Parallel-ring pyridine steroid synthetase inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a small-molecule inhibitor of steroid synthetase, and also provides application of the steroid synthetase inhibitor.

Description

A cyclic pyridine steroid synthase inhibitor and its preparation method and application

[0001] This application claims priority to the Chinese patent application with application number 202211162092.4 filed with the China National Intellectual Property Administration on September 23, 2022, the entire text of which is hereby incorporated by reference. Technical Field

[0002] The present invention relates to biopharmaceuticals, in particular to steroid synthase inhibitors, i.e., inhibitors that block the biosynthesis of endogenous steroid hormones, and also to the medical uses of these inhibitors. Background Art

[0003] Steroid hormones are important endogenous regulatory factors in the human body, widely involved in various physiological and pathological processes. Alterations in their biosynthesis, signal perception, and transduction processes can cause a variety of serious diseases. Enzymes involved in steroid synthesis are key factors in the biosynthesis of these steroid hormones. Inhibiting these enzymes can directly reduce steroid hormone concentrations and, in turn, treat related diseases.

[0004] Mineralocorticoids, represented by aldosterone, regulate renal tubular function, controlling the homeostasis of potassium, sodium, and water, and thereby regulating blood volume and blood pressure. Recent studies have also shown that aldosterone is a potent inflammatory factor that can induce reactive oxygen species and upregulate the expression of multiple fibrogenic factors, including plasminogen activator inhibitor (PAI). Excessive aldosterone levels are directly associated with conditions such as congestive heart failure, refractory hypertension, chronic kidney disease, diabetic nephropathy, hyperaldosteronism, cardiorenal fibrosis, cardiorenal syndrome, and metabolic syndrome. Aldosterone synthase (CYP11B2) is a key enzyme in aldosterone biosynthesis, and its inhibition can effectively lower aldosterone levels and thereby treat related diseases.

[0005] Cortisone is an important glucocorticoid in the human body that widely regulates immune responses, stress responses, and sugar and lipid metabolism. Abnormal overproduction of cortisone due to tumors in the hypothalamus-pituitary-adrenal glands is known as Cushing's syndrome. High cortisone levels are also directly linked to metabolic syndrome, insulin resistance, obesity, and type 2 diabetes. 11β-hydroxylase (CYP11B1) is a key enzyme in cortisone biosynthesis, and its inhibition can effectively reduce cortisone levels and thereby treat related diseases.

[0006] Bile acids are endogenous steroids secreted by the liver. Besides forming chylomicrons in the small intestine to aid fat absorption, they also serve as potent signaling factors, extensively regulating the synthesis and metabolism of sugars and lipids, as well as pathological processes such as inflammation and fibrosis. CYP7A1 and CYP8B1 are key enzymes in bile acid biosynthesis. Intervention in these enzymes can regulate liver function and metabolism, making them potential targets for the treatment of diseases such as non-alcoholic fatty liver disease, fatty liver disease, cirrhosis, and liver fibrosis.

[0007] Summary of the Invention

[0008] In one aspect, provided herein are compounds of formula (I),

[0009] in

[0010] n is selected from 0, 1 and 2;

[0011] m is selected from 0 and 1;

[0012] X is selected from C, N, O and S;

[0013] L1 is selected from hydrogen, -SO2-, -CO- and -CH2-;

[0014] is a single bond or a double bond;

[0015] Indicates that one or more ring carbon atoms are or are not carbonylated;

[0016] R 11 R is selected from the group consisting of aryl, heteroaryl, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, bicyclic hydrocarbon, azaheterocyclic hydrocarbon and azaheterocyclic ketone; the aryl, heteroaryl, spirocyclic hydrocarbon, bicyclic alkyl, azaheterocyclic hydrocarbon and azaheterocyclic ketone are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, cyclic ether and alkyl optionally substituted with one to three halogens; or R 11 Has the following structure:

[0017] R 12R is selected from hydrogen, alkyl, azacycloalkyl, bicycloalkyl, spirocycloalkyl, azaspirocycloalkyl, oxaspirocycloalkyl, aryl, heteroaryl and is absent, said alkyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, cyclic ether and alkyl optionally substituted with one to three halogens, said azacycloalkyl, bicycloalkyl and spirocycloalkyl being optionally substituted with cyano, fluorophenyl, fluorophenylalkyl or fluorophenylamino; or, R 12 Selected from the following structures:

[0018] wherein q1 and q2 are selected from 1, 2 and 3, R 13 Selected from hydrogen, cyano, cyclic ether and -L2-R 14 , wherein L2 is selected from -SO2-, -CO-, hydrocarbon group and does not exist, R 14 Selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one to three substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate ester.

[0019] In some embodiments, the aryl group is selected from phenyl and naphthyl, and the heteroaryl group is selected from quinolinyl, thienyl, thiazolyl, indolinyl, pyridinyl, furanyl, indazolyl, imidazopyridinyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridinyl, thienopyridinyl, benzoxazolyl, indolonyl, quinolinonyl, triazolopiperazine, imidazopiperazine, and benzoxazinonyl.

[0020] In some embodiments, R 11 is an aryl or heteroaryl group, which is optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens; preferably, R 11 is cyano-substituted phenyl, halogen-substituted benzofuranyl and cyano-substituted benzofuranyl; more preferably, R 11 are p-cyanophenyl, 5-chlorobenzofuran-2-yl and 5-cyanobenzofuran-2-yl.

[0021] In some embodiments, R 12Selected from phenyl, naphthyl, quinolyl, thienyl, pyridinyl, furanyl, indazolyl, imidazopyridinyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridinyl, thienopyridinyl, triazolopiperazine, imidazopiperazine, azetidinyl, azetidinyl, azacyclohexanyl, azabicyclic spiro [3.3]heptane, oxabicyclospiro[3.3]heptane and bicyclo[1.1.1]pentane, which are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, cyclic ether and alkyl optionally substituted with one to three halogens.

[0022] In some embodiments, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0023] In some embodiments, in the compound: n is selected from 0, 1 and 2; m is 1; X is O; L1 is selected from -SO2- and -CO-; is a single bond; R 11 is an aryl, heteroaryl, spirocyclic hydrocarbon group, azaspirocyclic hydrocarbon group, oxaspirocyclic hydrocarbon group, bicyclic hydrocarbon group, azaheterocyclic hydrocarbon group and azaheterocyclic keto group, which is optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximino, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, R 11 is a cyano-substituted phenyl, a cyano-substituted bicyclic hydrocarbon group, a cyano-substituted azaspirocyclic hydrocarbon group, or a cyano-substituted azaheterocyclic hydrocarbon group; more preferably, R 11 is p-cyanophenyl, 1-cyano-bicyclo[1.1.1]pentane, 1-cyanopiperazinyl and 1-cyanodihydropyridinyl; R 12 The alkyl group is selected from the group consisting of alkyl, azacycloalkyl, bicyclic alkyl, spirocycloalkyl, azaspirocycloalkyl, oxaspirocycloalkyl, aryl and heteroaryl, wherein the alkyl, azacycloalkyl, bicyclic alkyl, spirocycloalkyl, azaspirocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, cyclic ether, sulfonyl fluoride, borate ester and alkyl optionally substituted with one to three halogens.

[0024] In some embodiments, the compound is of formula (II):

[0025] wherein: n is selected from 0, 1 and 2; L1 is selected from -SO2- and -CO-; R 15 is selected from alkyl, azacycloalkyl, bicyclic hydrocarbon, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, aryl and heteroaryl, wherein the alkyl, azacycloalkyl, bicyclic hydrocarbon, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted with one to three halogens; preferably, the alkyl is selected from methyl and ethyl, The aryl group is selected from phenyl and naphthyl, the heteroaryl group is selected from quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl, thienopyridinyl, the azacycloalkyl group is selected from azetidinyl, the bicycloalkyl group is selected from bicyclo[1.1.1]pentanyl and bicyclo[2.2.2]octanyl, and the azaspirocycloalkyl group is selected from 2,6-diazabicyclospiro[3.3]heptyl.

[0026] In some embodiments, the compound is of formula (III):

[0027] Among them, R 16 Has the following structure:

[0028] Among them, q1, q2, R 13 and R 14 As defined above.

[0029] In some embodiments, in the compound: n is 0; m is 1; X is S; L1 is selected from -SO2-, -CO- and -CH2-; is a single bond; R 11 is selected from aryl, heteroaryl, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, bicyclic hydrocarbon, azaheterocyclic hydrocarbon and azaheterocyclic keto, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, cyclic ether and alkyl optionally substituted with one to three halogens; preferably, R 11 is cyano-substituted phenyl, halogen-substituted benzofuranyl and cyano-substituted benzofuranyl; more preferably, R 11is p-cyanophenyl, 5-chlorobenzofuran-2-yl and 5-cyanobenzofuran-2-yl; R 12 The alkyl radicals are selected from aryl, heteroaryl, azacycloalkyl, bicyclic alkyl, spirocycloalkyl, azaspirocycloalkyl and oxaspirocycloalkyl, wherein the aryl, heteroaryl, azacycloalkyl, bicyclic alkyl, spirocycloalkyl, azaspirocycloalkyl and oxaspirocycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, thioether, sulfonyl fluoride, borate ester and alkyl optionally substituted with one to three halogens.

[0030] In some embodiments, the compound is a compound of formula (IV):

[0031] Wherein: L1 is selected from -SO2-, -CO- and -CH2-; R 17 is selected from aryl and heteroaryl; the aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogen; preferably, the aryl is phenyl, and the heteroaryl is selected from quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl, thienopyridinyl, indolonyl, quinolinonyl; more preferably, R 17 is p-cyanophenyl, 5-chlorobenzofuran-2-yl and 5-cyanobenzofuran-2-yl; R 18The alkyl radicals are selected from aryl, heteroaryl, azacycloalkyl, bicyclic hydrocarbon, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon and oxaspirocyclic hydrocarbon, wherein the aryl, heteroaryl, azacycloalkyl, bicyclic hydrocarbon, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon and oxaspirocyclic hydrocarbon are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, the aryl is phenyl and naphthyl, and the heteroaryl is phenyl and naphthyl. The radical is selected from quinolinyl, thienyl, pyrazolyl, pyridinyl, furanyl, indazolyl, imidazopyridinyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridinyl, thienopyridinyl, triazolopiperazine, imidazopiperazine, the azacycloalkyl is selected from azetidinyl, the bicycloalkyl is selected from bicyclo[1.1.1]pentanyl and bicyclo[2.2.2]octanyl, the azaspirocycloalkyl is selected from 2-azabicyclospiro[3.3]heptanyl.

[0032] In some embodiments, the compound is a compound of formula (XI):

[0033] Wherein L1 is selected from -SO2-, -CO-, -CH2- or none; R 17 As defined in 10 above, R 29 is cyano, cyclic ether, or phenyl which is optionally substituted by one to three substituents selected from halogen, cyano, and alkoxy.

[0034] In some embodiments, the compound is a compound of formula (XII):

[0035] where R 30 R is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or two substituents selected from halogen, cyano and alkyl; preferably, the aryl is phenyl, and the heteroaryl is selected from pyridyl, indazolyl, benzothiazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyrazolyl, indolonyl, imidazopyridinyl, pyrazolopyridinyl, quinolinonyl, pyrrolopyridinyl; R 31 is selected from the group consisting of phenyl and pyridyl, said phenyl being optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, alkoxy, nitro, amino, hydroxy, acetamido, and alkyl optionally substituted with one to three halogens.

[0036] In some embodiments, the compound is a compound of formula (XIII):

[0037] where R 32 is selected from phenyl and quinolinone, wherein the phenyl and quinolinone groups are optionally substituted by one or two substituents selected from halogen, cyano and alkyl; L4 is selected from -SO2- and -CH2-; R 32 is selected from aryl and heteroaryl, the phenyl and heteroaryl groups are optionally substituted with substituents selected from cyano, nitro and hydroxy; preferably, the heteroaryl group is selected from thienyl and pyridyl.

[0038] In some embodiments, the compound is of formula (XIV):

[0039] where R 13 As defined above.

[0040] In some embodiments, in the compound: n is selected from 0, 1 and 2; m is 0; X is C; L1 is selected from -SO2- and -CO-; is a single bond; R 11 is selected from aryl, heteroaryl, bicyclic hydrocarbon, azacycloalkyl, azaspirocyclic hydrocarbon and azacycloketone; the aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, R 11 is phenyl substituted by cyano, 1-cyano-piperidinyl, 1(2H)-cyano-3,6-dihydropyridinyl; more preferably, R 11 is p-cyanophenyl; R 12 is selected from alkyl, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted with one to three halogens.

[0041] In some embodiments, the compound is of formula (V):

[0042] Among them, R 19is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, the aryl is selected from phenyl and naphthyl, and the heteroaryl is selected from quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl and thienopyridinyl.

[0043] In some embodiments, the compound is a compound of formula (VI):

[0044] Among them, R 11 As defined above; R 20 is selected from alkyl, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, the aryl is phenyl, and the heteroaryl is selected from quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl and thienopyridinyl.

[0045] In some embodiments, the compound is a compound of formula (VII):

[0046] Among them, R 21 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens.

[0047] In some embodiments, the compound is of formula (VIII):

[0048] Among them, R 22is an aryl group, which is optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, the aryl group is phenyl.

[0049] In some embodiments, in the compound: n is 0; m is 0; X is C; L1 is selected from -SO2- and -CO-; is a double bond; R 11 is selected from aryl and heteroaryl; the aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, R 11 is a phenyl group substituted with a cyano group; more preferably, R 11 is p-cyanophenyl; R 12 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens.

[0050] In some embodiments, the compound is a compound of formula (IX):

[0051] wherein L1 is selected from -SO2- and -CO-; R 23 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens.

[0052] In some embodiments, the compound is of formula (X):

[0053] where R 24 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens.

[0054] In some embodiments, the compound is of formula (XV):

[0055] where R 33 Selected from hydrocarbon groups and cycloalkyl groups.

[0056] In some embodiments, the compound is a compound of formula (XVI):

[0057] where R 34 is selected from cyano and halogen, R 13 As defined above, Indicates that one or more ring carbon atoms are or are not carbonylated.

[0058] In some embodiments, the compound is selected from: 4-(4-(benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O1); 4-(4-((4-fluorobenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O2); 4-(4-((3-fluorobenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O3); 4-(4-methylbenzenesulfonyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O4); 4-(4-(3-methylbenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O5); 4-(4-(4-Methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O5); 4-(4-(4-chlorobenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O6); 4-(4-(3-chlorobenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O7); 4-(4-(4-methoxybenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O8); 4-(4-(4-nitrobenzenesulfonyl)-3,4-dihydro-2H-pyrido[ 4,3-b][1,4]oxazin-8-yl)benzonitrile (O9); 4-(4-(3-nitrobenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O10); 4-(4-(4-trifluoromethyl)benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O11); 4-(4-(3-trifluoromethyl)benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O12); 4-(4-(pyridine-3-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1, 4-(4-(oxazin-8-yl)benzonitrile (O13); 4-(4-(methylbenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O14); 4-(4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O15); 4-(4-(thiophene-2-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O16); 4-(4-(naphthalene-1-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O17);4-(4-(naphthalene-2-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O18); 4-(4-(4-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O19); 4-(4-(3-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O20); 4-(4-(2-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl) Benzonitrile (O21); 4-(4-(4-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O22); 4-(4-(3-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O23); 4-(4-(4-trifluoromethylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O24); 4-(4-(3-trifluoromethylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O25); )-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O25); 4-(4-(4-nitrobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O26); 4-(4-(3-nitrobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O27); 4-(4-(4-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O28); 8-yl)benzonitrile (O28); 4-(4-(3-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O29); 4-(4-nicotinoyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O30); 4-(4-(furan-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O31); 4-(4-(2-cyanoacetyl)-3,4-dihydro-2H- Pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O32); 4-(4-(2-chloroacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O33); 4-(4-(2-bromoacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O34); 4-(4-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O35);4-(4-(2-(4-Fluorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O36); 4-(4-(2-(3-Fluorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O37); 4-(4-(2-(4-chlorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O38); 4-(4-(2-(3-chlorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O39); 4-( 4-(2-(4-methoxyphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O40); 4-(4-(2-(3-methoxyphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O41); 4-(4-(2-(4-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O42); 4-(4-(2-(3-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O43); -(4-(2-(2-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O44); 4-(4-(2-(4-trifluoromethylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O45); 4-(4-(2-(3-trifluoromethylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O46); 4-(4-(3-(4-fluorophenyl)propanoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O47 ); 4-(4-(3-(3-fluorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O48); 4-(4-(3-(4-chlorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O49); 4-(4-(3-(3-chlorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O50); 4-(4-(3-(4-methoxyphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O51);4-(4-(3-(4-trifluoromethylphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O53); 4-(4-(3-(3-(trifluoromethylphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O54); 4-(4-(1-((3-fluorophenyl)sulfonyl)piperidine-4-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O55); 4-(4-(azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4] oxazin-8-yl)benzonitrile (O56); 4-(4-(1-(4-fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O57); 4-(4-(1-(3-fluorobenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O58); N-(2-(8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-2-oxoethyl)-4-fluorobenzamide (O59); 4-(4-(1-(4-fluorophenyl)sulfonyl)- )azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O60); 4-(4-(1-((3-fluorophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O61); 4-(4-(1-((4-nitrophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O62); 4-(4-(1-((3-nitrophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O63). -pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O63); 4-(4-1-(thiophen-2-ylsulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O64); 4-(4-(1-toluenesulfonylazetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O65); 4-(4-(1-((3-methoxyphenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O66);4-(4-(1-((4-methoxyphenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O67); 3-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O68); 4-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O69); 4-(4-(1-(m-toluenesulfonyl)azetidine-3-carbonyl)-3,4- dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O70); 4-(4-(3-((3-fluorophenyl)amino)bicyclo[1.1.1]pentane-1-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O71); 4-(4-(5-(4-fluorophenoxy)thiophene-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O72); 4-(4-(6-(3-fluorobenzyl))-2,6-diazabicyclospiro[3.3]heptane-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile )benzonitrile (O73); 3-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O74); 4-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O75); 4-(4-(1-(3-methoxybenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-8-yl)benzonitrile (O76); 4-(4-(1-(4-methoxybenzoyl)azetidine-3 4-(1-(4-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O78); 4-(4-(1-(4-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O79); 3-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-4-carbonyl)azetidin-1-yl)methyl)benzonitrile (O80);4-(4-(1-(4-cyanophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O81); 4-(4-(1-(3-methoxybenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O82); 4-(4-(1-(4-methoxybenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O83); 4-(4-(1-(3-fluorophenyl)azetidine-3-carbonyl)-3,4 4-(4-(1-(4-fluorophenyl)azetidin-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O84); 4-(4-(1-(4-fluorophenyl)azetidin-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O85); 3-(3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-4-carbonyl)azetidin-1-yl)benzonitrile (O86); 4-(3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-4-carbonyl)azetidin-1-yl)benzonitrile ( O87); (8-(Benzo[d]thiazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O88); 5-(4-(1-(3-fluorobenzyl)azetidin-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)indol-2-one (O89); (1-(3-fluorobenzyl)azetidin-3-yl)(8-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone (O90) ; (8-(6-chloro-1H-indol-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O91); 2-(4-(1-(3-fluorobenzyl)azetidin-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-6-cyano-1H-indole (O92); (8-(6-fluoro-1H-indol-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O93);2-(4-(1-(3-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-1H-indole (O94); (8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O95); 2-(4-(1-(3-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyanobenzofuran (O96); 4-(4-(1-(3-Fluorobenzyl)azetidine 4-(4-(1-(3-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-3-oxopiperazine (O99); 4-(4-((3-(3-methoxyphenyl)-4,5-dihydroisoxazol-5-yl)-1-yl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-3-oxopiperazine (O97); 4-(4-(1-(3-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-3-oxopiperazine (O98); 4-(4-(1-(3-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-3-oxopiperazine (O99); 4-(4-((3-(3-methoxyphenyl)-4,5-dihydroisoxazol-5-yl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)azetidine-3-carbonyl 4-(4-((3-phenyl-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O102); 4-(4-((3-benzyl-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O100); 3-(5-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)-4,5-dihydroisoxazol-3-yl)benzonitrile (O101); ][1,4]oxazin-8-yl)benzonitrile (O103); (S)-4-(4-(1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O104); (R)-4-(4-(1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O105); 2-(4-((S)-1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-2,3-dihydro-benzofuran (O106);2-(4-((R)-1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-2,3-dihydrobenzofuran (O107); 8-(5-chlorobenzofuran-2-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (O108); 2-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-benzofuran (O109); 4-(4-((1-(3-cyanobenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b ][1,4]oxazin-8-yl)benzonitrile (O110); 4-(4-((1-(4-cyanobenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O111); 4-(4-((1-(3-methoxybenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O112); 4-(4-((1-(4-methoxybenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile )benzonitrile (O113); 4-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)sulfonyl)benzonitrile (O114); 3-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)sulfonyl)benzonitrile (O115); 4-(4-((1-((4-fluorophenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O116); 16); 4-(4-((1-((3-fluorophenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O117); 4-(4-((1-((3-methoxyphenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O119); 4-(4-((1-((4-methoxyphenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O118);3-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)methyl)benzonitrile (O120); 4-(4-((1-(4-cyanobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O121); 4-(4-((1-(3-fluorobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O122); 4-(4-((1-(4-fluorobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O123); )sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O123); 4-(4-((1-(3-methoxybenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O124); 4-(4-((1-(4-methoxybenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O125); 4-(4-((1-(3-fluorophenyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1 ,4]oxazin-8-yl)benzonitrile (O126); 4-(4-((1-(4-fluorophenyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O127); 4-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O128); 2-(4-((4-cyanophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyanobenzofuran (O129); 4-((8-(4-cyanophenyl)-2,3-dihydro-4H 4-((8-(2-oxoindole-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O130); 4-((8-(benzo[d]oxazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O131); 4-((8-(2-oxoindole-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O132); 3-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-bicyclo[1.1.1]pentane (O133);6-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-2-cyano-2,6-diazabicyclospiro[3.3]heptane (O134); (8-(5,6-dihydro-[1,2,4]triazolo[4,3-a]piperazin-7(8H)-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidine-3-yl)methanone (O135); 4-(4-(3-(3-fluorobenzyl)azetidine-1-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl) )benzonitrile (O136); (8-(5,6-dihydro-[1,2,4]imidazo[4,3-a]piperazin-7(8H)-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O137); 4-(4-(3-fluorobenzyl)-3 ,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S1); 4-(4-(4-fluorobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S2); 4-(4-(3-nitrobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][ 1,4]thiazin-8-yl)benzonitrile (S3); 4-(4-(3-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S4); 4-(4-(4-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S5) ; 4-(4-(4-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S6); 4-(4-nicotinoyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S7); 4-(4-(phenylsulfonyl)-3,4-dihydro-2 benzonitrile (S8); 4-(4-((3-fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S9); 4-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S10); 4-(4-(m-tolylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S11); 4-(4-tolyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S12);4-(4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S13); 4-(4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S14); 4-(4-((4-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S15); 4-(4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S16); 4-(4-((4-trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S17); 4-((4-((4-nitrophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S18); 4-(4-((4-nitrophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S19); 3-(((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S20); 4-((8-(4-cyanophenyl)-2,3-dihydro- 4-(4-(naphthalen-1-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S23); 4-(4-(thiophen-2-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S24); 4-(4-(pyridin-3-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S25); 4-(4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S25); 4-(4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S26); 3-(4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S27); 8-(4-chlorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S28); 8-(3-chlorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S29);8-(4-Fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S30); 8-(3-Fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S31); 4-((4-methoxyphenyl)sulfonyl)-8-(4-trifluoromethylphenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S32); 8-(4-Fluoro-3-methylphenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b] [1,4]thiazine (S33); 8-(3-chloro-4-fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S34); 2-fluoro-4-(4-(((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S35); 4-((4-methoxyphenyl)sulfonyl)-8-(thiophen-3-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S36); 4-((4-methoxyphenyl)sulfonyl)-8-(thiophen-2-yl)-3,4- Dihydro-2H-pyrido[4,3-b][1,4]thiazine (S37); 8-(furan-2-yl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S38); 4-((4-methoxyphenyl)sulfonyl)-8-(1H-pyrazol-4-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S39); 4-((8-(benzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S40); 4-((8-(5-chlorobenzofuran-2-yl)- 2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S41); 2-(4-((4-cyanophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)-5-cyano-benzofuran (S42); 4-((8-(Benzo[b]thiophen-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S43); 4-((8-(Benzofuran-5-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S44);4-((8-(1-methyl-1H-indol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S45); 4-((8-(Benzo[d]thiazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S46); 4-((8-(Benzoxazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S47); 4-((8-(1H-indazol-5-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile 4-((8-(1H-benzo[d]imidazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S49); 4-((8-(imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S50); 4-((8-(2-indolin-5-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S51); 4-((8-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) )-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S52); 8-(5-chlorobenzofuran-2-yl)-4-((6-methoxypyridin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)pyridin-2-ol (S54); 8-(5-chlorobenzofuran-2-yl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)pyridin-2-ol (S55); [1,4]thiazine (S55); 8-(5-chlorobenzofuran-2-yl)-4-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S56); N-(5-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-4-methylthiazol-2-yl)acetamide (S57); 1-(5-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)indol-1-yl)ethan-1-one (S58);6-((8-(5-chloro-benzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (S59); 8-(5-chlorobenzofuran-2-yl)-4-((5-chlorothien-2-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S60); 8-(5-chlorobenzofuran-2-yl)-4-(piperidin-4-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S61); 4-(azetidin-3-ylsulfonyl)- 4-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyano-piperidine (S63); 3-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyano-azetidine (S64); 3-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyano-azetidine (S65); b][1,4]thiazin-4-yl)sulfonyl)-1-cyano-bicyclo[1.1.1]pentane (S65); 4-((2-oxabicyclospiro[3.3]heptan-6-yl)sulfonyl)-8-(5-chlorobenzofuran-2-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-2-cyano-2-azabicyclospiro[3.3]pentane (S67); 4-(4-(3-cyclobutylamino-sulfonyl)-3,4-dihydro-2H-pyrido[ 4,3-b][1,4]thiazin-8-yl)benzonitrile (11); 4-(4-((1-(4-fluorophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S68); 4-(4-((1-(3-fluorophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S69); 4-(4-((1-(4-cyanophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S70);3-(3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyclobutylaminocarbonyl)benzonitrile (S71); 4-(4-((1-(4-methoxyphenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S72); 4-(4-((1-(3-methoxyphenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S73); 4-(4-((1-((4-fluorophenyl)sulfonyl)-3 4-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyclobutylamino)sulfonyl)benzonitrile (S76); 3-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S77); 4-((1-((3-fluorophenyl)sulfonyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S78); 4-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyclobutylamino)sulfonyl)benzonitrile (S79); 4-(4-((1-((4-methoxyphenyl)sulfonyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S78); 4-(4-((1-((3-methoxyphenyl)sulfonyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S79); 4-(4-((1-(4-cyanophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4 ,3-b][1,4]thiazin-8-yl)benzonitrile (S80); 3-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyclobutylamino)methyl)benzonitrile (S81); 4-(4-((1-(4-fluorophenyl)3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S82); 4-(4-((1-(3-fluorophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S83);4-(4-((1-(4-methoxyphenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S84); 4-(4-((1-(3-methoxyphenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S85); N-(2-(8-(4-cyanophenyl)-3,4-dihydro -2H-pyrido[4,3-b][1,4]thiazin-4-carbonyl)phenyl)acetamide (S86); 4-(4-(3-(trifluoromethyl)benzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S87); 4-(4-(4-(trifluoromethyl)benzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S88); 4-(4-(4 4-(4-(2-Methylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S89); 4-(4-(2-Methylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S90); 4-(4-(3-Methylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S91); 4-(4- (4-Chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S92); 4-(4-(3-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S93); 4-(4-(4-cyanobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S94); 3-(8- (4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-4-carbonyl)benzonitrile (S95); 4-(4-(3-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S96); 4-(4-(4-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S97); 2- (4-(4-Methoxyphenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)-5-carbonitrile-benzofuran (S98); 4-(3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S99); 4-(4-(4-chlorobenzoyl)-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S100);1-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-3-cyano-azetidine (S101); 8-(5-chlorobenzofuran-2-yl)-4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]piperazin-7(8H)-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S102); 8-(5-chlorobenzofuran-2-yl)-4-((1-(oxetan-3-yl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S103); 103); 4-(1-toluenesulfonyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C1); 4-{1-[(4-nitrophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C2); 4-{1-[(4-methoxyphenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C3); 4-(1-{[4-(trifluoromethyl)phenyl]sulfonyl}-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C4); 4-{1-[(6-chloropyridin-3-yl)sulfonyl]-2,3-dihydro-1H- Pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C5); 4-{1-[(3-fluorophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C6); 4-{1-[(4-fluorophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C7); 4-[1-(m-toluenesulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C8); 4-{1-[(3-nitrophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C9); 4-[1-(pyridin-3-ylsulfonyl) -2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C10); 4-[1-(quinolin-8-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C11); 4-[1-(naphthalen-2-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C12); 4-{1-[(4-chlorophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C13); 4-{1-[(3-chlorophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C14);4-{[4-(4-cyanophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]sulfonyl}benzonitrile (C15); 3-{[4-(4-cyanophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]sulfonyl}benzonitrile (C16); 4-[1-(thiophen-2-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C17); 4-[1-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C18); 4-{1-[(3-methoxyphenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2 ,3-c]pyridin-4-yl}benzonitrile (C19); 4-{1-[(3-[trifluoromethyl]phenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C20); 4-[1-(phenylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C21); 4-[1-(4-(trifluoromethyl)benzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C22); 4-[1-(3-(trifluoromethyl)benzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C23); 4-[1-(4-methoxyphenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C24); benzonitrile (C24); 4-[1-(4-fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C25); 4-[1-(3-methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2, 3-c]pyridin-4-yl]benzonitrile (C26); 4-[1-(3-nitrobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C27); 4-[1-(3-fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C28); 4-( 1-nicotinoyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C29); 4-[1-(4-nitrobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C30); 4-[1-(2-fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3 -c]pyridin-4-yl]benzonitrile (C31); 4-[1-(2-(trifluoromethyl)benzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C32); 4-[1-(4-methylbenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C33);4-[1-(2-Methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C34); 4-[1-(2-nitrobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C35); 4-[1-(2-methylbenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C36); 3-[4-(4-cyanophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carbonyl]benzonitrile (C37); 4-[1-(4-chlorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl]benzonitrile (C38); benzonitrile (C38); 4-[1-(3-chlorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C39); 4-[1-(3-methylbenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C40); 4-(1-benzoyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C41); 4-(1-pivaloyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C42); 4-[1-(2-chloroacetyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C43); C43); 4-[1-(furan-2-carbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C44); 4-[1-(3-methylthiophene-2-carbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C45); 4-[1-(thiophene-2-carbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C46); methyl 4-[4-(4-cyanophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carbonyl]benzoate (C47); 4-[1-(4-cyanobenzoyl)-2,3-dihydro-1H-pyrrolo[2, 3-c]pyridin-4-yl]benzonitrile (C48); 4-{1-[4-(bromomethyl)benzoyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C49); [4-(1H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C50); (2-fluorophenyl)[4-(1-methyl-1H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (C51); (2-fluorophenyl)(4-(3-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)methanone (C52);(2-Fluorophenyl)[4-(3-nitrophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (C53); [4-(4-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C54); 3-[1-(2-fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C55); (2-Fluorophenyl)[4-(furan-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (C56); (2-Fluorophenyl)[4-[imidazo[1,2-a]pyridin-6-yl]benzoyl] ]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl}methanone (C57); {4-(Benzo[d]thiazol-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl}(2-fluorophenyl)methanone (C58); [4-(1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C59); [4-(Benzofuran-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C60); [4-(Benzo[b]thiophen-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C61); [4-(1H-indol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C62); [4-(benzofuran-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C63); 4-{1-(2-[o-tolyl]acetyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C64); 4-{1-[2-(2-bromophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c ]pyridin-4-yl}benzonitrile (C65); 4-{1-[2-(m-tolyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C66); 4-{1-[2-(2-fluorophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C67); 4-{1-[2-(3-methoxyphenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C68); 4-{1-[2-(4-fluorophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C69);4-{1-[2-(2-nitrophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C70); 4-{1-[2-(3-chlorophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C71); 4-{1-[2-(p-tolyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C72); 4-{1-[2-(4-bromophenyl)acetyl] -2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C73); 4-(1-{2-[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C74); 4-(1-{2-[4-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C75); 4-{1-[2-(4-methoxyphenyl)acetyl}-2,3-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C76); 4-{1-[2-(4-chlorophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C77); 4-(4-(5-chlorobenzofuran-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)benzonitrile (C78); 2-(1-(4 (4-(5-Chloro-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (C80); 2-(1-(1-(3-fluorobenzyl)azetidin-3-yl)methanone (C81); (4-(5-Chloro-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-cyanobenzofuran (C79); (4-(5-Chloro-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (C80); (4-(5-Chloro-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (C81); (4-(5-Chloro-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (C82); (4-(5-Chloro-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (C83); (4-(5-Chloro-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c] -carbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-cyano-1H-indole (C81); 4-(1-(3-methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1(2H)-cyano-3,6-dihydropyridine (C82); 4-(1-(3-methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[ 2,3-c]pyridin-4-yl)-1-cyanopiperazine (C83); 4-{1-[(4-nitrophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E1); 4-(1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (E2); 4-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E3);4-[1-(m-Toluenesulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E4); 4-{1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E5); 4-{1-[(4-fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E6); 4-{1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E7); 4-{1-[(4-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E8); 4-{1-[(4- benzonitrile (E11); 4-{1-[(3-fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E12); 4-{1-[(3-nitrophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E13); 4-{[4-(4-cyanophenyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]sulfonyl}benzonitrile (E14); Pyrrolo[2,3-c]pyridin-1-yl]sulfonyl}benzonitrile (E14); 4-[1-(naphthalen-1-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E15); 4-[1-(naphthalen-2-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E16); 4-[1-(thiophen-2-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E17); 4-{1-[(6-chloropyridin-3-yl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E18); 4-[1-(perfluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin- -4-yl]benzonitrile (E19); 4-{1-[4-(trifluoromethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E20); 4-[1-(2-iodobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E21); 4-[1-(3-nitrobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E22); 4-{1-[3-(trifluoromethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E23); 4-[1-(3-methoxybenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E24);4-[1-(2-methoxybenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E25); 4-{1-[2-(trifluoromethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E26); 4-[1-(2-methylbenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E27); 4-[1-(2-fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E28); 28); 4-[1-(2-nitrobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E29); 4-[1-(4-fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E30); [4-(Benzo[b]thiophen-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E31); [4-(Benzofuran-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl] ](4-fluorophenyl)methanone (E32); [4-(Benzofuran-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E33); [4-(1H-indol-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E34); (4-fluorophenyl)[4-(1-methyl-1H-indazol-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (E35); [4-(Benzofuran-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (E36); [d]thiazol-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E36); (4-fluorophenyl)[4-(imidazo[1,2-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (E37); (4-(benzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)(4-fluorophenyl)methanone (E38); (4-fluorophenyl)(4-(imidazo[1,2-a]pyridin- 7-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methanone (E39); 4-(1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-b]piperazin-8-yl)benzonitrile (N1); 8-(4-fluorophenyl)-1-methyl-1,4-dihydropyrido[3,4-b]piperazine-2,3-dione (N2); 4-(1-methyl-1,2, 3,4-tetrahydropyrido[3,4-b]piperazin-8-yl)benzonitrile (N3); 4-((8-(4-cyanophenyl)-1-methyl-2,3-dihydropyrido[3,4-b]piperazin-4(1H)-yl)sulfonyl)benzonitrile (N4); 4-(4-(4-fluorobenzoyl)-1-methyl-1,2,3,4-tetrahydropyrido[3,4-b]piperazin-8-yl)benzonitrile (N5);4-(1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)benzonitrile (N6); and 4-(1-cyclopropyl-1H-imidazo[4,5-c]pyridin-7-yl)benzonitrile (N7).

