDA0002577091620002203
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 162)
Scheme 93
Figure BDA0002577091620002201
Step 1.(R) -2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002204
Azol-2-yl) pyrile Oxazine-2-carboxamido) methyl) -4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester
3-amino-6- [ 3-methylimidazo [1,2-a ] at 0 ℃ in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002205
Azol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.446mmol, 1 equiv.) and tert-butyl (2R) -2- (aminomethyl) -4, 4-difluoropyrrolidine-1-carboxylate (210.75mg, 0.892mmol, 2.00 equiv.), DIEA (172.93mg, 1.338mmol, 3.00 equiv.) to a stirred mixture in DMF was added T dropwise3P (283.83mg, 0.892mmol, 2.00 equiv.) the resulting mixture is diluted with EtOAc (50mL) the resulting mixture is washed with 2 × 50mL of water and 2 × 50mL of saturated NaCl, over anhydrous Na2SO4The organic layer was dried, and the resulting mixture was concentrated under reduced pressure. By preparative TLC (CH) 2Cl2MeOH 20:1) to give (2R) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002206
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (220mg, 88.95%). LCMS M/z (ESI), [ M + H]+＝555.2；1H-NMR(400MHz,DMSO-d6)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),8.31(2H,d),9.03(1H,d)
Step 2.(R) -3-amino-N- ((4, 4-difluoropyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (
Figure BDA0002577091620002211
Azol-2-yl) pyrazine-2-carboxamides
To (2R) -2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) at room temperature under an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002212
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]To a stirred solution of tert-butyl (4, 4-difluoropyrrolidine-1-carboxylate (220mg, 0.397mmol, 1 eq) in DCM was added TFA (2mL, 26.926mmol, 67.87 eq). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. Evaporation of DCM and TFA gave 3-amino-N- [ [ (2R) -4, 4-difluoropyrrolidin-2-yl as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002213
Oxazol-2-yl) pyrazine-2-carboxamide (99.84%) (crude material). LCMS M/z (ESI), [ M + H]+＝455.2H-NMR(400MHz, DMSO-d6)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-, (
Figure BDA0002577091620002214
Azol-2-yl) pyrazine-2-carboxamide (Compound 162)
To 3-amino-N- [ [ (2R) -4, 4-difluoropyrrolidin-2-yl at room temperature under an air atmosphere]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002215
Oxazol-2-yl) pyrazine-2-carboxamide (180mg, 0.396mmol, 1 equiv.) and HCHO (118.93mg, 3.961mmol, 10.00 equiv.), DIEA (307.15mg, 2.377mmol, 6.00 equiv.) in CH2Cl2To a stirred mixture in (6mL)/MeOH (3mL) was added NaBH dropwise3CN (149.35mg, 2.377mmol, 6.00 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The reaction was quenched by the addition of water (50mL) at room temperature. By CH2Cl2(2 × 50mL) extract the aqueous layer, combine the organic layers and dry Na2SO4Drying and evaporating off the solventA yellow solid was obtained. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10MMOL/L NH)4HCO3) And the mobile phase B: ACN; flow rate: 20 mL/min; gradient: 32% B to 45% B within 8 min; 254; 220 nm; rt: 7.67min) to give 3-amino-N- [ [ (2R) -4, 4-difluoro-1-methylpyrrolidin-2-yl ] as a yellow solid]Methyl radical ]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002216
Oxazol-2-yl) pyrazine-2-carboxamide (compound 162) (40mg, 21.56%). LCMS M/z (ESI), [ M + H]+＝469.21H NMR(400MHz,DMSO-d6)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 171.3-amino-N- [ (6- [ 1-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl radical]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002222
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 171)
Scheme 94
Figure BDA0002577091620002221
Step 1.6- (6-cyanopyridin-2-yl) -1, 6-diazaspiro [3.3]Heptane-1-carboxylic acid tert-butyl ester
6-Fluoropyridine-2-carbonitrile (1.5g, 12.29mmol, 1 eq.) and 1, 6-diazaspiro [3.3 ] were reacted at 50 ℃ under an air atmosphere]Heptane-1-carboxylic acid tert-butyl ester (2.92g, 14.73mmol, 1.20 equiv.) and K2CO3(5.09g, 36.829mmol, 3.00 equiv.) A mixture in DMF (20mL) was stirred 10H, the resulting mixture was extracted with EtOAc (4 × 20mL), H was used2The combined organic layers were washed with O (2 × 10mL), anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By silica gel column chromatographyThe residue was purified by elution with PE/EtOAc (6:1) to give 6- (6-cyanopyridin-2-yl) -1, 6-diazaspiro [3.3 ] as a white solid]Heptane-1-carboxylic acid tert-butyl ester (2.69g, 72.17%). LCMS M/z (ESI), [ M + H ]+＝301.3。
Step 2.1- (6- [ 1-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl radical]Pyridin-2-yl) methylamines
Reacting 6- (6-cyanopyridin-2-yl) -1, 6-diazaspiro [3.3 ] at 50 ℃ under an air atmosphere]Heptane-1-carboxylic acid tert-butyl ester (0.5g, 1.665mmol, 1 eq.) and LiAlH4A mixture of (0.13g, 3.425mmol, 2.06 equiv.) in THF (10mL) was stirred for 6 h, the reaction quenched by addition of EtOAc (20mL) at room temperature, and then extracted with EtOAc (4 × 20mL), the combined organic layers were washed with water (3 × 10mL), dried Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gave 1- (6- [ 1-methyl-1, 6-diazaspiro [3.3 ] as a white solid]Heptane-6-yl radical]Pyridin-2-yl) methylamine (200mg, 53.93%). LCMS M/z (ESI), [ M + H]+＝219.2。
Step 3.3-amino-N- [ (6- [ 1-methyl-1, 6-diazaspiro [3.3 ]]Heptane-6-yl radical]Pyridin-2-yl) methyl Base of]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002223
Azol-2-yl) pyrazine-2-carboxamides 171)
3-amino-6- [ imidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002224
Azol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.31mmol, 1 eq.) and 1- (6- [ 1-methyl-1, 6-diazaspiro [3.3 ] ]Heptane-6-yl radical]Pyridin-2-yl) methylamine (101.6mg, 0.465mmol, 1.50 equiv.) to a stirred solution/mixture in DMF (3mL) was added HATU (235.96mg, 0.621mmol, 2.00 equiv.) and DIEA (120.31mg, 0.931mmol, 3.0 equiv.) dropwise by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 40%B within 7 min; 254; 220 nm; rt: 6.37min) to give 3-amino-N- [ (6- [ 1-methyl-1, 6-diazaspiro [3.3 ] as a yellow solid]Heptane-6-yl radical]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002232
Oxazol-2-yl) pyrazine-2-carboxamide (compound 171) (20mg, 12.01%). LCMS M/z (ESI), [ M + H]+＝537.3。1HNMR(400MHz,DMSO-d6)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 172.3-amino-N- ((6- ((8-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002233
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 172)
Scheme 95
Figure BDA0002577091620002231
Step 1.2-cyano-6- ((1R,5S) -3-methyl-3, 8-diazabicyclo [3.2.1]Octane-3-yl) pyridines
6-Fluoropyridine-2-carbonitrile (594mg, 4.865mmol, 1 eq.) and 3-methyl-3, 8-diazabicyclo [3.2.1 ] at room temperature under an air atmosphere ]To a stirred solution of octane (675.35mg, 5.351mmol, 1.10 equiv.) in DMF (10.5mL) was added K in portions2CO3(2756.59mg, 19.946mmol, 4.10 equiv.). The resulting mixture was stirred at 50 ℃ under an air atmosphere for 6.0 hours. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (hexane/EtOAc 1:1) to give 6- [ 3-methyl-3, 8-diazabicyclo [3.2.1 ] as a pale yellow oil]Octane-8-yl]Pyridine-2-carbonitrile (613mg, 55.19%). LCMS M/z (ESI), [ M + H]+＝229.3
Step 2.(6- ((1R,5S) -3-methyl-3, 8)-diazabicyclo [3.2.1]Octane-3-yl) pyridin-2-yl) methyl Amines as pesticides
Reaction of 6- [ 8-methyl-3, 8-diazabicyclo [3.2.1 ] in a hydrogen atmosphere at room temperature]Octane-3-yl]Pyridine-2-carbonitrile (613mg, 2.685mmol, 1 eq.) and NH3.H2To a stirred solution of O (1.2mL, 190.218mmol, 65.14 equiv) in MeOH (15mL) was added raney nickel (345.07mg, 4.028mmol, 1.50 equiv) dropwise. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1.0 hour. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give 1- (6- [ 8-methyl-3, 8-diazabicyclo [3.2.1 ] as a yellow oil]Octane-3-yl]Pyridin-2-yl) methylamine (580mg, 94.99%). LCMS M/z (ESI), [ M + H ]+＝233.3。
Step 3.3-amino-N- ((6- ((1R,5S) -3-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl) pyridine Pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002242
Azol-2-yl) pyrazine-2-carboxamides
3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002243
Oxazol-2-yl) pyrazine-2-carboxamide (200mg, 0.596mmol, 1 eq) and 1- (6- [ 3-methyl-3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl]Pyridin-2-yl) methylamine (207.85mg, 0.895mmol, 1.50 equiv.) to a stirred solution in DMF (4.00mL, 205.218mmol, 324.98 equiv.) was added HATU (453.56mg, 1.193mmol, 2.00 equiv.) and DIEA (308.34mg, 2.386mmol, 4.00 equiv.) in portions. The desired product can be detected by LCMS. By preparative TLC (CH)2Cl2MeOH 20:1) to give 3-amino-N- [ (6- [ 3-methyl-3, 8-diazabicyclo [3.2.1 ] as a yellow solid]Octane-8-yl]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002244
Oxazole-2-Yl) pyrazine-2-carboxamide (100mg, 30.45%). the crude product (100mg) was purified by preparative HPLC with the following conditions (column: X Bridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 43% B over 7 min; 254; 220 nm; Rt: 6.77min) to give 3-amino-N- [ (6- [ 3-methyl-3, 8-diazabicyclo [3.2.1 ] as a yellow solid ]Octane-8-yl]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002245
Oxazol-2-yl) pyrazine-2-carboxamide (compound 172) (39mg, 23.9%). LCMS M/z (ESI), [ M + H]+＝551.3。1H NMR(400MHz,DMSO-d6)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 175.3-amino-N- ((6- (6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002246
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 175)
Scheme 96
Figure BDA0002577091620002241
Step 1.2-cyano-6- (6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl) pyridines
6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 eq) oxalic acid was added to a 40mL sealed tube at room temperature; 2, 6-diazaspiro [3.4 ]]Octane-6-carboxylic acid tert-butyl ester (1609.41mg, 5.323mmol, 1.3 equiv.), K2CO3(1697.83mg, 12.285mmol, 3 equiv.) and DMF (10 mL.) the resulting mixture was stirred at 50 ℃ for 3 h, the reaction was quenched by the addition of saturated NaCl (aq) (250mL) at room temperature, the resulting mixture was extracted with EtOAc (2 × 125mL), saturatedThe combined organic layers were washed with NaCl (aq) (250mL) and over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 30:1) to give 6- [ (1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1 ] as a white solid ]Heptane-2-yl radical]Pyridine-2-carbonitrile (700 mg, 79.78%). LCMS M/z (ESI), [ M + H]+＝259.2
Step 2.(6- (6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl) pyridin-2-yl) methylamine
2- (6-cyanopyridin-2-yl) -2, 6-diazaspiro [3.4 ] was added to a 40mL sealed tube]Octane-6-carboxylic acid tert-butyl ester (500mg, 1.590mmol, 1 equiv.) in THF (10mL) followed by addition of LiAlH at 0 deg.C4(301.81mg, 7.952mmol, 5 equiv.). This solution was stirred at 70 ℃ for 2 hours. The desired product can be detected by LCMS. The reaction was quenched by the addition of water (0.5mL) at 0 ℃. The solid was filtered off. The filtrate was concentrated in vacuo to give 1- (6- [ 6-methyl-2, 6-diazaspiro [3.4 ] as a yellow oil]Octane-2-yl]Pyridin-2-yl) methylamine (250mg, 67.66%). LCMS M/z (ESI), [ M + H]+＝233.3。
Step 3.3-amino-N- ((6- (6-methyl-2, 6-diazaspiro [3.4 ]]Octane-2-yl) pyridin-2-yl) methyl 6- (3-methylimidazo [1, 2-a) methyl ester]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002251
Azol-2-yl) pyrazine-2-carboxamides
1- (6- [ 6-methyl-2, 6-diazaspiro [3.4 ] is added to a 10mL sealed tube at room temperature]Octane-2-yl]Pyridin-2-yl) methylamine (150mg, 0.646mmol, 1 eq), 3-amino-6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002252
Oxazol-2-yl) pyrazine-2-carboxylic acid (65.14mg, 0.194mmol, 1.50 equiv.), HATU (490.98mg, 1.291mmol, 2.00 equiv.), and DIEA (333.77mg, 2.583mmol, 4 equiv.) in DMF (10mL) for 2 hours. The desired product can be detected by LCMS. By preparative HPLC with the following conditions (column: XBrid) ge Prep OBDC18 column 19 × 250mm,5 μm; mobile phase A: and the mobile phase B: MeOH — HPLC; flow rate: 20 mL/min; gradient: 66% B to 70% B within 7 min; 254; 220 nm; rt: 6.32min) to give 3-amino-N- [ (6- [ 6-methyl-2, 6-diazaspiro [3.4 ] as a yellow solid]Octane-2-yl]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002253
Oxazol-2-yl) pyrazine-2-carboxamide (compound 175) (15mg, 14.3%). LCMS M/z (ESI), [ M + H]+＝551.3。1H NMR(400mHz,DMSO-d6)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 198.3-amino-6- (3- (aminomethyl) imidazo [1, 2-a)]Pyridin-6-yl) -N- ((3-Fluoropyridin-2-yl) methyl) -5-, (
Figure BDA0002577091620002262
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 198)
Scheme 97
Figure BDA0002577091620002261
(S) -2-methyl-N- ((6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidamide Azole [1,2-a ]]Pyridin-3-yl) methyl) propane-2-sulfinamide
N- ([ 6-bromoimidazo [1,2-a ] is reacted at 90 ℃ under a nitrogen atmosphere]Pyridin-3-yl]Methyl) carbamic acid tert-butyl ester (700 mg, 2.146mmol, 1 eq) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (817.42mg, 3.219mmol, 1.50 eq) and Pd (dppf) Cl2(157.02mg, 0.215mmol, 0.1 equiv.) and AcOK (421.22mg, 4.292mmol, 2 equiv.) in 1, 4-bis
Figure BDA0002577091620002263
The mixture in alkane (10mL) was stirred for 2 hours. By preparative TLC (H)2Cl2/MeOH 30:1) to give N- [ [6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] as a brown-yellow solid]Pyridin-3-yl]Methyl radical]Carbamic acid tert-butyl ester (500mg, 49.94%). LCMS m/z (ES)+),[M+H]+＝432.3
Step 2.(S) -3-amino-6- (3- (((tert-butylsulfinyl) amino) methyl) imidazo [1,2-a]Pyridine-6- -N- ((3-fluoropyridin-2-yl) methyl) -5-, (
Figure BDA0002577091620002264
Azol-2-yl) pyrazine-2-carboxamides
To (S) -2-methyl-N- [ [6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] in a hydrogen atmosphere at room temperature]Pyridin-3-yl]Methyl radical]Propane-2-sulfinamide (649.19mg, 1.721mmol, 2.00 equivalents) and 3-amino-6-chloro-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620002265
Azol-2-yl) pyrazine-2-carboxamide (300mg, 0.860mmol, 1 equivalent) in bis
Figure BDA0002577091620002266
alkane/H2K was added dropwise/portion by portion to a stirred solution in 7:1(16mL)3PO4(547.83mg, 2.581mmol, 3.0 equiv.) and Pd (dppf) Cl2.CH2Cl2(147.53mg, 0.181mmol, 0.21 equiv.). The resulting mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2.0 hours. The desired product can be detected by LCMS: m/z (ES)+), [M+H]+＝564.3
Step 3.3-amino-6- (3- (aminomethyl) imidazo [1, 2-a) ]Pyridin-6-yl) -N- ((3-fluoropyridin-2-yl) Methyl) -5-, (
Figure BDA0002577091620002267
Azol-2-yl) pyrazine-2-carboxamides
At room temperature10.0mL of a sealed tube was added 3-amino-N- [ (3-fluoropyridin-2-yl) methyl group]-6- [3- ([ [ (S) -2-methylpropane-2-sulfinyl group]Amino group]Methyl) imidazole [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002272
Azol-2-yl) pyrazine-2-carboxamide (150 mg) and Diphenyl Ether-N-methyl
Figure BDA0002577091620002273
alkane/HCl (6.0 mL). The resulting mixture was stirred at room temperature under an air atmosphere for 60 min. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DMF (4 mL). And subjected to preparative HPLC. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250 mm, 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 21% B to 31% B within 8 min; 254/220 nm; rt: 7.53min) to give 3-amino-6- [3- (aminomethyl) imidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ (3-fluoropyridin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620002274
Oxazol-2-yl) pyrazine-2-carboxamide (compound 198) (20mg, 6.12%). LCMS m/z (ES)+),[M+H]+＝460.2。1H-NMR(DMSO-d6,40MHz)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 199.3-amino-5- (4-fluorophenyl) -N- ([3- [2- (methylamino) ethoxy ] pyridin-2-yl ] methyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] pyrazine-2-carboxamide (Compound 199)
Scheme 98
Figure BDA0002577091620002271
Step 1.N- [2- [ (2-cyanopyridin-3-yl) oxy group]Ethyl radical]-N-methylcarbamic acid tert-butyl ester
In 2A0-mL vial was charged with 3-fluoropyridine-2-carbonitrile (800mg, 6.552mmol, 1 eq.), tert-butyl N- (2-hydroxyethyl) -N-methylcarbamate (1.38g, 7.875mmol, 1.20 eq.), DMF (4mL), K2CO3(2.26g, 16.352mmol, 2.50 equiv.). The resulting mixture was stirred at 80 ℃ for 16 hours. Using 20mL of H2The resulting mixture was diluted O, the resulting solution was extracted with 3 × 8mL ethyl acetate and the organic layers were combined, the resulting solution was washed with 3 × 10mL brine, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo the residue was purified by preparative TLC (EtOAc: petroleum ether: 1) which yielded 738mg (40.62%) of N- [2- [ (2-cyanopyridin-3-yl) oxy) as a purple solid]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester. LCMS M/z (ESI), [ M + H-tBu]+＝222.11H-NMR(300 MHz,DMSO-d6)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.N- (2- [ [2- (aminomethyl) pyridin-3-yl)]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester
Placing N- [2- [ (2-cyanopyridin-3-yl) oxy in a 25-mL round bottom flask purged and maintained with an inert hydrogen atmosphere]Ethyl radical ]-N-methyl-carbamic acid tert-butyl ester (738mg, 2.661mmol, 1 equiv.), MeOH (10mL), NH3.H2O (1mL, 25.681mmol, 9.65 equiv.), Raney nickel (227.99mg, 2.661mmol, 1.00 equiv.). The resulting solution was stirred at 16 ℃ for 2 hours. The solid was filtered off. The resulting mixture was concentrated in vacuo. This gave 700mg (93.49%) of N- (2- [ [2- (aminomethyl) pyridin-3-yl) as a violet solid]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester. LCMS M/z (ESI), [ M + H]+＝282.2
Step 3.N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a) ]]Pyridine-6- Base of]Pyrazin-2-yl radicals]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester
Place N- (2- [ [2- (aminomethyl) pyridin-3-yl) in a 6-mL vial]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester (154.87mg, 0.550mmol, 2.00 equiv.), 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxylic acid (100mg, 0.275 mmo)l, 1 eq), DIEA (0.34mL, 2.061mmol, 7.49 eq), DMF (2.5mL), T3P (262.70mg, 0.826mmol, 3.00 equiv.). The resulting solution was stirred at 16 ℃ for 16 hours. Using 20mL of H2The resulting solution was diluted O, the resulting solution was extracted with 3 × 10mL ethyl acetate and the organic layers were combined, the resulting solution was extracted with 3 × 10mL brine, the organic layers were combined and dried over anhydrous sodium sulfate the residue was purified by preparative TLC (DCM: MeOH ═ 7:1) which yielded 93mg (53.92%) of N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]Pyrazin-2-yl radicals]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester. LCMS M/z (ESI), [ M/2+ H]+＝314.3
Step 4.3-amino-5- (4-fluorophenyl) -N- ((3- (2- (methylamino) ethoxy) pyridin-2-yl) methyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) pyrazine-2-carboxamide 2,2, 2-trifluoroacetate (Compound 199)
Place N- (2- [ [2- ([ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a) ] in a 6-mL vial]Pyridin-6-yl]Pyrazin-2-yl radicals]Carboxamido radical]Methyl) pyridin-3-yl]Oxy radical]Tert-butyl ethyl) -N-methylcarbamate (80mg, 0.128 mmol, 1 equiv.), DCM (3.00mL), TFA (1.00mL, 13.46mmol, 105.2 equiv.) the resulting solution is stirred at 20 ℃ for 2 hours the resulting mixture is concentrated in vacuo the pH of the solution is adjusted to 9 with saturated sodium bicarbonate solution the resulting solution is extracted with 3 × 10mL ethyl acetate and the organic layer is combined the resulting mixture is concentrated in vacuo the residue is purified by preparative TLC (DCM: MeOH ═ 3:1) the crude product is purified by preparative HPLC (column: Sunfire Prep C18OBD column, 10 μm, 19 × 250 mm; mobile phase a: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 10% B to 25% B in 10 min; 254,220 nm; Rt: 8.7min) this gives 20.22mg of crude product as yellow solid, 3-amino-5- (3-fluoro-phenyl) -N-methyl-2- (3-fluoro phenyl) -2-methyl-2-amino-2-methyl-2-fluoro-methyl-2-methyl-2-ethyl-2-methyl-2-methyl-2-ethyl-2-methyl-2- ]Pyridin-6-yl) pyrazine-2-carboxamide 2,2, 2-trifluoroacetate (compound 199). LCMS M/z (ESI), [ M + H]+＝527.31H-NMR(300MHz,DMSO-d6)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)。19F NMR(300 MHz,DMSO-d6)-111.615(1F),-74.101(7.27F)
Example 202/206.3-amino-N- [ [ 1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002292
Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 202)
3-amino-N- [ 1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002293
Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 206)
Scheme 99
Figure BDA0002577091620002291
Step 1.6-bromo-3- (trifluoromethyl) imidazole [1,2-a ]]Pyridine compound
Reacting 6-bromo-3-iodoimidazo [1,2-a ] at 50 DEG C]Pyridine (1.5g, 4.645mmol, 1 equiv.), 15- (trifluoromethyl) -1 λ 4,12 λ 4-diaza-15-copper tetracyclo [10.2.1.0^ 5,14].0^[8,13]]A mixture of pentadeca-1, 3,5(14),6,8,10, 12-heptan-15-ylium (1.74g, 5.574mmol, 1.2 eq.) in DMF (15mL) was stirred overnight. By CH2Cl2Diluting the resulting mixture (100mL), filtering the resulting mixture, washing the filter cake with DCM (2 × 50mL), washing the resulting mixture with 2 × 150 mL of water, concentrating the organic phase under reduced pressure, purifying the residue by silica gel column chromatography (detection by mAU 220 nm), using CH2Cl2Elution with PE (40:60) gave 6-bromo-3- (trifluoromethyl) imidazo [1,2-a as a white solid ]Pyridine (780mg, 63.36%). LCMS M/z (ESI), [ M + H]+＝267.1。1H NMR(300MHz,DMSO-d6) 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) imidazole [1,2-a ]]Pyridin-6-yl]Boric acid
To 6-bromo-3- (trifluoromethyl) imidazole [1,2-a ]]Pyridine (500mg, 1.887mmol, 1 equiv.) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (958.14mg, 3.773mmol, 2.00 equiv.) in dioxane
Figure BDA0002577091620002301
AcOK (555.45mg, 5.660mmol, 3 equiv.) and Pd (dppf) Cl were added to a solution in alkane (20mL)2(276.08mg, 0.377mmol, 0.2 equiv.). After stirring at 90 ℃ for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH/water, 10% to 50% gradient over 10 min; detector, UV 254nm, [3- (trifluoromethyl) imidazo [1,2-a ] is obtained as a white solid]Pyridin-6-yl]Boric acid (370mg, 85.29%). LCMS M/z (ESI), [ M + H]+＝231.1
Step 3.3-amino-N- [ [ (2S) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002302
Oxazol-2-yl) -6- [3- (trifluoromethyl) imidazole [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxamides
To [3- (trifluoromethyl) imidazole [1,2-a ]]Pyridin-6-yl]Boronic acid (350mg, 1.522mmol, 1 equiv.) and 3-amino-6-chloro-N- [ (1-methylpyrrolidin-2-yl) methyl ]-5-(1,3-
Figure BDA0002577091620002303
Azol-2-yl) pyrazine-2-carboxamide (512.60mg, 1.522 mmol, 1.00 equiv.) in Diphenyl Ether
Figure BDA0002577091620002304
Alkane (20mL) and H2To a solution in O (2mL) was added K3PO4(969.25mg, 4.566mmol, 3 equiv.) and Pd (dppf) Cl2(222.74mg, 0.304mmol, 0.2 equiv.). After stirring at 90 ℃ for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. Color by preparative TLC/silica gel columnThe residue was purified by chromatography using CH2Cl2MeOH (15:1) elution gave 3-amino-N- [ [ 1-methylpyrrolidin-2-yl ] as a pale yellow solid]Methyl radical]-5-(1,3-
Figure BDA0002577091620002305
Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (200mg, 27.01%). LCMS M/z (ESI), [ M + H]+＝487.3
Step 4.3-amino-N- [ [ 1-methylpyrrolidin-2-yl group]Methyl radical]-5-(1,3-
Figure BDA0002577091620002306
Azol-2-yl) -6- [3- (tris) Fluoromethyl) imidazole [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 202)/(Compound 206)
The crude product (100mg) was purified by preparative chiral HPLC accompanied by the following conditions (column: CHIRALPAK IG, 2.0cm I.D. 25cm L (5 μm); mobile phase A: CO2:75, mobile phase B: ETOH: ACN ═ 1: 25; flow rate: 40 mL/min; 220 nm; RT 1: 10; RT 2: 12.65) to give 3-amino-N- [ 1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002307
Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a ]Pyridin-6-yl]Pyrazine-2-carboxamide (Compound 202) (50mg, 27.78%) and 3-amino-N- [ 1-methylpyrrolidin-2-yl) as a yellow solid]Methyl radical]-5-(1,3-
Figure BDA0002577091620002308
Azol-2-yl) -6- [3- (trifluoromethyl) imidazole [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamide (compound 206). 3-amino-N- [ 1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002312
Azol-2-yl) -6- [3- (trifluoromethyl) imidazo [1,2-a]Pyridin-6-yl]Pyrazine-2-carboxamides.
(Compound 202) LCMS M/z (ESI), [ M + H]+＝487.3。1H NMR(400MHz,DMSO-d6)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(400MHz,DMSO-d6)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)。
Example 214/209.3-amino-6- (3-chloroimidazo [1, 2-a)]Pyridin-6-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) -5-, (
Figure BDA0002577091620002313
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 214/209)
Scheme 100
Figure BDA0002577091620002311
Step 1. (3-Chloroimidazo [1, 2-a)]Pyridin-6-yl) boronic acid.
Mixing [ imidazole [1,2-a ]]Pyridin-6-yl]Boric acid (600mg, 3.705mmol, 1 equiv.) and NCS (1.24g, 9.262mmol, 2.50 equiv.) were dissolved in 3mL DMF. The mixture was stirred at room temperature for 3 hours. LCMS showed no problem with the reaction. The crude product was purified by reverse phase HPLC to give [ 3-chloroimidazo [1,2-a ] as a white solid]Pyridin-6-yl]Boric acid (235mg, 32.3%). LCMS M/z (ESI), [ M + H]+＝197.2。
Step 2.3-amino-6- (3-chloroimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002314
Azol-2-yl) pyrazine-2-carboxylic acid esters And (4) acid.
[ 3-Chloroimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (169.69mg, 0.864mmol, 1.00 equiv.), 3-amino-6-chloro-5- (1, 3-)
Figure BDA0002577091620002315
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (220mg, 0.864mmol, 1 eq), Pd(dppf)Cl2(126.44mg, 0.173mmol, 0.2 equiv.) and Cs2CO3(1126.03mg, 3.456mmol, 4 equiv.) was dissolved in 2.4mL of two
Figure BDA0002577091620002321
alkane/H2O (5: 1). The mixture was stirred at 70 ℃ for 2 hours. LCMS showed no problem for the reaction. The mixture was concentrated, acidified with acetic acid and purified by reverse phase HPLC to give 3-amino-6- [ 3-chloroimidazo [1,2-a ] as a white solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002322
Oxazol-2-yl) pyrazine-2-carboxylic acid methyl ester (100mg, 31.22%). LCMS M/z (ESI), [ M + H]+＝371.2。
Step 3.3-amino-6- [ 3-chloroimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidine-2- Base of]Methyl radical]-5-(1,3-
Figure BDA0002577091620002323
Azol-2-yl) pyrazine-2-carboxamide (Compound 214)
Reacting 3-amino-6- [ 3-chloroimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002324
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.280 mmol, 1 equiv.), 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (48.02mg, 0.420mmol, 1.5 equiv.), DIEA (253.61mg, 1.962mmol, 7 equiv.), and T3P (267.58mg, 0.841mmol, 3 equiv.) was added to DMF (3 mL). The resulting suspension was stirred at room temperature for 3 hours. With saturated NH 4The reaction mixture was quenched with Cl (15mL) and extracted with EtOAc (3 × 50mL), over Na2SO4The organic layer was dried, filtered and evaporated to give a yellow gum. The residue was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 29% B to 37% B within 8 min; 254; 220 nm; Rt: 6.57/7.42min) to give 3-amino-6- [ 3-chloroimidzolone as a pale yellow solid[1,2-a]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002325
Oxazol-2-yl) pyrazine-2-carboxamide (compound 214) (23.9mg, 18.8%). LCMS M/z (ESI), [ M + H]+＝453.2。1H-NMR (400MHz, methanol-d)4)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-methylpyrrolidine-2- Base of]Methyl radical]-5-(1,3-
Figure BDA0002577091620002326
Azol-2-yl) pyrazine-2-carboxamide (Compound 209)
Reacting 3-amino-6- [ 3-chloroimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002327
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.280 mmol, 1 equiv.), 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (48.02mg, 0.420mmol, 1.5 equiv.), DIEA (253.61mg, 1.962mmol, 7 equiv.), T3P (267.58mg, 0.841mmol, 3 equiv.) was added to DMF (3 mL). The resulting suspension was stirred at room temperature for 3 hours. With saturated NH 4The reaction mixture was quenched with Cl (15mL), extracted with EtOAc (3 × 50mL), and extracted with Na2SO4The organic layer was dried, filtered and evaporated to give a yellow gum. The residue was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 29% B to 37% B within 8 min; 254; 220 nm; Rt: 6.57/7.42min) to give 3-amino-6- [ 3-chloroimidazo [1,2-a ] as a pale yellow solid]Pyridin-6-yl]-N- [ [ (2S) -1-methylpyrrolidin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002332
Azol-2-yl) pyrileOxazine-2-carboxamide (18.9 mg, 14.8%). LCMS M/z (ESI), [ M + H]+＝453.2。1H-NMR (400MHz, methanol-d)4)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 219.3-amino-N- [ [ (3R) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002333
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 219)
Scheme 101
Figure BDA0002577091620002331
Step 1.N- [ [ (3R) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical](iii) carbamic acid tert-butyl ester.
TEA (757.86mg, 7.489mmol, 3 equiv.), cyclopropanecarbonyl chloride (391.44 mg, 3.745mmol, 1.5 equiv.) and N- [ [ (3S) -pyrrolidin-3-yl ] were added under an air atmosphere at room temperature]Methyl radical ]A mixture of tert-butyl carbamate (500mg, 2.496 mmol, 1 eq) in DCM (15mL) was stirred for 16 h, the reaction was diluted with DCM (90mL), the organic layer was washed with water (2 × 100mL), and over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give N- [ [ (3R) -1-cyclopropanecarbonyl-pyrrolidin-3-yl ] as a brown oil]Methyl radical]Tert-butyl carbamate (750mg, 111.95%).1H-NMR (300MHz, chloroform-d) 0.77(2H, d),1.01(2H, d),1.46(9H, d),1.61(1H, d),1.68-1.85 (1H, m),2.07(1H, d),2.33-2.58(1H, m),3.03-3.28(2H, m),3.28-3.49(1H, m),3.58-3.72(1H, m),3.72-3.87(1H, m)
Step 2.1- [ (3R) -1-Cyclopropanecarbonylpyrrolidin-3-yl]Methylamine.
TFA (1mL) and N- [ [ (3R) -1-cyclopropanecarbonyl pyrrolidin-3-yl were reacted at room temperature under an air atmosphere]Methyl radical]A mixture of tert-butyl carbamate (300mg, 1.118mmol, 1 eq) in DCM (3mL) was stirred for 1 h. Concentrating the obtained mixture under reduced pressureAnd (4) shrinking. With saturated NaHCO3The residue was basified to pH 7 (aqueous solution). By CH2Cl2(2 × 50mL) the resulting mixture was extracted the combined organic layers were washed with water (2 × 50mL) and dried over anhydrous Na 2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 1- [ (3R) -1-cyclopropanecarbonyl-pyrrolidin-3-yl group as a brown oil]Methylamine (180 mg, 95.71%). LCMS M/z (ESI), [ M + H]+＝169.1。1H NMR(300MHz,DMSO-d6,)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-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002342
Oxazol-2-yl) pyrazine-2-carboxamide (compound 219).
DIEA (215.21mg, 1.665mmol, 7 equiv.), T was added under air atmosphere at room temperature3P (378.44mg, 1.189mmol, 5 equiv.), 1- [ (3R) -1-cyclopropanecarbonyl-pyrrolidin-3-yl]Methylamine (160.08mg, 0.952mmol, 4 equivalents) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002343
A mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238MMOL, 1 eq) in DMF (3mL) was stirred overnight the desired product could be detected by LCMS preparative HPLC was followed by conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (10MMOL/L NH)4HCO3) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 28% B within 7 min; 254/220 nm; rt: 5.37min) to give 3-amino-N- [ [ (3R) -1-cyclopropanecarbonyl-pyrrolidin-3-yl as a yellow solid ]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002344
Azol-2-yl) Pyrazine-2-carboxamide (compound 219) (60mg, 50.81%). LCMS M/z (ESI), [ M + H]+＝487.3。1H-NMR(300MHz,DMSO-d6)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 221.3-amino-N- [ [ (3S) -1-cyclopropanecarbonyl ] pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002345
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 221)
Scheme 102
Figure BDA0002577091620002341
Step 1.N- [ [ (3S) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical]Carbamic acid tert-butyl ester
To a stirred mixture of TEA (1515.71mg, 14.979mmol, 6.00 equiv.) and cyclopropanecarbonyl chloride (521.91mg, 4.993mmol, 2.00 equiv.) in DCM (10mL) was added N- [ [ (3R) -pyrrolidin-3-yl in portions at 25 deg.C under a nitrogen atmosphere]Methyl radical]Carbamic acid tert-butyl ester (500mg, 2.496mmol, 1 eq). The resulting mixture was stirred at 25 ℃ for 2 hours under an air atmosphere. By CH2Cl2(3 × 20mL) the resulting mixture was extracted and then over anhydrous Na2SO4The organic phase was dried. After filtration, the filtrate was concentrated under reduced pressure to give N- [ [ (3S) -1-cyclopropanecarbonylpyrrolidin-3-yl ] as a yellow solid]Methyl radical]Tert-butyl carbamate (670mg, 100.01%).1H-NMR(300MHz, MeOD-d4)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- [ (3S) -1-Cyclopropanecarbonylpyrrolidin-3-yl ]Methylamine
To N- [ [ (3S) -1-cyclopropanecarbonyl pyrrolidin-3-yl ester at 25 ℃ under a nitrogen atmosphere]Methyl radical]To a stirred mixture of tert-butyl carbamate (300mg, 1.118mmol, 1 eq) in DCM (3mL) was added TFA (1 mL). The resulting mixture was stirred at 25 ℃ for 20min under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 1- [ (3S) -1-cyclopropanecarbonyl-pyrrolidin-3-yl group as a yellow oil]Methylamine (170mg, 90.39%). LCMS M/z (ESI), [2M + H]+＝337.2。
Step 3.3-amino-N- [ [ (3S) -1-cyclopropanecarbonyl pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002351
Azol-2-yl) pyrazine-2-carboxamide (Compound 221)
3-amino-6- [ 3-methylimidazo [1,2-a ] at 25 ℃ in a nitrogen atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002352
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (99.95mg, 0.297mmol, 0.50 equiv.) and DIEA (153.64mg, 1.189mmol, 2 equivalents) in DMF (5mL) was added T in portions3P (472.81mg, 1.486mmol, 2.50 equiv.) and 1- [ (3S) -1-cyclopropanecarbonyl-pyrrolidin-3-yl]Methylamine (100mg, 0.594MMOL, 1 eq.) the resulting mixture is stirred at 25 ℃ under nitrogen atmosphere for 4 hours by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase a: water (10MMOL/L NH) 4HCO3) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 28% B within 7 min; 254/220 nm; rt: 5.37min) to give 3-amino-N- [ [ (3S) -1-cyclopropanecarbonyl-pyrrolidin-3-yl as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002353
Oxazol-2-yl) pyrazine-2-carboxamide (60mg, 20.75%). LCMS M/z (ESI), [ M + H]+＝487.2。1H-NMR(300MHz,DMSO-d6)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 223.3 preparation of amino-N- [ (3-fluoropyridin-2-yl) methyl ] -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -5- (morpholin-4-yl) pyrazine-2-carboxamide (Compound 223)
Scheme 103
Figure BDA0002577091620002361
Step 1.3-amino-6-chloro-5- (morpholin-4-yl) pyrazine-2-carboxylic acid methyl ester
To a stirred mixture of methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (50mg, 0.225mmol, 1 equiv.) and DIEA (87.31mg, 0.676mmol, 3 equiv.) in DMSO was added morpholine (39.24mg, 0.450mmol, 2 equiv.) portionwise at room temperature the resulting mixture was stirred overnight at room temperature the reaction was quenched with water at room temperature the precipitated solid was collected by filtration and washed with water (1 × 100mL) and dried in vacuo to give methyl 3-amino-6-chloro-5- (morpholin-4-yl) pyrazine-2-carboxylate (1.8g, 97.71%) as a yellow solid. 1H-NMR (400MHz, chloroform-d) 3.61-3.72 (4H, m),3.75-3.88(4H, m),3.94(3H, s).