[0059] In another aspect, provided herein is a pharmaceutical composition comprising the above-mentioned compound and a pharmaceutically acceptable carrier thereof.

[0060] In another aspect, the present invention provides the use of the above-mentioned compound in the preparation of a medicament for treating diseases related to the synthesis of steroidal compounds.

[0061] In another aspect, provided herein is a method for treating a disease associated with endogenous steroid compounds in a subject, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition described above.

[0062] In some embodiments, the steroidal compound is selected from aldosterone, Cortisol, and / or bile acid.

[0063] In some embodiments, the aldosterone-related disease is selected from primary aldosteronism, secondary aldosteronism, heart failure, renal failure, hypertension, obesity, renal fibrosis, coronary heart disease, cardiac hypertrophy, cardiac fibrosis, arrhythmia, edema, hypokalemia and resulting muscle weakness, cardiac fibrillation, weak myocardial contractility, congestive heart failure, chronic kidney disease, diabetic nephropathy, cardiorenal syndrome, metabolic syndrome, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver fibrosis, and cirrhosis.

[0064] In some embodiments, the disease associated with the synthesis of Cortisol is selected from Cushing's syndrome, metabolic syndrome, insulin resistance, obesity and type II diabetes, breast cancer, prostate cancer, tumor metastasis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, addiction to substances, addiction to behaviors, substance use disorders, mood disorders, anxiety disorders, bipolar disorder, sleep disorders, insomnia, post-traumatic stress syndrome, borderline personality disorder, disruptive behavior disorders, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, eating disorders, obesity, depression, premenstrual syndrome (PMS), obsessive-compulsive disorder (OCD), social anxiety disorder, generalized anxiety disorder.

[0065] In some embodiments, the disease associated with bile acid synthesis is selected from cardiovascular disease, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, liver fibrosis, hepatocellular carcinoma, chronic colitis, ulcerative colitis.

[0066] In another aspect, provided herein is any of the following compounds:

[0067] In another aspect, provided herein are methods for preparing the above-described compounds. DETAILED DESCRIPTION

[0068] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0069] "Optionally substituted with one or more..." herein means that the described group may be substituted with one, two, three, four, five, six or more identical or different substituents among the listed substituents, or is not substituted with any substituent; preferably, it means that the described group may be substituted with one, two or three identical or different substituents among the listed substituents, or is not substituted with any substituent; more preferably, it means that the described group may be substituted with one, two or three identical substituents among the listed substituents, or is not substituted with any substituent.

[0070] The term "alkyl" herein refers to a straight or branched chain saturated hydrocarbon group (C 1-12 In some embodiments, the alkyl group has 1 to 7 carbon atoms (C 1-7 In a preferred embodiment, the alkyl group has 1 to 4 carbon atoms (C 1-4 Examples of alkyl groups include methyl, ethyl, propyl and isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Particularly preferred alkyl groups are methyl and ethyl.

[0071] The term "alkoxy" herein refers to a group of formula RO-, wherein R is an alkyl group, for example, C 1-12 Alkyl, preferably C 1- 7 alkyl, more preferably C 1-4 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Preferred alkoxy groups include methoxy.

[0072] The term "aryl" as used herein refers to a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. A particularly preferred aryl group is phenyl.

[0073] The term "cyano" refers herein to an N≡C- group.

[0074] The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. Preferred halogens are chlorine and fluorine. A particularly preferred halogen is fluorine.

[0075] The term "heteroaryl" herein refers to an aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. The example of heteroaryl includes but is not limited to pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridyl, purinyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl, thienopyridyl, quinolyl, isoquinolyl, quinazolinyl and quinoxalinyl. Preferred heteroaryl includes pyridyl, thienyl, quinolyl and pyrazolyl.

[0076] "Alkoxyacyl" herein refers to Where R is an alkyl group, for example, C 1-12 Alkyl, preferably C 1-7 Alkyl, more preferably C 1-4 alkyl.

[0077] "Borate group" herein refers to where R 25 and R 26 are independently alkyl or hydrogen (R 25 and R 26 are not hydrogen at the same time), for example, C 1-12 Alkyl, preferably C 1-7 Alkyl, more preferably C 1-4 alkyl.

[0078] "Sulfoximino" refers to where R 27 and R 28 are independently hydrogen, alkyl, aryl, or heteroaryl.

[0079] "Azacycloalkyl" herein refers to a monoazacycloalkyl or diazacycloalkyl group, wherein the cycloalkyl group may be a five-membered or six-membered saturated hydrocarbon group (i.e., an azacycloalkyl group) or an unsaturated hydrocarbon group. Examples of azacycloalkyl groups include, but are not limited to, piperidinyl, dihydropyridinyl, piperazinyl, and the like.

[0080] "Azacycloketo" herein refers to an oxazacycloalkyl group, such as 3-oxopiperazine.

[0081] "Bicycloalkyl" herein refers to a bicyclic bridged cycloalkyl group which may be further substituted, for example, by a cyano group. Examples of bicycloalkyl groups include, but are not limited to, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.2]nonanyl, and bicyclo[3.3.2]decanyl. In this context, bicycloalkyl groups preferably include bicyclo[1.1.1]pentanyl groups of the formula

[0082] "Spirocyclic hydrocarbon group" herein refers to a monocyclic hydrocarbon group, especially a saturated monocyclic hydrocarbon group containing at least one heteroatom (such as O and N) in the ring. Examples of spirocyclic hydrocarbon groups include, but are not limited to, the following substituents:

[0083] The ring carbon atoms and / or nitrogen atoms may be further substituted.

[0084] The above-mentioned alkyl, aryl, heteroaryl, azacycloalkyl, azacycloketo, spirocycloalkyl, and bicycloalkyl groups may be substituted with one or more substituents. In some embodiments, the alkyl group may be substituted with one or more substituents selected from halogen and cyano. Preferred substituted alkyl groups include cyanoalkyl, chloroalkyl, fluoroalkyl, and bromoalkyl, such as cyanomethyl, cyanoethyl, chloromethyl, chloroethyl, bromoethyl, bromomethyl, bromoethyl, trifluoromethyl, and the like.

[0085] In some embodiments, the aryl group may be substituted with one or more substituents selected from halogen, cyano, nitro, alkoxy, alkoxyacyl, and optionally substituted alkyl. Preferred substituted aryl groups include halophenyl, cyanophenyl, alkylphenyl, alkoxyphenyl, and nitrophenyl. The substitution position on the phenyl group may be ortho, meta, and para, or a combination thereof. The number of substituents on the phenyl group may be 1, 2, 3, 4, or 5, preferably 1 or 2. The example of substituted phenyl includes but is not limited to, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-cyanophenyl, 4-cyanophenyl, perfluorophenyl, 4-fluoro-3-methylphenyl, 3-chloro-4-fluorophenyl and 3-fluoro-4-cyanophenyl, wherein the alkyl as substituent can be further substituted by halogen or cyano. When aryl is naphthyl, it can be 1-naphthyl or 2-naphthyl.

[0086] In some embodiments, the heteroaryl group may be substituted with one or more substituents selected from halogen, cyano, nitro, alkoxy, and optionally substituted alkyl. The substitution positions on the heteroaryl group may be different ring carbon atoms, and the number of substituents may be 1, 2, 3, 4, or 5, preferably 1 or 2. Examples of substituted heteroaryl groups include, but are not limited to, chloroheteroaryl groups, such as pyridyl; and alkyl-substituted heteroaryl groups, such as methylthienyl and methylindazolyl.

[0087] When aryl and heteroaryl are used as substituents, they can be connected to the substituted group at different ring carbon atoms, for example:

[0088] The thick solid line The position of attachment to the substituted group is shown.

[0089] In some embodiments, provided herein are compounds of formula (I),

[0090] in

[0091] n is selected from 0, 1 and 2;

[0092] m is selected from 0 and 1;

[0093] X is selected from C, O and S;

[0094] L1 is selected from -SO2-, -CO- and -CH2-;

[0095] is a single bond or a double bond;

[0096] R 11 is selected from the group consisting of aryl, heteroaryl, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, bicyclic hydrocarbon, azaheterocyclic hydrocarbon and azaheterocyclic ketone; the aryl, heteroaryl, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, bicyclic hydrocarbon, azaheterocyclic hydrocarbon and azaheterocyclic ketone are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate ester and alkyl optionally substituted with one to three halogens;

[0097] R 12is selected from alkyl, azacycloalkyl, bicyclic hydrocarbon, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, aryl and heteroaryl, wherein the alkyl, azacycloalkyl, bicyclic hydrocarbon, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximino, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted with one to three halogens; or, R 12 Has the following structure:

[0098] wherein q1 and q2 are selected from 1, 2 and 3, R 13 Selected from hydrogen and -L2-R 14 , wherein L2 is selected from -SO2- or -CO-, R 14 Selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one to three substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate ester.

[0099] The above-mentioned alkyl, aryl and heteroaryl groups and substituted alkyl, aryl and heteroaryl groups are as defined above. Therefore, the compounds of formula (I) may include the specific compounds explicitly listed herein, and also include specific compounds that are not explicitly listed but are obtained by selecting specific substituents.

[0100] In some specific embodiments, provided herein are compounds of formula (II):

[0101] in:

[0102] n is selected from 0, 1 and 2;

[0103] L1 is selected from -SO2- and -CO-;

[0104] R 15 As defined above.

[0105] In other specific embodiments, provided herein are compounds of formula (III):

[0106] in,

[0107] R 16 Has the following structure:

[0108] Among them, q1, q2, R 13 and R 14 As defined above.

[0109] In other specific embodiments, provided herein are compounds of formula (IV):

[0110] in:

[0111] L1 is selected from -SO2-, -CO- and -CH2-;

[0112] R 17 and R 18 As defined above.

[0113] In other specific embodiments, provided herein are compounds of formula (V):

[0114] Among them, R 19 As defined above.

[0115] In other specific embodiments, provided herein are compounds of formula (VI):

[0116] Among them, R 20 As defined above.

[0117] In other specific embodiments, provided herein are compounds of formula (VII):

[0118] Among them, R 21 As defined above.

[0119] In other specific embodiments, provided herein are compounds of formula (VIII):

[0120] Among them, R 22 As defined above.

[0121] In other specific embodiments, provided herein are compounds of formula (IX):

[0122] wherein L1 is selected from -SO2- and -CO-; R 23 As defined above.

[0123] In other specific embodiments, provided herein are compounds of formula (X):

[0124] where R 24 As defined above.

[0125] The compounds of formula (I)-(X) encompass all conformational isomers thereof, such as cis-trans isomers. The compounds of formula (I)-(X) encompass all optical isomers thereof, such as enantiomers and diastereomers, as well as racemates. The compounds of formula (I)-(X) also encompass tautomers and stereoisomers thereof, as well as any mixtures thereof.

[0126] Also provided herein are methods for preparing compounds of formula (I)-(X), as well as intermediates involved in preparing compounds of formula (I)-(X). These intermediates include, but are not limited to, the following compounds:

[0127] as well as

[0128] In other embodiments, provided herein are pharmaceutical compositions comprising at least one compound of Formula (I)-(X) and a pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" herein refers to a solid or liquid diluent, filler, antioxidant, stabilizer, or the like that can be safely administered, is suitable for administration to humans and / or animals without excessive adverse side effects, and is suitable for maintaining the activity of the drug or active agent contained therein. Standard pharmaceutical carriers can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed., 1995. Depending on the route of administration, various carriers well known in the art may be used, including, but not limited to, sugars, starches, cellulose and its derivatives, maltose, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer, emulsifiers, isotonic saline and / or pyrogen-free water, and the like. The pharmaceutical compositions provided herein can be administered to a subject using any appropriate route, for example, orally, intravenously, intramuscularly, subcutaneously, subperitoneally, rectally, sublingually, by inhalation, transdermally, or the like.

[0129] When used for oral administration to a subject, the carrier allows the compound of formula (I)-(X) to be formulated into tablets, pills, lozenges, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained by adding the compound of formula (I)-(X) of the present disclosure to a solid excipient, optionally grinding the resulting mixture, and, if desired, processing the particle mixture to obtain a tablet or lozenge core after adding a suitable adjuvant. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant can also be added.

[0130] When used for parenteral administration to a subject, the compound of formula (I)-(X) can be formulated to be suitable for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations can be present in unit dosage form, for example in ampoules or multi-dose containers, with the addition of preservatives. Pharmaceutical compositions can take the form of suspensions, solutions or emulsions in oily or aqueous media, and can contain preparatons, such as suspending agents, stabilizers and / or dispersants. Pharmaceutical compositions for parenteral administration include aqueous solutions of the compound of formula (I)-(X) in water-soluble form. In addition, suspensions of the compound of formula (I)-(X) can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound and allow the preparation of highly concentrated solutions. Alternatively, the pharmaceutical compositions provided herein may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water or a lipophilic solvent, before use.

[0131] The compounds of formula (I)-(X) can also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases. In addition to the preparations previously described, the compounds of the present disclosure can also be formulated into depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present disclosure can be formulated together with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins.

[0132] In particular, the compounds of formula (I)-(X) can be administered orally, buccally or sublingually in tablet form containing excipients such as starch or lactose, or in capsule form alone or in admixture with excipients, or in elixir or suspension form containing flavorings or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives such as suspending agents.

[0133] The exact formulation, route of administration and dosage of the pharmaceutical composition can be determined by the individual physician according to the diagnosed condition or disease. The dosage and dosing interval can be adjusted individually to provide sufficient to maintain the desired therapeutic effect.

[0134] In other embodiments, provided herein is the use of a compound of Formula (I)-(X) for the preparation of a medicament for treating a disease related to the synthesis and / or metabolism of a steroidal compound in a subject.

[0135] "Steroids" herein refer to a class of natural compounds that are widely present in nature, including mineralocorticoids, glucocorticoids, phytosterols, bile acids, C21 steroids, insect allergens, cardiac glycosides, steroidal saponins, steroidal alkaloids, saponins and sex hormones. Steroids have one thing in common in their structure, that is, they have the basic skeleton structure of cyclopentane polyhydrophenanthrene, and in addition, they usually have two angular methyl groups (C-10, C-13) and a side chain or oxygen-containing group such as hydroxyl, carbonyl, etc. (C-17) containing different numbers of carbon atoms on the cyclopentane polyhydrophenanthrene mother nucleus. Examples of steroids include aldosterone, cortisol / cortisone, corticosterone and / or bile acid. Preferably, the above-mentioned diseases are associated with an increase in aldosterone, cortisol, corticosterone and / or bile acid levels in the body.

[0136] In other embodiments, provided herein are methods for treating a disease associated with abnormal steroid levels in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I)-(X) or the aforementioned pharmaceutical composition. The compounds of Formula (I)-(X) can, for example, act as inhibitors of the aldosterone synthase CYP11B2, the cortisone biosynthetic enzyme CYP11B1 (11β hydroxylase), and the bile acid biosynthetic enzyme CYP7A1 and / or CYP8B1 in vivo, thereby inhibiting the synthesis of aldosterone, cortisol, corticosterone, and / or bile acids.

[0137] Diseases associated with abnormal (e.g., elevated) aldosterone levels include, but are not limited to, primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy and cardiac fibrosis, cardiovascular damage, plasma renin suppression, renal fibrosis, arrhythmia, nephropathy, edema and muscle weakness caused by hypokalemia, cardiac fibrillation and weakened myocardial contraction, congestive heart failure, refractory hypertension, chronic kidney disease, diabetic nephropathy, hyperaldosteronism, cardiorenal fibrosis, cardiorenal syndrome, metabolic syndrome. Preferably, the diseases associated with abnormal (e.g., elevated) aldosterone levels are primary and secondary aldosteronism.

[0138] Diseases associated with abnormal (e.g., elevated) cortisol levels primarily include those associated with abnormal HPA axis activity. The HPA axis refers to the hypothalamus-pituitary-adrenal axis, which includes the positive and negative feedback interactions between the following three endocrine glands: the hypothalamus, pituitary gland, and adrenal glands, which form the neuroendocrine system. The hormones released by the endocrine glands influence the body's response to stress, regulating body processes (such as digestion), the immune system, emotions and mood, sexual desire, and energy storage and consumption. Corticotropin-releasing hormone (CRH or CRF) is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress. Other factors that affect CRH release include physical activity, disease, blood levels of cortisol, and circadian rhythms. Under the influence of neurotransmitters such as dopamine, serotonin, and norepinephrine (norepinephrine), stress activates the HPA axis. Chronic stress activates the HPA axis in different ways, depending on many factors, including whether the stressor is controllable, threats to physical integrity, trauma, individual physiology, social quality, etc. For example, oxytocin secreted under positive social influences inhibits the HPA axis and resists stress. In healthy individuals, cortisol levels show a special diurnal variation, wherein levels reach a peak shortly after waking up, gradually decline during the late morning and midday, rise again in the late afternoon, and decline again at night, reaching a trough in the middle of the night. Abnormalities in this cycle lead to pathological conditions. For example, a flat cortisol cycle leads to chronic fatigue syndrome, insomnia and fatigue, and increased cortisol production mediates the alert response to stress, systemic adaptation syndrome, immunosuppression, etc. For example, Cushing's syndrome, Cushing's disease, pseudo-Cushing's syndrome, or pituitary or ectopic tumors are characterized by increased cortisol levels in plasma. Preferably, the disease associated with abnormal (e.g., elevated) Cortisol levels is selected from substance addiction, behavioral addiction, substance use disorders, mood disorders, anxiety disorders, bipolar disorder, sleep disorders, insomnia, post-traumatic stress syndrome, borderline personality disorder, disruptive behavior disorder, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, eating disorders, obesity, depression, amenorrhea, premenstrual syndrome (PMS), obsessive-compulsive disorder (OCD), social anxiety disorder, generalized anxiety disorder, dysthymia, schizophrenia, Cushing's syndrome, metabolic syndrome, insulin resistance, obesity, and type 2 diabetes.

[0139] Bile acids are physiological detergents that play an important role in intestinal absorption and the transport of lipids, nutrients, and vitamins. They are also signaling molecules that activate nuclear receptors and regulate cellular signaling pathways that regulate lipid, glucose, and energy metabolism. Therefore, diseases that require inhibition of bile acid levels include, for example, cardiovascular disease, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, and liver disease. Such cardiovascular diseases, fatty acid metabolism and glucose utilization disorders include, but are not limited to, hypercholesterolemia; fatty acid metabolism disorders; type I and type II diabetes; complications of diabetes, including cataracts, microvascular disease and macrovascular disease, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmias and vascular restenosis; diabetes-related diseases, such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, hyperlipidemia including hypertriglyceridemia, metabolic syndrome (Syndrome X), atherosclerosis and hypertension; and for increasing high-density lipoprotein levels. Such gastrointestinal diseases and disorders include constipation (including chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent / occasional constipation, constipation secondary to diabetes, constipation secondary to stroke, constipation secondary to chronic kidney disease, constipation secondary to multiple sclerosis, constipation secondary to Parkinson's disease, constipation secondary to systemic sclerosis, medication-induced constipation, irritable bowel syndrome with constipation (IBS-C), mixed irritable bowel syndrome (IBS-M), pediatric functional constipation, and opioid-induced constipation); Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileal inflammation; and reflux disease and its complications, such as Barrett's esophagus. esophagus), bile reflux esophagitis and bile reflux gastritis. The liver disease is any disease in the liver and its connected organs (such as the pancreas, portal vein, liver parenchyma, intrahepatic biliary tree, extrahepatic biliary tree and gallbladder). In some embodiments, the liver disease is a bile acid-dependent liver disease, including but not limited to inherited liver metabolism disorders; inborn errors of bile acid synthesis; congenital bile duct anomalies; biliary atresia; post-Kasai biliary atresia; post-liver transplant biliary atresia; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; cerebrotendinous xanthomatosis; secondary BA synthesis defects; Zellweger's syndrome; cystic fibrosis-related liver disease; α1-antitrypsin deficiency;Alagilles syndrome (ALGS); Byler syndrome; primary bile acid (BA) synthesis defect; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3, and nonspecific PFIC, PFIC after bile shunt surgery, and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2, and nonspecific BRIC, BRIC after bile shunt surgery, and BRIC after liver transplantation; autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); portal hypertension; cholestasis; Down syndrome cholestasis cholestasis); drug-induced cholestasis; intrahepatic cholestasis of pregnancy (jaundice of pregnancy); intrahepatic cholestasis; extrahepatic cholestasis; parenteral nutrition-associated cholestasis (PNAC); hypophospholipidemia-associated cholestasis; lymphedema cholestasis syndrome 1 (LSC1); primary sclerosing cholangitis (PSC); immunoglobulin G4-associated cholangitis; primary biliary cholangitis; cholelithiasis (gallstones); bile duct stones; common bile duct stones; cholelithiasis pancreatitis; Caroli's disease disease); bile duct malignancy; malignancy causing biliary tree obstruction; biliary stricture; AIDS cholangiopathy; ischemic cholangiopathy; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease causing progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; iron overload; congenital bile acid synthesis deficiency type 1 (BAS type 1); drug-induced liver injury (DILI); hepatic fibrosis; congenital hepatic fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic adult-onset bile duct deficiency (IAD); idiopathic neonatal hepatitis (INH); nonsymptomatic interlobular bile duct deficiency (NSB PILBD); North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; serum bile acid toxicity, including cardiac arrhythmias with abnormal serum bile acid profiles (e.g., atrial fibrillation), cardiomyopathy ("cholecardia") associated with cirrhosis, and skeletal muscle atrophy associated with cholestatic liver disease; polycystic liver disease; viral hepatitis (including hepatitis A, B, C, D, and E); hepatocellular carcinoma (liver cancer); bile duct cancer; bile acid-related gastrointestinal cancers; and cholestasis caused by tumors and neoplasms of the liver, biliary tract, and pancreas.

[0140] The therapeutically effective amount of a compound of Formula (I)-(X) herein required for treatment varies with the nature of the condition being treated, the desired duration of activity, and the age and condition of the subject, and is ultimately determined by the attending physician. Dosage and interval can be individually adjusted to provide plasma levels of a compound of Formula (I)-(X) sufficient to maintain the desired therapeutic effect. The desired dose can be administered as a single dose or as multiple doses administered at appropriate intervals.

[0141] The compounds of Formula (I)-(X) used in the treatment methods provided herein can be administered in an amount of about 0.005 mg to about 500 mg per dose, about 0.05 mg to about 250 mg per dose, or about 0.5 mg to about 100 mg per dose. For example, the compounds of Formula (I)-(X) can be administered in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg per dose, including all doses between 0.005 and 500 mg.

[0142] The dosage of the pharmaceutical composition containing the compound of Formula (I)-(X) can be about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg. The dosage of the pharmaceutical composition can be any dosage, including but not limited to about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg. kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg In some embodiments, the dosage of the present invention is about 1mg / kg, about 20mg / kg, about 25mg / kg, about 30mg / kg, about 35mg / kg, about 40mg / kg, about 45mg / kg, about 50mg / kg, about 60mg / kg, about 70mg / kg, about 80mg / kg, about 90mg / kg, about 100mg / kg, about 125mg / kg, about 150mg / kg, about 175mg / kg, about 200mg / kg or more.Above-mentioned dosage is the example of general situation, but can there be wherein the individual situation of needing higher or lower dosage, and these are also within the application's protection domain.In practice, the doctor determines the actual application scheme that is most suitable for experimenter, and it can change with age, body weight and reaction of specific individual.

[0143] The compounds of Formula (I)-(X) provided herein can also be administered in combination with other drugs to enhance the therapeutic effect of the compounds of Formula (I)-(X) or to enhance the therapeutic effect of the other drugs. It is expected that the compounds of Formula (I)-(X) can have a synergistic effect when used in combination with certain drugs, for example, the amount of one of the drugs is lower than the therapeutically effective amount when it is used alone, or preferably, the amount of both drugs is lower than the therapeutically effective amount when they are used alone. Synergistic effects can also be manifested in the generation of new therapeutic effects, the reduction of therapeutic side effects, the extension of the dosing interval, the shortening of treatment time, etc.

[0144] "Subject" refers to an animal in this article, such as a mammal, including but not limited to humans, rodents, monkeys, felines, canines, equines, bovines, porcines, sheep, goats, mammalian experimental animals, mammalian farm animals, mammalian sports animals, and mammalian pets. The subject can be male or female and can be any age-appropriate subject, including infants, young children, young people, adults, and elderly subjects. In some instances, the subject refers to an individual in need of treatment for a disease or condition. In some instances, the subject being treated can be a patient who suffers from a condition associated with the treatment or is at risk of developing the condition. In other instances, the subject is a healthy individual or an individual suffering from a disease not of interest. In a specific instance, the subject is a human, such as a human patient. The term is generally used interchangeably with "patient," "test subject," "treatment subject," etc.

[0145] The following examples illustrate in detail the preparation methods and activity test results of the compounds provided herein.

[0146] Example 1.

[0147] This example provides the preparation method and structural characterization data of the compound.

[0148] General methods for compound synthesis

[0149] General Method A: Dissolve the corresponding amine (1 mmol), DMAP (0.3 mmol), and triethylamine (3 mmol) in anhydrous dichloromethane (5 mL). Add the corresponding acid chloride (1.5 mmol) dropwise to the reaction mixture in an ice bath. The reaction mixture is then warmed to room temperature and stirred under N2 for 12 hours. After TLC, the reaction mixture is diluted with water (6 mL) and extracted with DCM (3 x 6 mL). The combined organic phases are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated under reduced pressure to remove the solvent. The crude product is purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0150] General Method B: Dissolve the corresponding amine (1 mmol) and the corresponding sulfonyl chloride (2 mmol) in pyridine (4 mL). The reaction system is protected with N2, heated to 120°C, and stirred for 12 hours. After TLC, the reaction mixture is cooled to room temperature, diluted with water (6 mL), and extracted with ethyl acetate (3 x 12 mL). The organic phase is washed with saturated copper sulfate (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product is then purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0151] General Method C: Add the corresponding bromide (1 mmol), potassium carbonate (4 mmol), and the corresponding boronic acid (1.5 mmol) to a mixed solution of 1,4-dioxane (3 mL) and water (1 mL). The mixture is ventilated and, under a nitrogen purge, PdCl2(PPh3)2 (0.1 mmol) and tricyclohexylphosphine (0.2 mmol) are added. The mixture is then heated and stirred at 90°C for 24 hours. After completion of the reaction as determined by TLC, the reaction mixture is cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (3 x 5 mL). The combined organic phases are washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (PE / EA) to afford the title compound.

[0152] General Procedure D: Dissolve the corresponding amine (1 mmol) in anhydrous dichloromethane (5 mL). Slowly add triethylamine (1.1 mmol) and the corresponding anhydride (1.1 mmol) at 0°C, then warm to room temperature and stir overnight. After TLC, dilute with water (6 mL) and extract with dichloromethane (2 x 6 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0153] General Method E: Dissolve the corresponding amine (1 mmol), carboxylic acid (1.1 mmol), and N,N-diisopropylethylamine (3 mmol) in anhydrous dichloromethane (5 mL). Add HATU (1.05 mmol) at 0°C, then warm to room temperature and stir overnight. After the reaction is complete as determined by TLC, dilute with water (6 mL) and extract with dichloromethane (2 x 6 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0154] General Procedure F: Dissolve the corresponding amine (0.30 mmol), benzyl chloride (0.45 mmol) or benzyl bromide (0.45 mmol), and potassium carbonate (0.59 mmol) in dry DMF and stir at room temperature for 2 h. After completion of the reaction as monitored by TLC, dilute with water (10 mL) and extract with ethyl acetate (3 x 10 mL). The combined organic layers are washed sequentially with water (2 x 10 mL) and saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by column chromatography using dichloromethane / methanol as the eluent to afford the desired compound.

[0155] General Method G: The corresponding amine (0.30 mmol) and cesium carbonate (0.89 mmol) were dissolved in toluene (5 mL) by ultrasound as much as possible. The corresponding bromide (0.59 mmol) was then added and the atmosphere was replaced with N2 three times. After stirring for 5 min, XantPhos (0.02 mmol) and Pd2(dba)3 (0.02 mmol) were added. The atmosphere was replaced with N2 three times and stirred at 90°C for 3 h. After the reaction was complete as monitored by TLC, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed sequentially with water (2 × 10 mL) and saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the desired compound.

[0156] General Method H: Dissolve vinylsulfonamide (0.15 mmol) and the corresponding oxime (0.08 mmol) in anhydrous dichloromethane. Slowly add sodium hypochlorite solution (0.15 mmol) dropwise at 0°C, then bring to room temperature for 1 h. After completion of the reaction as determined by TLC, dilute the reaction mixture with water and extract with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product is purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0157] General Method I: Dissolve the corresponding amine (0.2 mmol), DMAP (7.2 mg, 0.06 mmol) and triethylamine (0.6 mmol) in anhydrous dichloromethane (5 mL) and add the corresponding sulfonyl chloride (0.3 mmol) dropwise at 0°C. Warm to room temperature and stir for 8 hours. After the reaction is complete as monitored by TLC, dilute with water (5 mL) and extract three times with dichloromethane (5 mL). The combined organic layer is washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the pure product.

[0158] Synthesis steps and structural characterization of compounds

[0159] 3-Nitro-4-hydroxy-5-bromopyridine (1)

[0160] 3-bromo-5-nitropyridin-4-ol(1)

[0161] 4-Hydroxy-5-nitropyridine (50 mg, 0.36 mmol) was dissolved in 50% AcOH aqueous solution (10 mL). Bromine (0.02 mL, 0.36 mmol) was slowly added dropwise at 0°C. The mixture was then warmed to room temperature and stirred for 1 hour. After TLC, the reaction mixture was filtered, the filter cake was washed with water, and then dried at 60°C to obtain Compound 1 (62 mg, 80% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ12.75(s,1H),8.82(s,1H),8.37(s,1H).

[0162] 3-Bromo-4-hydroxy-5-aminopyridine (2)

[0163] 3-amino-5-bromopyridin-4-ol(2)

[0164] Compound 1 (200 mg, 0.93 mmol) was dissolved in a mixed solution of ethanol (60 mL) and water (20 mL), followed by the addition of iron powder (308 mg, 5.52 mmol) and ammonium chloride (98 mg, 1.84 mmol). The mixture was heated to reflux at 80°C for 1 hour under nitrogen protection. After TLC detection of the reaction completion, the reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethanol, and the filtrate was concentrated under reduced pressure to obtain a gray solid compound 2 (104 mg, 60% yield). 1 H NMR (400MHz, DMSO-d6): δ11.51(s,1H),7.81(s,1H),7.14(s,1H),4.80(s,2H).

[0165] 8-Bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (3)

[0166] 8-bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine(3)

[0167] Compound 2 (200 mg, 1.06 mmol) was dissolved in N,N-dimethylformamide (40 mL), and potassium carbonate (441 mg, 3.20 mmol) was added. 1,2-dibromoethane (199 mg, 1.06 mmol) was slowly added at room temperature under nitrogen protection, and the temperature was then raised to 80°C and stirred for 24 hours. After TLC detection, the reaction was complete, cooled to room temperature, diluted with water (20 mL), and extracted with EA (3×20 mL). The combined organic phases were washed with water (3×5 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate for 1 hour, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain the target compound 3 (68 mg, 30% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ7.94(s,1H),7.75(s,1H),4.43(s,1H),3.69–3.56(m,2H),3.22–3.07(m,2H).

[0168] 4-(3,4-Dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (4)

[0169] 4-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(4)

[0170] According to General Method C, compound 3 (500 mg, 2.34 mmol), potassium carbonate (1.29 g, 9.346 mmol), 4-cyanophenylboronic acid (514 mg, 3.5 mmol), PdCl2(PPh3)2 (164 mg, 0.23 mmol), and tricyclohexylphosphine (131 mg, 0.47 mmol) were synthesized in a mixed solvent of 1,4-dioxane (15 mL) and water (5 mL). The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to give the target compound 4 (500 mg, 90% yield) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ7.94–7.82(m,3H),7.78–7.66(m,3H),6.17(s,1H),4.32–4.12(m,2H),3.35–3.29(m,2H).

[0171] 4-(4-(Benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O1)

[0172] 4-(4-(phenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O1)

[0173] According to general method B, compound 4 (50 mg, 0.21 mmol) and benzenesulfonyl chloride (74 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 2) to synthesize the target compound O1 (58 mg, yield 73%) as a white solid with a melting point of 181.0-182.0°C. 1 H NMR (400MHz, CDCl3): δ9.00 (s, 1H), 8.27 (s, 1H), 7.74 (d, J = 7.6Hz, 2H), 7.69 (d,J=8.3Hz,2H),7.64(s,1H),7.56–7.49(m,4H),3.91(s,2H),3.89(s,2H); 13 C NMR (101MHz, CDCl3): δ149.88,146.73,146.07,138.44,138.08,133.93,132.06(2C),130.07(2C ),129.67(2C),127.37(2C),124.21,121.94,118.56,111.77,64.06,43.31.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 16 N3O3S + 378.0907,found 378.0908.

[0174] 4-(4-((4-Fluorophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O2)

[0175] 4-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]o×azin-8-yl)benzonitrile(O2)

[0176] According to general method B, compound 4 (50 mg, 0.21 mmol) and 4-fluorobenzenesulfonyl chloride (81 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O2 (60 mg, yield 72%) as a light yellow solid with a melting point of 184.0–185.0°C. 1 H NMR (400MHz, CDCl3): δ9.01(s,1H),8.31(s,1H),7.78(s,2H),7.69(s,2H),7.55(s,2H),7.21(s,2H),3.93(s,4H); 13 C NMR (101MHz, CDCl3): δ167.02,164.46( 1 J CF =257.5),149.84,146.98,146.04,138.35,134.18,134.15,132.07(2C),130.23,130.14( 3 J CF =9.5),130.07(2C),124.29,121.74,118.54,117.16,116.93( 2 J CF =22.6),111.82,64.13,43.37.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 15 N3O3S + 396.0813, found 396.0809.

[0177] 4-(4-((3-Fluorophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O3)

[0178] 4-(4-((3-fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O3)

[0179] According to general method B, compound 4 (50 mg, 0.21 mmol) and 3-toluenesulfonyl chloride (81.50 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O3 (55 mg, yield 66%) as a white solid with a melting point of 165.0-166.0°C.1 H NMR (400MHz, CDCl3): δ8.97(s,1H),8.29(s,1H),7.69(d,J=8.4Hz,2H),7.53(s,4H),7.44(s,1H),7.34(s,1H),3.94(s,4H); 13 C NMR (101MHz, CDCl3): δ163.83,161.31( 1 J CF =253.7),149.81,147.08,145.92,140.10,140.04( 3 J CF =7.8),138.33,132.07(2C),131.58,131.50( 3 J CF =7.8),130.08(2C),124.26,123.20,123.16( 4 J CF =3.5),121.63,121.33,121.12( 2 J CF =21.2),118.54,114.87,114.62( 2 J CF =21.2),111.82,64.19,43.44.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 15 FN3O3S + 396.0813, found 396.0709.

[0180] 4-(4-Methylbenzenesulfonyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O4)

[0181] 4-(4-tosyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O4)

[0182] According to general method B, compound 4 (50 mg, 0.21 mmol) and 4-toluenesulfonyl chloride (80 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O4 (62 mg, yield 80%) as a white solid with a melting point of 141.0-142.0°C. 1H NMR (400MHz, CDCl3): δ9.00(s,1H),8.27(s,1H),7.69(d,J=8.2Hz,2H),7.61(d,J= 8.2Hz,2H),7.54(d,J=8.2Hz,2H),7.30(d,J=8.2Hz,2H),3.89(s,4H),2.42(s,3H); 13 C NMR (101MHz, CDCl3): δ149.86,146.61,146.13,145.06,138.50,135.06,132.04(2C),130.26(2C),1 30.07(2C),127.41(2C),124.12,122.04,118.56,111.73,64.04,43.27,21.62.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 18 N3O3S + 392.1063, found 392.1058.

[0183] 4-(4-(3-Methylphenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O5)

[0184] 4-(4-(m-tolylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O5)

[0185] According to general method B, compound 4 (50 mg, 0.21 mmol) and 3-methylbenzenesulfonyl chloride (80 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O5 (40 mg, yield 49%) as a light yellow solid with a melting point of 153.0-154.0°C. 1 H NMR (400MHz, CDCl3): δ8.98(s,1H),8.27(s,1H),7.69(d,J=6.9Hz,2H),7.53(d,J=13.7Hz,4H),7.41(d,J=27.6Hz,2H),3.91(s,4H),2.39(s,3H); 13C NMR (101MHz, CDCl3): δ148.89,145.67,145.07,139.07,137.51,136.97,133.73,131.07(2C),129.07(2 C),128.50,126.63,123.54,123.16,121.01,117.58,110.75,63.13,42.30,20.35.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 18 N3O3S + 392.1063, found 392.1042.

[0186] 4-(4-(4-Chlorophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O6)

[0187] 4-(4-((4-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O6)

[0188] According to general method B, compound 4 (50 mg, 0.21 mmol) and 4-chlorobenzenesulfonyl chloride (88 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O6 (51 mg, yield 59%) as a white solid with a melting point of 168.0–169.0°C. 1 H NMR (400MHz, CDCl3): δ8.98 (s, 1H), 8.28 (s, 1H), 7.69 (d, J = 14.3Hz, 4H), 7.55 (d, J = 8.4Hz, 2H), 7.49 (d, J = 8.6Hz, 2H), 3.94 (d, J = 3.3Hz, 4H); 13 C NMR (101MHz, CDCl3): δ149.82,147.00,145.93,140.69,138.31,136.55,132.07(2C),130.08(2C),130.00(2C),128.76(2C),124.26,121.69, 118.54,111.82,64.16,43.40.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 15 ClN3O3S+ 412.0517, found 412.0511.

[0189] 4-(4-(3-Chlorophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O7)

[0190] 4-(4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O7)

[0191] According to general method B, compound 4 (50 mg, 0.21 mmol) and 3-chlorobenzenesulfonyl chloride (88 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O7 (66 mg, yield 80%) as a white solid with a melting point of 130.0-131.0°C. 1 H NMR (400MHz, CDCl3): δ8.97(s,1H),8.30(s,1H),7.74(s,1H),7.70(d,J=8.1Hz, 2H),7.62(s,2H),7.55(d,J=8.3Hz,2H),7.47(s,1H),3.98(s,2H),3.93(s,2H); 13 C NMR (101MHz, CDCl3): δ149.03,145.83,144.63,138.84,137.22,135.03,133.09,131.11(2C),129.9 6,129.10(2C),126.32,124.47,120.68,120.50,117.53,110.92,63.33,42.42.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 15 ClN3O3S + 412.0517,found 412.0517.

[0192] 4-(4-(4-Methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O8)

[0193] 4-(4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O8)

[0194] According to general method B, compound 4 (50 mg, 0.21 mmol) and 4-methoxybenzenesulfonyl chloride (87 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O8 (43 mg, yield 50%) as a white solid with a melting point of 148.0-149.0°C. 1 H NMR (400MHz, CDCl3): δ8.99(s,1H),8.27(s,1H),7.68(dd,J=12.8,8.5Hz,4H),7.55(d,J=8.3Hz,2H),6.96(d,J=8.8Hz,2H),3.90(s,4H),3.86(s,3H); 13 C NMR (101MHz, CDCl3): δ163.85,152.91,150.05,146.38,146.02,138.44,132.07(2C),130.09(2C),1 29.64(2C),129.39,124.69,118.57,114.81(2C),111.80,64.11,55.73,43.24.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 18 N3O4S + 408.1013, found 408.1005.

[0195] 4-(4-(4-Nitrophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O9)

[0196] 4-(4-((4-nitrophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O9)

[0197] According to general method B, compound 4 (50 mg, 0.21 mmol) and 4-nitrobenzenesulfonyl chloride (93 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O9 (33 mg, yield 37%) as a yellow solid with a melting point of 222.0–227.0°C. 1 H NMR(400MHz, CDCl3): δ8.99 (s, 1H), 8.37 (d, J = 8.8Hz, 2H), 8.31 (s, 1H), 7.97 (d, J = 8.8Hz, 2H), 7.70 (d, J = 8.3Hz, 2H), 7.54 (d, J = 8.3Hz, 2H), 4.00 (s, 4H); 13 C NMR (101MHz, CDCl3): δ150.72,149.88,149.31,147.25,145.36,143.80,137.99,135.29,132.13 (2C),130.08(2C),128.67(2C),124.88(2C),118.46,112.03,64.46,43.62.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 15 N4O5S + 423.0758, found 423.0747.

[0198] 4-(4-(3-Nitrophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O10)

[0199] 4-(4-((3-nitrophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O10)

[0200] According to general method B, compound 4 (50 mg, 0.21 mmol) and 3-nitrobenzenesulfonyl chloride (93 mg, 0.42 mmol) were used as raw materials. The crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O10 (63 mg, yield 70%) as a yellow solid with a melting point of 209.0–212.0°C. 1H NMR (400MHz, CDCl3): δ8.96(s,1H),8.61(s,1H),8.48(s,1H),8.31(s,1H),8.10(s,1H ),7.77(s,1H),7.70(d,J=8.2Hz,2H),7.54(d,J=8.3Hz,2H),4.05(s,2H),4.01(s,2H); 13 C NMR (101MHz, CDCl3): δ149.91,148.56,147.15,145.22,142.53,140.46,138.06,137.98,132.79,13 2.12(2C),131.18,130.08(2C),128.27,122.41,118.47,111.99,64.62,43.63.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 15 N4O5S + 423.0758,found 423.0755.

[0201] 4-(4-(4-Trifluoromethyl)benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O11)

[0202] 4-(4-((4-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O11)

[0203] According to general method B, compound 4 (50 mg, 0.21 mmol) and 4-trifluoromethylbenzenesulfonyl chloride (103 mg, 0.42 mmol) were used as raw materials. The crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O11 (41 mg, 42% yield) as a white solid with a melting point of 192.0–193.0°C. 1 H NMR (400MHz, CDCl3): δ8.98 (s, 1H), 8.30 (s, 1H), 7.90 (d, J = 8.2Hz, 2H), 7.80 (d,J=8.3Hz,2H),7.70(d,J=8.3Hz,2H),7.54(d,J=8.4Hz,2H),3.97(s,4H); 13C NMR (101MHz, CDCl3): δ149.80,147.12,145.60,141.72,138.19,135.70,135.36( 2 J CF =33.3),132.10(2C),130.08(2C),127.93(2C),126.89,126.85( 3 J CF =3.5),126.82,126.78( 3 J CF =3.6),124.38,124.22,121.64,121.50( 1 J CF =273.3),118.50,111.90,64.38,43.51.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 F3N3O3S + 446.0781,found 446.0766.

[0204] 4-(4-(3-Trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O12)

[0205] 4-(4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O12)

[0206] According to general method B, compound 4 (50 mg, 0.21 mmol) and 3-trifluoromethylbenzenesulfonyl chloride (103 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O12 (52 mg, yield 55%) as a white solid with a melting point of 64.0–66.0°C. 1 H NMR (400MHz, CDCl3): δ8.98 (s, 1H), 8.31 (s, 1H), 7.94 (d, J = 33.6Hz, 3H), 7.71 (d, J = 7.7Hz, 3H), 7.53 (d, J = 8.1Hz, 2H), 3.97 (s, 4H); 13C NMR (101MHz, CDCl3): δ150.00,147.15,145.80,139.50,138.20,137.10,132.60,132.26( 2 J CF =34.0),132.10(2C),130.56(2C),130.51,130.48( 3 J CF =3.6),130.06(2C),124.34,124.30( 3 J CF =3.7),124.16,121.45( 1 J CF =273.2),118.50,113.32,111.92,64.25,43.47.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 F3N3O3S + 446.0781,found 446.0772.

[0207] 4-(4-(Pyridine-3-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O13)

[0208] 4-(4-(pyridin-3-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O13)

[0209] According to general method B, compound 4 (50 mg, 0.21 mmol) and 3-pyridinesulfonyl chloride (93 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O13 (45 mg, yield 57%) as a white solid with a melting point of 181.0–183.0°C. 1 H NMR (400MHz, CDCl3): δ9.00(s,2H),8.86(s,1H),8.30(s,1H),8.05(s,1H),7.70 (d,J=8.3Hz,2H),7.54(d,J=8.3Hz,2H),7.49(s,1H),4.01(s,2H),3.98(s,2H); 13C NMR (101MHz, CDCl3): δ154.41,152.79,150.00,148.07,147.07,145.52,143.07,138.15,135.0 5,132.14(2C),130.13(2C),124.20,121.48,118.54,111.98,64.47,43.48.HRMS(ESI)m / z[M+H] + calcd.for C 19 H 15 N4O3S + 379.0859,found379.0847.