Step 2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (morpholin-4-yl) pyrazine-2-carboxylic acid methyl ester Acid methyl ester
To methyl 3-amino-6-chloro-5- (morpholin-4-yl) pyrazine-2-carboxylate (600mg, 2.200 mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at 95 ℃ under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (580.81mg, 3.300mmol, 1.5 equiv.) in bis
Figure BDA0002577091620002362
Cs was added in portions to a stirred mixture in an alkane (50mL)2CO3(2150.70mg, 6.601mmol, 3 equiv.) and Pd (dppf) Cl2(321.99mg, 0.440mmol, 0.2 equiv.). The resulting mixture was stirred at 95 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By silica gel column chromatography with CH2Cl2The residue was purified by elution with MeOH (20:1) to give a yellowish green solid3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-methyl 5- (morpholin-4-yl) pyrazine-2-carboxylate (400mg, 49.35%). LCMS M/z (ESI), [ M + H]+＝369.3。1H-NMR(400 MHz,DMSO-d6)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) pyrazine-2-carboxylic acid methyl ester Acid(s)
To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a solution of methyl (400mg, 1.086mmol, 1 eq) 5- (morpholin-4-yl) pyrazine-2-carboxylate in THF (50mL) and methanol (10mL) was added LiOH (156.01mg, 6.515mmol, 6 eq) portionwise. The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The mixture was acidified to pH 6 with HCl (aq). The resulting mixture was concentrated in vacuo to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5- (morpholin-4-yl) pyrazine-2-carboxylic acid (350mg, 90.96%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝355.1。
Step 4.3-amino-N- [ (3-fluoropyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridine-6- Base of]-5- (morpholin-4-yl) pyrazine-2-carboxamide (Compound 223)
3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]To a stirred mixture of-5- (morpholin-4-yl) pyrazine-2-carboxylic acid (100mg, 0.282mmol, 1 eq) and 1- (3-fluoropyridin-2-yl) methylamine (71.19mg, 0.564mmol, 2 eq) in DMF (10mL) was added HATU (214.59mg, 0.564mmol, 2 eq) and DIEA (109.41mg, 0.847mmol, 3 eq) in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 2.5 hours. The resulting mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC with the following conditions (column: Xbridge Prep OBDC18 column 19 x 250mm, 5 μm; mobile phase A: 5% ammonia, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 33% B to 48% B within 8 min; 254; 220 nm; Rt: 7.47min) to give 3-amino-N- [ (3-fluoropyridin-2-yl) methyl as a white solid ]-6- [ 3-methylAlkylimidazo [1,2-a ]]Pyridin-6-yl]-5- (morpholin-4-yl) pyrazine-2-carboxamide (9mg, 6.83%) (compound 223). LCMS M/z (ESI), [ M + H]+＝463.3。1H NMR(400MHz,DMSO-d6)2.54(3H,d),3.63(4H,t),4.61-4.74(4H,m),7.36-7.45(2H, m),7.57-7.64(1H,m),7.66-7.79(2H,m),8.36(1H,dt),8.63(1H,s),8.93(1H,t)
Example 227/224 Trans/cis-3-amino-N- ((6- ((3- (dimethylamino) cyclobutyl) amino) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002372
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 227/224)
Scenario 104
Figure BDA0002577091620002371
Step 1.2-cyano-6- ((3- (dimethylamino) cyclobutyl) amino) pyridine
A mixture of 6-fluoropyridine-2-carbonitrile (136mg, 1.114mmol, 1 equiv.), N1, N1-dimethylcyclobutane-1, 3-diamine dihydrochloride (250mg, 1.336mmol, 1.20 equiv.), and dipotassium carbonate (462mg, 3.343mmol, 3.00 equiv.) in 3mL THF was stirred at 50 deg.C for 18 h after cooling to room temperature, water was added and extracted with EtOAc (3 × 100mL), the combined organic layers were washed with brine, washed with anhydrous Na2SO4And (5) drying. After filtration and concentration, the residue was purified by column (DCM/MeOH3/1) to give 6- [ [3- (dimethylamino) cyclobutyl ] as a white solid]Amino group]Pyridine-2-carbonitrile (155mg, 64.3%). LCMS M/z (ESI), [ M + H]+＝217.3。
Step 2, N1- (6- (aminomethyl) pyridin-2-yl) -N3, N3-dimethylcyclobutane-1, 3-diamine
Reacting 6- [ [3- (dimethylamino) cyclobutyl group]Amino group]Pyridine-2-carbonitrile (155mg, 0.717mmol, 1 equiv.), 1mL of Ammonia solution, and a mixture of Raney Nickel (100mg) in methanol (10mL) at 1atm H2Hydrogenated at room temperature for 3 hours. After filtration through celite, the filtrate was concentrated to dryness in vacuo and the residue was used directlyAnd (4) carrying out 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-, (
Figure BDA0002577091620002381
Azol-2-yl) pyrazine-2-carboxamide (Compound 224/227)
To 3-amino-6- (1-methyl-1H-1, 3-benzoxadiazol-6-yl) -5- (1,3-
Figure BDA0002577091620002382
Oxazol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.446mmol, 1 eq.) and N3- [6- (aminomethyl) pyridin-2-yl]To a mixture of N1, N1-dimethylcyclobutane-1, 3-diamine (145mg, 0.66mmol, 1.48 equivalents) in N, N-dimethylformamide (5mL) were added DIEA (0.39mL, 2.239mmol, 5.02 equivalents) and 50 wt% T3A solution of P in ethyl acetate (860mg, 1.351mmol, 3.03 equiv.). The mixture was stirred at room temperature for 18 hours. After concentration to dryness, the residue was purified by preparative HPLC with the following conditions: (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 29% B to 37% B within 8 min; 254; 220 nm; Rt: 6.57/7.42min) to give trans-3-amino-6- [ 3-methyl-imidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002383
Azol-2-yl) -N- [ (6- [ [3- (dimethylamino) cyclo-butyl ] methyl ] ethyl]Amino group]Pyridin-2-yl) methyl]Pyrazine-2-carboxamide (Compound 227) (6.6mg, 2.7%) (Compound 227) LCMS: M/z (ESI), [ M + H [ (])]+＝539.4。1H-NMR(300MHz,MeOH-d4) 1.87-1.95(2H, m),2.02-2.14(8H, m),2.43(3H, s),2.71-2.81(1H, m),3.97-4.02(1H, m),4.48 (2H, s),6.26-6.28(1H, d),6.55-6.57(1H, d),7.22-7.48(5H, m),7.99(1H, s),8.38(1H, s), and cis-3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002384
Azol-2-yl) -N- [ (6- [ [3- (di-methylamino) cyclobutyl ] -N]Amino group]Pyridin-2-yl) methyl]Pyrazine-2-carboxamide (Compound 224) (6.1mg, 2.5%) (Compound 224) LCMS: M/z (ESI), [ M + H [ (+ ])]+＝539.3。1H-NMR(300MHz,MeOH-d4) 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 229.3-amino-6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -N- [ [ (2R) -oxolane-2-yl ] methyl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 229) preparation
Scheme 105
Figure BDA0002577091620002391
Step 1.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) Pyrazine-2-carboxylic acid methyl ester
To methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (1g, 3.927mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (1.38g, 7.855mmol, 2 equiv.) in 1, 4-bis
Figure BDA0002577091620002392
Alkane (15mL) and H2Cs was added portionwise to a stirred mixture in O (1.5mL)2CO3(2.56g, 7.855mmol, 2.00 equiv.) and Pd (dppf) Cl2.CH2Cl2(0.64g, 0.785mmol, 0.2 equiv.). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 20:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-methyl 5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (1g, 72.68%). LCMS M/z (ESI), [ M + H]+＝ 351.1。1H-NMR:(300MHz,DMSO-d6)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) Pyrazine-2-carboxylic acid
To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a stirred solution of-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid methyl ester (950mg, 2.712mmol, 1 eq) in MeOH (15mL) and THF (3mL) was added LiOH (97.42mg, 4.067mmol, 1.5 eq) portionwise. The resulting mixture was stirred at room temperature for 4 hours. The residue was acidified to pH 5 with HCl (aq). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (400mg, 43.86%). LCMS M/z (ESI), [ M + H ]+＝337.1。
Step 3.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -oxolane-2- Base of]Methyl radical]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (Compound 229)
To 1- [ (2R) -Oxetan-2-yl radical at room temperature]Methylamine (60.15mg, 0.595mmol, 2 equivalents) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]To a stirred mixture of (E) -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297 mmol, 1 eq) in DMF (10mL) was added DIEA (76.86mg, 0.595mmol, 2 eq) and T3P (23.80mg, 0.595mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water at room temperature. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC with the following conditions (column: Xbridge Prep OBDC18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B:, flow rate: 20 mL/min; gradient: 30% B to 41% B within 8 min; 254; 220 nm; Rt: 7.17min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ (2R) -oxolane-2-yl]Methyl radical]-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxamide (compound 229) (43mg, 34.48%). LCMS M/z (ESI), [ M + H ]+＝420.3。1H NMR:(300MHz,DMSO-d6)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)。
Example 230-1/230-2.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002402
Preparation of oxazol-2-yl) -N- ((1,4, 4-trimetylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide (Compound 230-1/230-2)
Scenario 106
Figure BDA0002577091620002401
Step 1.2- ((3-amino-6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002403
Azol-2-yl) pyrazine- 2-carboxamido) methyl) -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester
3-amino-6- [ 3-methylimidazo [1,2-a ] at 0 ℃ in a nitrogen atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002404
Azol-2-yl) pyrazine-2-carboxylic acid (200mg, 0.595mmol, 1 equiv.), DIEA (230.58mg, 1.784mmol, 3 equiv.), and tert-butyl 2- (aminomethyl) -4, 4-dimethylpyrrolidine-1-carboxylate (271.58mg, 1.189mmol, 2 equiv.) to a stirred mixture in DMF (12mL) was added T dropwise3P (378.44mg, 1.189mmol, 2 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was quenched by the addition of water (20mL) at room temperature. By CH2Cl2(3 × 20mL) the resulting mixture was extracted over anhydrous Na2SO4The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 20:1) to give 2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002411
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-4, 4-Dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (180mg, 55.37%). LCMS M/z (ESI), [ M + H]+＝547.4。
Step 2.3-amino-N- ((4, 4-dimethylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (
Figure BDA0002577091620002412
Azol-2-yl) pyrazine-2-carboxamides
2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002413
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (160mg, 0.293mmol, 1 equivalent) to a stirred solution in DCM (8mL) was added TFA (3mL, 40.389mmol, 137.99 equivalents) dropwise. The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure to give 3-amino-N- [ (4, 4-dimethylpyrrolidin-2-yl) methyl group as a yellow oil]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002414
Oxazol-2-yl) pyrazine-2-carboxamide (135mg, 98.12%). LCMS M/z (ESI), [ M + H]+＝447.4。
Step 3.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002415
Oxazol-2-yl) -N- ((1,4, 4-trimethylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide
To 3-amino-N- [ (4, 4-dimethylpyrrolidin-2-yl) methyl group at room temperature under a nitrogen atmosphere ]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002416
Azol-2-yl) pyrazine-2-carboxamide (15)5mg, 0.347mmol, 1 equiv.), DIEA (89.73mg, 0.694mmol, 2 equiv.), and Paraformaldehyde (312.69mg, 3.471mmol, 10 equiv.) to a stirred mixture of DCM (12mL) and MeOH (4mL) was added NaBH portionwise3CN (65.44mg, 1.041mmol, 3 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction was quenched by the addition of water (20mL) at room temperature. By CH2Cl2(3 × 15mL) the resulting mixture was extracted over anhydrous Na2SO4The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 10:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002417
Azol-2-yl) -N- [ (1,4, 4-trimethylpyrrolidin-2-yl) methyl]Pyrazine-2-carboxamide (130mg, 81.32%). LCMS M/z (ESI), [ M + H]+＝ 461.4。
Step 4.3-amino-6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002418
Oxazol-2-yl) -N- ((1,4, 4-Trimethylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide (230-1/230-2)
Chiral preparative HPLC was performed with the following conditions (column: CHIRALPAK ID-03, 2.0cm i.d. 25cm L (5 μm); mobile phase a: Hex: DCM ═ 5:1(10mM NH) 3-MEOH) -HPLC, mobile phase B: IPA-HPLC; flow rate: 20 mL/min; gradient: 25B to 25B within 22 min; 220/254 nm; RT 1: 15.342, respectively; RT 2: 17.566) to give 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002422
Azol-2-yl) -N- [ (1,4, 4-trimethylpyrrolidin-2-yl) methyl]Pyrazine-2-carboxamide (Compound 230-1) (45mg, 43.41%) LCMS M/z (ESI), [ M + H]+＝461.3。1H-NMR(400MHz,DMSO-d6)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-
Figure BDA0002577091620002423
Azol-2-yl) -N- [ (1,4, 4-trimethylpyrrolidin-2-yl) methyl]Pyrazine-2-carboxamide (Compound 230-2) (45mg, 45%), LCMS: M/z (ESI), [ M + H ]]+＝461.3。1H NMR(400MHz,DMSO-d6)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
Figure BDA0002577091620002421
Step 1.3 preparation of methyl 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylate
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (1.5g, 6.756mmol, 1 equivalent) and (3-fluorophenyl) boronic acid (0.95g, 6.790mmol, 1.00 equivalent) in 1, 4-bis (phenyl) at room temperature under a nitrogen atmosphere
Figure BDA0002577091620002424
Alkane (100mL) and H2To a stirred mixture in O (5mL) was added Cs portion by portion2CO3(6.60g, 0.020mmol, 3 equiv.) and Pd (dppf) Cl2(0.74g, 0.001mmol, 0.15 equiv.). The resulting mixture was stirred at 70 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH2Cl2(1 × 30mL) the filter cake was washed, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel using CH2Cl2EtOAc (4:1) elution gave methyl 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylic acid as a yellow solidAcid ester (900mg, 47.30%). LCMS M/z (ESI), [ M + H]+＝282.0。1H-NMR (300MHz, chloroform-d) 4.03(3H, s),7.22(1H, m),7.41-7.59(2H, m),7.65(1H, ddd).
Step 2.3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) pyrazin-2-yl Acid methyl ester
To methyl 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylate (400mg, 1.420 mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (324.88mg, 1.846mmol, 1.30 equivalents) in 1, 4-bis
Figure BDA0002577091620002431
Alkane (20mL) and H2To a stirred mixture in O (2mL) was added Cs portion by portion2CO3(1388.09 mg, 4.260mmol, 3 equiv.) and Pd (dppf) Cl2(155.86mg, 0.213mmol, 0.15 equiv.). The resulting mixture was stirred at 90 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH 2Cl2(1 × 20mL) the filter cake was washed, the filtrate was concentrated under reduced pressure, by preparative TLC (CH)2Cl2MeOH 20:1) to give 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (300mg, 55.98%). LCMS M/z (ESI), [ M + H]+＝378.1。
1H-NMR (300MHz, chloroform-d) 2.22-2.65(3H, m),4.04(3H, s),6.91-7.05(1H, m),7.05-7.23(2H, m),7.30(2H, d),7.44(2H, d),8.11(1H, t).
Step 3.3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) pyrazin-2-yl Acid(s)
To 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (300mg, 0.795mmol, 1 equiv.) in THF (20mL) and H2To a stirred solution in O (4mL) was added LiOH (38.08mg, 1.590mmol, 2.00 equiv) portionwise. The resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified to pH 5 with HCl (aq). The resulting mixture was concentrated under reduced pressure to give 3-amino-5- (3-fluorophenyl) -6- [3-Methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine-2-carboxylic acid (280mg, 96.94%) was used in the next step without further purification. LCMS M/z (ESI), [ M + H ]+＝364.2。
Step 4.(R) -3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -N- ((1- Methylpyrrolidin-2-yl) methyl) pyrazine-2-carboxamide (Compound 231)
To 1- [ (2R) -1-methylpyrrolidin-2-yl group at room temperature]Methylamine (62.85mg, 0.550mmol, 2.00 equiv.) and 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]To a stirred mixture of pyrazine-2-carboxylic acid (100mg, 0.275mmol, 1 equiv.) in DMF (10mL) was added DIEA (106.71mg, 0.826mmol, 3.00 equiv.) and T in portions3P (175.14mg, 0.550mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A (5% NH)4HCO3In water): and the mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 37% B to 51% B within 8 min; 254; 220 nm; rt: 7.27min) to give 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 231) (20mg, 15.81%). LCMS M/z (ESI), [ M + H]+＝460.3。1H-NMR(400MHz,DMSO-d6)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)。
Example 235/232.3-amino-N- ((6- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a) ]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002442
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 235/232)
Scheme 109
Figure BDA0002577091620002441
Step 1.16- [3- (dimethylamino) pyrrolidin-1-yl]Pyridine-2-carbonitrile.
To a mixture of 6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 equiv.) and N, N-dimethylpyrrolidin-3-amine (701.41 mg, 6.142mmol, 1.5 equiv.) in 2mL DMF was added potassium carbonate (1.14g, 8.190mmol, 2.00 equiv.). The mixture was stirred at 50 ℃ for 8 hours. After concentration to dryness, the residue was purified by silica gel column chromatography using DCM/CH3OH 10/1 gave 6- [3- (dimethylamino) pyrrolidin-1-yl as a yellow solid]Pyridine-2-carbonitrile (810mg, 80.0%). LCMS M/z (ESI), [ M + H]+＝217.1。
Step 2.1- [6- (aminomethyl) pyridin-2-yl]-N, N-dimethylpyrrolidin-3-amine.