[0210] 4-(4-(Methylphenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O14)

[0211] 4-(4-(methylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O14)

[0212] According to General Method D, compound 4 (50 mg, 0.21 mmol) and methanesulfonic anhydride (40 mg, 0.23 mmol) were used as starting materials, and triethylamine (23 mg, 0.23 mmol) was added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O14 (20 mg, 30% yield) as a white solid with a melting point of 175.0–177.0°C. 1 H NMR (400MHz, CDCl3): δ8.86(s,1H),8.28(s,1H),7.74(d,J=8.1Hz,2H),7.62(d,J=8.2Hz,2H),4.41(s,2H),3.94(s,2H),3.12(s,3H); 13 C NMR (101MHz, CDCl3): δ149.55,146.21,144.00,138.34,133.73,132.14(2C),1 31.21,130.14(2C),118.56,111.93,65.62,43.29,40.03.HRMS(ESI)m / z[M+H] + calcd.for C 15 H 14 N3O3S + 316.0750, found 316.0748.

[0213] 4-(4-(Quinoline-8-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O15)

[0214] 4-(4-(quinolin-8-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O15)

[0215] According to general method B, compound 4 (100 mg, 0.42 mmol) and 8-quinolinesulfonyl chloride (192 mg, 0.84 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O15 (78 mg, yield 43%) as a yellow solid with a melting point of 215.0–217.0°C. 1 H NMR (400MHz, CDCl3): δ8.94(s,1H),8.81(s,1H),8.72(s,1H),8.27(s,1H),8.1 1(s,2H),7.73(d,J=7.7Hz,3H),7.53(d,J=14.0Hz,3H),4.37(d,J=9.8Hz,4H); 13 C NMR (101MHz, CDCl3): δ151.29,148.90,144.84,143.76,142.29,138.80,136.76,136.41,134.68,133.82,132.0 0(2C),130.05(2C),129.10,125.78,124.15,123.41,122.46,118.63,111.58,66.12,44.32.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 17 N4O3S + 429.1016, found 429.1001.

[0216] 4-(4-(Thiophene-2-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O16)

[0217] 4-(4-(thiophen-2-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O16)

[0218] According to general method B, compound 4 (50 mg, 0.21 mmol) and 2-thiophenesulfonyl chloride (77 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O16 (27 mg, yield 33%) as a yellow solid with a melting point of 147.0–148.0°C. 1 H NMR (400MHz, CDCl3): δ9.02(s,1H),8.29(s,1H),7.70(d,J=10.3Hz,2H),7.64(d,J=5.0Hz,1H),7.55(d,J=8.1Hz,3H),7.12(s,1H),3.94(s,4H); 13 C NMR (101MHz, CDCl3): δ149.99,147.03,146.36,138.41,137.83,133.72,133.38,132.06(2C ),130.08(2C),128.00,124.20,121.52,118.55,111.77,63.77,43.53.HRMS(ESI)m / z[M+H] + calcd.for C 18 H 14 N3O3S2 + 384.0471, found 384.0468.

[0219] 4-(4-(naphthalene-1-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O17)

[0220] 4-(4-(naphthalen-1-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O17)

[0221] According to general method B, compound 4 (50 mg, 0.21 mmol) and 1-naphthalenesulfonyl chloride (95 mg, 0.42 mmol) were used as raw materials. The crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O17 (30 mg, yield 33%) as a white solid with a melting point of 189.0–190.0°C. 1 H NMR (400MHz, CDCl3): δ8.82(s,1H),8.34(s,2H),8.15(s,1H),7.95(s,1H),7.67(d,J=7.5Hz,2H), 7.60(d,J=7.6Hz,2H),7.52(s,1H),7.42(d,J=7.8Hz,2H),7.26(s,1H),3.92(s,2H),3.85(s,2H); 13 C NMR (101MHz, DMSO-d6): δ150.02,146.73,146.03,145.45,138.34,137.69,135.61,134.04,132.69,132.16(2C),131. 10,130.05(2C),129.32,128.24,127.44,127.29,124.95,123.81,118.62,110.53,64.31,42.34.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 18 N3O3S + 428.1063, found 428.1053.

[0222] 4-(4-(naphthalene-2-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O18)

[0223] 4-(4-(naphthalen-2-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O18)

[0224] According to general method B, compound 4 (50 mg, 0.21 mmol) and 2-naphthalenesulfonyl chloride (95 mg, 0.42 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to synthesize the target compound O18 (15 mg, yield 17%) as a light yellow solid with a melting point of 177.0–178.0°C. 1H NMR (400MHz, CDCl3): δ9.07(s,1H),8.37(s,1H),8.27(s,1H),7.93(d,J=22.5H z,3H),7.66(d,J=34.9Hz,5H),7.50(d,J=8.3Hz,2H),3.97(s,2H),3.89(s,2H); 13 C NMR (101MHz, CDCl3): δ149.89,146.68,146.02,138.39,135.14,134.85,132.05,132.00(2C),130.07,130.05(2C),1 29.57,129.32,129.18,128.10,128.01,124.21,122.03,121.94,118.55,111.69,64.19,43.36.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 18 N3O3S + 428.1063, found 428.1055.

[0225] 4-(4-(4-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O19)

[0226] 4-(4-(4-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O19)

[0227] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 4-fluorobenzoyl chloride (50 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O19 (53 mg, 70% yield) as a white solid with a melting point of 191.0–193.0°C. 1 H NMR (400MHz, CDCl3): δ8.23 (d, J = 31.0 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8. 3Hz,2H),7.58(d,J=13.9Hz,2H),7.13(d,J=17.1Hz,2H),4.47(s,2H),4.07(s,2H);13 C NMR (101MHz, CDCl3): δ167.87,165.64,163.13( 1 J CF =253.30),149.09,146.00,145.60,138.59,132.10(2C),130.99,130.90( 3 J CF =8.84),130.10(2C),129.95,129.92( 4 J CF =3.42),124.12,118.60,116.20,115.98( 2 J CF =22.07),115.41,111.75,67.32,42.13.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 FN3O2 + 360.1143, found 360.1142.

[0228] 4-(4-(3-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O20)

[0229] 4-(4-(3-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O20)

[0230] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 3-fluorobenzoyl chloride (50 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O20 (55 mg, 72% yield) as a white solid with a melting point of 167.0–169.0°C. 1 H NMR (400MHz, CDCl3): δ8.35 (s, 1H), 8.21 (s, 1H), 7.74 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8. 4Hz,2H),7.42(s,1H),7.31(d,J=18.7Hz,2H),7.21(s,1H),4.47(s,2H),4.07(s,2H);13 C NMR (101MHz, CDCl3): δ167.52,163.84,161.36 ( 1 J CF =249.4),149.19,146.21,145.55,138.55,136.08,136.01,132.13(2C),130.76,130.68( 3 J CF =8.1),130.13(2C),124.03,124.00( 4 J CF =3.2),118.65,118.61,118.44( 2 J CF =21.1),115.72,115.49( 2 J CF =22.9),111.81,67.27,42.28.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 FN3O2 + 360.1143, found 360.1135.

[0231] 4-(4-(2-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O21)

[0232] 4-(4-(2-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O21)

[0233] According to General Method A, compound 4 (50 mg, 0.21 mmol) and o-fluorobenzoyl chloride (50.00 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O21 (30 mg, 42% yield) as a white solid with a melting point of 85.0–87.0°C. 1H NMR (400MHz, DMSO-d6): δ9.20(s,1H),8.23(s,1H),7.93(d,J=8.2Hz,2H),7.78(d,J=8.3Hz,2H ),7.69–7.51(m,2H),7.33(dt,J=24.2,7.6Hz,2H),4.43(s,2H),3.98(dd,J=35.6,28.5Hz,2H); 13 C NMR (101MHz, DMSO-d6): δ169.76,159.01,156.55( 1 J CF =247.7),149.43,146.04,144.41,138.71,134.70,132.79,132.71( 3 J CF =7.8),132.22(2C),130.25(2C),125.20,125.16( 4 J CF =3.1),123.39,123.21( 2 J CF =20.4),123.05,118.74,116.16,115.95( 2 J CF =21.1),115.10,110.50,66.96,47.85.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 FN3O2 + 360.1143, found 360.1139.

[0234] 4-(4-(4-Methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O22)

[0235] 4-(4-(4-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O22)

[0236] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 4-methoxybenzoyl chloride (54 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O22 (50 mg, 64% yield) as a white solid with a melting point of 176.0–178.0°C. 1 H NMR (400MHz, CDCl3): δ8.28(s,1H),8.17(s,1H),7.73(d,J=8.3Hz,2H),7.65(d,J=8.2Hz, 2H),7.54(d,J=8.7Hz,2H),6.92(d,J=8.7Hz,2H),4.45(s,2H),4.07(s,2H),3.85(s,3H); 13 C NMR (101MHz, CDCl3): δ168.72,162.17,148.97,145.66,145.54,138.76,132.07(2C),130.71(2C),130. 10(2C),125.73,124.37,124.01,118.65,114.09(2C),111.66,67.36,55.42,42.19.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 18 N3O3 + 372.1343, found 372.1340.

[0237] 4-(4-(3-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O23)

[0238] 4-(4-(3-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O23)

[0239] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 3-methoxybenzoyl chloride (54 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O23 (55 mg, 70% yield) as a white solid with a melting point of 169.0–171.0°C. 1 H NMR (400MHz, CDCl3): δ8.45(s,1H),8.20(s,1H),7.74(d,J=8.2Hz,2H),7.65(d,J=8. 3Hz,2H),7.34(s,1H),7.06(d,J=32.3Hz,3H),4.45(s,2H),4.06(s,2H),3.83(s,3H); 13 C NMR (101MHz, CDCl3): δ167.88,158.92,154.09,148.19,144.55,137.65,134.22,131.13(2C),129.15(2C), 128.96,126.22,124.09,119.32,117.64,116.06,112.85,110.78,66.43,54.48,28.70.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 18 N3O3 + 372.1343, found 372.1325.

[0240] 4-(4-(4-Trifluoromethylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O24)

[0241] 4-(4-(4-(trifluoromethyl)benzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O24)

[0242] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 4-trifluoromethylbenzoyl chloride (65.52 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O24 (47 mg, 54% yield) as a white solid with a melting point of 187.0–189.0°C. 1 H NMR (400MHz, CDCl3): δ8.33(s,1H),8.22(s,1H),7.76(s,4H),7.64(s,4H),4.49(s,2H),4.08(s,2H); 13 C NMR (101MHz, CDCl3): δ167.50,149.29,146.39,145.47,143.18,138.43,137.50,133.32,132.99( 2 J CF =32.9),132.1(2C),130.12(2C),128.77,125.98,125.94( 3 J CF =3.7),124.76,124.23,123.49,122.05( 1 J CF =272.5),118.58,111.90,67.31,47.83.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 15 F3N3O2 + 410.1111, found 410.1104.

[0243] 4-(4-(3-Trifluoromethylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O25)

[0244] 4-(4-(3-(trifluoromethyl)benzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O25)

[0245] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 3-trifluoromethylbenzoyl chloride (65.52 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O25 (70 mg, 81% yield) as a white solid with a melting point of 156.0–158.0°C. 1 H NMR (400MHz, CDCl3): δ8.33(t,J=21.4Hz,1H),8.23(s,1H),7.85(s,1H),7.81–7.75(m,2H),7.73(d ,J=11.0Hz,2H),7.65(d,J=8.4Hz,2H),7.59(t,J=7.7Hz,1H),4.52–4.45(m,2H),4.12–4.03(m,2H); 13 C NMR (101MHz, CDCl3): δ167.38,149.31,146.27,145.45,138.44,134.85,132.15(2C),131.76,131.52,131.43( 2 J CF =32.9),130.13(2C),129.46,128.10,128.06( 3 J CF =3.6),125.49,125.46 ( 3 J CF =3.6),124.73,124.24,123.46,122.02( 1 J CF =272.3),118.59,111.88,67.24,42.28.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 15 F3N3O2 + 410.1111, found 410.1096.

[0246] 4-(4-(4-Nitrobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O26)

[0247] 4-(4-(4-nitrobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O26)

[0248] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 4-nitrobenzoyl chloride (58 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O26 (48 mg, 59% yield) as a light yellow solid with a melting point of 229.0–232.0°C. 1 H NMR (400MHz, CDCl3): δ8.30(s,2H),8.23(s,2H),7.74(s,4H),7.66(s,2H),4.51(s,2H),4.09(s,2H); 13 C NMR (101MHz, CDCl3): δ166.51,149.53,149.22,146.39,145.02,144.31,139.89,138.15,132.19(2C), 130.12(2C),129.43,124.41,124.16(2C),123.45,118.52,112.05,67.36,41.83.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 N4O4 + 387.1088, found 387.1089.

[0249] 4-(4-(3-Nitrobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O27)

[0250] 4-(4-(3-nitrobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O27)

[0251] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 3-nitrobenzoyl chloride (58 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O27 (60 mg, 74% yield) as a light yellow solid with a melting point of 247.0–249.0°C. 1 H NMR (400MHz, CDCl3): δ8.38(s,2H),8.23(s,2H),7.90(s,1H),7.76(s,2H),7.67(s,3H),4.53(s,2H),4.12(s,2H); 13 C NMR (101MHz, CDCl3): δ166.21,149.38,148.19,146.63,145.30,138.29,136.89,135.72,134.26,132.17( 2C),130.25,130.18,126.02,123.50,121.81,118.56,113.98,111.96,67.33,42.73.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 N4O4 + 387.1088, found 387.1086.

[0252] 4-(4-(4-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O28)

[0253] 4-(4-(4-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O28)

[0254] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 4-chlorobenzoyl chloride (55 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O28 (33 mg, 42% yield) as a light yellow solid with a melting point of 200.0–202.0°C. 1H NMR (400MHz, CDCl3): δ8.28(d,J=55.9Hz,2H),7.75(d,J=8.2Hz,2H),7.65(d,J=8 .3Hz,2H),7.51(d,J=8.4Hz,2H),7.43(d,J=8.4Hz,2H),4.48(s,2H),4.07(s,2H); 13 C NMR (101MHz, CDCl3): δ167.88,149.54,145.50, 144.99,138.29,137.89,136.10,132.17(2C),132.14,130.14(2C),129.93( 2C),129.25(2C),124.24,118.56,111.96,67.37,42.17.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 ClN4O2 + 376.0847, found 376.0831.

[0255] 4-(4-(3-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O29)

[0256] 4-(4-(3-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O29)

[0257] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 3-chlorobenzoyl chloride (55 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O29 (40 mg, 51% yield) as a white solid with a melting point of 188.0–190.0°C. 1 H NMR (400MHz, CDCl3): δ8.37(s,1H),8.21(s,1H),7.74(d,J=8.4Hz,2H),7.65(d,J=8. 4Hz,2H),7.56(s,1H),7.47(s,1H),7.38(d,J=7.5Hz,2H),4.46(s,2H),4.05(s,2H); 13C NMR (101MHz, CDCl3): δ167.47,149.20,146.19,145.53,138.53,135.74,135.08,132.11(2C),131.51,1 30.16,130.11(2C),129.19,128.45,126.31,124.17,118.60,111.79,67.21,42.34.HRMS(ESI)m / z[M+H] + calcd.for C 21 H 15 ClN4O2 + 376.0847, found 376.0835.

[0258] 4-(4-nicotinoyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O30)

[0259] 4-(4-nicotinoyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O30)

[0260] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 3-pyridinecarbonyl chloride (56.00 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O30 (30 mg, 42% yield) as a white solid with a melting point of 210.0–212.0°C. 1 H NMR (400MHz, CDCl3): δ8.73(d,J=19.2Hz,2H),8.29(s,1H),8.18(s,1H),7.88(s,1H) ,7.71(d,J=8.3Hz,2H),7.62(d,J=8.3Hz,2H),7.39(s,1H),4.47(s,2H),4.07(s,2H); 13 C NMR (101MHz, CDCl3): δ166.42,151.99,149.27,149.08,146.35,145.40,138.37,136.13,132.06(2C ),130.28,130.05(2C),124.19,123.63,120.87,118.53,111.74,67.27,42.04.HRMS(ESI)m / z[M+H]+ calcd.for C 20 H 15 N4O2 + 343.1190, found 343.1181.

[0261] 4-(4-(Furan-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O31)

[0262] 4-(4-(furan-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O31)

[0263] According to General Method A, compound 4 (50 mg, 0.21 mmol) and 2-furoyl chloride (41 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O31 (30 mg, 43.16% yield) as a white solid with a melting point of 193.0–194.0°C. 1 H NMR (400MHz, CDCl3): δ8.47(s,1H),8.22(s,1H),7.74(d,J=8.0Hz,2H),7.66(d, J=8.2Hz,2H),7.51(s,1H),7.19(s,1H),6.56(s,1H),4.47(s,2H),4.18(s,2H); 13 C NMR (101MHz, CDCl3): δ157.93,149.18,146.58,146.06,145.19,145.10,138.77,132.07(2C),1 30.12(2C),124.05,123.60,118.87,118.66,112.10,111.66,67.24,41.81.HRMS(ESI)m / z[M+H] + calcd.for C 19 H 14 N3O3 + 332.1030, found 332.1017.

[0264] 4-(4-(2-cyanoacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O32)

[0265] 4-(4-(2-cyanoacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O32)

[0266] According to general method E, compound 4 (50 mg, 0.21 mmol) and cyanoacetic acid (20 mg, 0.32 mmol) were used as raw materials, N,N-diisopropylethylamine (81 mg, 0.63 mmol) and HATU (83.00 mg, 0.22 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 2) to synthesize the target compound O32 (20 mg, yield 31%) as a white solid with a melting point of 212.0–214.0°C. 1 H NMR (400MHz, DMSO-d6): δ9.07(s,1H),8.26(s,1H),7.93(d,J=8.1Hz,2H),7.76(d,J=8.1Hz,2H),4.44(d,J=8.4Hz,2H),4.38(s,2H),3.88(s,2H); 13 C NMR (101MHz, DMSO-d6): δ162.48,149.43,145.72,145.00,138.78,132.21(2C),130.25( 2C),123.44,118.74,115.63,114.40,110.48,66.53,42.86,26.42.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 13 N4O2 + 305.1033, found 305.1023.

[0267] 4-(4-(2-chloroacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O33)

[0268] 4-(4-(2-chloroacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O33)

[0269] According to General Method A, compound 4 (50 mg, 0.21 mmol) and chloroacetyl chloride (35 mg, 0.315 mmol) were used as starting materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O33 (18 mg, 27.38% yield) as a white solid with a melting point of carbonization upon heating. 1 H NMR (400MHz, CDCl3): δ8.42(s,1H),8.27(s,1H),7.74(d,J=8.3Hz,2H),7.64(d,J=8.3Hz,2H),4.73(s,2H),4.52(s,2H),4.23(s,2H); 13 C NMR (101MHz, CDCl3): δ190.42,170.14,149.53,146.88,144.97,138.17,13 2.14,130.09,124.28,121.17,118.53,111.91,90.47,73.49,66.57,42.97.

[0270] 4-(4-(2-Bromoacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O34)

[0271] 4-(4-(2-bromoacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O34)

[0272] According to General Method A, compound 4 (50 mg, 0.21 mmol) and bromoacetyl chloride (50 mg, 0.315 mmol) were used as raw materials, and DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O34 (20 mg, 27% yield) as a white solid with a melting point of 0.05% on heating. The molecular formula is: C 16 H 12 BrN3O2; 1 H NMR (400MHz, DMSO-d6): δ 8.45(s,1H),8.25(s,1H),7.93(d,J=8.3Hz,2H),7.79(d,J=8.3Hz,2H),4.84(s,2H),4.51(s,2H),4.16(s,2H); 13C NMR (101MHz, DMSO-d6): δ190.77,170.81,149.85,146.45,145.33,138.95,1 32.72,130.75,123.95,121.79,119.21,111.06,89.53,74.20,67.16,43.36.

[0273] 4-(4-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O35)

[0274] 4-(4-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O35)

[0275] According to General Method D, compound 4 (100 mg, 0.42 mmol) and trifluoroacetic anhydride (97 mg, 0.46 mmol) were used as starting materials, and triethylamine (47 mg, 0.46 mmol) was added. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to synthesize the target compound O35 (60 mg, 43% yield) as a white solid with a melting point of 156.0–158.0°C. 1 H NMR (400MHz, CDCl3): δ8.97(s,1H),8.12(s,1H),7.54(s,2H),7.42(s,2H),4.29(s,2H),3.87(s,2H); 13 C NMR (101MHz, CDCl3): δ148.99,146.84,144.71,137.23,131.17(2C),129.15(2C),1 23.36,120.92,117.56,116.47,113.61,110.95,65.60,41.67.HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 F3N3O2 + 334.0798,found 334.0790.

[0276] 4-(4-(2-(4-fluorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O36)

[0277] 4-(4-(2-(4-fluorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O36)

[0278] According to general method E, compound 4 (50 mg, 0.21 mmol) and 4-fluorophenylacetic acid (49 mg, 0.32 mmol) were used as raw materials, N,N-diisopropylethylamine (81 mg, 0.63 mmol) and HATU (83 mg, 0.22 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O36 (35 mg, yield 44.87%) as a white solid with a melting point of 168.0–169.0°C. 1 H NMR (400MHz, CDCl3): δ8.50(s,1H),8.28(s,1H),7.72(d,J=8.3Hz,2H),7.58( d,J=8.4Hz,2H),7.19(s,2H),7.01(t,J=8.4Hz,2H),4.28(s,2H),3.97(s,4H); 13 C NMR (101MHz, DMSO-d6): δ169.61,162.26,159.86( 1 J CF =242.1),151.93,149.44,145.39,138.94,132.18(2C),131.42,131.34( 3 J CF =8.1),131.24,131.21( 4 J CF =2.8),130.23(2C),124.14,123.33,118.75,115.07,114.86( 2 J CF =21.2),110.40,67.13,26.09,20.74.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 17 FN3O2 + 374.1299, found 374.1290.

[0279] 4-(4-(2-(3-fluorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O37)

[0280] 4-(4-(2-(3-fluorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O37)

[0281] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-fluorophenylacetic acid (97 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (163 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O37 (120 mg, yield 77%) as a white solid with a melting point of 95.0–96.0°C. 1 H NMR (400MHz, CDCl3): δ8.53(s,1H),8.25(s,1H),7.69(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),7.26(s,1H),6.93(s,3H),4.27(s,2H),3.97(s,4H); 13 C NMR (101MHz, CDCl3): δ168.87,163.99,161.53( 1 J CF =246.9),149.92,147.06,145.45,145.42,138.45,135.99,131.96(2C),130.28,130.20( 3 J CF =7.9),129.95(2C),124.39,123.98,118.51,115.82,115.61( 2 J CF =21.9),114.27,114.06( 2 J CF =20.9),111.55,77.20,67.41,40.58.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 17 FN3O2 + 374.1299, found 374.1300.

[0282] 4-(4-(2-(4-chlorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O38)

[0283] 4-(4-(2-(4-chlorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O38)

[0284] According to general method E, compound 4 (50 mg, 0.21 mmol) and 4-chlorophenylacetic acid (34 mg, 0.32 mmol) were used as raw materials, N,N-diisopropylethylamine (81 mg, 0.63 mmol) and HATU (83 mg, 0.22 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O38 (56 mg, yield 68%) as a light yellow solid with a melting point of 169.0–170.0°C. 1 H NMR (400MHz, CDCl3): δ8.63(s,1H),8.28(s,1H),7.73(d,J=8.4Hz,2H),7.58(d,J= 8.5Hz,2H),7.29(d,J=8.1Hz,2H),7.16(d,J=7.5Hz,2H),4.28(s,2H),3.97(s,4H); 13 C NMR (101MHz, CDCl3): δ169.27,159.31,150.02,147.26,145.43,138.43,133.29,132.12(2C),130.74,130. 14,130.05(2C),129.00,128.62,126.57,124.18,118.58,111.82,67.94,40.69,26.79.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 17 ClN3O2 + 390.1004, found 390.1009.

[0285] 4-(4-(2-(3-chlorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O39)

[0286] 4-(4-(2-(3-chlorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O39)

[0287] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-chlorophenylacetic acid (107 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O39 (127 mg, yield 77%) as a white solid with a melting point of 67.0–68.0°C. 1 H NMR (400MHz, CDCl3): δ8.55(s,1H),8.29(s,1H),7.72(d,J=8.3Hz,2H),7.59(d,J=8.4Hz,2H),7.18(d,J=52.5Hz,4H),4.29(s,2H),3.98(s,4H); 13 C NMR (101MHz, CDCl3): δ169.03,150.02,147.18,145.41,138.44,135.63,134.67,132.11(2C),130.06(2C), 128.90,127.56,127.00,124.19,121.37,118.58,116.43,111.82,77.20,60.44,40.67.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 17 ClN3O2 + 390.1004,found 390.1010.

[0288] 4-(4-(2-(4-methoxyphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O40)

[0289] 4-(4-(2-(4-methoxyphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O40)

[0290] According to general method E, compound 4 (100 mg, 0.42 mmol) and 4-methoxyphenylacetic acid (105 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (163 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O40 (121 mg, yield 74%) as a white solid with a melting point of 151.0–152.0 ℃. 1 H NMR (400MHz, CDCl3): δ8.65(s,1H),8.26(s,1H),7.71(d,J=8.3Hz,2H),7.57(d,J=8.3Hz,2H), 7.12(d,J=7.2Hz,2H),6.84(d,J=8.1Hz,2H),4.22(s,2H),3.94(d,J=8.6Hz,4H),3.77(s,3H); 13 C NMR (101MHz, CDCl3): δ170.03,158.76,149.87,146.90,145.58,138.52,132.08(2C),130.35,130.05(2C),129 .71,125.40,124.09,118.60,116.64,114.31,113.95,111.74,77.20,67.54,55.25,40.45.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 20 N3O3 + 386.1499,found 386.1499.

[0291] 4-(4-(2-(3-methoxyphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O41)

[0292] 4-(4-(2-(3-methoxyphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O41)

[0293] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-methoxyphenylacetic acid (105 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O41 (136 mg, yield 84%) as a white solid with a melting point of 60.0–61.0°C. 1 H NMR (400MHz, CDCl3): δ8.68(s,1H),8.24(s,1H),7.69(d,J=8.3Hz,2H),7.56(d,J=8. 4Hz,2H),7.21(s,1H),6.77(d,J=8.1Hz,3H),4.22(s,2H),3.95(s,4H),3.75(s,3H); 13 C NMR (101MHz, CDCl3): δ169.44,159.94,150.02,146.63,145.51,138.59,134.94,131.97(2C),129.97(2C),129 .83,123.99,120.76,118.54,114.89,114.24,112.59,111.57,77.20,67.33,55.10,41.51.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 20 N3O3 + 386.1499, found 386.1489.

[0294] 4-(4-(2-(4-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O42)

[0295] 4-(4-(2-(p-tolyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O42)

[0296] According to general method E, compound 4 (100 mg, 0.42 mmol) and 4-methylphenylacetic acid (95 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (162.85 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O42 (109 mg, yield 70%) as a white solid with a melting point of 89.0–91.0°C. 1 H NMR (400MHz, CDCl3): δ8.72(s,1H),8.25(s,1H),7.70(d,J=8.3Hz,2H),7.56(d,J=8.3Hz,2H),7.11(s,4H),4.22(s,2H),3.95(s,4H),2.30(s,3H); 13 C NMR (101MHz, CDCl3): δ169.94,149.83,146.90,145.77,145.71,138.65,136.8 8,132.00(2C),130.43,130.00(2C),129.53,128.44,124.30,123.92,120.80, 118.58,111.59,67.31,41.06,40.45,20.95.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 20 N3O2 + 370.1550, found 370.1546.