At 1atm H2At room temperature, 6- [3- (dimethylamino) pyrrolidin-1-yl]Pyridine-2-carbonitrile (200mg, 0.925 mmol, 1 eq), Raney nickel (158.45mg, 1.849mmol, 2 eq) and NH4A mixture of OH (50mg) in methanol (16 mL) was hydrogenated for 3 hours. After filtration through celite, the filtrate was concentrated to dryness in vacuo and the residue was used directly in the next step. LCMS M/z (ESI), [ M + H]+＝221.1。
Step 3.3-amino-N- ([6- [3- (dimethylamino) pyrrolidin-1-yl) ]Pyridin-2-yl]Methyl) -6- [ 3-methyl Alkylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002452
Azol-2-yl) pyrazine-2-carboxamide (Compound 235/232)
To 1- [6- (aminomethyl) pyridin-2-yl group]-N, N-dimethylpyrrolidin-3-amine (185mg, 0.840mmol, 1 equiv.), 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002453
Oxazol-2-yl) pyrazine-2-carboxylic acid (423mg, 1.260 mmol, 1.50 equiv.) to a mixture of N, N-bis-methylformamide (5mL) was added DIEA (651.14mg, 5.038 mmol,6 equiv.), HOBt (226.92mg, 1.679mmol, 2 equiv.), and EDCI (321.94mg, 1.679mmol, 2 equiv.). The mixture was stirred at room temperature for 3 hours. After concentration to dryness, chiral preparative HPLC was performed with the following conditions (column: CHIRAL ART Cellulose-SB S-5um, 2X 25cm,5 μm; mobile phase A: Hex (8 mmol/LNH)3MeOH) -HPLC, mobile phase B: MeOH to EtOH 1: 1-HPLC; flow rate: 20 mL/min; gradient: 50B to 50B within 13 min; 220/254 nm; rT1：8.028min；RT2: 10.436min) to give 3-amino-N- ([6- [3- (dimethylamino) pyrrolidin-1-yl)]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002454
Azol-2-yl) pyrazine-2-carboxamide (Compound 235) (77mg, 17.0%), LCMS: M/z (ESI), [ M + H]+＝539.4。1H-NMR (300MHz, methanol-d) 4)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-
Figure BDA0002577091620002455
Azol-2-yl) pyrazine-2-carboxamide (Compound 232) (30mg, 6.63%) LCMS M/z (ESI), [ M + H]+＝539.3。1H-NMR (300 MHz, methanol-d)4)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 rac-3-amino-N- (2- (methyl (tetrahydrofuran-3-yl) amino) ethyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002456
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 233)
Scenario 110
Figure BDA0002577091620002451
Step 1. (tert-butyl 2- (methyl (tetrahydrofuran-3-yl) amino) ethyl) carbamate
N- (2-bromoethyl) carbamic acid tert-butyl ester (400mg, 1.785mmol, 1 eq), N-methoxyoxolane-3-amine (180.54mg, 1.785mmol, 1 eq) and K2CO3(740.06mg, 5.355mmol, 3.0 equiv.) of a mixture in DMF (30mL) was stirred at 65 ℃ for 16 h, the resulting mixture was diluted with water (30mL), the resulting mixture was extracted with EtOAc (3 × 30mL), the combined organic layers were washed with saturated brine (20mL), dried Na 2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gave N- [2- [ methyl (Oxetastan-3-yl) amino ] as a pale yellow oil]Ethyl radical]Tert-butyl carbamate (410mg, 94.0%). LCMS M/z (ESI), [ M + H]+＝245.1。1H-NMR(300mHz,DMSO-d6)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,2H),2.37-2.39(3H,m),2.50-2.53(1H,m),2.87-2.69(1H,m), 2.91-2.94(1H,m),3.01-3.05(1H,m),3.12-3.15(1H,m)
Step 2. N1-methyl-N1- (tetrahydrofuran-3-yl) ethane-1, 2-diamine
Reacting N- [2- [ methyl (oxolane-3-yl) amino group]Ethyl radical]A solution of tert-butyl carbamate (200mg, 0.819mmol, 1 eq.) and TFA (3mL) in DCM (6mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. With saturated NaHCO3The residue was neutralized to pH 7 (aq.) the aqueous layer was extracted with EtOAc (3 × 20mL) the resulting mixture was concentrated under reduced pressure which gave N- (2-aminoethyl) -N-methyloxacyclopentane-3-amine (105mg, 88.95%) as a pale yellow oil, LCMS: M/z (ESI), [ M + H ] M]+＝145.1。1H-NMR(300mHz,DMSO-d6) 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-methylimidazole) And [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002461
Azol-2-yl) pyrazine-2-carboxamides
Reacting 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002462
Oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.), N- (2-aminoethyl) -N-methyloxolan-3-amine (41.17mg, 0.285mmol, 1.2 equiv.), T 3A solution of P (227.06mg, 0.714mmol, 3.0 equiv.) and DIEA (92.23mg, 0.714mmol, 3.0 equiv.) in DMF (2mL) was stirred at room temperature for 2 hours, the resulting mixture was diluted with water (30mL) and extracted with EtOAc (3 × 30mL), the combined organic layers were washed with saturated brine (10mL), anhydrous Na2SO4The crude product was purified by preparative HPLC with the following conditions (column: Xbridge Prep C18 OBD column 19 × 150mm5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 20% B to 37% B within 7 min; 254/220 nm; Rt: 6.58min) to give 3-amino-N- [2- [ methyl (oxolane-3-yl) amino ] as a yellow solid]Ethyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002472
Oxazol-2-yl) pyrazine-2-carboxamide (compound 233) (12.2mg, 11.09%). LCMS M/z (ESI), [ M + H]+＝463.41H-NMR(300mHz,MeOD-d4)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.(3S) -3- [ (3-amino-6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002473
Azole- 2-yl) pyrazine-2-radical) carboxamido radical]-N, N-dimethylbutanamidePreparation of (Compound 234)
Scheme 111
Figure BDA0002577091620002471
Step 1.(S) -4- (dimethylamino) -4-oxobutan-2-ylcarbamic acid tert-butyl ester
To (3S) -3- [ [ (tert-butoxy) carbonyl ] at room temperature under an air atmosphere]Amino group]To a stirred mixture of butyric acid (500mg, 2.460mmol, 1 eq) and dimethylamine (221.83mg, 4.920mmol, 2 eq) in DCM was added HATU (1870.86mg, 4.920mmol, 2 eq) portionwise and DIEA (1.59g, 12.301mmol, 5 eq) added dropwise. The resulting mixture was stirred at room temperature under an air atmosphere overnight. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient 5% to 20% within 10 min; detector, UV 220 nm. This gives N- [ (2S) -1- (dimethylcarbamoyl) propan-2-yl as a pink solid]Tert-butyl carbamate (550mg, 64.07%). LCMS (ESI) M/z [ M + H ]]+＝231.1；1H-NMR(400MHz,CDCl3-d)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)。
(S) -3-amino-N, N-dimethylbutanamide
N- [ (2S) -1- (dimethylcarbamoyl) propan-2-yl was added to a 50mL round bottom flask at room temperature]T-butyl carbamate (200mg, 0.868mmol, 1 equiv.) and TFA (0.99g, 8.684mmol, 10 equiv.). The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) M/z [ M + H ]]+＝ 131.1；1H-NMR(300MHz,CDCl3-d)1.40(3H,d),2.70(2H,d),2.95(3H,s),3.01(3H,s), 3.74(1H,s),7.78(3H,s),11.00(2H,s)。
Step 3.(S) -3-amino-N- (4- (dimethylamino) -4-oxobutan-2-yl) -6- (3-methylimidazo [1, 2-a]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002482
Azol-2-yl) pyrazine-2-carboxamide (Compound 234)
To (3S) -3-amino-N, N-dimethylbutanamide (77.42mg, 0.595mmol, 2 equiv.) and 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature under an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002483
To a stirred solution/mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 equivalent) in DMF was added DIEA (768.59mg, 5.947mmol, 20.00 equivalents) and T dropwise3P (946.09mg, 2.973mmol, 10.00 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere overnight. The crude product (100mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B: MeOH- -HPLC; flow rate: 20 mL/min; gradient: 49% B to 59% B over 8 min; 254; 220 nm; Rt: 6.97min) to give (3S) -3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002484
Azole-2-yl) pyrazin-2-yl) carboxamides]-N, N-dimethylbutanamide (15mg, 11.15%). LCMS (ESI) [ M + H ]]+＝449.3；1H- NMR(400MHz,DMSO-d6)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 (3R) -3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002485
Azol-2-yl) pyrazin-2-yl) carboxamides]Preparation of (E) -N, N-dimethylbutanamide (Compound 236)
Schema 112
Figure BDA0002577091620002481
Step 1.N- [ (2R) -1- (dimethylcarbamoyl) propan-2-yl](iii) carbamic acid tert-butyl ester.
DIEA (1589.80mg, 12.301mmol, 5 equiv.), HATU (1870.86mg, 4.920mmol, 2 equiv.), dimethylamine hydrochloride (401.20mg, 4.920mmol, 2 equiv.), and (3R) -3- [ [ (tert-butoxy) carbonyl ] were added under an air atmosphere at room temperature]Amino group]A mixture of butyric acid (500mg, 2.460mmol, 1 eq) in DCM (15mL, 1 eq) was stirred overnight. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (0-20% H)2O/ACN) to obtain N- [ (2R) -1- (dimethylcarbamoyl) propan-2-yl group as a colorless oil]Tert-butyl carbamate (550mg, 1.35%). LCMS M/z (ESI), [ M + H]+＝231.0。1H NMR (300 MHz, chloroform-d) 1.27(3H, d),1.44(9H, s),2.47(1H, d),2.64(1H, d),2.95(3H, s),3.04(3H, s), 4.02(1H, d)
Step 2.(3R) -3-amino-N, N-dimethylbutanamide.
TFA (1.00mL, 13.463mmol, 15.50 equiv.) and N- [ (2R) -1- (dimethylcarbamoyl) propan-2-yl]A mixture of tert-butyl carbamate (200mg, 0.868mmol, 1 eq) in DCM (3mL) was stirred at room temperature under an air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure to give (3R) -3-amino-N, N-dimethylbutanamide (100mg, 88.45%) as a pink oil. 1H NMR (300MHz, chloroform-d) 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-
Figure BDA0002577091620002491
Oxazole-2- Radical) pyrazin-2-yl) carboxamido radical]-N, N-dimethylbutanamide (Compound 236)
DIEA (245.95mg, 1.903mmol, 8 equiv.), T were mixed under an air atmosphere at room temperature3P (454.12mg, 1.427mmol, 6 equiv), (3R) -3-amino-N, N-dimethylbutanamide (123.88mg, 0.952mmol, 4 equiv) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002492
A mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 eq) in DMF (3mL) was stirred overnight. The desired product can be detected by LCMS. The crude product (100mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B: MeOH- -HPLC; flow rate: 20 mL/min; gradient: 47% B to 59% B over 8 min; 254; 220 nm; Rt: 7.40min) to give (3R) -3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002493
Azol-2-yl) pyrazin-2-yl) carboxamides]-N, N-dimethylbutanamide (compound 236) (60mg, 55.12%). LCMS M/z (ESI), [ M + H ]+＝449.3。1H-NMR(300 MHz,DMSO-d6)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)。
Example 247-1/247-2.3-amino-N- ((1, 2-dimethylpyrrolidin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5- (C)
Figure BDA0002577091620002494
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 247-1/247-2)
Scheme 113
Figure BDA0002577091620002501
Step 1.2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002502
Azole-2-yl) Pyrazin-2-yl) carboxamido radicals]Methyl radical]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester
3-amino-6- [ 3-methylimidazo [1,2-a ] at 25 ℃ in a nitrogen atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002503
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (200mg, 0.595mmol, 1 eq) and tert-butyl 2- (aminomethyl) -2-methylpyrrolidine-1-carboxylate (254.89 mg, 1.189mmol, 2 eq) in DMF was added T-dropwise3P (946.09mg, 2.973mmol, 5 equiv.) and DIEA (307.44mg, 2.379mmol, 4 equiv.). The resulting mixture was stirred at 25 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (50mL) and CH2Cl2(3 × 50mL) combined organic layers were washed with brine (3 × 50mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 20:1) to give 2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a yellow solid ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002504
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]-tert-butyl 2-methylpyrrolidine-1-carboxylate (280mg, 88.40%). LCMS M/z (ESI), [ M + H]+＝533.3。1H-NMR(300MHz, MeOD-d4)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 radical]-5-(1,3-
Figure BDA0002577091620002505
Azol-2-yl) pyrazine-2-carboxamides
To 2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] at 25 ℃ under a nitrogen atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002506
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]To a stirred solution of tert-butyl (2-methylpyrrolidine-1-carboxylate (280mg) in DCM was added TFA (1.5 mL). The resulting mixture was stirred at 25 ℃ under a nitrogen atmosphere for 30 min. Concentrating under reduced pressureCondensing the obtained mixture to obtain 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ (2-methylpyrrolidin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620002507
Oxazol-2-yl) pyrazine-2-carboxamide (200mg, 87.96%). LCMS M/z (ESI), [ M + H]+＝433.2。
Step 3.2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002511
Azole-2-yl) Pyrazin-2-yl) carboxamido radicals]Methyl radical]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester
3-amino-6- [ 3-methylimidazo [1,2-a ] at 25 ℃ in a nitrogen atmosphere]Pyridin-6-yl]-N- [ (2-methylpyrrolidin-2-yl) methyl]-5-(1,3-
Figure BDA0002577091620002512
Azol-2-yl) pyrazine-2-carboxamide (200mg, 0.462mmol, 1 equiv.) and PFA (138.73 mg, 4.624mmol, 10 equiv.) to a stirred mixture of MeOH (8mL) was added NaBH dropwise 3CN (145.30 mg, 2.312mmol, 5 equiv.) and DIEA (239.07mg, 1.850mmol, 4 equiv.). The resulting mixture was stirred at 25 ℃ under a nitrogen atmosphere for 2 hours. The mixture was purified by preparative HPLC with the following conditions (column: Atlantis Prep T3 OBD column 19: 150mm 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 10% B to 20% B within 7 min; 254/220 nm; Rt: 6.08min) to give 3-amino-N- [ (1, 2-dimethylpyrrolidin-2-yl) methyl as a yellow solid]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002513
Oxazol-2-yl) pyrazine-2-carboxamide (100mg, 58.12%).
Step 4.2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002514
Azole-2-yl) Pyrazin-2-yl) carboxamido radicals]Methyl radical]-2-Methylpyrrolidine-1-carboxylic acid tert-butyl ester (Compound 247-1/247-2)
By chiral preparative HPLC with the following conditions (column: CHIRALPAK IG, 5 × 25cm, 5 μm; mobile phase a: Hex: DCM ═ 3:1(10mM NH)3-MEOH) -HPLC, mobile phase B: EtOH- -HPLC; flow rate: 20 mL/min; gradient: 40B to 40B within 10 min; 220/254 nm; RT 1: 6.193, RT 2: 7.693) to give 3-amino-N- [ (1, 2-dimethylpyrrolidin-2-yl) as a yellow solid ]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002515
Oxazol-2-yl) pyrazine-2-carboxamide (Compound 247-1) (30mg, 30.0%) and 3-amino-N- [ (1, 2-dimethylpyrrolidin-2-yl)]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002516
Oxazol-2-yl) pyrazine-2-carboxamide (compound 247-2) (30mg, 30.0%).
(Compound 247-1) LCMS M/z (ESI), [ M + H]+＝447.2。1H-NMR(300MHz,MeOD-d4)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) LCMS M/z (ESI), [ M + H]+＝447.4。1H-NMR(300MHz,MeOD-d4)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)
Scenario 114
Figure BDA0002577091620002521
Step 1.3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxamide
To NH at room temperature3(g) To a solution in MeOH (15mL) was added methyl 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxylate (1000mg, 3.337mmol, 1 eq) portionwise. The mixture was stirred at 50 ℃ for 5 hours under an air atmosphere. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxamide as a yellow solid (930mg, 97.90%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝285.2。1H-NMR(400MHz,DMSO-d6)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 chloride (5mL) was added 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxamide (900mg, 3.162mmol, 1 equiv) portionwise at room temperature. The resulting mixture was stirred at 90 ℃ for 2 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. By CH2Cl2The residue was dissolved (100mL) and basified with saturated NaHCO3 (aq) to pH 8. By CH2Cl2(2 × 100mL) the resulting mixture was extracted the combined organic layers were washed with water (2 × 30mL) and dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (6:1) to give 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carbonitrile as a yellow solid (550 mg, 65.24%). LCMS M/z (ESI), [ M + H]+＝267.0。1H NMR(400MHz,DMSO-d6)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]Pyrazine- 2-carbonitriles
To 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carbonitrile (400mg, 1.500 mmol, 1 equiv.) and [ 3-methylimidazo [1,2-a ] at 90 ℃ under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (395.99mg, 2.250mmol, 1.5 equiv.) in bis
Figure BDA0002577091620002531
Cs was added in portions to a stirred mixture in an alkane (50mL) 2CO3(977.56mg, 3.000mmol, 2 equiv.) and Pd (dppf) cl2(219.53mg, 0.300mmol, 0.2 equiv.). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2The residue was purified with MeOH 20:1) to give 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carbonitrile (400mg, 55.19%). LCMS M/z (ESI), [ M + H]+＝363.3。
Step 4.3- (aminomethyl) -6- (3, 4-difluorophenyl) -5- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-amines
To 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]Pyrazine-2-carbonitrile (400mg, 1.104mmol, 1 equiv) to a solution of raney nickel (189.16mg, 2.208mmol, 2.00 equiv.) was added in portions to MeOH (50 mL.) the mixture was stirred at room temperature for 2 h under a hydrogen atmosphere, the resulting mixture was filtered, the cake was washed with MeOH (2 × 50mL), the filtrate was concentrated in vacuo to give 3- (aminomethyl) -6- (3, 4-difluorophenyl) -5- [ 3-methylimidazo [1,2-a ] as a beige solid]Pyridin-6-yl]Pyrazin-2-amine (300mg, 74.17%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H ]+＝367.3。
Step 5.(2R) -N- [ [ 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridine-6- Base of]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 257)
To a stirred mixture of 3- (aminomethyl) -5-chloro-6- (3, 4-difluorophenyl) pyrazin-2-amine (100mg, 0.369 mmol, 1 equiv.) and (2R) -1-methylpyrrolidine-2-carboxylic acid (95.44mg, 0.739mmol, 2 equiv.) in DMF (10 mL) was added HATU (210.72mg, 0.554mmol, 1.5 equiv.) and DIEA (191.00 mg, 1.478mmol, 4 equiv.) portionwise at room temperature under an air atmosphere. The resulting mixture was allowed to stand at room temperatureStirred under an air atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A: 5% ammonia in water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 50% B in 7 min; 254; 220 nm; Rt: 5.95min) to give (2R) -N- [ [ 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a white solid]Pyridin-6-yl]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (41mg, 23.17%) (Compound 257). LCMS M/z (ESI), [ M + H]+＝478.3。1H-NMR(400 MHz,DMSO-d6)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
Figure BDA0002577091620002541
Step 1.3-amino-6-chloro-5-phenylpyrazine-2-carboxylic acid methyl ester
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (600mg, 2.702mmol, 1 equiv.) and phenylboronic acid (336.09mg, 2.756mmol, 1.02 equiv.) in dioxane at room temperature under a nitrogen atmosphere
Figure BDA0002577091620002542
To a stirred mixture in an alkane (20mL) was added K in portions3PO4(1147.23mg, 5.405mmol, 2 equiv.) and Pd (dppf) Cl2(395.46mg, 0.540mmol, 0.2 equiv.). The resulting mixture was stirred at 70 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give methyl 3-amino-6-chloro-5-phenylpyrazine-2-carboxylate (400mg, 56.14%) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝264.3。1H NMR (400MHz,DMSO-d6)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-carboxylic acid ester
To methyl 3-amino-6-chloro-5-phenylpyrazine-2-carboxylate (150mg, 0.569mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (200.22mg, 1.138mmol, 2 equiv.) in bis