[0297] 4-(4-(2-(3-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O43)

[0298] 4-(4-(2-(m-tolyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O43)

[0299] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-methylphenylacetic acid (97 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O43 (126 mg, yield 81%) as a white solid with a melting point of 91.0–92.0°C. 1 H NMR (400MHz, CDCl3): δ8.66(s,1H),8.25(s,1H),7.69(d,J=8.2Hz,2H),7.56(d,J=8. 3Hz,2H),7.19(s,1H),7.04(d,J=20.8Hz,3H),4.21(s,2H),3.95(s,4H),2.29(s,3H); 13 C NMR (101MHz, CDCl3): δ169.60,149.80,146.73,145.61,138.54,133.35,131.95(2C),129.94(2C),129.20,128 .67,127.91,125.51,124.16,123.90,118.52,116.47,111.52,77.20,67.28,41.21,21.23.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 20 N3O2 + 370.1550, found 370.1557.

[0300] 4-(4-(2-(2-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O44)

[0301] 4-(4-(2-(o-tolyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O44)

[0302] According to general method E, compound 4 (100 mg, 0.42 mmol) and 2-methylphenylacetic acid (95 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (94.94 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O44 (114 mg, yield 73%) as a white solid with a melting point of 174.0–175.0°C. 1 H NMR (400MHz, CDCl3): δ8.84(s,1H),8.26(s,1H),7.71(d,J=8.3Hz,2H),7.61(d ,J=8.3Hz,2H),7.16(d,J=11.5Hz,4H),4.33(s,2H),3.95(s,4H),2.25(s,3H); 13 C NMR (101MHz, CDCl3): δ169.49,149.81,146.75,145.37,138.56,136.19,134.06,132.01(2C),130.55,130.03( 2C),128.77,127.43,126.28,124.01,118.56,116.52,111.61,77.20,67.54,39.07,19.61.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 20 N3O2 + 370.1550,found 370.1553.

[0303] 4-(4-(2-(4-trifluoromethylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O45)

[0304] 4-(4-(2-(4-(trifluoromethyl)phenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O45)

[0305] According to general method E, compound 4 (100 mg, 0.42 mmol) and 4-trifluoromethylphenylacetic acid (129 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (163 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O45 (128 mg, yield 72%) as a white solid with a melting point of 124.0–125.0°C. 1 H NMR (400MHz, CDCl3): δ8.52(s,1H),8.29(s,1H),7.72(d,J=8.3Hz,2H),7.58(d ,J=13.0Hz,4H),7.36(d,J=7.4Hz,2H),4.32(s,2H),4.06(s,2H),4.01(s,2H); 13 C NMR (101MHz, CDCl3): δ168.88,147.25,145.24,138.28,137.68,132.13(2C),130.04(2C),129.85,129.53( 2 J CF =32.9),129.76,129.30,125.75,125.73,125.43,125.39( 3 J CF =3.7),125.29,122.58( 1 J CF =272.2),124.30,118.55,116.43,111.90,77.20,67.25,40.77.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 17 F3N3O2 + 424.1267,found424.1262.

[0306] 4-(4-(2-(3-trifluoromethylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O46)

[0307] 4-(4-(2-(3-(trifluoromethyl)phenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O46)

[0308] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-trifluoromethylphenylacetic acid (129 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O46 (138 mg, yield 77%) as a white solid with a melting point of 58.0–60.0°C. 1 H NMR (400MHz, CDCl3): δ8.54(s,1H),8.30(s,1H),7.73(d,J=8.4Hz,2H),7.57(d, J=1.6Hz,2H),7.53(s,1H),7.45(s,3H),4.31(s,2H),4.07(s,2H),4.01(s,2H); 13 C NMR (101MHz, CDCl3): δ168.94,153.66,147.07,145.40,138.34,136.65,134.69,132.42,132.14(2C),131.32,131.02( 2 J CF =32.2),130.05(2C),129.30,125.68,125.64( 3 J CF =3.8),125.19,122.48( 1 J CF =272.3),124.28,124.23,118.57,111.90,77.20,67.83,40.73.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 17 F3N3O2 + 424.1267,found424.1274.

[0309] 4-(4-(3-(4-Fluorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O47)

[0310] 4-(4-(3-(4-fluorophenyl)propanoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O47)

[0311] According to general method D, compound 4 (50 mg, 0.21 mmol) and 4-fluorophenylpropionic acid (53 mg, 0.32 mmol) were used as raw materials, N,N-diisopropylethylamine (81 mg, 0.63 mmol) and HATU (83 mg, 0.22 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 2) to synthesize the target compound O47 (40 mg, yield 49.38%) as a white solid with a melting point of 148.0–150.0°C. 1 H NMR (400MHz, CDCl3): δ10.11–8.29(m,1H),8.25(s,1H),7.72(d,J=8.4Hz,2H),7.60(d,J=8.4Hz,2H),7.12( s,2H),6.93(t,J=8.5Hz,2H),4.26–4.19(m,2H),3.92(d,J=16.6Hz,2H),3.03(t,J=6.7Hz,2H),2.94(s,2H); 13 C NMR (101MHz, CDCl3): δ170.63,162.69,160.26( 1 J CF =244.8),149.85,147.00,145.54,138.51,135.85,132.08(2C),130.03(2C),129.88,129.80( 3 J CF =7.9),124.07,123.84,118.59,115.40,115.19( 2 J CF =21.2),111.73,77.20,67.99,35.48,30.76.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 19 FN3O2 + 388.1456, found 388.1441.

[0312] 4-(4-(3-(3-fluorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O48)

[0313] 4-(4-(3-(3-fluorophenyl)propanoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O48)

[0314] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-fluorophenylpropionic acid (106 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O48 (76 mg, yield 46.77%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ8.66(s,1H),8.25(s,1H),7.71(d,J=8.3Hz,2H),7.60(d,J=8.3Hz,2H) ,7.20(s,1H),6.93(s,1H),6.86(s,2H),4.22(s,2H),3.94(s,2H),3.04(s,2H),2.96(s,2H); 13 C NMR (101MHz, CDCl3): δ170.44,163.98,161.54( 1 J CF =246.2),149.89,147.03,145.46,142.74,142.67( 3 J CF =7.1),138.51,132.03(2C),130.01(2C),129.92,124.07,124.05,123.91,118.57,115.27,115.06( 2 J CF =20.9),113.38,113.18( 2 J CF =21.1),111.66,77.20,68.04,35.16,31.18.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 19 FN3O2 + 388.1456, found 388.1456.

[0315] 4-(4-(3-(4-chlorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O49)

[0316] 4-(4-(3-(4-chlorophenyl)propanoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O49)

[0317] According to general method E, compound 4 (100 mg, 0.42 mmol) and 4-chlorophenylpropionic acid (116 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O49 (45 mg, yield 26.67%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ8.52(s,1H),8.26(s,1H),7.72(d,J=8.4Hz,2H),7.60(d,J=8.4Hz,2H),7 .22(d,J=8.1Hz,2H),7.09(d,J=7.2Hz,2H),4.22(s,2H),3.94(s,2H),3.01(s,2H),2.94(s,2H); 13 C NMR (101MHz, CDCl3): δ170.51,149.93,147.02,145.52,138.64,138.47,132.20,132.09(2C),130.05(2C),12 9.79(2C),129.66,128.60,128.49,124.10,118.58,111.74,77.20,68.03,35.21,30.86.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 19 ClN3O2 + 404.1160, found 404.1167.

[0318] 4-(4-(3-(3-chlorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O50)

[0319] 4-(4-(3-(3-chlorophenyl)propanoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O50)

[0320] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-chlorophenylpropionic acid (116 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O50 (82 mg, yield 48%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ8.72(s,1H),8.25(s,1H),7.71(d,J=8.3Hz,2H),7.60(d,J=8.3 Hz,2H),7.15(s,3H),7.05(s,1H),4.22(s,2H),3.94(s,2H),3.02(s,2H),2.96(s,2H); 13 C NMR (101MHz, CDCl3): δ170.41,149.73,146.96,145.43,142.20,138.49,134.15,132.00(2C),130.00(2C),129 .73,128.34,126.63,126.53,124.01,123.91,118.55,111.62,77.20,67.89,35.00,31.09.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 19 ClN3O2 + 404.1160, found 404.1165.

[0321] 4-(4-(3-(4-methoxyphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O51)

[0322] 4-(4-(3-(4-methoxyphenyl)propanoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O51)

[0323] According to general method E, compound 4 (100 mg, 0.42 mmol) and 4-methoxyphenylpropionic acid (113 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O51 (54 mg, yield 32%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ8.75(s,1H),8.25(s,1H),7.71(d,J=8.3Hz,2H),7.60(d,J=8.3Hz,2H),7.0 7(s,2H),6.77(d,J=8.1Hz,2H),4.18(s,2H),3.92(s,2H),3.73(s,3H),2.99(s,2H),2.94(s,2H); 13 C NMR (101MHz, CDCl3): δ171.07,158.13,149.85,146.84,145.67,138.64,132.08,132.02(2C),130.03(2C),129.3 1(2C),129.16,123.96,118.59,113.88,113.80,111.64,77.20,67.76,55.17,35.62,30.83.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 22 N3O3 + 400.1656, found 400.1657.

[0324] 4-(4-(3-(3-methoxyphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O52)

[0325] 4-(4-(3-(3-methoxyphenyl)propanoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O52)

[0326] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-methoxyphenylpropionic acid (114 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O52 (96 mg, yield 57%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ8.64(s,1H),8.25(s,1H),7.72(d,J=8.4Hz,2H),7.60(d,J=8.4Hz,2H),7. 16(s,1H),6.70(d,J=21.3Hz,3H),4.18(s,2H),3.92(s,2H),3.72(s,3H),2.98(d,J=28.0Hz,4H); 13 C NMR (101MHz, CDCl3): δ170.87,159.66,150.01,146.69,145.40,141.67,138.52,132.04(2C),130.03(2C),129.50 ,129.38,124.08,120.69,118.58,114.03,111.70,111.68,77.20,67.88,55.06,38.94,31.76.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 22 N3O3 + 400.1656, found 400.1641.

[0327] 4-(4-(3-(4-trifluoromethylphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O53)

[0328] 4-(4-(3-(4-(trifluoromethyl)phenyl)propanoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O53)

[0329] According to general method E, compound 4 (100 mg, 0.42 mmol) and 4-trifluoromethylphenylpropionic acid (137 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O53 (78.41 mg, yield 43.7%) as a white solid with a melting point of 52.0–53.0°C. 1 H NMR (400MHz, CDCl3): δ8.43(s,1H),8.27(s,1H),7.73(d,J=8.2Hz,2H),7.60(d,J=8.2Hz,2H),7 .53(d,J=7.6Hz,2H),7.30(d,J=7.2Hz,2H),4.24(s,2H),3.96(s,2H),3.13(s,2H),2.98(s,2H); 13 C NMR (101MHz, CDCl3): δ170.30,150.12,145.26,144.39,138.37,134.15,132.14(2C),130.05(2C),129.04,128.72( 2 J CF =32.4),128.82(2C),128.64,125.50,125.46( 3 J CF =3.5),124.28,121.81,119.00( 1 J CF =263.9),118.57,116.38,111.89,77.20,44.23,34.99,30.63.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 19 F3N3O2 + 438.1424, found 438.1413.

[0330] 4-(4-(3-(3-(trifluoromethylphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O54)

[0331] 4-(4-(3-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O54)

[0332] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-trifluoromethylphenylpropionic acid (137 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O54 (40 mg, yield 22%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ8.56(s,1H),8.27(s,1H),7.72(d,J=8.4Hz,2H),7.60(d,J=8.4 Hz,2H),7.46(s,1H),7.38(s,3H),4.23(s,2H),3.96(s,2H),3.13(s,2H),2.99(s,2H); 13 C NMR (101MHz, CDCl3): δ170.22,149.89,147.02,145.39,141.22,138.47,132.09(2C),131.98,130.99,130.67( 2 J CF =32.0),130.05(2C),129.00,128.85,125.36,122.65( 1 J CF =272.3),125.00,124.96( 3 J CF =3.7),124.16,123.34,123.30( 3 J CF =3.8),118.59,111.77,77.20,67.81,35.18,31.19.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 19 F3N3O2 + 438.1424, found 438.1420.

[0333] 4-(4-(1-((3-fluorophenyl)sulfonyl)piperidine-4-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O55)

[0334] 4-(4-(1-((3-fluorophenyl)sulfonyl)piperidine-4-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O55)

[0335] According to General Method A, starting materials were compound 4 (50 mg, 0.21 mmol) and 1-((3-fluorophenyl)sulfonyl)piperidine-4-carbonyl chloride (96.00 mg, 0.315 mmol), followed by the addition of 4-DMAP (8 mg, 0.063 mmol) and triethylamine (64 mg, 0.63 mmol). The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to afford the target compound O55 (42 mg, 39.62% yield) as a white solid with a melting point of 245.0-246.0°C. 1 H NMR(400MHz, DMSO-d6): δ8.91(s,1H),8.20(s,1H),7.91(d,J=8.3Hz,2H),7.75(d,J=8.3Hz,3H),7.61(d,J=14.2Hz,3H),4.36(s, 2H),3.95(s,2H),3.69(d,J=11.6Hz,2H),2.94(s,1H),2.41(s,2H),1.85(d,J=11.9Hz,2H),1.64(d,J=32.9Hz,2H); 13 C NMR (101MHz, DMSO-d6): δ173.11,163.61,161.14( 1 J CF =248.9),149.97,146.06,139.44,137.97,137.91,132.65(2C),132.34,132.26( 3 J CF =7.9),130.72(2C),124.29,123.84,120.93,120.72( 2 J CF =21.3),119.24,115.11,114.87( 2 J CF=24.1),110.87,100.07,68.02,60.25,45.70,42.61,37.30,34.87,27.97.60.25,45.70,42.61,37.30,34.87,27.97.HRMS(ESI)m / z[M+H] + calcd.for C 26 H 23 FN4O4S + 507.1497, found 507.1501.

[0336] 4-(4-(Azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O56)

[0337] 4-(4-(azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O56)

[0338] According to General Procedure E, compound 4 (50 mg, 0.21 mmol) was dissolved in anhydrous dichloromethane (5 mL), and 1-Boc-azetidine-3-carboxylic acid (53 mg, 0.21 mmol) and N,N-diisopropylethylamine (81 mg, 0.63 mmol) were added. The reaction system was then placed at 0°C, HATU (83 mg, 0.22 mmol) was added, and the reaction system was brought to room temperature and allowed to react under N2 protection for 12 hours. After the reaction was complete as determined by TLC, the reaction mixture was diluted with water (6 mL) and extracted with dichloromethane (2 × 6 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was dissolved in methanol (3 mL), and 1 mL of hydrochloric acid was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was complete as determined by TLC, the reaction mixture was diluted with water (6 mL) and extracted with dichloromethane (2 × 3 mL). The aqueous phase was adjusted to pH 12 with solid NaOH and extracted with dichloromethane (2 x 3 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the target compound O56 (35 mg, 52.00% yield) as a white solid with a melting point of 169.0-170.0°C. The molecular formula is: C 18 H 16 N4O2, HRMS (ESI): [M+H] + :; 1H NMR (400MHz, DMSO-d6): δ7.89(s,1H),7.87(d,J=1.9Hz,2H),7.73(d,J=14.1Hz,3H),6 .18(s,1H),4.23(s,2H),3.34(s,2H),1.73(d,J=58.2Hz,2H),1.25(d,J=34.0Hz,2H); 13 C NMR (101MHz, DMSO-d6): δ146.21,140.29,138.91,136.84,132.70,132.56(2C),13 0.52(2C),123.03,119.35,110.41,66.01,34.66,26.84,26.73,26.33,26.26.

[0339] 4-(4-(1-(4-Fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O57)

[0340] 4-(4-(1-(4-fluorobenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O57)

[0341] According to General Method A, compound O56 (100 mg, 0.31 mmol) and 4-fluorobenzoyl chloride (74 mg, 0.47 mmol) were added with 4-DMAP (11 mg, 0.094 mmol) and triethylamine (95 mg, 0.94 mmol). The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the target compound O57 (50 mg, 36.50% yield) as a white solid with a melting point of 234.0-235.0°C. 1 H NMR (400MHz, DMSO-d6): δ9.19(s,1H),8.22(s,1H),7.92(d,J=8.3Hz,2H),7.75(d,J=18 .8Hz,4H),7.29(s,2H),4.56(s,1H),4.42(s,3H),4.18(d,J=92.2Hz,3H),3.80(s,2H); 13 C NMR (101MHz, DMSO-d6): δ170.35,168.41,165.30,162.83( 1 J CF=248.7),149.71,145.63,139.38,137.35,132.69(2C),130.94,130.85( 3 J CF =8.9),130.73(2C),129.72,129.69( 4 J CF =3.1),124.10,123.83,119.24,116.07,115.85( 2 J CF =21.7),110.92,66.99,55.00,50.91,42.33,32.47.HRMS(ESI)m / z[M+H] + calcd.for C 25 H 19 FN4O3 + 443.1514, found 443.1506.

[0342] 4-(4-(1-(3-Fluorobenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O58)

[0343] 4-(4-(1-(3-fluorobenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O58)

[0344] According to General Method A, compound O56 (100 mg, 0.31 mmol) and 3-fluorobenzoyl chloride (74 mg, 0.47 mmol) were added with DMAP (11 mg, 0.094 mmol) and triethylamine (95 mg, 0.94 mmol). The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the target compound O58 (89 mg, 65.00% yield) as a white solid with a melting point of 78.0-80.0°C. 1 H NMR (400MHz, CDCl3): δ8.31(s,1H),8.14(s,1H),7.73(d,J=8.2Hz,2H),7.62(d,J=8.0Hz,2H),7 .41(s,2H),7.33(s,1H),7.18(s,1H),4.66(s,1H),4.43(s,4H),4.32(s,2H),4.18–3.85(m,2H); 13C NMR (101MHz, DMSO-d6): δ169.79,168.95,163.72( 1 J CF =247.9),161.26,150.20,148.06,143.67,138.07,134.59,134.52( 3 J CF =6.5),132.14(2C),130.25,130.18( 3 J CF =7.9),130.07(2C),124.38,123.49,123.46( 4 J CF =3.0),121.75,118.52,118.28( 2 J CF =23.8),116.03,115.13,114.90( 2 J CF =22.8),111.94,68.20,55.14,51.67,38.97,31.81.HRMS(ESI)m / z[M+H] + calcd.for C 25 H 19 FN4O3 + 443.1514, found 443.1505.

[0345] N-(2-(8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-2-oxoethyl)-4-fluorobenzamide (O59)

[0346] N-(2-(8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-2-oxoethyl)-4-fluorobenzamide(O59)

[0347] According to general method E, compound 4 (50 mg, 0.21 mmol) and (4-fluorobenzoyl)glycine (63 mg, 0.32 mmol) were used as raw materials, N,N-diisopropylethylamine (81 mg, 0.63 mmol) and HATU (83 mg, 0.22 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to give the target compound O59 (50 mg, yield 56.81%) as a white solid with a melting point of 220.0-221.0°C. 1H NMR (400MHz, DMSO-d6): δ9.03(s,1H),8.90(s,1H),8.24(s,1H),7.95(d,J=23.0Hz,4H ),7.77(d,J=8.3Hz,2H),7.32(s,2H),4.44(s,2H),4.40(d,J=5.5Hz,2H),4.02(s,2H); 13 C NMR (101MHz, DMSO-d6): δ167.93,165.57,165.23,162.75( 1 J CF =248.9),149.34,145.79,145.01,138.89,132.19(2C),130.27(2C),130.02,129.93( 3 J CF =9.2),123.86,123.43,120.51,118.76,115.40,115.19( 2 J CF =21.9),110.44,71.51,67.00,42.04.HRMS(ESI)m / z[M+H] + calcd.for C 23 H 18 FN3O2 + 417.1358, found 417.1263.

[0348] 4-(4-(1-((4-fluorophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O60)

[0349] 4-(4-(1-((4-fluorophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O60)

[0350] According to General Method B, compound O56 (100 mg, 0.31 mmol) and 4-fluorobenzenesulfonyl chloride (120 mg, 0.62 mmol) were used as starting materials. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to give the target compound O60 (30 mg, 33% yield) as a white solid with a melting point of 172.0-173.0°C. 1H NMR (400MHz, CDCl3): δ8.26(s,1H),7.99(s,1H),7.84(d,J=13.8Hz,2H),7.69(d,J=8.1Hz,2 H),7.57(d,J=7.7Hz,2H),7.22(s,2H),4.32(s,2H),4.02(s,3H),3.94(s,2H),3.66(s,2H); 13 C NMR (101MHz, CDCl3): δ168.68,166.86,164.31( 1 J CF =256.1),150.12,148.11,143.45,138.01,132.09(2C),131.04,130.94( 2 J CF =22.6),130.51,130.01(2C),124.25,123.31,118.49,116.68,116.46( 3 J CF =9.4),111.84,68.09,52.98,38.90,30.55,20.88.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 19 FN4O4S + 479.1184, found 479.1093.

[0351] 4-(4-(1-((3-fluorophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O61)

[0352] 4-(4-(1-((3-fluorophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O61)

[0353] According to General Method B, compound O56 (100 mg, 0.31 mmol) and 3-fluorobenzenesulfonyl chloride (120 mg, 0.62 mmol) were used as starting materials. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to give the target compound O61 (30 mg, 33% yield) as a white solid with a melting point of 189.0-190.0°C. 1H NMR (400MHz, DMSO-d6): δ8.95(s,1H),8.19(s,1H),7.92(d,J=8.3Hz,2H),7.72( d,J=52.3Hz,6H),4.34(s,2H),4.02(d,J=27.9Hz,3H),3.87(s,2H),3.70(s,2H); 13 C NMR (101MHz, DMSO-d6): δ169.34,163.73,161.25( 1 J CF =249.1),149.71,145.80,145.32,139.36,136.14,136.06( 3 J CF =6.8),132.67(2C),132.42,132.34( 3 J CF =7.8),130.72(2C),125.12,125.09( 4 J CF =2.7),123.85,123.84,121.45,121.24( 2 J CF =21.1),119.23,115.88,115.64( 2 J CF =24.2),110.92,66.87,52.71,42.16,31.05,21.02.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 19 FN4O4S + 479.1184, found 479.1094.

[0354] 4-(4-(1-((4-nitrophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O62)

[0355] 4-(4-(1-((4-nitrophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O62)

[0356] According to General Method B, compound O56 (100 mg, 0.31 mmol) and 4-nitrobenzenesulfonyl chloride (137 mg, 0.62 mmol) were used as starting materials. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to give the target compound O62 (50 mg, 32% yield) as a yellow solid with a melting point of 230.0-231.0°C. 1 H NMR (400MHz, DMSO-d6): δ8.92(s,1H),8.50(d,J=8.8Hz,2H),8.18(s,1H),8.13(d,J=8.7Hz,2H),7.91 (d,J=8.3Hz,2H),7.73(d,J=7.5Hz,2H),4.34(s,2H),4.06(d,J=28.7Hz,4H),3.78(d,J=73.2Hz,3H); 13 C NMR (101MHz, DMSO-d6): δ168.74,150.28,149.26,145.35,144.87,139.34,138.85,132.20(2C),130.23(2C),129. 91,124.71(2C),123.32,119.44,118.75,114.55,110.45,66.43,52.52,48.59,41.69,30.94.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 19 N5O6S + 506.1129, found 506.1030.

[0357] 4-(4-(1-((3-nitrophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O63)

[0358] 4-(4-(1-((3-nitrophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O63)

[0359] According to General Method B, compound O56 (100 mg, 0.31 mmol) and 3-nitrobenzenesulfonyl chloride (137 mg, 0.62 mmol) were used as starting materials. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to give the target compound O63 (58 mg, 37% yield) as a white solid with a melting point of 216.0-217.0°C. 1 H NMR (400MHz, DMSO-d6): δ8.95(s,1H),8.62(s,1H),8.47(s,1H),8.32(s,1H),8.18(s,1H),8.01(s,1H),7.91(d,J= 8.2Hz,2H),7.72(d,J=7.6Hz,2H),4.33(s,2H),4.03(s,3H),3.86(s,2H),3.68(s,2H); 13 C NMR (101MHz, DMSO-d6): δ168.81,149.22,148.14,145.33,144.93,138.89,135.43,134.19,132.20(2C),131.71,13 0.23(2C),128.20,123.36,122.84,119.52,118.75,110.44,66.32,54.88,52.52,41.56,30.90.HRMS(ESI)m / z[M+H] + calcd.for C 24 H 19 N5O6S + 506.1129, found 506.1116.

[0360] 4-(4-1-(thiophen-2-ylsulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O64)

[0361] 4-(4-(1-(thiophen-2-ylsulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O64)

[0362] According to general method B, compound O56 (100 mg, 0.31 mmol) and 2-thiophenesulfonyl chloride (112.79 mg, 0.62 mmol) were used as starting materials, and the crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to obtain the target compound O64 (58 mg, yield 37%) as a white solid with a melting point of 176.0-177.0°C. 1 H NMR (400MHz, DMSO-d6): δ8.97(s,1H),8.19(s,1H),8.17(s,1H),7.92(d,J=8.1Hz,2H),7.76(d ,J=25.8Hz,3H),7.37(s,1H),4.34(s,2H),4.07(s,1H),3.99(s,2H),3.88(s,2H),3.72(s,2H); 13 C NMR (101MHz, DMSO-d6): δ168.82,160.32,150.07,144.89,142.49,134.74,134.33,132.74,132.19(2C),13 0.24(2C),128.59,123.37,118.74,110.43,109.16,66.43,52.63,41.57,30.65,14.13.HRMS(ESI)m / z[M+H] + calcd.for C 22 H 18 N4O4S2 + 467.0842,found 467.0846.

[0363] 4-(4-(1-Tosylazetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O65)

[0364] 4-(4-(1-tosylazetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O65)

[0365] According to General Method B, compound O56 (100.0 mg, 0.30 mmol) and 4-toluenesulfonyl chloride (85.0 mg, 0.45 mmol) were used as starting materials. DMAP (11.0 mg, 0.09 mmol) and triethylamine (91.1 mg, 0.90 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 2 / 1 as eluent to obtain the target compound O56 (65.2 mg, 46.3% yield) as a white solid with a melting point of 205.0-206.0°C and a R f =0.83 (dichloromethane:methanol (V / V)=40 / 1). 1 H NMR (400MHz, CDCl3): δ8.29(s,1H),8.02(s,1H),7.78-7.73(m,2H),7.73-7.70(m,2H),7.60(d,J=8.2Hz,2H),7. 39(d,J=8.2Hz,2H),4.34(t,J=4.4Hz,2H),4.08-3.98(m,3H),3.98-3.83(m,2H),3.83-3.52(m,2H),2.47(s,3H); 13 C NMR (101MHz, DMSO-d6): δ168.94,149.28,145.21,145.06,144.15,138.87,132.19(2C),130.51,130.25(2C),12 9.99(2C),128.36(2C),123.39(2C),118.76,110.46,66.48,52.13,41.64(2C),30.90,21.08; HRMS(ESI):calcd for C 25 H 22 N4O4S[M+H] + :475.1362,found:475.1426.