Figure BDA0002577091620002543
To a stirred mixture in an alkane (10mL) CS was added portionwise2CO3(556.05mg, 1.707mmol, 3 equiv.) and Pd (dppf) Cl2(83.25mg, 0.114mmol, 0.2 equiv.). The resulting mixture was stirred at 80 ℃ for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH) 2Cl2MeOH 20:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-phenylpyrazine-2-carboxylic acid methyl ester (130mg, 63.59%). LCMS M/z (ESI), [ M + H]+＝360.3。1H-NMR(400MHz,DMSO-d6)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 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a solution of methyl (130mg, 0.417mmol, 1 eq.) 5-phenylpyrazine-2-carboxylate in THF (15mL) and methanol (5mL) was added LiOH (19.99mg, 0.835mmol, 2.00 eq). The mixture was stirred at 50 ℃ under an air atmosphere for 2.5 hours. The mixture was acidified to pH 6 with HCl (aq). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-phenylpyrazine-2-carboxylic acid (100mg, 80.05%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝346.2。
Step 4.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridine compound-6-yl]-N- [ [ (2R) -1-methylpyrrolidine- 2-radical]Methyl radical]-5-phenylpyrazine-2-carboxamide (Compound 259)
3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere ]Pyridin-6-yl]-5-phenylpyrazine-2-carboxylic acid (100mg, 0.290mmol, 1 equiv.) and 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (66.13mg, 0.579mmol, 2 equiv.) in a stirred mixture of DMF (5mL) was added DIEA (112.27mg, 0.869mmol, 3 equiv.) and T in portions3P (368.52mg, 1.158mmol, 4 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 2.5 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 38% B to 50% B within 8 min; 254; 220 nm; Rt: 7.65min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]-5-phenylpyrazine-2-carboxamide (compound 259) (33mg, 25.81%). LCMS M/z (ESI), [ M + H]+＝442.3。1H NMR(400MHz,DMSO-d6)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 261.3-amino-N- ((6- (3- ((dimethylamino) methyl) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002552
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 261)
Scheme 116
Figure BDA0002577091620002551
Step 1.2-cyano 6- (3- ((dimethylamino) methyl) azetidin-1-yl) pyridine
In a 50-mL round-bottom flask was placed 6-bromopyridine-2-carbonitrile (423.10 m)g, 2.312mmol, 1.10 equiv.), DMF (4mL, 51.687mmol, 24.59 equiv.), K2CO3(871.41mg, 6.305mmol, 3 equiv.) and [ (azetidin-3-yl) methyl]Dimethylamine (240mg, 2.102mmol, 1 eq.) the resulting solution was stirred at 50 ℃ for 16 h, the resulting solution was extracted with 3 × 10mL ethyl acetate, the organic layers were combined and concentrated, the residue was applied to a silica gel column with dichloromethane/methanol (8:1), which yielded 190mg (41.80%) of 6- [3- [ (dimethylamino) methyl ] methyl as a light yellow solid]Azetidin-1-yl]Pyridine-2-carbonitrile. LCMS M/z (ESI), [ M + H]+＝217.1。1H-NMR(400 MHz,DMSO-d6)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-dimethylmethylamine
A50-mL round bottom flask was charged with MeOH (5mL, 0.094mmol, 2.03 equiv.), Raney nickel (0.75mg, 0.009mmol, 0.01 equiv.), 6- [3- [ (dimethylamino) methyl group]Azetidin-1-yl]Pyridine-2-carbonitrile (190mg, 0.878 mmol, 1 eq.), NH4OH (1mL, 25.681mmol, 29.23 equiv.). The resulting solution was stirred at room temperature for 1 hour. This gave 40mg (20.67%) of 1- (6- [3- [ (dimethylamino) methyl ] methyl as a tan oil ]Azetidin-1-yl]Pyridin-2-yl) methylamine. LCMS M/z (ESI), [ M + H]+＝220.95。1H-NMR(400MHz,DMSO-d6)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) methyl ester]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002561
Azol-2-yl) pyrazine-2-carboxamide (Compound 261)
Placing 3-amino-6- [ 3-methylimidazo [1,2-a ] in a 25-mL round-bottom flask]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002562
Oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.), DMF (0.041mmol, 0.17 equiv.), DIEA (307.44 mg, 2.379mmol, 10 equiv.), T3P (454.12mg, 1.427mmol, 6 equivalents), 1- (6- [3- [ (dimethylamino) methyl group]Azetidin-1-yl]Pyridin-2-yl) methylamine (104.82mg, 0.476mmol, 2 equiv.) the resulting solution is stirred at room temperature for 16 h, the resulting solution is diluted with water (15mL), extracted with 3 × 10mL of dichloromethane, and the organic layer is combined and concentrated the crude product is purified by preparative HPLC with conditions (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 40% B over 7 min; 254; 220 nm; Rt: 5.82 min.) and the product is obtained, this gives 23.6mg (18.42%) of 3-amino-N- [ (6- [3- [ (dimethylamino) methyl ] amino) methyl ] amine as a yellow solid ]Azetidin-1-yl]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002563
Oxazol-2-yl) pyrazine-2-carboxamide (compound 261). LCMS M/z (ESI), [ M + H]+＝539.5。1H-NMR (400MHz, methanol-d)4)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-imidazole- [1,2-a ] pyridin-6-yl ] pyrazin-2-yl ] methyl ] oxolane-2-carboxamide (Compound 268)
Scheme 117
Figure BDA0002577091620002571
Step 1.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide
To a 50mL sealed tube at room temperature was added a solution of methyl 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxylate (2.0g, 7.10mmol, 1 eq) and NH3(g) in MeOH (30mL, 7.0mmol/L), heated at 50 deg.C for 5 hours, addedTo concentrate, 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide was obtained as a light yellow solid (1.5g, 79%). LCMS M/z (ESI), [ M + H]+＝267.0。
Step 2.3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile
At 0 ℃ to POCl3To a stirred solution (20mL) was added 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carboxamide (5.0g, 18.750mmol, 1 eq) in portions, stirred at 90 ℃ for 3 hours, and concentrated. The residue was dissolved in DCM (300mL) and NaHCO was added3(aq.) to PH 8.0, extraction with DCM (3 × 50mL), drying of the combined organic layers and concentration gave 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (3.5g, 75%) as a 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]Pyrazine-2-carbonitriles
To 3-amino-6-chloro-5- (4-fluorophenyl) pyrazine-2-carbonitrile (500mg, 2.01mmol, 1 eq.) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (530.81mg, 3.02mmol, 1.5 equiv.) and Pd (dppf) Cl2(147mg, 0.20mmol, 0.1 equiv.) in II
Figure BDA0002577091620002572
To a stirred mixture in an alkane (15mL) was added K in portions3PO4(854 mg, 4.02mmol, 2.0 equiv.) of H2O (2.5mL) solution, the resulting mixture was stirred at 90 ℃ for 2 h, concentrated and purified by preparative TLC (DCM/MeOH ═ 40/1) to give 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a light yellow solid]Pyridin-6-yl]Pyrazine-2-carbonitrile (300mg, 43%). LCMS M/z (ESI), [ M + H]+＝345.2。
Step 4.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]-1-methylpyrrolidine-2-carboxamide
3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature under a hydrogen atmosphere]Pyridin-6-yl]Pyrazine-2-carbonitrile (500mg,1.45mmol, 1 equiv.) and Raney Nickel (62mg, 0.73mmol, 0.5 equiv.) in ethanol (10mL) was added NH 3.H2O (1.0mL), stirred at room temperature for 2 h, the resulting mixture was filtered, the filter cake was washed with MeOH (3 × 30mL), and the filtrate was concentrated under reduced pressure to give 3- (aminomethyl) -6- (4-fluorophenyl) -5- [ 3-methyl-imidazo [1,2-a ] as a light brown solid]Pyridin-6-yl]Pyrazin-2-amine (450mg, 89%).1H-NMR(300 MHz,DMSO-d6)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]Pyridine (II) Oxazin-2-yl]Methyl radical]Oxetane-2-carboxamide (Compound 268)
A solution of (2S) -oxolane-2-carboxylic acid (66.66 mg, 0.57mmol, 2.0 equiv.) in DMF (2.0mL) was treated with HATU (218mg, 0.57mmol, 2.0 equiv.) at room temperature for 20min, followed by dropwise addition of 3- (aminomethyl) -6- (4-fluorophenyl) -5- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]Pyrazin-2-amine (100mg, 0.29mmol, 1 equiv.), DIEA (111mg, 0.86mmol, 3.0 equiv.), stirred for 2 hours, quenched by water (20mL), extracted with DCM (3 × 20mL), dried and concentrated, followed by purification by preparative TLC to give (2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a white solid]Pyridin-6-yl]Pyrazin-2-yl radicals ]Methyl radical]Oxopentane-2-carboxamide (Compound 268) (45.2mg, 35%). LCMS M/z (ESI), [ M + H]+＝447.3。1H-NMR(300MHz,DMSO-d6)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(1H,t)。
EXAMPLE 272.preparation of 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -N- [ [ (2R) -1-methylpyrrolidin-2-yl ] methyl ] pyrazine-2-carboxamide (Compound 272)
Scenario 118
Figure BDA0002577091620002591
Step 1.3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxylic acid methyl ester
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (2000mg, 9.008mmol, 1 equiv.) and (3, 4-difluorophenyl) boronic acid (1450.87mg, 9.188mmol, 1.02 equiv.) in a nitrogen atmosphere at room temperature
Figure BDA0002577091620002592
To a stirred mixture in an alkane (100mL) was added K in portions3PO4(3824.10mg, 18.016mmol, 2 eq.) and Pd (dppf) Cl2(1318.20mg, 1.802mmol, 0.2 equiv.). The resulting mixture was stirred at 70 ℃ for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give methyl 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxylate (1500mg, 55.57%) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝300.2。1H-NMR(400MHz,DMSO-d6)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]Pyrazine- 2-formic acid ester
To methyl 3-amino-6-chloro-5- (3, 4-difluorophenyl) pyrazine-2-carboxylate (400mg, 1.335mmol, 1 equiv.) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere ]Pyridin-6-yl]Boric acid (469.81mg, 2.670mmol, 2 equiv.) in dioxane
Figure BDA0002577091620002593
To a stirred mixture in an alkane (40mL) CS was added portionwise2CO3(869.84mg, 2.670mmol, 2 equiv.) and Pd (dppf) Cl2(195.34mg, 0.267mmol, 0.2 equiv.). The resulting mixture was stirred at 80 ℃ under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 20:1) to give 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carboxylic acid methyl ester (300mg, 56.84%). LCMS M/z (ESI), [ M + H]+＝396.3。
Step 3.3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazine- 2-carboxylic acid
To 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a solution of pyrazine-2-carboxylic acid methyl ester (200mg, 0.506mmol, 1 eq) in THF (20mL) and methanol (5mL) was added LiOH (48.46mg, 2.023mmol, 4 eq). The mixture was stirred at room temperature under an air atmosphere for 3 hours and acidified to pH 6 with HCl (aqueous solution). The resulting solid was collected by filtration and dried in vacuo to give 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]Pyrazine-2-carboxylic acid (150mg, 77.76%). The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝382.2。
Step 4.3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamides (Compound 272)
3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature under an air atmosphere]Pyridin-6-yl]Pyrazine-2-carboxylic acid (150mg, 0.393mmol, 1 eq.) and 1- [ (2R) -1-methylpyrrolidin-2-yl]Methylamine (89.83mg, 0.787mmol, 2 equiv.) to a stirred mixture of DMF (15mL) was added DIEA (152.51mg, 1.180mmol, 3 equiv.) and T in portions3P (500.62mg, 1.573mmol, 4 equiv.) the resulting mixture is stirred at room temperature under an air atmosphere for 3 hours the resulting mixture is concentrated under reduced pressure and the crude product is purified by preparative HPLC with the following conditions (column: XBridgePrep OBD C18 column 30 × 150mm 5 μm; mobile phase A: 5% aqueous ammonia, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 36% B to 49% B over 7 min; 254; 220 nm; Rt: 6.83min) to give 3-amino-5- (3, 4-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-N- [ [ (2R) -1-methylpyrrolidin-2-yl]Methyl radical]Pyrazine-2-carboxamide (compound 272) (23mg, 12.25%). LCMS M/z (ESI), [ M + H]+＝478.3。1H-NMR(400MHz,DMSO-d6)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 273.3-amino-N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002602
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 273)
Scheme 119
Figure BDA0002577091620002601
Step 1.N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl]Methyl radical](iii) carbamic acid tert-butyl ester.
TEA (854.86mg, 8.448mmol, 5 equiv.), dimethylamine hydrochloride (206.66 mg, 2.534mmol, 1.50 equiv.), 4-nitrophenyl chloroformate (408.67mg, 2.028mmol, 1.20 equiv.) and N- [ [ (3R) -pyrrolidin-3-yl ] were reacted at 70 ℃ under an air atmosphere]Methyl radical]A mixture of tert-butyl carbamate hydrochloride (400mg, 1.690mmol, 1 equiv.) in ACN (20mL) was stirred overnight, the resulting mixture was diluted with water (50mL) and extracted with EtOAc (3 × 50mL), the combined organic layers were washed with brine (3 × 50mL), dried over Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl ] as a yellow oil ]Methyl radical]Tert-butyl carbamate (370mg, 80.70%). LCMS M/z (ESI), [ M + H]+＝272.1。1H-NMR (300MHz, chloroform-d) 1.47(9H, s),1.56-1.70(1H, m), 1.91-2.04(1H, m),2.27-2.43(1H, m),2.86(6H, s),3.16(3H, d),3.46(3H, q).
Step 2.(3S) -3- (aminomethyl) -N, N-dimethylpyrrolidine-1-carboxamide.
TFA (2mL, 26.926mmol, 42.98 equiv.) and N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl ] were added under an air atmosphere at room temperature]Methyl radical]A mixture of tert-butyl carbamate (170mg, 0.626mmol, 1 eq) in DCM (5 mL) was stirred 1And (4) hours. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give (3S) -3- (aminomethyl) -N, N-dimethylpyrrolidine-1-carboxamide as a colorless oil (100mg, 93.21%). LCMS m/z1H-NMR (300MHz, chloroform-d) 1.71(1H, s),2.14(1H, s),2.59(1H, s),2.90(6H, s),3.00 (1H, s),3.18(1H, s),3.36(1H, s),3.50(3H, q)
Step 3.3-amino-N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl]Methyl radical]-6- [ 3-methyl Imidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002611
Azol-2-yl) pyrazine-2-carboxamide (Compound 273)
DIEA (184.46mg, 1.427mmol, 6 equiv.) and T were combined at room temperature under an air atmosphere3P (227.06mg, 0.714mmol, 3 equiv.), (3S) -3- (aminomethyl) -N, N-dimethylpyrrolidine-1-carboxamide (81.47mg, 0.476mmol, 2 equiv.) and 3-amino-6- [ 3-methylimidazo [1,2-a ] ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002612
A mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 eq) in DMF (3mL) was stirred overnight. With water (30mL) and saturated NaHCO3The resulting mixture was diluted (30mL) with CH2Cl2(3 × 40mL) extraction over anhydrous Na2SO4The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2The residue was purified with MeOH 12:1) to give the crude product. The crude product (100mg) was purified by preparative HPLC with the following conditions (column: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A: mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 35% B within 7 min; 254; 220 nm; Rt: 6.93min) to give 3-amino-N- [ [ (3S) -1- (dimethylcarbamoyl) pyrrolidin-3-yl as a yellow solid]Methyl radical]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002613
Azol-2-yl) pyrazine-2-carboxamides273)(20mg，17.00％)。LCMS:m/z(ESI),[M+H]+＝490.4。1H NMR(300MHz,DMSO-d6)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 276.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [6- (morpholin-4-yl) pyridin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002622
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 276)
Scheme 120
Figure BDA0002577091620002621
Step 1.6- (Morpholin-4-yl) pyridine-2-carbonitrile
6-Fluoropyridine-2-carbonitrile (1g, 8.190mmol, 1 equiv.), morpholine (1.43g, 0.016mmol, 2 equiv.) and K were added to a 40mL round bottom flask at room temperature 2CO3(2.26g, 0.016mmol, 2 equiv.) in DMF (15 mL.) the resulting mixture is stirred at 80 ℃ for 6H, the reaction is quenched with water at room temperature, the precipitated solid is collected by filtration and washed with water (1 × 100mL), dried in vacuo to give 6- (morpholin-4-yl) pyridine-2-carbonitrile (1.5g, 96.79%) as a white solid, LCMS: M/z (ESI), [ M + H ] -% ]]+＝190.3。1H-NMR(300MHz,DMSO-d6)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]Methylamine
To 6- (morpholin-4-yl) pyridine-2-carbonitrile (200mg, 1.057mmol, 1 eq) in MeOH (15mL) and NH at room temperature3.H2Raney nickel (271.67mg, 3.171mmol, 3 equiv.) is added portionwise to a solution in O (1mL), the resulting mixture is stirred at room temperature under a hydrogen atmosphere for 2 hours, the resulting mixture is filtered, the filter cake is washed with MeOH (3 × 10mL), the filtrate is concentrated under reduced pressure to give 1- [6- (morpholin-4-yl) pyridin-2-yl as a purple oil]Methylamine (150mg, 7)3.44%) which was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝194.3。
Step 3.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [6- (morpholin-4-yl) pyridine- 2-radical]Methyl radical]-5-(1,3-
Figure BDA0002577091620002623
Azol-2-yl) pyrazine-2-carboxamide (Compound 276)
To 1- [6- (morpholin-4-yl) pyridin-2-yl at room temperature]Methylamine (172.39mg, 0.892mmol, 2 equiv.) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002632
Azol-2-yl) pyrazine-2-carboxylic acid (150mg, 0.446mmol, 1 equiv.) in DMF (15mL) T was added dropwise3P (283.83mg, 0.892mmol, 2 equiv.) and DIEA (115.29mg, 0.892mmol, 2 equiv.). The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (10mMOL/L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 31% B to 50% B within 8 min; 220/254 nm; Rt: 8.15min) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [6- (morpholin-4-yl) pyridin-2-yl]Methyl radical]-5-(1,3-
Figure BDA0002577091620002633
Oxazol-2-yl) pyrazine-2-carboxamide (compound 276) (60mg, 26.30%). LCMS M/z (ESI), [ M + H]+＝512.4。1H NMR:(300MHz,DMSO-d6)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
Figure BDA0002577091620002631
Step 1.3 preparation of amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxamide
At room temperature to 30% NH3(g) To a stirred solution in MeOH (20mL) was added 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylic acid methyl ester (900mg) portionwise. The resulting mixture was stirred at 50 ℃ for 4 hours. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxamide (600mg) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝267.0。1H NMR (400MHz, chloroform-d) 7.21(1H, m),7.42-7.58(2H, m),7.62(1H, m).
Step 2.3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carbonitrile
To a stirred solution of phosphoryl chloride (2mL) was added 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxamide (30mg) portionwise at room temperature. The resulting mixture was stirred at 90 ℃ for 3 hours. The resulting mixture was concentrated under reduced pressure and diluted with DCM (20 mL). Saturated NaHCO at room temperature3The reaction was quenched (aqueous solution). By CH2Cl2the resulting mixture was extracted (2 × 30mL) over anhydrous Na2SO4The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2EtOAc 5:1) to purify the residue to give 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carbonitrile as a yellow solid (400 mg). LCMS M/z (ESI), [ M + H ]+＝249.0。1H-NMR (300MHz, chloroform-d) 5.32(2H, d),7.21(1H, m),7.42-7.56(2H, m),7.61(1H, m).
Step 3.3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1,2-a ]]Pyridin-6-yl) pyrazin-2-yl Nitrile
To 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carbonitrile (350mg, 1.408mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (371.56mg, 2.111mmol, 1.50 equiv.) in bis
Figure BDA0002577091620002641
Alkane (20mL) and H2To a stirred mixture in O (2mL) was added Cs portion by portion2CO3(1375.87mg, 4.223mmol, 3 equiv.) and Pd (dppf) Cl2(205.99mg, 0.282mmol, 0.2 equiv.). The resulting mixture was stirred at 90 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH2Cl2(1 × 10mL) the filter cake was washed, the filtrate was concentrated under reduced pressure, and the filtrate was purified by preparative TLC (CH)2Cl2MeOH 40:1) to give 3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carbonitrile (300mg, 61.89%). LCMS M/z (ESI), [ M + H]+＝345.2。
Step 4.3- (aminomethyl) -6- (3-fluorophenyl) -5- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) pyrazine- 2-amines
3-amino-5- (3-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere ]Pyridin-6-yl]Pyrazine-2-carbonitrile (20mg, 0.058mmol, 1 eq.) and NH3.H2to a stirred solution of O (4.07mg, 0.116mmol, 2.00 equiv.) in EtOH (2mL) was added Raney nickel (9.95mg, 0.116mmol, 2.00 equiv.) to the resulting mixture in portions, the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours, the resulting mixture was filtered, the filter cake was washed with EtOH (1 × 10mL), the filtrate was concentrated under reduced pressure to give 3- (aminomethyl) -6- (3-fluorophenyl) -5- [ 3-methylimidazo [1,2-a ] as a tan solid]Pyridin-6-yl]Pyrazin-2-amine (180mg, 71.17%). LCMS M/z (ESI), [ M + H]+＝349.3。
Step 5.(R) -N- ((3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) pyridine Oxazin-2-yl) methyl) -1-methylpyrrolidine-2-carboxamide (Compound 278)
To a stirred mixture of (2R) -1-methylpyrrolidine-2-carboxylic acid (36.70mg, 0.284mmol, 1.10 equiv.) in DMF (10 mL) was added HATU (196.45mg, 0.517mmol, 2 equiv.) and DIEA (133.55mg, 1.033mmol, 4 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 10 min. To this stirred solution was added 3- (aminomethyl) -6- (3-fluorophenyl) -5- [ 3-methylimi dine in portions at room temperatureAzolo [1,2-a ] s ]Pyridin-6-yl]pyrazin-2-amine (90mg, 0.258mmol, 1 eq.) the resulting mixture is stirred at room temperature for 3 hours the resulting mixture is concentrated under reduced pressure by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase a (5% NH)3Water: and the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 43% B within 7 min; 254; 220 nm; rt: 6.48min) to give (R) -N- ((3-amino-5- (3-fluorophenyl) -6- (3-methylimidazo [1, 2-a) as a white solid]Pyridin-6-yl) pyrazin-2-yl) methyl) -1-methylpyrrolidine-2-carboxamide (compound 278) (26mg, 21.90%). LCMS M/z (ESI), [ M + H]+＝460.3。1H NMR(400MHz, DMSO-d6)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)。
Example 279/280.3-amino-N- ((3-methoxytetrahydrofuran-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002652
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 279/280)
Scenario 122
Figure BDA0002577091620002651
Step 1.3-Methoxyfuran-2-carbaldehyde oxime
A mixture of 3-methoxyfuran-2-carbaldehyde (252mg, 1.998mmol, 1 eq.) and hydroxylamine hydrochloride (210mg, 3.022mmol, 1.51 eq.) in pyridine (4mL) was stirred at room temperature for 18 h. After concentration to dryness, the residue was purified by column (PE/EA ═ 2/1) to give N- [ (3-methoxyfuran-2-yl) methylene group as a white solid ]Hydroxylamine (200mg, 70.9%). LCMS M/z (ESI), [ M + H]+＝142.2。
Step 2. (3-methoxytetrahydrofuran-2-yl) methylamine
Reacting N- [ (3-methylfuran-2-yl) methylene]Hydroxylamine (460mg, 3.2)6mmol, 1 equiv.) and Raney nickel (300mg, 3.502mmol, 1.07 equiv.) in ethanol (70mL) at 1atm H2Hydrogenation was carried out at room temperature for 1 hour. After filtration through celite, the filtrate was concentrated to dryness in vacuo and the residue was used directly in the next step. LCMS M/z (ESI), [ M + H]+＝132.2。
Step 3.3-amino-N- ((3-methoxytetrahydrofuran-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)] Pyridin-6-yl) -5-, (
Figure BDA0002577091620002662
Azol-2-yl) pyrazine-2-carboxamides
To 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002663
To a mixture of oxazol-2-yl) -pyrazine-2-carboxylic acid (313mg, 0.931mmol, 1 equiv.) and 1- (3-methoxyfuran-2-yl) methylamine (366mg, 2.790mmol, 3.00 equiv.) in 5mL DMF was added DIEA (1.62mL, 9.300mmol, 9.99 equiv.) and 50 wt% T3A solution of P in ethyl acetate (1.77g, 2.793mmol, 2.99 equivalents) the mixture was stirred at room temperature for 3 hours, the mixture was purified by preparative HPLC (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH) 3H2O), mobile phase B ACN, flow rate 60mL/min, gradient 23% B to 33% B over 7min 254, 220nm, Rt 6.45min and chiral separation (column: CHIRALPAK IG, 20 × 250mM, 5 μm; mobile phase A Hex DCM ═ 3:1(10mM NH)3MeOH) -HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL/min; gradient: 30B to 30B within 50 min; 254/220 nm; RT 1: 15.377, respectively; RT 2: 24.388) to give 3-amino-N- ((3-methoxytetrahydrofuran-2-yl) methyl) -6- (3-methylimidazo [1, 2-a) as a yellow solid]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002664
Oxazol-2-yl) pyrazine-2-carboxamide (Compound 279) (15mg, 3.5%) and 3-amino-N- ((3-methoxytetrahydrofuran-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl)-5-(
Figure BDA0002577091620002665
Oxazol-2-yl) pyrazine-2-carboxamide (compound 280) (15mg, 3.5%). (Compound 279) LCMS M/z (ESI), [ M + H]+＝450.2。1H-NMR(300 MHz,DMSO-d6)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。1H-NMR(300MHz,DMSO-d6) 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 281.3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002666
Azol-2-yl) pyrazin-2-yl) methylamide]Preparation of (E) -N, N,2, 2-tetramethylpropionamide (Compound 281)
Scheme 123
Figure BDA0002577091620002661
Step 1.2- (5-bromo-2-oxo-1, 2-dihydropyridin-1-yl) propionitrile
To the 3- [ [ (tert-butoxy) carbonyl group at 0 deg.C]Amino group]to a stirred mixture of-2, 2-dimethylpropionic acid (250mg, 1.151mmol, 1 equiv.), HATU (525.02mg, 1.381mmol, 1.2 equiv.), and DIEA (743.58mg, 5.753mmol, 5 equiv.) in DMF (5mL) was added dropwise a solution of dimethylamine (1.15mL, 2.301mmol, 2 equiv.), followed by stirring at 0 ℃ for 2 hours, the resulting mixture was diluted with EtOAc (30mL), the combined organic layers were washed with water (3 × 10mL), over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give N- [2- (dimethylamino) amine as a yellow solidFormyl) -2, 2-dimethylethyl]Tert-butyl carbamate (200mg, 71.1%). LCMS M/z (ESI), [ M + H]+＝245.4。
Step 2.3-amino-N, N,2, 2-tetramethylpropionamide
N- [2- (dimethylcarbamoyl) -2, 2-dimethylethyl group was added to a 6mL vial at room temperature]Tert-butyl carbamate (190mg, 0.778mmol, 1 eq.), and hydrochloric acid in bis
Figure BDA0002577091620002671
Alkane (4M, 5mL) and bis
Figure BDA0002577091620002672
Solution in alkane (3 mL). The mixture was then stirred at room temperature for 1.5 hours. And the reaction mixture was concentrated to give 3-amino-N, 2, 2-tetramethylpropionamide (110mg, 98.0%) as a yellow solid. LCMS M/z (ESI), [ M + H ]+＝145.4。
Step 3.3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002673
Azole-2-yl) Pyrazin-2-yl) carboxamido radicals]-N, N,2, 2-tetramethylpropionamide
3-amino-N, N,2, 2-tetramethylpropionamide (110mg, 0.72mmol, 2 equiv.) and 3-amino-6- [ 3-methylimidazo [1,2-a ] are added at room temperature in a 6mL vial]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002674
oxazol-2-yl) pyrazine-2-carboxylic acid (120mg, 0.36mmol, 1 equiv.), HATU (164mg, 0.432mmol, 1.2 equiv.), DIEA (140mg, 1.08mmol, 3 equiv.), and DMF (1.5 mL.) the mixture was then stirred at room temperature for 2 h, the resulting mixture was diluted with EtOAc (20mL), the residue was washed with brine (3 × 10mL), anhydrous Na2SO4drying, after filtration, the filtrate was concentrated under reduced pressure, by preparative HPLC with the following conditions (column: × Bridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 25% B to 40% B within 7 min; 254/220 nm; t is tR: 5.77min) to give 3- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002675
Azol-2-yl) pyrazin-2-yl) carboxamides ]-N, 2, 2-tetramethylpropionamide (10mg, 6.0%). LCMS M/z (ESI), [ M + H]+＝463.3。1H-NMR(400MHz,DMSO-d6) 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 284.3-amino-N- [ (6- [ 6-methyl-2, 6-diazaspiro [3.3 ]]Heptane-2-yl radical]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002682
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 284)
Scenario 124
Figure BDA0002577091620002681
Step 1.6- (6-cyanopyridin-2-yl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester
To 6-fluoropyridine-2-carbonitrile (1g, 8.190mmol, 1 equiv.) and 2, 6-diazaspiro [3.3 ] at room temperature]To a mixture of tert-butyl heptane-2-carboxylate (3.25g, 16.380mmol, 2 equiv.) in DMF (25mL) was added K2CO3(2.26g, 16.380mmol, 2 equiv.) in portions. The resulting mixture was stirred at 50 ℃ for 3 hours under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (2:1) to give 6- (6-cyanopyridin-2-yl) -2, 6-diazaspiro [3.3 ] as a white solid]Tert-butyl heptane-2-carboxylate (1.2g, 48.78%). LCMS M/z (ESI), [ M + H]+＝301.2。1H-NMR:(300MHz,DMSO-d6)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 ]]Heptane-2-yl radical]Pyridin-2-yl) methylamines
To 6- (6-cyanopyridin-2-yl) -2, 6-diazaspiro [3.3 ] at 0 ℃ under an air atmosphere]To a solution of tert-butyl heptane-2-carboxylate (300mg, 0.999mmol, 1 eq) in THF (15mL) was added LiAlH in portions 4(189.54mg, 4.994mmol, 5 equiv.) the mixture was stirred at room temperature for 1 h the resulting mixture was stirred at 70 ℃ under an air atmosphere for 3 h, the reaction was quenched with water/ice at room temperature and extracted with EtOAc (3 × 50mL) over anhydrous Na2SO4The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure to give 1- (6- [ 6-methyl-2, 6-diazaspiro [3.3 ] as a yellow oil]Heptane-2-yl radical]Pyridin-2-yl) methylamine (100mg, 45.86%).1H-NMR:(300MHz,DMSO-d6)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 ]]Heptane-2-yl radical]Pyridin-2-yl) methyl Base of]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002683
Azol-2-yl) pyrazine-2-carboxamides(Compound 284)
To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002684
Oxazol-2-yl) pyrazine-2-carboxylic acid (90 mg, 0.268mmol, 1 eq) and 1- (6- [ 6-methyl-2, 6-diazaspiro [3.3 ]]Heptane-2-yl radical]Pyridin-2-yl) methylamine (116.84 mg, 0.535mmol, 2 equiv.) to a solution in DMF (10mL) was added T3P (170.30mg, 0.535mmol, 2 equiv.) and DIEA (69.17mg, 0.535mmol, 2 equiv.) dropwise. The resulting mixture was stirred at room temperature under an air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A: water (0.05% NH) 3H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 29% B to38% B within 8 min; 254; 220 nm; rt: 6.95min) to give 3-amino-N- [ (6- [ 6-methyl-2, 6-diazaspiro [3.3 ] as a yellow solid]Heptane-2-yl radical]Pyridin-2-yl) methyl]-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002692
Oxazol-2-yl) pyrazine-2-carboxamide (compound 284) (30mg, 20.89%). LCMS M/z (ESI), [ M + H]+＝537.4。1H NMR:(300MHz,DMSO-d6)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 285.3-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-
Figure BDA0002577091620002693
Azol-2-yl) pyrazine-2-carboxamide (Compound 285)
Scheme 125
Figure BDA0002577091620002691
step 1
step 2
step 3
Raney Ni Raney nickel
50℃ 50℃
Step 1.6- [ (3R) -3, 4-dimethylpiperazin-1-yl]Pyridine-2-carbonitriles
(2R) -1, 2-dimethylpiperazine (607.9mg, 5.32mmol, 1.3 equiv.), 6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 equiv.), K were added to a 40mL sealed tube at room temperature2CO3(1131.89mg, 8.190mmol, 2 equiv.) and DMF (10 mL.) the resulting mixture was stirred at 50 ℃ for 3 h, the reaction was quenched by the addition of saturated NaCl (aq) (250mL) at room temperature, the resulting mixture was extracted with EtOAc (2 × 125mL), the combined organic phases were washed with saturated NaCl (aq) (250mL) Layer of anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 30:1) to give 6- [ (3R) -3, 4-dimethylpiperazin-1-yl as a colorless oil]Pyridine-2-carbonitrile (540mg, 60.97%). LCMS M/z (ESI), [ M + H]+＝217.3
Step 2.1- [6- [ (3R) -3, 4-dimethylpiperazin-1-yl ] -E]Pyridin-2-yl]Methylamine
At room temperature under hydrogen atmosphere to 6- [ (3R) -3, 4-dimethylpiperazin-1-yl]Pyridine-2-carbonitrile (200mg, 0.925 mmol, 1 eq) in MeOH (5mL) and NH3.H2Raney nickel (15.84mg, 0.185mmol, 0.20 equiv.) is added dropwise/portion-wise to a stirred mixture in O (0.5 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product/the resulting mixture gave 1- [6- [ (3R) -3, 4-dimethylpiperazin-1-yl ] as a colorless oil]Pyridin-2-yl]Methylamine (162mg, 79.52%) and was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝221.4。
Step 3.3-amino-N- ([6- [ (3R) -3, 4-dimethylpiperazin-1-yl)]Pyridin-2-yl]Methyl) -6- [ 3-methyl Alkylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002701
Azol-2-yl) pyrazine-2-carboxamides
3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002702
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq.) and 1- [6- [ (3R) -3, 4-dimethylpiperazin-1-yl ]Pyridin-2-yl]Methylamine (98.27mg, 0.446mmol, 1.5 equiv.) in a stirred solution/mixture of DMF (5mL) was added HATU (226.12mg, 0.595mmol, 2 equiv.) and DIEA (115.29mg, 0.892mmol, 3 equiv.) dropwise/portion. By CH2Cl2the resulting mixture was extracted (3 × 20mL), the combined organic layers were washed with water (3 × 10mL), dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Tong (Chinese character of 'tong')Over preparative TLC (CH)2Cl2MeOH 15:1) to purify the residue. The crude product (80mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 34% B to 45% B within 8 min; 254; 220 nm; Rt: 7.53min) to give 3-amino-N- ([6- [ (3R) -3, 4-dimethylpiperazin-1-yl) as a yellow solid]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002703
Oxazol-2-yl) pyrazine-2-carboxamide (compound 285) (20mg, 12.49%). LCMS M/z (ESI), [ M + H]+＝539.4。1H-NMR(DMSO-d6,40MHz)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-, (
Figure BDA0002577091620002704
Azol-2-yl) pyrazine-2-carboxamide (Compound 287-2)
Scheme 126
Figure BDA0002577091620002711
Step 1.6- [ (3S) -3, 4-dimethylpiperazin-1-yl]Pyridine-2-carbonitriles
(3S) -1, 3-dimethylpiperazine (607.89mg, 5.323mmol, 1.3 equivalents), 6-fluoropyridine-2-carbonitrile (500mg, 4.095mmol, 1 equivalent), K were added to a 40mL sealed tube at room temperature2CO3(1131.89mg, 8.190mmol, 2 equiv.) and DMF (10 mL.) the resulting mixture was stirred at 50 ℃ for 3 h, the reaction was quenched by the addition of saturated NaCl (aq) (250mL) at room temperature, the resulting mixture was extracted with EtOAc (2 × 125mL), the combined organic layers were washed with saturated NaCl (aq) (250mL), anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 30:1) to give 6- [ (2S) -2, 4-dimethylpiperazin-1-yl) as a colorless oil]Pyridine-2-carbonitrile (280mg, 31.61%). LCMS M/z (ESI), [ M + H]+＝217.3
Step 2.1- [6- [ (2S) -2, 4-dimethylpiperazin-1-yl ] -2]Pyridin-2-yl]Methylamine
To 6- [ (2S) -2, 4-dimethylpiperazin-1-yl under a hydrogen atmosphere at room temperature]Pyridine-2-carbonitrile (280mg, 1.295 mmol, 1 eq) in MeOH (5mL) and NH2NH2.H2Raney nickel (22.18mg, 0.259mmol, 0.2 equiv.) is added dropwise/portion-wise to a stirred solution/mixture in O (0.5 mL). The resulting mixture was filtered and concentrated under reduced pressure to give 1- [6- [ (2S) -2, 4-dimethylpiperazin-1-yl ] as a colorless solid ]Pyridin-2-yl]Methylamine (200mg, 70.12%). LCMS M/z (ESI), [ M + H]+＝221.4。
Step 3.3-amino-N- ([6- [ (2S) -2, 4-dimethylpiperazin-1-yl)]Pyridin-2-yl]Methyl) -6- [ 3-methyl Alkylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002712
Azol-2-yl) pyrazine-2-carboxamide (Compound 287-2)
3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature in an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002713
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 equivalent) and 1- [6- [ (2S) -2, 4-dimethylpiperazin-1-yl]Pyridin-2-yl]Methylamine (98.27mg, 0.446mmol, 1.50 equivalents) in a stirred solution/mixture of DMF (10mL) was added HATU (226.12mg, 0.595mmol, 2 equivalents) and DIEA (115.29mg, 0.892mmol, 3 equivalents) dropwise/portion wise. By CH2Cl2the resulting mixture was extracted (3 × 20mL), the combined organic layers were washed with water (3 × 20mL), dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 15:1) to purify the residue. The crude product (80mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 19 x 250mm, 5 μm; mobile phase A:, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 36% B to 47% B within 8 min; 254; 220 nm; Rt: 7.65min) to give 3-amino-N- ([6- [ (2S) -2, 4-dimethylpiperazin-1-yl) as a yellow solid ]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002722
Oxazol-2-yl) pyrazine-2-carboxamide (compound 287-2) (20mg, 12.49%). LCMS M/z (ESI), [ M + H]+＝539.4。1H NMR(400MHz,DMSO-d6)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 listed in the table below were prepared using the method described for compound 287-2.
Figure BDA0002577091620002721
Figure BDA0002577091620002731
EXAMPLE 290 preparation of (2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methyl-imidazole- [1,2-a ] pyridin-6-yl ] pyrazin-2-yl ] methyl ] oxolane-2-carboxamide (Compound 290)
Scheme 127
Figure BDA0002577091620002732
Step 1, methyl 3-methyl-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazole-2-) Radical) pyrazines
Under nitrogen atmosphere at room temperature with [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (4.15g, 23.6mmol, 2.00 equiv.), Pd (dppf) Cl2(0.86g，1.19mmol, 0.1 equiv.) and K3PO4(7.50g, 35.3mmol, 3.0 equivalents) of H2O (5.0mL) treatment of methyl 3-amino-6-chloro-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (3.0g, 11.8 mmol, 1 eq) to bis
Figure BDA0002577091620002741
A solution in an alkane (50mL) was heated at 90 ℃ for 2 hours, cooled to room temperature, and concentrated. Purifying the residue by silica gel column chromatography using CH2Cl2MeOH (20/1) elution gave 3-methyl-6- [ 3-methylimidazo [1,2-a ] as a pale yellow solid]Pyridin-6-yl]-methyl 5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (1.8g, 44%). LCMS M/z (ESI), [ M + H ]+＝351.3。
Step 2.3-methyl-6- [ 3-methyl-imidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) Pyrazine-2-carbaldehyde
A solution of methyl 3-amino-6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carboxylate (1.0g, 2.85mmol, 1 equivalent) in THF (20mL) was treated with LiAlH4(162.5mg, 4.28mmol, 1.5 equivalents) at-70 ℃, stirred for 2 hours, quenched with EA (2.5mL), purified by preparative TLC to provide 3-methyl-6- [ 3-methylimidazo [1,2-a ] pyridin-6-yl ] -5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carbaldehyde as a light yellow solid (280mg, 31%). LCMS M/z (ESI), [ M + H ] + ═ 321.1.