[0366] 4-(4-(1-((3-methoxyphenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O66)

[0367] 4-(4-(1-((3-methoxyphenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O66)

[0368] According to General Method B, compound O56 (85.0 mg, 0.25 mmol) and m-methoxybenzenesulfonyl chloride (78.5 mg, 0.38 mmol) were used as starting materials. DMAP (9.8 mg, 0.08 mmol) and triethylamine (75.9 mg, 0.75 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 2 / 1 as eluent to obtain the target compound O66 (60.7 mg, 48.9% yield) as a white solid with a melting point of 206.0-207.0°C and a R f =0.30 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1 H NMR (400MHz, CDCl3): δ8.29(s,1H),8.03(s,1H),7.74(d,J=8.3Hz,2H),7.61(d,J=8.2Hz,2H),7.51(t,J=8.0Hz,1H),7.42(d,J=7.8Hz,1H ),7.34(s,1H),7.20(dd,J=7.8,3.1Hz,1H),4.35(t,J=4.7Hz,2H),4.17-4.01(m,3H),4.00-3.92(m,2H),3.88(s,3H),3.87-3.48(m,2H); 13 C NMR (101MHz, DMSO-d6): δ168.93,159.68,149.31,144.93(2C),138.90,134.68,132.20(2C),130.77,130.25(2C) ,123.37(2C),120.40,119.55,118.76,112.99,110.45,66.46,55.72,52.27,41.66(2C),30.85; HRMS(ESI):calcd for C 25 H 22 N4O5S[M+H] + :491.1311,found:491.1382.

[0369] 4-(4-(1-((4-methoxyphenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O67)

[0370] 4-(4-(1-((4-methoxyphenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O67)

[0371] According to General Method B, compound O56 (100.0 mg, 0.30 mmol) and p-methoxybenzenesulfonyl chloride (92.2 mg, 0.45 mmol) were used as starting materials. DMAP (11.0 mg, 0.09 mmol) and triethylamine (91.1 mg, 0.90 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 2 / 1 as eluent to obtain the target compound O67 (56.5 mg, 38.8% yield) as a white solid with a melting point of 204.0-205.0°C and a R f =0.63 (dichloromethane:methanol (V / V)=40 / 1). 1 H NMR (400MHz, CDCl3): δ8.28(s,1H),8.03(s,1H),7.78(d,J=8.8Hz,2H),7.73(d,J=8.3Hz,2H),7.60(d,J=8.1Hz,2H) ,7.05(d,J=8.8Hz,2H),4.34(t,J=4.8Hz,2H),4.06-3.97(m,3H),3.97-3.91(m,2H),3.90(s,3H),3.88-3.65(m,2H); 13 C NMR (101MHz, DMSO-d6): δ168.98,163.12,149.30,144.85(2C),138.87,132.20(2C),130.58,130.24(2C),124 .93(2C),123.39(2C),118.75,114.67(2C),110.45,66.56,55.77,52.02,41.64(2C),30.85; HRMS(ESI):calcd for C 25 H 22 N4O5S[M+H] + :491.1311,found:491.1375.

[0372] 3-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O68)

[0373] 3-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile(O68)

[0374] According to General Method B, compound O56 (100.0 mg, 0.30 mmol) and m-cyanobenzenesulfonyl chloride (90.0 mg, 0.45 mmol) were used as starting materials. DMAP (11.0 mg, 0.09 mmol) and triethylamine (91.1 mg, 0.90 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 1 / 1 as eluent to obtain the target compound O68 (117.1 mg, 81.3% yield) as a white solid with a melting point of 182.0-183.0°C and a R f =0.37 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1 H NMR (400MHz, CDCl3): δ8.32(s,1H),8.14(s,1H),8.09(d,J=8.1Hz,1H),8.01(s,1H),7.95(d,J=7.8Hz,1H),7.77(d,J=7.9Hz,1H ),7.73(d,J=8.8Hz,2H),7.61(d,J=8.3Hz,2H),4.37(t,J=4.8Hz,2H),4.16-4.02(m,4H),4.00-3.95(m,1H),3.94-3.69(m,2H); 13 C NMR (101MHz, CDCl3): δ168.63,150.38,148.32,143.57,138.11,136.91,136.62,132.25,132.17(2C),131.77,130.5 0,130.16(2C),124.47,123.38,118.65,117.20,113.98,112.02,68.24,53.50,39.10(2C),30.48; HRMS(ESI):calcd for C 25 H 19 N5O4S[M+H] + :486.1158,found:486.1234.

[0375] 4-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O69)

[0376] 4-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile(O69)

[0377] According to General Method B, compound O56 (100.0 mg, 0.30 mmol) and 4-cyanobenzenesulfonyl chloride (90.0 mg, 0.45 mmol) were used as starting materials. DMAP (11.0 mg, 0.09 mmol) and triethylamine (91.1 mg, 0.90 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 1 / 1 as eluent to obtain the target compound O69 (119.2 mg, 82.7% yield) as a white solid with a melting point of 226.0-227.0°C and a R f =0.21 (petroleum ether:ethyl acetate (V / V)=1 / 2.5). 1 H NMR (400MHz, CDCl3): δ8.32(s,1H),8.18-7.92(m,3H),7.90(d,J=8.3Hz,2H),7.73(d,J=8.3Hz,2H),7 .60(d,J=8.2Hz,2H),4.37(t,J=4.8Hz,2H),4.18-4.02(m,4H),4.00-3.95(m,1H),3.95-3.62(m,2H); 13 C NMR (101MHz, DMSO-d6): δ168.78,149.27,145.35,144.59,138.90,137.88,133.64(2C),132.21(2C),130.24(2C ),129.02(2C),123.38(2C),118.77,117.62,116.01,110.47,66.44,52.48,41.71(2C),30.85; HRMS(ESI):calcd for C 25 H 19 N5O4S[M+H] + :486.1158,found:486.1230.

[0378] 4-(4-(1-(m-Toluenesulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O70)

[0379] 4-(4-(1-(m-tolylsulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O70)

[0380] According to General Method B, compound O56 (85.0 mg, 0.25 mmol) and 3-toluenesulfonyl chloride (72.4 mg, 0.38 mmol) were used as starting materials. DMAP (9.8 mg, 0.08 mmol) and triethylamine (75.9 mg, 0.75 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 2 / 1 as eluent to obtain the target compound O70 (39.1 mg, 32.6% yield) as a white solid with a melting point of 227.0-228.0°C and a R f =0.38 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1 H NMR (400MHz, CDCl3): δ8.29(s,1H),8.03(s,1H),7.72(d,J=8.2Hz,2H),7.65(d,J=4.9Hz,2H),7.61(t,J=7.6Hz,2H) ,7.47(d,J=5.0Hz,2H),4.34(t,J=4.8Hz,2H),4.16-4.00(m,3H),3.98-3.88(m,2H),3.88-3.57(m,2H),2.46(s,3H); 13 C NMR (101MHz, DMSO-d6): δ168.93,149.23,145.31,144.90,139.36,138.89,134.30,133.46,132.19(2C),130.23(2C ),129.37,128.38(2C),125.45,123.34,118.75,110.44,66.48,52.16,41.65(2C),30.85,20.84; HRMS(ESI):calcd for C 25 H 22 N4O4S[M+H] + :475.1362,found:475.1437.

[0381] 4-(4-(3-((3-fluorophenyl)amino)bicyclo[1.1.1]pentane-1-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O71)

[0382] 4-(4-(3-((3-fluorophenyl)amino)bicyclo[1.1.1]pentane-1-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O71)

[0383] According to general method E, compound 4 (100 mg, 0.42 mmol) and 3-(3-fluorophenylamino)bicyclo[1.1.1]pentane-1-carboxylic acid (139 mg, 0.63 mmol) were used as raw materials, N,N-diisopropylethylamine (95 mg, 1.26 mmol) and HATU (168 mg, 0.44 mmol) were added, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O71 (59 mg, yield 32%) as a light yellow oil. 1 H NMR (400MHz, CDCl3): δ8.56(s,1H),8.03(s,2H),7.75(d,J=8.3Hz,2H),7.60(d,J=8.1Hz,2H),7.33-7.27(m,1H),7.14-6.98(m ,2H),6.96-6.88(m,1H),4.42(t,J=4.8Hz,2H),3.85(t,J=4.8Hz,2H),2.17-2.13(m,3H),1.99-2.07(m,3H).HRMS(ESI):calcd for C 26 H 22 FN4O2[M+H] + :441.1721,found:441.1712.

[0384] 4-(4-(5-(4-Fluorophenoxy)thiophene-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O72)

[0385] 4-(4-(5-(4-fluorophenoxy)thiophene-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O72)

[0386] According to general method A, compound 4 (132.8 mg, 0.56 mmol) and intermediate 5-(4-fluorophenoxy)thiophene-2-yl chloride (215.6 mg, 0.84 mmol) were used as starting materials. DMAP (20.8 mg, 0.17 mmol) and triethylamine (170.0 mg, 1.68 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 1 / 1 as eluent to obtain the target compound O72 (152.5 mg, 59.5% yield) as a white solid with a melting point of 79.0-80.0°C and a R f =0.50 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1 H NMR (400MHz, CDCl3): δ8.55(s,1H),8.20(s,1H),7.73(d,J=8.4Hz,2H),7.64(d,J=8.4Hz,2H),7.1 9-7.11(m,3H),7.10-7.02(m,2H),6.35(d,J=4.2Hz,2H),4.45(t,J=4.7Hz,2H),4.17-4.11(m,3H). 13 C NMR (101MHz, CDCl3): δ168.22,162.19,161.15( 1 J CF =245.3Hz),153.41,149.30,146.28,146.04,138.83,132.25(2C),131.58,130.25(2C),125.08,124.22,124.09,120.49( 3 J CF =8.6Hz)(2C),118.79,116.95( 2 J CF =23.8Hz)(2C),111.87,111.03,67.52,42.61; 19 F NMR (376MHz, CDCl3): δ-116.97; HRMS (ESI): calcd for C 25 H 16 FN3O3S[M+H] + :458.0896,found:458.0956.

[0387] 4-(4-(6-(3-fluorobenzyl))-2,6-diazabicyclospiro[3.3]heptane-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O73)

[0388] 4-(4-(6-(3-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O73)

[0389] To a solution of compound 4 (100 mg, 0.42 mmol) and pyridine (79 mg, 0.63 mmol) in chloroform (10 mL) in an ice bath was slowly added dropwise a solution of triphosgene (623 mg, 2.1 mmol) in chloroform (3 mL). The mixture was stirred at 60°C under nitrogen for 12 hours. After completion of the reaction as monitored by TLC, 1N aqueous HCl (10 mL) was added dropwise. The mixture was extracted with chloroform, washed sequentially with saturated Na2CO3 solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil. This intermediate was dissolved in anhydrous dioxane (10 mL), and triethylamine (0.63 mmol) and 2-(3-fluorobenzyl)-2,6-diazabicyclospiro[3.3]heptane (475 mg, 0.63 mmol) were added. The mixture was stirred at room temperature under nitrogen for 12 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated to dryness under vacuum. The resulting oil was extracted with chloroform / water, and the organic phases were combined, washed sequentially with saturated Na2CO3 solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate) afforded product O73. 1 H NMR (400MHz, CDCl3): δ8.72(s,1H),8.19(s,1H),7.76(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.36-7.25(m,1H),7.13-6.98 (m,2H),6.95-6.83(m,1H),4.42(t,J=4.8Hz,2H),3.80-3.72(m,4H),3.61-3.58(m,3H),3.25-3.17(m,4H).HRMS(ESI):calcd for C 27 H 25 FN5O2[M+H] + :470.5279,found:470.5283.

[0390] 3-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O74)

[0391] 3-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile(O74)

[0392] According to General Method B, compound O56 (100.0 mg, 0.30 mmol) and m-cyanobenzenesulfonyl chloride (90.0 mg, 0.45 mmol) were used as starting materials. DMAP (11.0 mg, 0.09 mmol) and triethylamine (91.1 mg, 0.90 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 1 / 1 as eluent to obtain the target compound O74 (117.1 mg, 81.3% yield) as a white solid with a melting point of 182.0-183.0°C and a R f =0.37 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1 H NMR (400MHz, CDCl3): δ8.32(s,1H),8.14(s,1H),8.09(d,J=8.1Hz,1H),8.01(s,1H),7.95(d,J=7.8Hz,1H),7.77(d,J=7.9Hz,1H ),7.73(d,J=8.8Hz,2H),7.61(d,J=8.3Hz,2H),4.37(t,J=4.8Hz,2H),4.16-4.02(m,4H),4.00-3.95(m,1H),3.94-3.69(m,2H); 13 C NMR (101MHz, CDCl3): δ168.63,150.38,148.32,143.57,138.11,136.91,136.62,132.25,132.17(2C),131.77,130.5 0,130.16(2C),124.47,123.38,118.65,117.20,113.98,112.02,68.24,53.50,39.10(2C),30.48; HRMS(ESI):calcd for C 25 H 19 N5O4S[M+H] + :486.1158,found:486.1234.

[0393] 4-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O75)

[0394] 4-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile(O75)

[0395] According to General Method B, compound O56 (100.0 mg, 0.30 mmol) and 4-cyanobenzenesulfonyl chloride (90.0 mg, 0.45 mmol) were used as starting materials. DMAP (11.0 mg, 0.09 mmol) and triethylamine (91.1 mg, 0.90 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 1 / 1 as eluent to obtain the target compound O75 (119.2 mg, 82.7% yield) as a white solid with a melting point of 226.0-227.0°C and a R f =0.21 (petroleum ether:ethyl acetate (V / V)=1 / 2.5). 1 H NMR (400MHz, CDCl3): δ8.32(s,1H),8.18-7.92(m,3H),7.90(d,J=8.3Hz,2H),7.73(d,J=8.3Hz,2H),7 .60(d,J=8.2Hz,2H),4.37(t,J=4.8Hz,2H),4.18-4.02(m,4H),4.00-3.95(m,1H),3.95-3.62(m,2H); 13 C NMR (101MHz, DMSO-d6): δ168.78,149.27,145.35,144.59,138.90,137.88,133.64(2C),132.21(2C),130.24(2C ),129.02(2C),123.38(2C),118.77,117.62,116.01,110.47,66.44,52.48,41.71(2C),30.85; HRMS(ESI):calcd for C 25 H 19 N5O4S[M+H] + :486.1158,found:486.1230.

[0396] 4-(4-(1-(3-methoxybenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O76)

[0397] 4-(4-(1-(3-methoxybenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O76)

[0398] According to General Method B, compound O56 (100.0 mg, 0.30 mmol) and m-anisyl chloride (76.1 mg, 0.45 mmol) were used as starting materials. DMAP (11.0 mg, 0.09 mmol) and triethylamine (91.1 mg, 0.90 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 50 / 1 as the eluent to obtain the target compound O76 (125.2 mg, 92.8% yield) as a white solid with a melting point of 104.0-105.0°C and a R f =0.87 (dichloromethane:methanol (V / V)=10 / 1). 1 H NMR (400MHz, CDCl3): δ8.31(s,1H),8.14(s,1H),7.74(d,J=8.2Hz,2H),7.62(d,J=8.2Hz,2H),7.32(t,J=7.9Hz,1H),7.17(d,J =10.6Hz,2H),7.01(d,J=8.2Hz,1H),4.74-4.59(m,1H),4.56-4.38(m,4H),4.36-4.27(m,2H),4.26-3.97(m,2H),3.83(s,3H); 13 C NMR (101MHz, CDCl3): δ170.44,167.28,159.80,150.21,148.27,143.97(2C),138.34,133.91,132.31(2C),130.23(2C), 129.62,124.50,123.64,120.06,118.69,117.64,113.09,112.08,68.29,55.55,51.55,39.35,32.12; HRMS(ESI):calcd for C 26 H 22 N4O4[M+H] + :455.1641,found:455.1711.

[0399] 4-(4-(1-(4-methoxybenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O77)

[0400] 4-(4-(1-(4-methoxybenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O77)

[0401] According to General Method B, compound O56 (100.0 mg, 0.30 mmol) and 4-methoxybenzoyl chloride (76.1 mg, 0.45 mmol) were used as starting materials. DMAP (11.0 mg, 0.09 mmol) and triethylamine (91.1 mg, 0.90 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 20 / 1 as the eluent to obtain the target compound O77 (119.9 mg, 88.9% yield) as a white solid with a melting point of 84.0-85.0°C and a R f =0.83 (dichloromethane:methanol (V / V)=10 / 1). 1 H NMR (400MHz, CDCl3): δ8.31(s,1H),8.15(s,1H),7.74(d,J=8.4Hz,2H),7.65-7.63(m,2H),7.63-7.59(m,2H),6 .91(d,J=8.8Hz,2H),4.93-4.56(m,1H),4.55-4.37(m,4H),4.36-4.15(m,2H),4.14-3.85(m,2H),3.84(s,3H); 13 C NMR (101MHz, CDCl3): δ170.31,167.42,162.13,150.20,148.12,143.91,138.35,132.28(2C),130.23(2C),129.97(2 C),124.83,124.46,123.88,118.69,113.85(2C),112.02,68.38,55.51(2C),51.89,39.17,32.07; HRMS(ESI):calcd for C 26 H 22 N4O4[M+H] + :455.1641,found:455.1712.

[0402] 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O78)

[0403] 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O78)

[0404] According to General Method F, compound O56 (95.0 mg, 0.28 mmol) and m-fluorobenzyl chloride (61.3 mg, 0.42 mmol) were used as starting materials, and potassium carbonate (77.4 mg, 0.56 mmol) was added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 50 / 1 as the eluent to obtain the target compound O78 (35.0 mg, 28.9% yield) as a white solid with a melting point of 79.0-80.0°C and a R f =0.21 (ethyl acetate). 1 H NMR (400MHz, CDCl3): δ8.51(s,1H),8.02(s,1H),7.72(d,J=8.3Hz,2H),7.62(d,J=8.1Hz,2H),7.31-7.22(m,1H),7. 09-6.98(m,2H),6.97-6.89(m,1H),4.38(t,J=4.8Hz,2H),4.17-3.72(m,3H),3.69-3.53(m,4H),3.51-3.36(m,2H); 13 C NMR (101MHz, CDCl3): δ170.60,164.20( 1 J CF =246.7Hz),149.85,147.57,144.34,140.15,138.64,132.18(2C),130.19(2C),130.01( 3 J CF =8.1Hz),124.13,124.07,123.78,118.71,115.39,114.32( 2 J CF =21.4Hz),111.81,68.29,62.60,57.02(2C),39.03,33.64; 19 F NMR (376MHz, CDCl3): δ-113.34; HRMS (ESI): calcd for C25 H 21 FN4O2[M+H] + :429.1649,found:429.1728.

[0405] 4-(4-(1-(4-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O79)

[0406] 4-(4-(1-(4-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O79)

[0407] According to General Method F, compound O56 (100.0 mg, 0.30 mmol) and 4-fluorobenzyl chloride (64.5 mg, 0.45 mmol) were used as starting materials, and potassium carbonate (82.9 mg, 0.60 mmol) was added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 25 / 1 as the eluent to obtain the target compound O79 (47.0 mg, 36.9% yield) as a white solid with a melting point of 155.0-156.0°C and a R f =0.16 (ethyl acetate). 1 H NMR (400MHz, CDCl3): δ8.27(s,1H),8.18(s,1H),7.73(d,J=8.3Hz,2H),7.62(d,J=8.3Hz,2H),7.26-7.21(m,2H),6. 99(t,J=8.7Hz,2H),4.38(t,J=5.1Hz,2H),4.14-3.65(m,3H),3.61(s,2H),3.60-3.52(m,2H),3.40(t,J=7.6Hz,2H); 13 C NMR (101MHz, CDCl3): δ170.60,163.42( 1 J CF =245.9Hz),150.84,147.68,143.90,138.76,133.31,132.24(2C),130.23(2C),130.18( 3 J CF =8.1Hz,2C),124.18,123.60,118.74,115.48( 2 J CF=21.4Hz,2C),111.91,68.04,62.54,57.03(2C),39.04,33.52; 19 F NMR (376MHz, CDCl3): δ-115.49; HRMS (ESI): calcd for C 25 H 21 FN4O2[M+H] + :429.1649,found:429.1724.

[0408] 3-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)methyl)benzonitrile (O80)

[0409] 3-((3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)methyl)benzonitrile(O80)

[0410] According to General Method F, compound O56 (100.0 mg, 0.30 mmol) and m-cyanobenzyl bromide (87.4 mg, 0.45 mmol) were used as starting materials, and potassium carbonate (82.9 mg, 0.60 mmol) was added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 20 / 1 as the eluent to obtain the target compound O80 (51.4 mg, 39.7% yield) as a white solid with a melting point of 83.0-84.0°C and a R f =0.21 (ethyl acetate). 1 H NMR (400MHz, CDCl3): δ8.28(s,1H),8.17(s,1H),7.72(d,J=8.3Hz,2H),7.67-7.57(m,3H),7.53(t,J=7.2Hz,2H),7. 43(d,J=7.7Hz,1H),4.39(t,J=4.8Hz,2H),4.15-3.72(m,3H),3.68(s,2H),3.65-3.52(m,2H),3.44(t,J=7.4Hz,2H); 13C NMR (101MHz, CDCl3): δ170.62,149.98,147.60,144.10,139.27,138.59,132.94,132.24(2C),131.96,131.12,130.21(2 C),129.38,124.22,123.81,118.88,118.72,112.65,111.91,68.52,62.29,57.15(2C),39.09,33.83; HRMS(ESI):calcd for C 26 H 21 N5O2[M+H] + :436.1695,found:436.1757.

[0411] 4-(4-(1-(4-cyanophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O81)

[0412] 4-(4-(1-(4-cyanobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O81)

[0413] According to General Method F, compound O56 (110.0 mg, 0.33 mmol) and 4-cyanobenzyl bromide (96.1 mg, 0.49 mmol) were used as starting materials, and potassium carbonate (82.9 mg, 0.60 mmol) was added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 20 / 1 as the eluent to obtain the target compound O81 (61.8 mg, 43.4% yield) as a white solid with a melting point of 168.0-169.0°C and a R f =0.17 (ethyl acetate). 1 H NMR (400MHz, CDCl3): δ8.28(s,1H),8.11(s,1H),7.72(d,J=8.4Hz,2H),7.67-7.56(m,4H),7.40(d,J=8.2 Hz,2H),4.39(t,J=4.9Hz,2H),4.12-3.74(m,3H),3.71(s,2H),3.64-3.53(m,2H),3.44(t,J=7.4Hz,2H); 13C NMR (101MHz, CDCl3): δ170.65,150.09,147.76,144.26,143.34,138.54,132.38(2C),132.25(2C),130.21(2C),129. 05(2C),124.23,123.85,118.94,118.72,111.94,111.17,68.37,62.74,57.25(2C),39.02,34.00; HRMS(ESI):calcd for C 26 H 21 N5O2[M+H] + :436.1695,found:436.1758.

[0414] 4-(4-(1-(3-methoxybenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O82)

[0415] 4-(4-(1-(3-methoxybenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O82)

[0416] According to General Method F, compound O56 (100.0 mg, 0.30 mmol) and 3-methoxybenzyl chloride (70.0 mg, 0.45 mmol) were used as starting materials, and potassium carbonate (82.9 mg, 0.60 mmol) was added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 25 / 1 as the eluent to obtain the target compound O82 (45.0 mg, 34.3% yield) as a white solid with a melting point of 135.0-136.0°C and a R f =0.16 (ethyl acetate). 1 H NMR (400MHz, CDCl3): δ8.41-7.98(m,2H),7.73(d,J=8.4Hz,2H),7.62(d,J=8.3Hz,2H),7.22(t,J=7.8Hz,1H),6.89-6.83(m,2H) ,6.80(dd,J=7.8,3.0Hz,1H),4.46-4.30(m,2H),4.13-3.84(m,2H),3.81-3.67(m,4H),3.65-3.55(m,4H),3.42(t,J=7.5Hz,2H); 13C NMR (101MHz, CDCl3): δ170.87,159.85,149.95,147.73,144.41,139.08,138.68,132.23(2C),130.22(2C),129.53,124 .17,123.53,120.91,118.75,113.94,113.00,111.87,68.24,63.29,57.03(2C),55.33,39.08,33.78; HRMS(ESI):calcd for C 26 H 24 N4O3[M+H] + :441.1848,found:441.1925.

[0417] 4-(4-(1-(4-methoxybenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O83)

[0418] 4-(4-(1-(4-methoxybenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O83)

[0419] According to General Method F, compound O56 (100.0 mg, 0.30 mmol) and 1-(chloromethyl)-4-methoxybenzene (69.8 mg, 0.45 mmol) were used as starting materials, and potassium carbonate (82.9 mg, 0.60 mmol) was added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 20 / 1 as the eluent to obtain the target compound O83 (45.0 mg, 34.3% yield) as a white solid with a melting point of 134.0-135.0°C and a R f =0.09 (ethyl acetate). 1 H NMR (400MHz, CDCl3): δ8.37-7.93(m,2H),7.73(d,J=8.6Hz,2H),7.62(d,J=8.4Hz,2H),7.20(d,J=8.7Hz,2H),6.85( d,J=8.7Hz,2H),4.43-4.32(m,2H),4.07-3.82(m,2H),3.82-3.68(m,4H),3.62-3.53(m,4H),3.39(t,J=7.3Hz,2H); 13C NMR (101MHz, CDCl3): δ170.69,158.97,149.97,147.74,144.30,138.66,132.22(2C),130.22(2C),129.82(2C),129 .56,124.13,123.42,118.74,113.93(2C),111.86,68.18,62.72,56.88(2C),55.35,39.06,33.83; HRMS(ESI):calcd for C 26 H 24 N4O3[M+H] + :441.1848,found:441.1926.

[0420] 4-(4-(1-(3-Fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O84)

[0421] 4-(4-(1-(3-fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O84)

[0422] According to General Method G, compound O56 (100.0 mg, 0.30 mmol) and m-fluorobromobenzene (104.0 mg, 0.59 mmol) were used as starting materials. Cesium carbonate (293.2 mg, 0.90 mmol), XantPhos (11.6 mg, 0.02 mmol), and Pd2(dba)3 (18.3 mg, 0.02 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (v / v) = 3 / 1 as eluent to obtain the target compound O84 (82.6 mg, 67.0% yield) as a white solid with a melting point of 176.0-177.0°C and an R f =0.38 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1H NMR (400MHz, CDCl3): δ8.32(s,1H),8.23(s,1H),7.75(d,J=8.3Hz,2H),7.64(d,J=8.3Hz,2H),7.20-7.10(m,1H) ,6.45(t,J=9.7Hz,1H),6.22(d,J=8.1Hz,1H),6.15(d,J=11.0Hz,1H),4.43(t,J=4.8Hz,2H),4.20-3.78(m,7H); 13 C NMR (101MHz, CDCl3): δ170.38,165.14( 1 J CF =244.5Hz),152.81( 3 J CF =10.3Hz),150.13,148.04,144.22,138.51,132.28(2C),130.40,130.23(2C),124.35(2C),118.72,112.00,107.32,105.00,98.93( 2 J CF =25.0Hz),68.42,54.74(2C),39.07,32.95; 19 F NMR (376MHz, CDCl3): δ-112.61; HRMS (ESI): calcd for C 24 H 19 FN4O2[M+H] + :415.1492,found:415.1562.