Step 3.N- [ (3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (2H-1,2, 3-triazole-2-) Radical) pyrazin-2-yl) methyl]-2-methylpropane-2-sulfinamide
At room temperature with Ti (Oi-Pr)4(2.5mL) treatment of 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]A mixture of-5- (2H-1,2, 3-triazol-2-yl) pyrazine-2-carbaldehyde (260mg, 0.81mmol, 1 equiv.) and 2-methylpropane-2-sulfinamide (195mg, 1.62mmol, 2.0 equiv.) in THF (2.5mL) was heated at 70 deg.C for 2 hours, cooled to room temperature, and NaBH was added4(123mg, 3.25mmol, 4.0 equiv.), stirred for 2 hours, quenched by 2.0 ml water, and filtered. The solid was washed by DCM/MeOH ═ 5/1(20mL), the organic layers were combined, concentrated, and purified by preparative TLC (r) DCM/MeOH ═ 50/1) to give N- [ (3-amino-6- [ 3-methylimidazo [1, 2-a) as a light yellow solid]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazin-2-yl) methyl]2-methylpropane-2-sulfinamide (230mg, 67%). LCMS M/z (ESI), [ M + H]+＝426.3。
Step 4.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1, 2-a)]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]-1-methylpyrrolidine-2-carboxamide
For 1, 4-bis at room temperature
Figure BDA0002577091620002742
Treatment of N- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] with HCl (gas) in an alkane (2.0mL, 4.0mol/L)]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazin-2-yl) methyl]A solution of (2-methylpropane-2-sulfinamide (160mg, 0.36mmol, 1 equiv.) in DCM (2.0mL) was stirred for 2 hours and concentrated to give 3- (aminomethyl) -5- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-6- (2H-1,2, 3-triazol-2-yl) pyrazin-2-amine (160mg, crude material). LCMS M/z (ESI), [ M + H]+＝322.3。
Step 5.(2S) -N- [ [ 3-amino-5- (4-fluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyridine (II) Oxazin-2-yl]Methyl radical]Oxetane-2-carboxamide (Compound 290)
A solution of (2R) -1-methylpyrrolidine-2-carboxylic acid (112.5 mg, 0.87mmol, 2.0 equiv.) in DMF (3.0mL) was treated with HATU (331mg, 0.87mmol, 2.00 equiv.) at room temperature for 20min, followed by dropwise addition of 3- (aminomethyl) -5- [ 3-methylimidazo [1,2-a ] at room temperature ]Pyridin-6-yl]-6- (2H-1,2, 3-triazol-2-yl) pyrazin-2-amine (140mg, 0.44mmol, 1 eq), DIEA (167mg, 1.31mmol, 3.0 eq), stirred for 2H and the residue was purified by preparative TLC (DCM/MeOH ═ 30/1) to give (2R) -N- [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a white solid]Pyridin-6-yl]-5- (2H-1,2, 3-triazol-2-yl) pyrazin-2-yl) methyl]-1-methylpyrrolidine-2-carboxamide (65 mg, 35%). LCMS (liquid Crystal display Module) [ M + H ]]＝433.3。1H NMR(400MHz,DMSO-d6)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)
Scheme 128
Figure BDA0002577091620002751
Step 1.3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxylic acid methyl ester
To methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (4g, 18.016mmol, 1 equivalent) and (3, 5-difluorophenyl) boronic acid (2.90g, 18.376mmol, 1.02 equivalent) in 1, 4-bis (phenyl) at room temperature under a nitrogen atmosphere
Figure BDA0002577091620002752
Alkane (100mL) and H2To a stirred mixture in O (5mL) was added K in portions3PO4(7.65g, 36.031mmol, 2 equiv.) and Pd (dppf) Cl2(2.64g, 3.603mmol, 0.2 equiv.). The resulting mixture was stirred at 70 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH 2Cl2(1 × 30mL) washing the filter cake, concentrating the filtrate under reduced pressure, purifying the residue by column chromatography on silica gel using CH2Cl2EtOAc (4:1) elution afforded methyl 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxylate (4g, 74.09%) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝300.2。1H-NMR:(300MHz, DMSO-d6)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
At room temperature to 30% NH3To a stirred solution in MeOH (100mL) was added methyl 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxylate (4g, 13.348mmol, 1 eq) portionwise. The resulting mixture was stirred at 50 ℃ for 4 hours. The resulting mixture was concentrated in vacuo to give 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxamide as a yellow solid (3.5g, 92).11％)。LCMS:m/z(ESI),[M+H]+＝285.2。1H-NMR:(300MHz,DMSO-d6) 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 chloride (40mL) was added 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carboxamide (2g, 7.026mmol, 1 eq) portionwise at room temperature. The resulting mixture was stirred at 90 ℃ for 12 hours. The resulting mixture was concentrated under reduced pressure and diluted with DCM (20 mL). Saturated NaHCO at room temperature3The reaction was quenched (aqueous solution). By CH2Cl2the resulting mixture was extracted (2 × 30mL) over anhydrous Na 2SO4The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carbonitrile as a yellow solid (700mg, 37.36%).1H-NMR:(300MHz,DMSO-d6)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]Pyrazine- 2-carbonitriles
To 3-amino-6-chloro-5- (3, 5-difluorophenyl) pyrazine-2-carbonitrile (600mg, 2.250 mmol, 1 eq) and [ 3-methylimidazo [1,2-a ] at room temperature under a nitrogen atmosphere]Pyridin-6-yl]Boric acid (791.99mg, 4.500mmol, 2.00 equivalents) in 1, 4-bis
Figure BDA0002577091620002761
To a stirred mixture of alkane (30mL) and H2O (4mL) were added Cs2CO3(1466.34 mg, 4.500mmol, 2 equiv.) and Pd (dppf) Cl2(329.30mg, 0.450mmol, 0.2 equiv.) in portions. The resulting mixture was stirred at 90 ℃ for 3 hours under a nitrogen atmosphere. Filtering the resulting mixture with CH2Cl2(1 × 10mL) the filter cake was washed, the filtrate was concentrated under reduced pressure, and the filtrate was purified by preparative TLC (CH)2Cl2MeOH 30:1) to give 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazine-2-carbonitrile (300 mg, 36.79%). LCMS M/z (ESI), [ M + H ]+＝363.3。1H-NMR:(300MHz,DMSO-d6)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]Pyridine (II) Oxazin-2-amines
To the reaction mixture at room temperature under a nitrogen atmosphere, 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Pyrazidine-2-carbonitrile (100mg, 0.276mmol, 1 eq.) and NH3.H2O (1mL) was added in portions to a stirred solution of Raney nickel (47.29mg, 0.552mmol, 2 equiv.) in MeOH (15 mL.) the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours, the resulting mixture was filtered, the filter cake was washed with MeOH (1 × 10mL), the filtrate was concentrated under reduced pressure to give 3- (aminomethyl) -6- (3, 5-difluorophenyl) -5- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazin-2-amine (90mg, 89.01%). LCMS M/z (ESI), [ M + H]+＝367.3。
Step 6.(2R) -N- [ [ 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ]]Pyridine-6- Base of]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 291)
To a stirred mixture of (2R) -1-methylpyrrolidine-2-carboxylic acid (56.41mg, 0.437mmol, 2.00 equiv.) in DMF (10 mL) was added HATU (166.05mg, 0.437mmol, 2 equiv.) and DIEA (56.44 mg, 0.437mmol, 2 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 10 min. To this stirred solution was then added 3- (aminomethyl) -6- (3, 5-difluorophenyl) -5- [ 3-methylimidazo [1,2-a ] portionwise at room temperature ]Pyridin-6-yl]Pyrazin-2-amine (80 mg, 0.218mmol, 1 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep C18OBD column, 5 μm, 19X 150 mm; mobile phase A: water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 35% B to 48% B over 7 min; 254/220 nm; Rt: 6.77min) to give (2R) -N- [ [ 3-amino-5- (3, 5-difluorophenyl) -6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]Pyrazin-2-yl radicals]Methyl radical]-1-methylpyrrolidine-2-carboxamide (Compound 291) (7mg, 6.71)％)。LCMS:m/z(ESI),[M+H]+＝478.4。1H NMR:(300MHz,DMSO-d6) 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 296-1.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002772
Azol-2-yl) -N- [ (2S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Preparation of pyrazine-2-carboxamide (Compound 296-1)
Scheme 129
Figure BDA0002577091620002771
Step 1. methanesulfonic acid (S) -2- ((tert-butoxycarbonyl) amino) propyl ester
To N- [ (2S) -1-hydroxypropan-2-yl group at 0 ℃ under a nitrogen atmosphere]To a stirred solution of tert-butyl carbamate (5.0g, 28.534 mmol, 1 eq) and TEA (3753.60mg, 37.095mmol, 1.3 eq) in DCM was added MsCl (4.90g, 42.801mmol, 1.5 eq) dropwise. By CH 2Cl2the resulting mixture was extracted (2 × 20mL), the combined organic layers were washed with water (2 × 20mL), dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives methanesulfonic acid (S) -2- (S) as a white solidTertiary amineButoxycarbonyl) amino) propyl ester (6.5g, 89.9%). LCMS M/z (ESI), [ M + H]+No MS signal.
Step 2.(S) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamic acid tert-butyl ester
To N- [ (2S) -1- (methanesulfonyloxy) propan-2-yl]To a stirred solution of tert-butyl carbamate (3g, 11.843mmol, 1 eq) and 1H-1,2, 3-triazole (1.23g, 17.765mmol, 1.50 eq) in DMF (50mL) was added K in portions2CO3(3.27g, 23.686mmol, 2.00 equiv.) the resulting mixture was stirred at 90 ℃ under nitrogen, the resulting mixture was diluted with EA (10mL), washed with water (2 × 10mL), and concentrated in vacuoTo obtain a mixture. The residue was purified by reverse phase HPLC to give tert-butyl (S) - (1- (2H-1,2, 3-triazol-2-yl) propan-2-yl) carbamate (1.2g, 44.7%) and tert-butyl (S) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamate (0.62g, 23.1%) as white solids.
(S) - (1- (2H-1,2, 3-triazol-2-yl) propan-2-yl) carbamic acid tert-butyl ester1H-NMR (300MHz, chloroform-d) 1.09(3H, d),1.43(9H, s),4.21(1H, s),4.51(2H, d),7.63(2H, s).
(S) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamic acid tert-butyl ester1H-NMR(300MHz,DMSO-d6) 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 tert-butyl (S) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamate (280mg, 1 eq) in 1, 4-bis at 25 deg.C
Figure BDA0002577091620002781
To a stirred solution in an alkane (5mL) was added dropwise a 1, 4-bis solution of 4M HCl
Figure BDA0002577091620002782
Alkane (5mL) solution. The mixture was stirred at room temperature for 1 hour. Concentration to dryness gave (S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine dihydrochloride (266mg, 90.5%) as a white solid. The crude product was used directly in the next step without further purification. .1H-NMR(300MHz,DMSO-d6)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-
Figure BDA0002577091620002783
Oxazol-2-yl) -N- [ (2S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamides
To (2S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine (45mg, 0.357mmol, 1.50 equivalents), 3-amino-6- [ 3-methylimidazole at 0 deg.CAnd [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002792
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.) and DIEA (184.46mg, 1.427mmol, 6.00 equiv.) in DMF was added T dropwise 3P (454.12mg, 0.714mmol, 3.00 eq, 50%). The reaction mixture was purified by preparative HPLC with the following conditions (column: Shiseido CAPCELLCORE C18, 2.1 × 50mm, 2.7 μm; mobile phase A: water/0.05% TFA; mobile phase B: ACN/0.05% TFA; flow rate: 1.0 mL/min; gradient: 5% B to 95% B over 2.0min, hold for 0.7 min; 254nm) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002793
Azol-2-yl) -N- [ (2S) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamide (compound 296-1) (75mg, 70.9%). LCMS M/z (ESI), [ M + H]+＝445.3。1H-NMR(300MHz,DMSO-d6) 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 296-2.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002794
Azol-2-yl) -N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Preparation of pyrazine-2-carboxamide (Compound 296-2)
Scenario 130
Figure BDA0002577091620002791
Step 1. methanesulfonic acid (R) -2- ((tert-butoxycarbonyl) amino) propyl ester
To N- [ (2R) -1-hydroxypropan-2-yl group at 0 DEG C]To a stirred solution of tert-butyl carbamate (3g, 17.121mmol, 1 eq) and MsCl (2.55g, 22.257mmol, 1.3 eq) in DCM (50mL) was added TEA (3.46g,34.241mmol, 2 equivalents) for 2 hours. By H2O and NaHCO3the reaction mixture was quenched (10mL), extracted with DCM (3 × 20mL), and washed with Na 2SO4The organic layer was dried, which yielded (R) -2- ((tert-butoxycarbonyl) amino) propyl methanesulfonate (6.5g, 89.9%) as a white solid. LCMS M/z (ESI), [ M + H-tBu + MeCN]+＝ 239.1。
Step 2.N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Carbamic acid tert-butyl ester
Add N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl to a 10mL vial at 0 deg.C]T-butyl carbamate (5g, 19.739mmol, 1 eq.), 1H-1,2, 3-triazole (2.04g, 29.608mmol, 1.50 eq.), K2CO3(5.46g, 39.477mmol, 2.00 equiv.) and DMF (50mL) the mixture was then stirred at 90 ℃ under a nitrogen atmosphere for 1h, the resulting mixture was diluted with EtOAc (50mL), the organic layer was washed with brine (3 × 10mL), and over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC with the following conditions: column, C18Silica gel; mobile phase, MeOH/water, 10% to 50% gradient over 10 min; detector, UV 254nm, yielding:
n- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Carbamic acid tert-butyl ester (1g, 22.3%)1H-NMR(300 MHz,DMSO-d6)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)；
N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl as white solid]Tert-butyl carbamate (2.9g, 64.9%). 1H-NMR(300MHz,DMSO-d6)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)。
(R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine dihydrochloride
To (R) - (1- (1H-1,2, 3-triazol-1-yl) propan-2-yl) carbamic acid tert-butyl ester (280mg, 1.24 mmol, 1 eq) in 1, 4-bis (hydroxymethyl) amine at 25 deg.C
Figure BDA0002577091620002801
In an alkane (5mL)Stirring the solution to add dropwise 4M HCl 1, 4-bis
Figure BDA0002577091620002802
Alkane (5mL) solution. The mixture was stirred at room temperature for 1 hour. Concentration to dryness gave (R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine dihydrochloride (266mg, quantitative) as a white solid. The crude product was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H]+＝127.1。
Step 4.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002803
Oxazol-2-yl) -N- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamides
3-amino-6- [ 3-methylimidazo [1,2-a ] was added at 0 ℃ in a 10mL vial]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002804
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq), (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine (56.27 mg, 0.446mmol, 1.5 eq), T3P (283.83mg, 0.892MMOL, 3 equivalents), DIEA (192.15mg, 1.487MMOL, 5 equivalents) and DMF (10 mL.) the mixture was then stirred at room temperature under nitrogen atmosphere for 3 hours by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (10MMOL/L NH) 4HCO3) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 10% B to 50% B within 7 min; 254/220 nm; rt: 5.48min) to obtain 3-amino-6- [ 3-methylimidazo [1,2-a ] as a white solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002812
Azol-2-yl) -N- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamide (compound 296-2) (20mg, 15.1%). LCMS M/z (ESI), [ M + H]+＝445.2。1H-NMR(300MHz,DMSO-d6)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 297.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002813
Azol-2-yl) -N- [ (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Preparation of pyrazine-2-carboxamides
Scheme 131
Figure BDA0002577091620002811
Step 1.(2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride
To N- [ (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl at room temperature]Tert-butyl carbamate (260mg, 1.15 mmol, 1 eq) in 5mL 1, 4-bis
Figure BDA0002577091620002814
Adding HCl dropwise to a stirred mixture in an alkane
Figure BDA0002577091620002815
Solution in alkane (5 mL). After stirring for 1 hour, the mixture was concentrated to give (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride (230mg, 90.0%) as a white solid. LCMS M/z (ESI), [ M + H]+＝127.2。
And 2. step 2. 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002816
Oxazol-2-yl) -N- [ (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl ]Pyrazine-2-carboxamides.
To (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride (71mg, 0.357 mmol, 1.50 equivalents) and 3-amino-6- [ 3-methylimidazo [1,2-a ] at 0 ℃ under an air atmosphere]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002817
To a stirred solution of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.), DIEA (184mg, 1.427mmol, 6.00 equiv.) in DMF was added T dropwise3P (454mg, 0.714mmol, 3.00 equiv., 50 wt%). The reaction mixture was purified by preparative HPLC (column: Shiseido CAPCELLCORE C18, 2.1 × 50mm, 2.7 μm; mobile phase A: water/0.05% TFA, mobile phase B: ACN/0.05% TFA; flow rate: 1.0 mL/min; gradient: 5% B to 95% B over 2.0min, hold for 0.7 min; 254nm) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002822
Azol-2-yl) -N- [ (2S) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Pyrazine-2-carboxamide (compound 297) (37mg, 35.0%). LCMS M/z (ESI), [ M + H]+＝445.3。1H-NMR(300MHz,DMSO-d6) 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 298.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002823
Azol-2-yl) -N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl]Preparation of pyrazine-2-carboxamide (Compound 298)
Scheme 132
Figure BDA0002577091620002821
Step 1.(2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride.
To N- [ (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-yl at room temperature under an air atmosphere]To a stirred solution of tert-butyl carbamate (200mg, 0.88mmol, 1 eq) was added dropwise to 1, 4-bis
Figure BDA0002577091620002824
4MHCl (gas) support in alkane (4mL)It lasts for 1 hour. The solvent was evaporated. This gave (2R) -1- (2H-1,2, 3-triazol-2-yl) propan-2-amine dihydrochloride (180mg, quantitative) as a white solid. LCMS M/z (ESI), [ M + H]+＝127.2。
And 2. step 2. 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002825
Oxazol-2-yl) -N- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamides.
3-amino-6- [ 3-methylimidazo [1,2-a ] was added at 0 ℃ in a 10mL vial]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002826
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq), (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-amine (56.27 mg, 0.446mmol, 1.5 eq), T3P (283.83mg, 0.892MMOL, 3 equivalents), DIEA (192.15mg, 1.487MMOL, 5 equivalents) and DMF (10 mL.) the mixture was then stirred at room temperature under nitrogen atmosphere for 4 hours by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (10MMOL/L NH)4HCO3) And the mobile phase B: ACN; flow rate: 60 mL/min; gradient: 10% B to 50% B within 7 min; 254/220 nm; rt: 5.48min) to obtain 3-amino-6- [ 3-methylimidazo [1,2-a ] as a white solid ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002827
Azol-2-yl) -N- [ (2R) -1- (1H-1,2, 3-triazol-1-yl) propan-2-yl]Pyrazine-2-carboxamide (compound 298) (20mg, 15.1%). LCMS M/z (ESI), [ M + H]+＝445.3。1H-NMR(300MHz,DMSO-d6)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-
Figure BDA0002577091620002832
Azol-2-yl) pyrazine-2-carboxamide (Compound 301)
Protocol 133
Figure BDA0002577091620002831
And (1).N- [2- [ (2- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002833
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-3-yl) oxy]Ethyl radical]-N-methylcarbamic acid tert-butyl ester
Place N- (2- [ [2- (aminomethyl) pyridin-3-yl) in a 6-mL vial]Oxy radical]Ethyl) -N-methylcarbamic acid tert-butyl ester (209.15mg, 0.743mmol, 2.50 equivalents), 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002834
Oxazol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq), DIEA (0.36mL, 2.805mmol, 9 eq), DMF (2.5mL), T3P (283.83mg, 0.892mmol, 3.00 equiv.). The resulting solution was stirred at 0 ℃ for 16 hours. Using 20mL of H2the resulting solution was diluted O, the resulting solution was extracted with 3 × 15mL dichloromethane, and the organic layers were combined the residue was purified by preparative TLC (DCM: MeOH ═ 5:1) which yielded 60mg (33.65%) of N- [2- [ (2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid ]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002835
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-3-yl) oxy]Ethyl radical]-N-methyl-carbamic acid tert-butyl ester. LCMS M/z (ESI), [ M + H]+＝600.3。
Step 2.3-amino-N- ([3- [2- (methylamino) ethoxy ] ethyl]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002836
Azol-2-yl) pyrazine-2-carboxamides
In a 25mL round bottom flask was placed N- [2- [ (2- [ [ (3-amino-6- [ 3-methylimidazo [1,2-a ])]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002837
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-3-yl) oxy]Ethyl radical]-tert-butyl N-methylcarbamate (60mg, 0.100mmol, 1 equiv.), DCM (3mL), TF (1mL, 13.463mmol, 134.55 equiv.), the resulting solution is stirred at 20 ℃ for 1 hour, the resulting mixture is concentrated in vacuo, the pH of the solution is adjusted to 8 with saturated sodium bicarbonate (aq.) the resulting mixture is concentrated in vacuo, the residue is purified by preparative TLC (DCM: MeOH ═ 5:1) to give a yellow solid, the crude product is purified by preparative HPLC (column: XBidge Prep C18OBD column 19 × 150mm 5 μm, mobile phase A:, mobile phase B: ACN, flow rate: 20mL/min, gradient: 20% B to 38% B over 8 min; 254/220 nm; Rt: 7.19 min.) this gives 10.53mg (19.59%) of 3-amino-N- ([3- [2- (methylamino) ethoxy) as a yellow solid ]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002842
Oxazol-2-yl) pyrazine-2-carboxamide. LCMS M/z (ESI), [ M + H]+＝500.4。1H-NMR(300MHz,DMSO-d6)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 302.3-amino-N- ((6- (4- (dimethylamino) piperidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002843
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 302)
Scheme 134
Figure BDA0002577091620002841
Step 1.2-cyano-6- (4- (dimethylamino) piperidin-1-yl) pyridine
6-chloropyridine-2-carbonitrile (500mg, 3.609mmol, 1 eq.) and N, N-dimethylpiperidin-4-amine (508.99mg, 3.970mmol, 1.10 eq.), K were added at room temperature to a 20mL vial2CO3(1496.27mg, 10.826mmol, 3.00 equiv.) in DMF (10 mL.) the resulting mixture is stirred at 60 ℃ under an air atmosphere for 15 hours, the resulting mixture is diluted with EtOAc (100mL), the resulting mixture is washed with 2 × 100mL of water and 2 × 100mL of saturated brine, anhydrous Na2SO4The organic layer was dried and the solid was filtered off and the solvent was evaporated to give a yellow oil. The crude product was purified by TLC (EA: PE ═ 1:2) to give 6- [4- (dimethylamino) piperidin-1-yl group as a yellow oil]Pyridine-2-carbonitrile (438mg, 52.7%). LCMS M/z (ESI), [ M + H ]+＝231.3。1H-NMR(400MHz,MeOD-d4) 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 ] -n-butyl in a 50mL round bottom flask at room temperature]Pyridine-2-carbonitrile (438mg, 1.902mmol, 1 equiv.) and Raney Nickel (162.93mg, 1.902mmol, 1.00 equiv.), NH3.H2O (66.65mg, 1.902mmol, 1.00 equiv.). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The solid is filtered off and the solvent is evaporated off to give 1- [6- (aminomethyl) pyridin-2-yl ] as a yellow oil]-N, N-dimethylpiperidin-4-amine (406mg, 91.1%). LCMS M/z (ESI), [ M + H]+＝235.1。1H-NMR(400MHz,MeOD-d4)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-methyl) Imidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002851
Azol-2-yl) pyrazine-2-carboxamide (Compound 302)
1- [6- (aminomethyl) pyridin-2-yl ] at 0 ℃ in an air atmosphere]-N, N-dimethylpiperidin-4-amine (55.75mg, 0.238mmol, 1.00 eq.) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002852
To a stirred mixture of oxazol-2-yl) pyrazine-2-carboxylic acid (80mg, 0.238mmol, 1 equiv.), DIEA (92.23mg, 0.714mmol, 3.00 equiv.) in DMF was added T dropwise3P (151.37mg, 0.476mmol, 2.00 equiv.) the resulting mixture is stirred at room temperature under an air atmosphere for 12 h, the resulting mixture is diluted with EtOAc (50mL), the resulting mixture is washed with 1 × 50mL of water and 3 × 50mL of brine, anhydrous Na 2SO4The organic layer was dried, filtered and evaporated to give a crude solid. By preparative TLC (CH)2Cl2the residue was purified by MeOH 12:1) to give a yellow solid by preparative HPLC with the following conditions (column: Xbridge Prep OBD C18 column 30 × 150mm 5 μm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 37% B to 50% B within 7 min; 254; 220 nm; rt: 5.52min) to give 3-amino-N- ([6- [4- (dimethylamino) piperidin-1-yl) as a yellow solid]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002853
Oxazol-2-yl) pyrazine-2-carboxamide (compound 302) (20mg, 15.21%). LCMS M/z (ESI), [ M + H]+＝553.4。1H-NMR(400MHz, MeOD-d4)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(1H,s)
Example 303.3-amino-N- ((6- (3- (methylamino) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3-methylimidazoleAnd [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002854
Preparation of oxazol-2-yl) pyrazine-2-carboxamide (Compound 303)
Scheme 135
Figure BDA0002577091620002861
Step 1 preparation of tert-butyl (1- (6-cyanopyridin-2-yl) azetidin-3-yl) (methyl) carbamate
6-bromopyridine-2-carbonitrile (500mg, 2.732mmol, 1 equiv.), N- (azetidin-3-yl) -N-methylcarbamic acid tert-butyl ester (559.76mg, 3.005mmol, 1.1 equiv.) and K were reacted at 60 deg.C 2CO3(1132.78mg, 8.196mmol, 3.0 equiv.) A mixture in DMF (20mL) was stirred for 3 hours the resulting mixture was diluted with water (40mL), the resulting mixture was extracted with EtOAc (3 × 50mL), the combined organic layers were washed with brine (20mL), dried Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (9:1) to give N- [1- (6-cyanopyridin-2-yl) azetidin-3-yl as a pale yellow solid]-N-methylcarbamic acid tert-butyl ester (600mg, 76.16%). LCMS M/z (ESI), [ M + H]+＝289.2。1H-NMR(300mHz,DMSO-d6)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
At room temperature in H2The reaction is carried out by reacting N- [1- (6-cyanopyridin-2-yl) azetidin-3-yl]A mixture of tert-butyl N-methylcarbamate (500mg, 1.734mmol, 1 equiv.), ammonium hydroxide (20.00mL), and Raney's nickel (99.54mg) in MeOH (20mL) was stirred for 1 hour, the resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10mL), the filtrate was concentrated under reduced pressure, this gave N- [1- [6- (aminomethyl) pyridin-2-yl ] as a pale yellow oil]Azetidin-3-yl]-N-methylaminocarboxylic acid tert-butyl ester Butyl ester (502mg, 99.02%). LCMS M/z (ESI), [ M + H]+＝293.1。1H-NMR(300mHz, DMSO-d6)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 (1- (6- ((3-amino-6- (3-methylimidazo [1, 2-a))]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002862
Azol-2-yl) pyrile Oxazine-2-carboxamido) methyl) pyridin-2-yl) azetidin-3-yl) (methyl) carbamic acid tert-butyl ester
Reacting 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002863
Azol-2-yl) pyrazine-2-carboxylic acid (100mg, 0.297mmol, 1 eq.), N- [1- [6- (aminomethyl) pyridin-2-yl]Azetidin-3-yl]-tert-butyl N-methylcarbamate (173.88mg, 0.595mmol, 2.0 equiv.), DIEA (192.15mg, 1.487mmol, 5.0 equiv.), and T3A solution of P (189.22mg, 0.595mmol, 2.0 equiv.) in DMF (10mL) was stirred at room temperature for 2 h, the resulting mixture was diluted with water (20mL), the resulting mixture was extracted with EtOAc (3 × 30mL), the combined organic layers were washed with brine (20mL), dried over Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography using CH2Cl2MeOH (10:1) to give N- [1- (6- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) ] as a pale yellow oil]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002871
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-2-yl) azetidin-3-yl ]-N-methyl-carbamic acid tert-butyl ester (80mg, 44.06%). LCMS M/z (ESI), [ M + H]+＝611.3
Step 4.3-amino-N- ((6- (3- (methylamino) azetidin-1-yl) pyridin-2-yl) methyl) -6- (3- Methylimidazo [1,2-a ]]Pyridin-6-yl) -5-, (
Figure BDA0002577091620002872
Azol-2-yl) pyrazine-2-carboxamides
N- [1- (6- [ [ (3-amino-6- [ 3-methylimidazo [1, 2-a) ] is reacted at room temperature]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002873
Azol-2-yl) pyrazin-2-yl) carboxamides]Methyl radical]Pyridin-2-yl) azetidin-3-yl]A solution of tert-butyl-N-methylcarbamate (80mg, 0.131 mmol, 1 eq) and TFA (2mL) in DCM (5mL) was stirred for 2 h. With saturated NaHCO3the residue was neutralized to pH 7 (aq.) the resulting mixture was extracted with EtOAc (3 × 50mL), the combined organic layers were washed with water (2 × 30mL), anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative HPLC with the following conditions (column: Xbridge Shield RP18OBD column, 5 μm, 19X 150 mm; mobile phase A: water (0.05% NH)3H2O), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 32% B to 52% B within 8 min; 254/220 nm; rt: 7.88min) to give 3-amino-N- ([6- [3- (methylamino) azetidin-1-yl) as a yellow solid ]Pyridin-2-yl]Methyl) -6- [ 3-methylimidazo [1,2-a]Pyridin-6-yl]-5-(1,3-
Figure BDA0002577091620002874
Oxazol-2-yl) pyrazine-2-carboxamide (compound 303) (30mg, 44.85%). LCMS M/z (ESI), [ M + H]+＝511.31H-NMR(300 mHz,DMSO-d6)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)。
Example 304/305.preparation of 3-amino-6- (3-methylimidazo [1,2-a ] pyridin-6-yl) -5- (pyridin-2-yl) -N- ((tetrahydrofuran-3-yl) methyl) pyrazine-2-carboxamide (Compound 304/305)
Scheme 136
Figure BDA0002577091620002881
Step 1.3-amino-6-chloro-5- (pyridin-2-yl) pyrazine-2-carboxylic acid ester
2- (tributylstannyl) pyridine (1658.12mg, 5.05mmol, 2.00 equiv.), methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (500mg, 2.525mmol, 1 equiv.), Pd (PPh)3)2Cl2(158.06mg, 0.226mmol, 0.1 equiv.) and LiCl (190.94mg, 5.05mmol, 2 equiv.) in 1, 4-bis
Figure BDA0002577091620002882
The solution in alkane (20mL) was stirred at 90 ℃ under a nitrogen atmosphere for 16 hours. This reaction was purified with another batch of E02189-006. Subjecting the mixture to rapid silica gel column chromatography using CH2Cl2MeOH (1:1) elution afforded the crude product. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 30:1) to give methyl 3-amino-6-chloro-5- (pyridin-2-yl) pyrazine-2-carboxylate (180mg, 30.20%) as a yellow solid. LCMS M/z (ESI), [ M + H]+＝265.2。1H NMR(300MHz,DMSO-d6)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-yl]-5- (pyridin-2-yl) pyrazin-2-ylmethane Acid esters
3-amino-6-chloro-5- (pyridin-2-yl) pyrazine-2-carboxylic acid methyl ester (120mg, 0.453mmol, 1 eq), [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]Boric acid (159.58mg, 0.907mmol, 2 equiv.), Pd (dppf) Cl2CH2Cl2(37.03 mg, 0.045mmol, 0.1 equiv.) and Cs2CO3(295.45mg, 0.907mmol, 2 equiv.) in 1, 4-bis
Figure BDA0002577091620002883
Alkane (12.5mL) and H2Solution in O (1.5mL) in N2Stirred for 4 hours. The resulting mixture was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 25:1) to give 3-amino-6- [ 3-methyl-amide as a yellow solidAlkylimidazo [1,2-a ]]Pyridin-6-yl]-methyl 5- (pyridin-2-yl) pyrazine-2-carboxylate (50mg, 30.60%). LCMS M/z (ESI), [ M + H]+＝361.3
Step 3.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-5- (pyridin-2-yl) pyrazin-2-ylmethane Acid(s)
To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]-methyl 5- (pyridin-2-yl) pyrazine-2-carboxylate (1 eq) in 1, 4-bis
Figure BDA0002577091620002891
Alkane (10mL) and H2To a stirred solution in O (1mL) was added LiOH (3 equiv) in portions. The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 3 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The crude product (50mg) was used directly in the next step without further purification. LCMS M/z (ESI), [ M + H ]+＝347.3
Step 4.3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ (Oxetan-3-yl) methyl Base of]-5- (pyridin-2-yl) pyrazine-2-carboxamides
To 3-amino-6- [ 3-methylimidazo [1,2-a ] at room temperature]Pyridin-6-yl]To a stirred solution of-5- (pyridin-2-yl) pyrazine-2-carboxylic acid (50 mg, 0.144mmol, 1 equiv.), DMF (5mL) and 1- (oxacyclopent-3-yl) methylamine (73.01mg, 0.722mmol, 5 equiv.) in DMF (5mL) was added DIPEA (93.29mg, 0.722mmol, 5 equiv.) in portions. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (20mL) at room temperature. By CH2Cl2the resulting mixture was extracted (2 × 25mL), the combined organic layers were washed with water (2 × 20mL), dried over anhydrous Na2SO4And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. By preparative TLC (CH)2Cl2MeOH 15:1) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ (Oxetan-3-yl) methyl]-5- (pyridin-2-yl) pyrazine-2-carboxamide (30mg, 48.39%). LCMS M/z (ESI), [ M + H]+＝430.3
Step 5, relative-3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl ]-N- [ [ (3R) -Oxirane Alk-3-yl]Methyl radical]-5- (pyridin-2-yl) pyrazine-2-carboxamides
By preparative chiral HPLC with the following conditions (column: Chiralpak ID-2, 2X 25cm, 5 μm; mobile phase A: MTBE (10mM NH)3-MEOH) -HPLC, mobile phase B: MeOH — HPLC; flow rate: 20 mL/min; gradient: 15B to 15B within 20 min; 220/254 nm; RT 1: 12.919, respectively; RT 2: 16.74) to give 3-amino-6- [ 3-methylimidazo [1,2-a ] as a yellow solid]Pyridin-6-yl]-N- [ [ oxolane-3-yl ] radical]Methyl radical]-5- (pyridin-2-yl) pyrazine-2-carboxamide (Compound 304) (8mg, 26.67%) and 3-amino-6- [ 3-methylimidazo [1,2-a ]]Pyridin-6-yl]-N- [ [ oxolane-3-yl ] radical]Methyl radical]-5- (pyridin-2-yl) pyrazine-2-carboxamide (compound 305).
(Compound 304) LCMS M/z (ESI), [ M + H]+＝430.3。1H NMR(400MHz,DMSO-d6)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(400MHz,DMSO-d6)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 to 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 by cell membrane chromatographic binding analysis.
Using hA1 membrane (from PerkinElmer) and [ 2 ]3H]-8-cyclopentyl-1, 3-Dipropylxanthine (DPCPX) incubation of compounds at different concentrations for 50min while adding 100. mu.L of a 0.5% PEI solution at 4 ℃ to UNFILTER-96GF/B filter plates for 60min, followed by washing the UNIFILTER-96GF/B filter plates twice with 50ml washing buffer, transferring the membrane mixture to the UNIFILTER-96GF/B filter plates and washing the filter plates 4 times, after which incubation at 55 ℃ is performed And culturing for 10 min. Finally, 40 μ L ULTIMA GOLD was added to each well and CPMs were read by TopCount.
At 25 ℃ with a hA2a membrane (from Perkin Elmer) and3H]-CGS21680 incubation of compounds at different concentrations was continued for 90min while 100 μ Ι _ of 0.5% PEI solution was added to the UNFILTER-96GF/B filter plates for 60min at 4 ℃, followed by washing the UNFILTER-96GF/B filter plates twice with 50ml wash buffer, transferring the membrane mixture to the UNFILTER-96GF/B filter plates and washing the filter plates 4 times, followed by incubation for 10min at 55 ℃. Finally, 40 μ L ULTIMAGOLD was added to each well and CPMs were read by TopCount.
At 27 ℃ with a hA2b membrane (from Perkin Elmer) and3H]DPCPX were incubated with compounds at different concentrations for 60min and binding reactions were stopped by rapid filtration through UNIFILTER-96GF/C plates coated with 0.5% BSA using a cell collector. The filter plates were subsequently washed three times with ice-cold wash buffer and dried at 37 ℃ for 120 min. Finally, 50 μ L scintillation cocktail was added to each well and CPMs were read by TopCount.
At 27 ℃ with a hA3 membrane (from Perkin Elmer) and [ [ alpha ] ], a125I]AB-MECA incubation of compounds at different concentrations for 60min, binding reactions were stopped by rapid filtration using a cell harvester via UNIFILTER-96GF/C plates coated with 0.5% BSA. The filter plates were subsequently washed three times with ice-cold wash buffer and dried at 37 ℃ for 120 min. Finally, 50 μ L scintillation cocktail was added to each well and CPMs were read by TopCount.
The binding affinities and specificities of exemplary compounds for human a1, A2a, A2b and A3 receptors are shown in table 3 below. The empty boxes in the table below indicate that no data has been collected.
Table 3: binding affinities of exemplary Compounds
Figure BDA0002577091620002911
Example 308: FLIPRTMAnd cAMP inhibition assay
The day before the start of the experimenthADORA1/CHO (expression hA1) cells (King. (Genscript)) at 1 × 104Individual cells/well were plated in 384-well polystyrene culture plates. On the day of the experiment, the supernatant was discarded and replaced with 40 μ L of dye per well (FLIPR calcium 5Assay Kit), and 5% CO was added at 37 ℃2Lower incubation plate for 60 min. Subsequently to FLIPRTMInhibition assay test compounds were added at different concentrations. Following 400s incubation with compound, 10 μ M adenosine was added to the cells and the signal captured by FLIPR.
on the day of the experiment, hA2a/CHO, hA2b/CHO, hA3/CHO and mA2a/CHO (Kinsley) were mixed at 5 × 103Individual cells/well were plated in 384-well polystyrene culture plates. At 37 ℃ 5% CO2Next, the compound was preincubated with the cells for 30 min. Subsequently 10. mu.M adenosine was added to the cells and 5% CO at 37 ℃ 2And then the cultivation is carried out for 30 min. The detection reagent (CISBIO) was added and the plates were incubated at room temperature for 60 min. The signal is captured by Envision.
FLIPR of exemplary Compounds in different adenosine receptor overexpressing cell linesTMAnd cAMP inhibitory activity are shown in table 4 below.
Table 4: FLIPR and cAMP inhibitory Activity of exemplary Compounds
Figure BDA0002577091620002921
Figure BDA0002577091620002931
Figure BDA0002577091620002941
Figure BDA0002577091620002951
Figure BDA0002577091620002961
Figure BDA0002577091620002971
Figure BDA0002577091620002981

Claims (12)

1. A compound of formula (Ia-ii):
Figure FDA0002577091610000011
or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
ring a is azaindolizinyl; m is 1, R1Is C1-3An alkyl group; z is a bond; y is cyclobutyl, which may optionally be substituted by R3Mono-or independently poly-substituted therewith, wherein each R3Independently selected from C1-12An alkoxy group.
2. The compound of claim 1, wherein R1Is methyl.
3. The compound of claim 1, wherein Y is cyclobutyl monosubstituted with methoxy.
4. The compound of claim 1, wherein the compound is selected from the group consisting of:
3-amino-N- ((1r,3r) -3-methoxycyclobutyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure FDA0002577091610000012
Oxazol-2-yl) pyrazine-2-carboxamide;
3-amino-N- ((1s,3s) -3-methoxycyclobutyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure FDA0002577091610000013
Oxazol-2-yl) pyrazine-2-carboxamide;
3-amino-N- (3-methoxycyclobutyl) -6- (3-methylimidazo [1, 2-a)]Pyridin-6-yl) -5-, (
Figure FDA0002577091610000014
Oxazol-2-yl) pyrazine-2-carboxamide.
5. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
6. Use of one or more compounds according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of an adenosine receptor-related disease.
7. The use of claim 6, wherein the adenosine receptor-related disease is cancer, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive disorders, HIV, adenosine deaminase-severe combined immunodeficiency (ADA-SCID), acute and chronic heart failure, Chronic Obstructive Pulmonary Disease (COPD), or asthma.
8. The use of claim 7, wherein the cancer is NSCLC, RCC, prostate cancer, or breast cancer.
9. The use of claim 6, wherein the medicament is used in combination with radiation therapy, chemotherapy, or immunotherapy.
10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4 in combination with an immunotherapeutic or chemotherapeutic agent.
11. The compound of claim 10, wherein the immunotherapeutic agent is selected from the group consisting of: an anti-PD-1/PD-L1 antibody, an anti-CTLA-4 antibody, an anti-CD 73 antibody, an anti-CD 39 antibody, an anti-CCR 2 antibody, and any combination thereof.
12. The compound of claim 10, wherein the chemotherapeutic agent is selected from the group consisting of: platinum-based chemotherapeutic agents (cisplatin (CISPLATIN), oxaliplatin (OXALIPLATION)), Docetaxel (Docetaxel), Paclitaxel (Paclitaxel), Doxorubicin (Doxorubicin), Etoposide (Etoposide), Mitoxantrone (Mitoxantrone), and any combination thereof.
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CN115181092A (en) * 2018-08-17 2022-10-14 迪哲(江苏)医药股份有限公司 Pyrazine compounds and uses thereof

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CN1938296A (en) * 2004-04-01 2007-03-28 安斯泰来制药有限公司 Pyrazine derivatives and pharmaceutical use thereof as adenosine antagonists

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