[0423] 4-(4-(1-(4-Fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O85)

[0424] 4-(4-(1-(4-fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O85)

[0425] According to General Method G, compound O56 (70.0 mg, 0.21 mmol) and p-fluorobromobenzene (72.8 mg, 0.42 mmol) were used as starting materials. Cesium carbonate (203.3 mg, 0.62 mmol), XantPhos (5.8 mg, 0.01 mmol), and Pd2(dba)3 (9.2 mg, 0.01 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 3 / 1 as eluent to obtain the target compound O85 (53.0 mg, 61.3% yield) as a white solid with a melting point of 188.0-189.0°C and an R f =0.27 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1 H NMR (400MHz, CDCl3): δ8.31(s,1H),8.25(s,1H),7.74(d,J=8.4Hz,2H),7.64(d,J=8.3Hz ,2H),6.93(t,J=8.7Hz,2H),6.45-6.37(m,2H),4.43(t,J=4.8Hz,2H),4.18-3.63(m,7H); 13 C NMR (101MHz, CDCl3): δ170.44,157.69( 1 J CF =237.1Hz),150.07,147.88(2C),144.09,138.63,132.28(2C),130.23(2C),124.35(2C),118.72,115.76( 2 J CF =22.8Hz,2C),112.76( 3 J CF =7.4Hz,2C),112.00,68.40,55.16(2C),39.11,33.00; 19 F NMR (376MHz, CDCl3): δ-126.89; HRMS (ESI): calcd for C 24 H 19 FN4O2[M+H] + :415.1492,found:415.1573.

[0426] 3-(3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)benzonitrile (O86)

[0427] 3-(3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)benzonitrile(O86)

[0428] According to General Method G, compound O56 (100.0 mg, 0.30 mmol) and m-bromobenzonitrile (59.5 mg, 0.33 mmol) were used as starting materials. Cesium carbonate (293.2 mg, 0.90 mmol), XantPhos (11.6 mg, 0.02 mmol), and Pd2(dba)3 (18.3 mg, 0.02 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (v / v) = 2 / 1 as eluent to obtain the target compound O86 (57.4 mg, 45.8% yield) as a white solid with a melting point of 210.0-211.0°C and an R f =0.33 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1 H NMR (400MHz, CDCl3): δ8.33(s,1H),8.21(s,1H),7.75(d,J=8.4Hz,2H),7.64(d,J=8.2Hz,2H),7.29( d,J=7.6Hz,1H),7.03(d,J=7.6Hz,1H),6.70-6.62(m,2H),4.45(t,J=4.8Hz,2H),4.23-3.81(m,7H); 13 C NMR (101MHz, CDCl3): δ170.25,150.95,150.37,148.16,144.16,138.48,132.28(2C),130.22(2C),129.86,124.43 (2C),121.52,119.32,118.69,115.76,114.30,112.83,112.04,68.40,54.59(2C),39.19,32.72; HRMS(ESI):calcd for C 25 H 19 N5O2[M+H] + :422.1539,found:422.1615.

[0429] 4-(3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)benzonitrile (O87)

[0430] 4-(3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)benzonitrile(O87)

[0431] According to General Method G, compound O56 (50.0 mg, 0.15 mmol) and 4-bromobenzonitrile (29.9 mg, 0.16 mmol) were used as starting materials. Cesium carbonate (146.6 mg, 0.45 mmol), XantPhos (4.6 mg, 0.01 mmol), and Pd2(dba)3 (7.3 mg, 0.01 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 1 / 1 as eluent to obtain the target compound O87 (29.3 mg, 46.7% yield) as a white solid with a melting point of 257.0-258.0°C and an R f =0.24 (petroleum ether:ethyl acetate (V / V)=1 / 2). 1 H NMR (400MHz, CDCl3): δ8.33(s,1H),8.19(s,1H),7.75(d,J=8.3Hz,2H),7.64(d,J=8.3Hz,2H),7.46( d,J=8.7Hz,2H),6.40(d,J=8.7Hz,2H),4.46(t,J=4.8Hz,2H),4.33-4.11(m,5H),4.10-3.81(m,2H); 13 C NMR (101MHz, CDCl3): δ169.92,152.79,150.17,148.39,143.90,138.46,133.51(2C),132.31(2C),130.22(2C) ,124.45(2C),120.36,118.68,112.09,110.93(2C),99.49,68.74,54.17(2C),39.24,32.68; HRMS(ESI):calcd for C 25 H 19 N5O2[M+H] + :422.1539,found:422.1611.

[0432] tert-Butyl 3-(8-bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidine-1-carboxylate (5)

[0433] tert-butyl 3-(8-bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidine-1-carboxylate(5)

[0434] According to General Method E, starting from Intermediate 3 (5.000 g, 23.25 mmol) and 1-Boc-azetidine-3-carboxylic acid (7.018 g, 34.88 mmol), HATU (18.565 g, 48.83 mmol) and DIPEA (9.015 g, 69.75 mmol) were added. The crude product was purified by column chromatography using petroleum ether:ethyl acetate (V / V) = 3 / 1 as eluent to afford Intermediate 25 (9.223 g, 99.9% yield) as a yellow gummy solid. f =0.56 (petroleum ether:ethyl acetate (V / V)=1 / 1). This compound can be directly used for the next reaction without further characterization.

[0435] Azetidin-3-yl(8-bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone (6)

[0436] azetidin-3-yl(8-bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone(6)

[0437] To the intermediate 5 (8.888 g, 22.39 mmol) was added trifluoroacetic acid (25.529 g, 223.90 mmol) to obtain the intermediate 6 (486.2 mg, 67.0% yield) as a yellow gummy solid. f =0.14 (dichloromethane:methanol (V / V)=10 / 1). This compound can be directly used for the next reaction without further characterization.

[0438] (8-Bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (7)

[0439] (8-bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone(7)

[0440] According to General Method F, intermediate 6 (4.700 g, 15.82 mmol) and m-fluorobenzyl chloride (3.432 g, 23.74 mmol) were used as starting materials, and potassium carbonate (4.373 g, 31.64 mmol) was added. The crude product was subjected to column chromatography using dichloromethane:methanol (V / V) = 100 / 1 as eluent to obtain intermediate 7 (2.523 g, 39.4% yield) as a white colloidal solid. f =0.46 (petroleum ether:acetone (V / V)=1 / 1). 1 H NMR (400MHz, CDCl3): δ8.49-7.73(m,2H),7.29-7.22(m,1H),7.06-6.88(m,3H),4.45(t, J=4.8Hz,2H),4.12-3.67(m,3H),3.62(s,2H),3.59-3.47(m,2H),3.37(t,J=7.0Hz,2H).

[0441] (8-(Benzo[d]thiazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O88)

[0442] (8-(benzo[d]thiazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone(O88)

[0443] According to General Method C, starting from intermediate 7 (61.9 mg, 0.15 mmol) and benzo[d]thiazole-6-boronic acid (41.2 mg, 0.23 mmol), potassium carbonate (82.9 mg, 0.60 mmol), PdCl2(PPh3)2 (14.0 mg, 0.02 mmol), and Pcy3 (8.4 mg, 0.03 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (v / v) = 40 / 1 as eluent to afford the title compound O88 (58.9 mg, 83.7% yield) as a white solid with a melting point of 83.0-84.0°C and a R f =0.18 (petroleum ether:acetone (V / V)=1 / 1). 1H NMR (400MHz, CDCl3): δ9.03(s,1H),8.34(s,1H),8.18(d,J=8.6Hz,2H),8.09(s,1H),7.64(d,J=6.7Hz,1H),7.29-7.22(m,1H), 7.07-6.98(m,2H),6.93(td,J=8.6,3.2Hz,1H),4.46-4.33(m,2H),4.14-3.70(m,3H),3.66-3.56(m,4H),3.42(t,J=7.6Hz,2H); 13 C NMR (101MHz, CDCl3): δ170.90,164.23( 1 J CF =246.7Hz),154.81,152.95,149.97,148.20,143.61,140.33,134.14,131.41,130.00( 3 J CF =8.8Hz),125.29,124.05,123.75,123.44,122.77(2C),115.39( 2 J CF =21.4Hz),114.07,68.22,62.70(2C),57.12,39.02,33.66; 19 F NMR (376MHz, CDCl3): δ-113.32; HRMS (ESI): calcd for C 25 H 21 FN4O2S[M+H] + :461.1369,found:461.1447.

[0444] 5-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)indol-2-one (O89)

[0445] 5-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)indolin-2-one(O89)

[0446] According to General Method C, intermediate 7 (111.0 mg, 0.27 mmol) and 2-oxoindoline-5-boronic acid pinacol ester (106.5 mg, 0.41 mmol) were used as starting materials. Potassium carbonate (149.3 mg, 1.08 mmol), PdCl2(PPh3)2 (21.1 mg, 0.03 mmol), and Pcy3 (14.0 mg, 0.05 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 20 / 1 as the eluent to obtain the target compound O89 (66.1 mg, 52.7% yield) as a white solid with a melting point of 135.0-136.0°C and a R f =0.59 (dichloromethane:methanol (V / V)=10 / 1). 1 H NMR (400MHz, CDCl3): δ9.25(s,1H),8.25(s,1H),8.12(s,1H),7.40-7.31(m,2H),7.29-7.22(m,1H),7.07-6.97(m ,2H),6.97-6.90(m,2H),4.41-4.33(m,2H),4.10-3.74(s,3H),3.64(s,2H),3.62-3.52(m,4H),3.46-3.38(m,2H); 13 C NMR (101MHz, CDCl3): δ177.91,170.81,164.17( 1 J CF =246.7Hz),149.91,147.90,142.97,140.88,140.19,131.09,129.98( 3 J CF =8.1Hz),129.23,127.69,125.77,125.65,124.03,123.61,115.36( 2 J CF =21.6Hz),114.25,109.78,68.10,62.63(2C),57.09,39.25,36.42,33.67; 19 F NMR (376MHz, CDCl3): δ-113.30; HRMS (ESI): calcd for C 26 H 23 FN4O3[M+H] + :459.1754,found:459.1847.

[0447] (1-(3-Fluorobenzyl)azetidin-3-yl)(8-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone (O90)

[0448] (1-(3-fluorobenzyl)azetidin-3-yl)(8-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone(O90)

[0449] According to General Method C, intermediate 7 (57.5 mg, 0.14 mmol) and imidazo[1,2-a]pyridine-6-boronic acid (34.5 mg, 0.21 mmol) were used as starting materials. Potassium carbonate (77.4 mg, 0.56 mmol), PdCl2(PPh3)2 (7.0 mg, 0.01 mmol), and Pcy3 (8.4 mg, 0.03 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 20 / 1 as the eluent to obtain the target compound O90 (32.6 mg, 51.8% yield) as a yellow solid with a melting point of 89.0-90.0°C and a R f =0.36 (dichloromethane:methanol (V / V)=10 / 1). 1 H NMR (400MHz, CDCl3): δ8.31(d,J=11.6Hz,2H),8.17(s,1H),7.69-7.64(m,2H),7.63(s,1H),7.33-7.28(m,1H),7.28-7.23(m,1H) ,7.07-6.99(m,2H),6.94(td,J=7.7,2.8Hz,1H),4.47-4.35(m,2H),4.14-3.72(m,3H),3.67-3.56(m,4H),3.43(t,J=7.5Hz,2H); 13 C NMR (101MHz, CDCl3): δ170.56,164.21( 1 J CF =246.6Hz),150.59,147.46,144.68,143.91,140.32,134.31,129.98( 3 J CF =8.2Hz),126.38,125.52,124.03(2C),122.04,119.18,117.40,115.36( 2 J CF=21.6Hz),114.26,112.91,68.80,62.70(2C),57.13,38.99,33.79; 19 F NMR (376MHz, CDCl3): δ-113.34; HRMS (ESI): calcd for C 25 H 22 FN5O2[M+H] + :444.1758,found:444.1834.

[0450] (8-(6-Chloro-1H-indol-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O91)

[0451] (8-(6-chloro-1H-indol-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone(O91)

[0452] According to General Method C, starting from Intermediate 7 (200.0 mg, 0.49 mmol) and (1-(tert-butoxycarbonyl)-6-chloro-1H-indol-2-yl)boronic acid (219.0 mg, 0.74 mmol), potassium carbonate (273.1 mg, 1.98 mmol), PdCl2(PPh3)2 (34.4 mg, 0.05 mmol), and Pcy3 (27.8 mg, 0.01 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 30 / 1 as the eluent to afford the target compound O91 (76.0 mg, 32.3% yield) as a white solid with a melting point of 162.0-163.0°C and a R f =0.16 (dichloromethane:methanol (V / V)=20 / 1). 1H NMR (400MHz, CDCl3): δ9.30(s,1H),8.76(s,1H),8.08(s,1H),7.54(d,J=8.4Hz,1H),7.40(s,1H),7.29-7.26(m,1H),7.09(dd,J=8.5,1.9H z,1H),7.07-6.97(m,2H),6.97-6.90(m,2H),4.67-4.50(m,2H),4.20-3.72(m,3H),3.65(s,2H),3.62-3.51(m,2H),3.43(d,J=7.0Hz,2H); 13 C NMR (101MHz, DMSO-d6): δ170.62,163.43( 1 J CF =243.7Hz),158.43,148.74,143.62,141.27,136.98(2C),132.03,130.17( 3 J CF =8.4Hz),126.73,126.38,124.21,123.81,121.48,119.73,116.24,114.83( 2 J CF =21.4Hz),113.76,110.93,102.73,67.05,61.37(2C),55.95,33.50; 19 F NMR (376MHz, DMSO-d6): δ-113.58; HRMS (ESI): calcd for C 26 H 22 ClFN4O2[M+H] + :477.1415,found:477.1473.

[0453] 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-6-cyano-1H-indole (O92)

[0454] 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1H-indole-6-carbonitrile(O92)

[0455] According to General Method C, starting from Intermediate 7 (200.0 mg, 0.49 mmol) and 1-Boc-6-cyanoindole-2-boronic acid (212.0 mg, 0.74 mmol), potassium carbonate (273.1 mg, 1.98 mmol), PdCl2(PPh3)2 (34.4 mg, 0.05 mmol), and Pcy3 (27.8 mg, 0.01 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (v / v) = 40 / 1 as the eluent to afford the target compound O92 (49.2 mg, 21.3% yield) as a white solid with a melting point of 128.0-129.0°C and a R f =0.07 (petroleum ether:acetone (V / V)=1 / 1). 1 H NMR (400MHz, CDCl3): δ9.82(s,1H),8.78(s,1H),8.14(s,1H),7.74(s,1H),7.68(d,J=8.2Hz,1H),7.33(dd,J=8.2,1.5Hz,1H),7.26-7.21(m,1H ),7.07-6.96(m,3H),6.93(td,J=8.5,3.1Hz,1H),4.68-4.54(m,2H),4. 21-3.71(m,3H),3.62(s,2H),3.61-3.50(m,2H),3.41(t,J=7.5Hz,2H); 13 C NMR (101MHz, CDCl3): δ170.69,158.77,164.21( 1 J CF =246.7Hz),149.07,146.41,143.36,140.11,135.33(2C),131.17,130.04( 3 J CF =8.1Hz),124.07,123.05,121.48,120.86,116.13,116.05,115.38( 2 J CF =21.4Hz),114.32,104.55,102.30,68.79,62.67(2C),56.96,39.28,33.90; 19 F NMR (376MHz, CDCl3): δ-113.28; HRMS (ESI): calcd for C 27 H 22 FN5O2[M+H] + :468.1758,found:468.1833.

[0456] (8-(6-Fluoro-1H-indol-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O93)

[0457] (8-(6-fluoro-1H-indol-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone(O93)

[0458] According to General Method C, starting from Intermediate 7 (200.0 mg, 0.49 mmol) and 1-Boc-6-fluoroindole-2-boronic acid (206.8 mg, 0.74 mmol), cesium carbonate (643.8 mg, 1.98 mmol), Pd(OAc)2 (5.6 mg, 0.03 mmol), dppf (27.2 mg, 0.05 mmol), and CuCl (48.9 mg, 0.49 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 30 / 1 as the eluent to afford the target compound O93 (18.7 mg, 19.7% yield) as a white solid. f =0.15 (petroleum ether:acetone (V / V)=1 / 1). 1 H NMR (400MHz, CDCl3): δ9.26(s,1H),8.76(s,1H),8.07(s,1H),7.56(dd,J=8.7,5.4Hz,1H),7.30-7.26(m,1H),7.09(dd,J=9.6,2.6Hz,1H),7 .07-6.98(m,2H),6.96(s,1H),6.95-6.87(m,2H),4.66-4.52(m,2H), 4.20-3.75(m,3H),3.65(s,2H),3.63-3.50(m,2H),3.46-3.36(m,1H).

[0459] 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-1H-indole (O94)

[0460] 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1H-indole-5-carbonitrile(O94)

[0461] According to General Method C, starting from Intermediate 7 (237.0 mg, 0.59 mmol) and 1-Boc-5-cyanoindole-2-boronic acid (236.8 mg, 0.88 mmol), cesium carbonate (762.4 mg, 2.34 mmol), Pd(OAc)2 (6.5 mg, 0.03 mmol), dppf (32.7 mg, 0.06 mmol), and CuCl (57.9 mg, 0.59 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 40 / 1 as the eluent to afford the target compound O94 (66.3 mg, 24.3% yield) as a white solid. f =0.22 (petroleum ether:acetone (V / V)=1 / 1). 1 H NMR (400MHz, CDCl3): δ9.70 (s, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.46 (d, J = 8.4Hz, 1H), 7.42 (dd, J = 8.5, 1.5Hz, 1H), 7.24 (d, J = 7.9Hz, 1H),7.07-6.97(m,3H),6.93(td,J=8.4,2.9Hz,1H),4.66-4.52(m,2H),4 .21-3.72(m,3H),3.64(s,2H),3.62-3.51(m,2H),3.41(t,J=7.5Hz,2H).

[0462] (8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O95)

[0463] (8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone(O95)

[0464] According to General Method C, starting from intermediate 7 (80.7 mg, 0.20 mmol) and 5-chlorobenzofuran-2-boronic acid (58.7 mg, 0.30 mmol), potassium carbonate (110.0 mg, 0.80 mmol), PdCl2(PPh3)2 (14.0 mg, 0.02 mmol), and Pcy3 (11.2 mg, 0.04 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 30 / 1 as the eluent to obtain the target compound O95 (18.7 mg, 19.7% yield) as a white solid. f =0.31 (dichloromethane:methanol (V / V)=30 / 1). 1 H NMR (400MHz, CDCl3): δ8.96(s,1H),8.13(s,1H),7.55(d,J=2.2Hz,1H),7.45(d,J=8.8Hz,1H),7.32-7.26(m,3H),7.04(dd,J=17 .7,8.6Hz,2H),6.94(t,J=8.4Hz,1H),4.65-4.50(m,2H),4.22-3.75(m,3H),3.66(s,2H),3.64-3.53(s,2H),3.48-3.37(m,2H).

[0465] 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyanobenzofuran (O96)

[0466] 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzofuran-5-carbonitrile(O96)

[0467] According to General Method C, starting from Intermediate 7 (110.0 mg, 0.27 mmol) and 5-cyano-1-benzofuran-2-boronic acid (76.3 mg, 0.41 mmol), potassium carbonate (150.6 mg, 1.09 mmol), PdCl2(PPh3)2 (21.1 mg, 0.03 mmol), and Pcy3 (14.0 mg, 0.05 mmol) were added. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 30 / 1 as eluent to afford the target compound O96 (63.5 mg, 49.9% yield) as a white solid with a melting point of 157.0-158.0°C and a R f=0.40 (petroleum ether:acetone (V / V)=1 / 1). 1 H NMR (400MHz, CDCl3): δ8.98(s,1H),8.17(s,1H),7.92(s,1H),7.66-7.56(m,2H),7.36(s,1H),7.30-7.23(m,1H),7.03( dd,J=17.7,8.9Hz,2H),6.97-6.90(m,1H),4.70-4.52(m,2H),4.17-3.73(m,3H),3.70-3.53(m,4H),3.50-3.37(m,2H); 13 C NMR (101MHz, CDCl3): δ170.73,164.22( 1 J CF =246.7Hz),155.71,151.34,149.59,145.34,144.04,140.31,129.99( 3 J CF =8.1Hz),129.66,128.62,126.17,124.03,123.58,119.41,115.36( 2 J CF =21.4Hz),114.51,114.27,112.39,107.62,107.11,68.67,62.70(2C),57.06,38.81,33.59; 19 F NMR (376MHz, CDCl3): δ-113.34; HRMS (ESI): calcd for C 27 H 21 FN4O3[M+H] + :469.1598,found:469.1649.

[0468] 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-3,6-1(2H)-cyano-dihydropyridine (O97)

[0469] 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-3,6-dihydropyridine-1(2H)-carbonitrile(O97)

[0470] The product was synthesized according to General Method C using Intermediate 7 (200.0 mg, 0.49 mmol) and (1-cyano-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (111 mg, 0.75 mmol), potassium carbonate (273.1 mg, 1.98 mmol), PdCl2(PPh3)2 (34.4 mg, 0.05 mmol), and Pcy3 (27.8 mg, 0.01 mmol) in a mixture of 1,4-dioxane (3 mL) and water (1 mL). The crude product was purified by silica gel column chromatography to afford the target compound O97 (110 mg, 52.0% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.32-7.85 (m, 2H), 7.31-7.22 (m, 1H), 7.13-6.92 (m, 3H), 6.25 (s, 1H), 4.18 (t, J = 8 .4Hz,2H),3.83(d,J=4.8Hz,3H),3.31-3.26(m,2H),3.27-3.21(m,4H),2.15-2.11(m,2H); HRMS(ESI):calcd for C 24 H 24 FN5O2[M+H] + :433.1914,found:433.1917.

[0471] 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-piperazine (O98)

[0472] 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)piperazine-1-carbonitrile(O98)

[0473] Intermediate 7 (125 mg, 0.30 mmol), cesium carbonate (343.3 mg, 1.05 mmol), XANTPHOS (52.1 mg, 0.09 mmol), palladium acetate (7.2 mg, 0.03 mmol), and 4-cyanopiperazine (33.3 mg, 0.30 mmol) were suspended in 1,4-dioxane (9 mL) and stirred at 100°C for 18 h under N2 protection. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, quenched with water (5 mL), and extracted with ethyl acetate (5 mL x 5). The combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate for 30 min, and concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane:methanol (v / v) = 100:1 to 10:1 as the eluent to afford compound O98 (46 mg, 35% yield). 1 H NMR (400MHz, CDCl3): δ8.16(s,1H),7.96(s,1H),7.33-7.25(m,1H),7.09-6.95(m,3H),4.21(t,J=4.8 Hz,2H),3.82-3.67(m,6H),3.53-3.41(m,2H),3.33-3.28(m,4H),3.23-3.17(m,5H).HRMS(ESI):calcd for C 23 H 26 FN6O2[M+H] + :437.2096,found:437.2110.

[0474] 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-3-oxopiperazine (O99)

[0475] 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-3-oxopiperazine-1-carbonitrile(O99)

[0476] Intermediate 7 (125 mg, 0.30 mmol), cesium carbonate (343.3 mg, 1.05 mmol), XANTPHOS (52.1 mg, 0.09 mmol), palladium acetate (7.2 mg, 0.03 mmol), and 4-cyano-3-oxopiperazine (37.5 mg, 0.30 mmol) were suspended in 1,4-dioxane (9 mL) and stirred at 100°C for 18 h under N2 protection. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, quenched with water (5 mL), and extracted with ethyl acetate (5 mL x 5). The combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate for 30 min, and concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane:methanol (v / v) = 100:1 to 10:1 as the eluent to afford compound O98 (16 mg, 12% yield). 1 H NMR (400MHz, CDCl3): δ8.15(s,1H),8.02(s,1H),7.31-7.25(m,1H),7.09-6.99(m,3H),4.15(t,J=4.8Hz ,2H),3.79-3.65(m,8H),3.53-3.41(m,2H),3.36(t,J=4.0Hz,2H),3.17-3.13(m,3H).HRMS(ESI):calcd for C 23 H 24 FN6O3[M+H] + :451.1888,found:451.1879.

[0477] 4-(4-(vinylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(12)

[0478] 4-(4-(vinylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (12)

[0479] According to General Method I, compound 4 (100 mg, 0.42 mmol) and 2-chloroethanesulfonyl chloride (82.5 mg, 0.51 mmol) were used as starting materials, and DMAP (15.5 mg, 0.13 mmol) and triethylamine (64.1 mg, 0.51 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound 12 (20 mg, 15% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ8.65(s,1H),8.29(s,1H),7.93(d,J=8.3Hz,2H),7.77(d,J=8 .3Hz,2H),7.07(dd,J=16.3,9.9Hz,1H),6.32-6.24(m,2H),4.37(s,2H),3.88(s,2H).

[0480] 4-(4-((3-(3-methoxyphenyl)-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O100)

[0481] 4-(4-((3-(3-methoxyphenyl)-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O100)

[0482] According to the general method H, compound 12 (30.0 mg, 0.09 mmol), m-anisaldehyde oxime (6.9 mg, 0.05 mmol) and sodium hypochlorite (6.9 mg, 0.09 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O100 (25.0 mg, yield 59.5%) as a white solid. 1 H NMR (400MHz, Chloroform-d): δ8.94(s,1H),8.20(s,1H),7.72(s,2H),7.57(s ,2H),7.33(t,J=8.0Hz,1H),7.20(s,1H),7.13(s,1H),7.03(s,1H),5.74(s,1 H),4.63(ddd,J=11.5,7.3,2.9Hz,1H),4.54(ddd,J=11.5,5.2,3.0Hz,1H),4. 19-4.13(m,1H),4.03(dd,J=18.4,4.3Hz,1H),3.95-3.84(m,2H),3.81(s,3H).

[0483] 3-(5-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)-4,5-dihydroisoxazol-3-yl)benzonitrile(O101)

[0484] 3-(5-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)-4,5-dihydroisoxazol-3-yl)benzonitrile (O101)

[0485] According to general method H, compound 12 (30.0 mg, 0.09 mmol), m-cyanobenzaldehyde oxime (6.7 mg, 0.05 mmol) and sodium hypochlorite (6.9 mg, 0.09 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O101 (15.0 mg, yield 35.7%) as a white solid. 1 H NMR (400MHz, Chloroform-d): δ8.92(s,1H),8.25(s,1H),7.96(s,1H),7.87(dt,J=7.9,1.4Hz,1H),7.73(s,3H) ,7.61(s,3H),5.82(s,1H),4.64(s,2H),4.21(ddd,J=14.5,4.9,2.9Hz,1H),4.02(d,J=4.3Hz,1H),3.91(s,2H).

[0486] 4-(4-((3-phenyl-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O102)

[0487] 4-(4-((3-phenyl-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O102)

[0488] According to the general method H, compound 12 (50.0 mg, 0.15 mmol), benzaldehyde oxime (9.3 mg, 0.08 mmol) and sodium hypochlorite (11.3 mg, 0.15 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O102 (20.0 mg, yield 30.2%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ8.70(s,1H),8.23(s,1H),7.91(s,2H),7.75(s,2H),7.48 (s,5H),6.44(s,1H),4.47(s,2H),4.15-4.05(m,2H),3.95(dt,J=15.6,4.5Hz,2H).

[0489] 4-(4-((3-benzyl-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O103)

[0490] 4-(4-((3-Benzyl-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O103)

[0491] According to general method H, compound 12 (30.0 mg, 0.09 mmol), phenylacetaldehyde oxime (24.9 mg, 0.18 mmol) and sodium hypochlorite (13.7 mg, 0.18 mmol) were used as raw materials, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to synthesize the target compound O103 (20.0 mg, yield 50.0%) as a white solid. 1 H NMR (400MHz, Chloroform-d): δ8.84 (s, 1H), 8.27 (d, J = 6.1Hz, 1H), 7.75-7.72 (m ,2H),7.64-7.61(m,2H),7.34-7.30(m,3H),7.24-7.20(m,2H),5.53(dd,J=10.5, 4.3Hz,1H),4.63-4.58(m,1H),4.46-4.40(m,1H),4.20-4.12(m,1H),3.82-3.76 (m,1H),3.73(d,J=2.0Hz,2H),3.53-3.47(m,1H),3.36(dd,J=18.8,10.5Hz,1H).

[0492] (S)-4-(4-(1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O104)

[0493] (S)-4-(4-(1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O104)

[0494] According to General Method C, starting with (S)-(8-bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)pyrrolidin-3-yl)methanone (90.0 mg, 0.21 mmol) and 4-cyanophenylboronic acid (47.2 mg, 0.32 mmol), Pd(OAc)2 (2.4 mg, 0.011 mmol), dppf (11.86 mg, 0.02 mmol), CuCl (21.2 mg, 0.214 mmol), and Cs2CO3 (278.9 mg, 0.86 mmol) were added. The crude product was purified by silica gel column chromatography (EA) to yield the target compound O104 (56 mg, 59.6% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.21(s,1H),7.91(d,J=8.2Hz,2H),7.75(d,J=8.1Hz,2H),7.35(td,J= 7.9,6.0Hz,1H),7.15(t,J=8.8Hz,2H),7.06(td,J=8.6,2.7Hz,1H),4.38(t,J=4.6Hz,2H),3.97 (dd,J=6.2,3.6Hz,2H),3.66-3.60(m,2H),3.55(dd,J=14.6,6.5Hz,1H),2.82(t,J=8.7Hz ,1H),2.70(t,J=8.0Hz,1H),2.66-2.58(m,1H),2.47(d,J=7.9Hz,1H),2.10-1.96(m,2H); 13 C NMR (101MHz, DMSO-d6): δ172.82,161.04( 1 J CF=241.5Hz),149.47,145.54,142.28,142.21,139.02,132.21,130.28,130.04( 3 J CF =8.3Hz),124.42,124.08,123.38,118.80,115.05,114.83,113.50( 2 J CF =20.8Hz),110.42,59.79,58.48,53.48,20.78; 19 F NMR (377MHz, DMSO-d6): δ-113.78; HRMS (ESI): calcd for C 26 H 23 FN4O2[M+H] + :442.4944,found:443.1868.

[0495] (R)-4-(4-(1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O105)

[0496] (R)-4-(4-(1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O105)

[0497] According to General Method C, starting with (R)-(8-bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)pyrrolidin-3-yl)methanone (90.0 mg, 0.21 mmol) and 4-cyanophenylboronic acid (47.2 mg, 0.32 mmol), Pd(OAc)2 (2.4 mg, 0.011 mmol), dppf (11.86 mg, 0.02 mmol), CuCl (21.2 mg, 0.214 mmol), and Cs2CO3 (278.9 mg, 0.86 mmol) were added. The crude product was purified by silica gel column chromatography (pure EA) to give the target compound O105 (57 mg, 59.7% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6): δ8.95(s,1H),8.21(s,1H),7.96-7.88(m,2H),7.79-7.72(m,2H),7.3 6(td,J=8.0,6.1Hz,1H),7.19-7.11(m,2H),7.06(ddd,J=10.3,8.0,2.7Hz,1H),4.38(t,J=4. 6Hz,2H),3.97(p,J=4.5,3.8Hz,2H),3.68-3.60(m,2H),3.56(dd,J=14.5,6.4Hz,1H),2.82(t ,J=8.7Hz,1H),2.71(dd,J=14.1,6.1Hz,1H),2.64(dt,J=8.8,6.4Hz,1H),2.11-1.97(m,2H); 13 C NMR (101MHz, DMSO-d6): δ173.26,161.49( 1 J CF =241.6Hz),149.91,145.99,142.72,142.65,139.47,132.66,130.72,130.48( 3 J CF =8.2Hz),124.86,124.84,124.53,123.82,119.24,115.49,115.28,113.95( 2 J CF =20.8Hz),110.87,58.92,56.75,53.93,21.53; 19 F NMR (377MHz, DMSO-d6): δ-113.78; HRMS (ESI): calcd for C 26 H 23 FN4O2[M+H] + :442.4944,found:443.1882.

[0498] 2-(4-((S)-1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-2,3-dihydro-benzofuran (O106)

[0499] 2-(4-((S)-1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-2,3-dihydrobenzofuran-5-carbonitrile(O106)

[0500] According to General Method C, starting with (S)-(8-bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)pyrrolidin-3-yl)methanone (120.0 mg, 0.284 mmol) and 5-cyano-1-benzofuran-2-boronic acid (80.0 mg, 0.426 mmol), Pd(OAc)2 (3.2 mg, 0.014 mmol), dppf (16.0 mg, 0.028 mmol), CuCl (28.0 mg, 0.284 mmol), and Cs2CO3 (368.8 mg, 1.14 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to give the target compound O106 (50 mg, 36.8% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.78(s,1H),8.24(d,J=1.6Hz,1H),7.86(d,J=8.5Hz,1H),7.78(dd,J=8. 6,1.7Hz,1H),7.52(s,1H),7.35(td,J=8.0,6.0Hz,1H),7.20-7.11(m,2H),7.06(td,J=8.6,8.2,2. 7Hz,1H),4.61(t,J=4.5Hz,2H),4.03(dt,J=7.2,3.3Hz,2H),3.62(d,J=4.7Hz,2H),3.60-3.52(m, 1H),2.83(t,J=8.7Hz,1H),2.75-2.68(m,1H),2.64(dt,J=8.6,6.5Hz,1H),2.02(d,J=24.9Hz,2H); 13 C NMR (101MHz, DMSO-d6): δ172.82,161.02( 1 J CF =241.6Hz),155.19,151.22,142.27,142.20,130.08( 3 J CF=8.3Hz),129.35,128.76,126.54,124.38,124.35,119.26,115.01,114.80,113.46( 2 J CF =20.8Hz),112.60,107.25,106.19,58.45,53.44,20.75; 19 F NMR (377MHz, DMSO-d6): δ-113.79; HRMS (ESI): calcd for C 28 H 25 FN4O3[M+H] + :482.5154,found:483.1821.

[0501] 2-(4-((R)-1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-2,3-dihydrobenzofuran (O107)

[0502] 2-(4-((R)-1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-2,3-dihydrobenzofuran-5-carbonitrile(O107)

[0503] According to General Method C, starting materials were (R)-(8-bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)pyrrolidin-3-yl)methanone (120.0 mg, 0.284 mmol) and 5-cyano-1-benzofuran-2-boronic acid (80.0 mg, 0.426 mmol). Pd(OAc)2 (3.2 mg, 0.014 mmol), dppf (16.0 mg, 0.028 mmol), CuCl (28.0 mg, 0.284 mmol), and Cs2CO3 (368.8 mg, 1.14 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to yield the target compound O107 (50 mg, 36.8% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6): δ8.96(s,1H),8.76(s,1H),8.23(d,J=1.7Hz,1H),7.85(d,J=8.6Hz,1H),7.77(d d,J=8.5,1.7Hz,1H),7.50(s,1H),7.35(td,J=7.9,6.0Hz,1H),7.19-7.11(m,2H),7.06(ddd,J=10.6,8.2 ,2.7Hz,1H),4.60(t,J=4.6Hz,2H),4.03(q,J=3.3,2.1Hz,2H),3.62(d,J=4.9Hz,2H),3.59-3.51(m,1H) ,2.83(t,J=8.7Hz,1H),2.71(t,J=8.0Hz,1H),2.63(dt,J=8.9,6.4Hz,1H),2.03(dd,J=13.3,6.7Hz,2H); 13 C NMR (101MHz, DMSO-d6): δ172.81,161.03( 1 J CF =241.6Hz),155.18,151.21,149.30,145.55,142.25,142.18,130.01( 3 J CF =8.1Hz),129.35,128.75,126.53,124.37,119.27,115.03,114.82,113.48( 2 J CF =20.7Hz),112.59,107.24,106.18,67.80,58.46,56.29,53.45,29.03; 19 F NMR (377MHz, DMSO-d6): δ-113.78; HRMS (ESI): calcd for C 28 H 25 FN4O3[M+H] + :482.5154,found:483.1828.

[0504] 8-(5-chlorobenzofuran-2-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (O108)

[0505] 8-(5-chlorobenzofuran-2-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine(O108)

[0506] According to the general method C, the compound 8-bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (200.0 mg, 0.93 mmol), 5-chlorobenzofuran-2-boronic acid (548 mg, 2.79 mmol), Cs2CO3 (1515 mg, 4.65 mmol), tetrakis(triphenylphosphine)palladium (53.7 mg, 0.046 mmol) and 1,4-dioxane (3 mL) and water (1 mL) were used to synthesize. The product was purified by silica gel column chromatography (dichloromethane / methanol = 400 / 1) to give O108 (20.1 mg, 7.5% yield) as a light yellow solid. 1 H NMR(400MHz,Chloroform-d)δ8.58(s,1H),7.90(s,1H),7.53(d,J=2.1Hz,1H),7.43( d,J=8.7Hz,1H),7.23(d,J=6.2Hz,2H),4.51(t,J=4.4Hz,2H),3.53(t,J=4.4Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ152.42,151.50,146.92,138.79,136.84,130.58,128.37,124.72,120.50,112.04,106.81,66.34,39.92.HRMS(ESI)m / z calcd.for C 15 H 11 ClN2O2 + [M+H] + :287.0582,found 287.0574.

[0507] 2-(3,4-Dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-benzofuran (O109)

[0508] 2-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzofuran-5-carbonitrile(O109)

[0509] According to the general method C, the compound 8-bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (200.0 mg, 0.93 mmol), 5-cyano-1-benzofuran-2-boronic acid (527.2 mg, 2.79 mmol), Cs2CO3 (1515 mg, 4.65 mmol), tetrakis(triphenylphosphine)palladium (53.7 mg, 0.046 mmol) and 1,4-dioxane (3 mL) and water (1 mL) were used to synthesize. The product was purified by silica gel column chromatography (dichloromethane / methanol = 400 / 1) to give O109 (21.3 mg, 8.26% yield) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.94(s,1H),7.90(dd,J=1.6,0.7Hz,1H),7.60(dt,J=8.5, 0.9Hz, 1H), 7.56 (dd, J=8.5, 1.6Hz, 1H), 7.34 (d, J=0.9Hz, 1H), 4.56–4.49 (m, 2H), 3.59–3.50 (m, 2H). 13 C NMR(101MHz,Chloroform-d)δ155.65,152.53,147.10,138.73,137.25,129.91,128 .15,125.89,119.56,113.79,112.22,106.77,106.67,66.43,39.87.HRMS(ESI)m / z calcd.for C 16 H 11 N3O2 + [M+H] + :278.0924,found 278.0918.

[0510] tert-Butyl 3-(acetylthio)azetidine-1-carboxylate (8)

[0511] tert-butyl 3-(acetylthio)azetidine-1-carboxylate(8)

[0512] The raw materials 1-Boc-3-iodoazetidine (100.0 mg, 0.35 mmol) and thioacetic acid (53.74 mg, 0.71 mmol) were dissolved in a DMF solution (1.0 ml). Cesium carbonate (230.03 mg, 0.71 mmol) was added, and the reaction system was placed at 70°C for 1 h. TLC was performed using iodine as a colorimetric tool. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (PE / EA = 100 / 1) to obtain the target compound 8 (51 mg, 62% yield) as a yellow oily liquid. 1 H NMR (400MHz, Chloroform-d): δ4.31 (s, 2H), 4.10 (tt, J = 8.2, 5.5Hz, 1H), 3.74 (s, 2H), 2.29 (s, 3H), 1.38 (s, 9H).

[0513] tert-Butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (9)

[0514] tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate(9)

[0515] Compound 8 (50.0 mg, 0.22 mmol) was dissolved in acetonitrile (1.25 ml) at 0°C. 2M HCl (0.80 ml) was slowly added dropwise to the reaction mixture, followed by NCS (115.37 mg, 0.86 mmol). The mixture was stirred for 1 hour and TLC was performed using potassium permanganate. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (PE / EA = 8 / 1) to obtain the target compound 9 (20.0 mg, 37% yield) as a yellow solid. 1 H NMR (400MHz, Chloroform-d): δ4.50 (td, J=9.5, 8.7, 4.1Hz, 1H), 4.36 (td, J=10.2, 6.5Hz, 4H), 1.44 (s, 9H).

[0516] 4-(4-(azetidine-3-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (10)

[0517] 4-(4-(azetidin-3-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(10)

[0518] Compound 4-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (30.0 mg, 0.13 mmol) and DMAP (4.6 mg, 0.04 mmol) were dissolved in anhydrous dichloromethane (1.0 ml). The reaction system was placed at 0°C, and triethylamine (38.25 mg, 0.38 mmol) was added dropwise. Then, compound 3,3-(chlorosulfonyl)azetidine-1-carboxylic acid tert-butyl ester (38.66 mg, 0.15 mmol) was added. The reaction system was brought to room temperature and stirred for 1 hour. After TLC showed that the starting material was completely reacted, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain a light yellow solid (43 mg, yield 75%). 1 H NMR (400MHz, Chloroform-d): δ8.71(s,1H),8.27(s,1H),7.76-7.71(m,2H),7.63-7.58(m,2H),4.41-4 .37(m,2H),4.31(dd,J=9.3,5.7Hz,2H),4.23(q,J=3.4,1.8Hz,3H),3.92(t,J=4.5Hz,2H),1.45(s,9H).

[0519] The solid (50 mg, 0.11 mmol) was dissolved in anhydrous dichloromethane (1.0 ml) at 0°C, and trifluoroacetic acid (0.08 ml, 1.05 mmol) was added dropwise. The reaction system was brought to room temperature and stirred for 2 h. After TLC indicated complete reaction of the starting material, the reaction mixture was diluted with water, adjusted to pH 10, and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (DCM / MeOH = 12 / 1) to afford the target compound 10 (33 mg, 90% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ8.64(s,1H),8.25(s,1H),7.95-7.91(m,2H), 7.80-7.76(m,2H),4.79(p,J=7.5Hz,1H),4.34(dd,J=5.2,3.8Hz,2H),3.85(t,J=4.5Hz,3H),3.80(s,2H),3.68(d,J=8.5Hz,2H).

[0520] 4-(4-((1-(3-cyanobenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O110)

[0521] 4-(4-((1-(3-cyanobenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O110)

[0522] According to General Method A, compound 10 (80 mg, 0.22 mmol) and 3-cyanobenzoyl chloride (55.8 mg, 0.34 mmol) were used as starting materials, and DMAP (8.21 mg, 0.07 mmol) and triethylamine (68 mg, 0.67 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to synthesize the target compound O110 (100 mg, 86% yield) as a white solid with a melting point of 125.0-126.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.69(s,1H),8.28(s,1H),7.94-7.85(m,2H),7.81(dt,J=7.8,1.4Hz,1H ),7.76-7.70(m,2H),7.64-7.57(m,3H),4.59(s,4H),4.40(q,J=3.7,2.8Hz,3H),3.94(d,J=6.0Hz,2H); 13C NMR (101MHz, Chloroform-d): δ168.32,150.22,146.60,143.96,138.06,135.19,133.24,132.37(2C),132.19,13 1.61,130.30(2C),129.97,121.79,118.64,117.86,113.41,112.32,66.51,50.12(2C),44.07; HRMS(ESI):calcd for C 25 H 19 N5O4S[M+H] + :485.5180,found:486.1197.

[0523] 4-(4-((1-(4-cyanobenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O111)

[0524] 4-(4-((1-(4-cyanobenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O111)

[0525] According to General Method A, compound 10 (80 mg, 0.22 mmol) and 4-cyanobenzoyl chloride (55.8 mg, 0.34 mmol) were used as starting materials, and DMAP (8.21 mg, 0.07 mmol) and triethylamine (68 mg, 0.67 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to synthesize the target compound O111 (95 mg, 81% yield) as a white solid with a melting point of 253.0-254.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.33(s,1H),7.93(s,1H),7.39(q,J=6.1,3.7Hz,6H),7 .25(d,J=7.9Hz,2H),4.25(d,J=40.7Hz,4H),4.04(q,J=8.6,6.6Hz,3H),3.58(s,2H); 13C NMR (101MHz, Chloroform-d): δ167.56,149.82,146.22,144.44,138.56,136.03,132.70(2C),132.22,130.35,128. 66(2C),123.83,121.72,118.73,118.18,113.89,110.62,66.07,53.76(2C),50.10,48.77,43.05; HRMS(ESI):calcd for C 25 H 19 N5O4S[M+H] + :485.5180,found:486.1202.

[0526] 4-(4-((1-(3-methoxybenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O112)

[0527] 4-(4-((1-(3-methoxybenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O112)

[0528] According to General Method A, compound 10 (60 mg, 0.17 mmol) and 3-methoxybenzoyl chloride (42.89 mg, 0.25 mmol) were used as starting materials, and DMAP (6.11 mg, 0.05 mmol) and triethylamine (51 mg, 0.50 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to synthesize the target compound O112 (75 mg, 85% yield) as a white solid with a melting point of 176.0-177.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.71(s,1H),8.27(s,1H),7.73(d,J=8.2Hz,2H),7.60(d,J=8.3Hz,2H),7.33(t,J=7.9Hz, 1H),7.19-7.11(m,2H),7.04(dd,J=8.2,2.6Hz,1H),4.60(d,J=50.5Hz,4H),4.42-4.31(m,3H),3.93(s,2H),3.83(s,3H); 13C NMR (101MHz, Chloroform-d): δ170.65,161.23,151.52,147.68,144.17,138.22,133.14,132.32(2C),130.30(2C),1 29.86,124.87,121.85,119.99,118.67,118.02,113.25,112.20,64.56,55.59(2C),49.50,44.04; HRMS(ESI):calcd for C 25 H 22 N4O5S [M+H] + :490.5340,found:491.1350.

[0529] 4-(4-((1-(4-methoxybenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O113)

[0530] 4-(4-((1-(4-methoxybenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O113)

[0531] According to General Method A, compound 10 (60 mg, 0.17 mmol) and 4-methoxybenzoyl chloride (42.89 mg, 0.25 mmol) were used as starting materials, and DMAP (6.11 mg, 0.05 mmol) and triethylamine (51 mg, 0.50 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to synthesize the target compound O113 (72 mg, 81% yield) as a white solid with a melting point of 200.0-201.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.71(s,1H),8.27(s,1H),7.78-7.70(m,2H),7.65-7.54(m, 4H),6.98-6.86(m,2H),4.53(s,4H),4.41-4.31(m,3H),3.93(t,J=4.6Hz,2H),3.84(s,3H); 13C NMR (101MHz, Chloroform-d): δ170.88,162.53,150.41,146.84,144.36,138.30,132.86(2C),130.29(2C),130.0 5(2C),124.78,124.03,122.28,119.14,114.08(2C),112.13,66.41,56.19(2C),51.98,44.98; HRMS(ESI):calcd for C 25 H 22 N4O5S[M+H] + :490.5340,found:491.1378.

[0532] 4-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)sulfonyl)benzonitrile (O114)

[0533] 4-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)sulfonyl)benzonitrile(O114)

[0534] According to General Method B, compound 10 (60 mg, 0.17 mmol) and 4-cyanobenzenesulfonyl chloride (50.81 mg, 0.25 mmol) were used as starting materials, and DMAP (6.11 mg, 0.05 mmol) and triethylamine (51 mg, 0.50 mmol) were added. The crude product was purified by silica gel column chromatography (EA / MeOH = 50 / 1) to synthesize the target compound O114 (70 mg, 75% yield) as a white solid with a melting point of 260.0-261.0°C. 1 H NMR (400MHz, DMSO-d6): δ8.48(s,1H),8.26(s,1H),8.22-8.17(m,2H),8.07-8.01(m,2H),7.95-7.89(m,2H),7.80-7.73 (m,2H),4.68(tt,J=8.4,6.0Hz,1H),4.30-4.25(m,2H),4.21(t,J=9.0Hz,2H),4.03-3.96(m,2H),3.80(t,J=4.5Hz,2H); 13C NMR (101MHz, DMSO-d6): δ149.66,146.35,144.66,138.59,137.40,134.39(2C),132.23(2C),130.85(2C),129 .14(2C),123.82,121.91,119.16,118.15,116.24,110.62,65.94,52.86(2C),47.89,43.75; HRMS(ESI):calcd for C 24 H 19 N5O5S2[M+H] + :521.5660,found:522.0893.

[0535] 3-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)sulfonyl)benzonitrile (O115)

[0536] 3-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)sulfonyl)benzonitrile(O115)

[0537] According to General Method B, compound 10 (60 mg, 0.17 mmol) and 3-cyanobenzenesulfonyl chloride (50.81 mg, 0.25 mmol) were used as starting materials, and DMAP (6.11 mg, 0.05 mmol) and triethylamine (51 mg, 0.50 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to synthesize the target compound O115 (75 mg, 80.6% yield) as a white solid with a melting point of 211.0-212.0°C. 1H NMR (400MHz, DMSO-d6): δ8.53(s,1H),8.28(s,1H),8.15(d,J=1.8Hz,1H),8.08(d,J=8.0Hz,1H),7.98(d,J=7.8Hz,1H),7.80(t,J=7.9Hz,1H),7.74(d ,J=8.2Hz,2H),7.59(d,J=8.1Hz,2H),4.37-4.32(m,2H),4.26(dd,J=8.8,6 .2Hz,2H),4.23-4.17(m,2H),4.15(d,J=5.5Hz,1H),3.82(t,J=4.5Hz,2H); 13 C NMR (101MHz, DMSO-d6): δ149.66,146.33,144.28,138.59,137.47,134.67,132.80,132.23(2C),132.05,130.99, 130.36(2C),123.82,121.52,118.77,117.54,113.13,110.62,65.53,52.69(2C),47.14,43.95; HRMS(ESI):calcd for C 24 H 19 N5O5S2[M+H] + :521.5660,found:522.0897.

[0538] 4-(4-((1-((4-fluorophenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O116)

[0539] 4-(4-((1-((4-fluorophenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O116)

[0540] According to General Method B, compound 10 (80 mg, 0.22 mmol) and 4-fluorobenzenesulfonyl chloride (65.58 mg, 0.34 mmol) were used as starting materials, and DMAP (8.21 mg, 0.07 mmol) and triethylamine (68 mg, 0.67 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O116 (102 mg, 83.0% yield) as a white solid with a melting point of 204.0-205.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.56(s,1H),8.27(s,1H),7.87(dd,J=8.5,4.9Hz,2H),7.73(d,J=7.8Hz,2H) ,7.59(d,J=8.0Hz,2H),7.31(t,J=8.4Hz,2H),4.40-4.30(m,2H),4.23-4.05(m,5H),3.82(t,J=4.5Hz,2H); 13 C NMR (101MHz, Chloroform-d): δ167.49( 1 J CF =247.1Hz),149.81,147.20,144.54,138.25,132.33(2C),131.34( 3 J CF =9.5Hz),130.29(2C),124.86,121.46,118.68,116.94( 2 J CF =22.5Hz),112.20,66.68,53.05(2C),47.78,44.62; 19 F NMR (377MHz, Chloroform-d): δ-102.60; HRMS (ESI): calcd for C 23 H 19 FN4O5S2[M+H] + :514.5464,found:515.0849.

[0541] 4-(4-((1-((3-fluorophenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O117)

[0542] 4-(4-((1-((3-fluorophenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O117)

[0543] According to General Method B, compound 10 (80 mg, 0.22 mmol) and 3-fluorobenzenesulfonyl chloride (65.58 mg, 0.34 mmol) were used as starting materials, and DMAP (8.21 mg, 0.07 mmol) and triethylamine (68 mg, 0.67 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O117 (100 mg, 83.0% yield) as a white solid with a melting point of 199.0-200.0°C. 1 H NMR (400MHz, DMSO-d6): δ8.51(s,1H),8.26(s,1H),7.92(d,J=8.1Hz,2H),7.82 -7.65(m,6H),4.69(s,1H),4.28(s,2H),4.19(s,2H),4.00(s,2H),3.80(s,2H); 13 C NMR (101MHz, DMSO-d6): δ161.34( 1 J CF =205.2Hz),149.61,146.28,144.25,138.58,135.08,132.19(2C),131.94( 3 J CF =8.1Hz),130.33(2C),124.68,123.77,121.52,121.29( 2 J CF =21.1Hz),118.73,115.54,115.30,110.59,65.89,52.45,47.86,43.72; 19 F NMR (377MHz, DMSO-d6): δ-109.83; HRMS (ESI): calcd for C 23 H 19 FN4O5S2[M+H] + :514.5464, found:515.0849.

[0544] 4-(4-((1-((3-methoxyphenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O119)

[0545] 4-(4-((1-((3-methoxyphenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O119)

[0546] According to General Method B, compound 10 (80 mg, 0.22 mmol) and 3-methoxybenzenesulfonyl chloride (69.61 mg, 0.34 mmol) were used as starting materials, and DMAP (8.21 mg, 0.07 mmol) and triethylamine (68 mg, 0.67 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O119 (109 mg, 84.0% yield) as a white solid with a melting point of 200.0-201.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.54(s,1H),8.25(s,1H),7.72(d,J=8.1Hz,2H),7.59(d,J=8.0Hz,2H),7.53( t,J=8.0Hz,1H),7.41(d,J=7.7Hz,1H),7.32(t,J=2.1Hz,1H),7.22(dd,J=8.3,2.6Hz,1H),4.37-4.29(m,2H), 4.14(s,5H),3.89(s,3H),3.80(t,J=4.5Hz,2H); 13 C NMR (101MHz, Chloroform-d): δ159.96,149.77,147.10,144.52,138.31,135.44,132.67(2C),130.72,130.29(2C), 124.76,121.52,120.60,120.31,118.70,113.29,112.14,66.67,57.26,53.04(2C),48.83,42.88; HRMS(ESI):calcd for C 24 H 22 N4O6S2[M+H] + :526.5820,found:527.1051.

[0547] 4-(4-((1-((4-methoxyphenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O118)

[0548] 4-(4-((1-((4-methoxyphenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O118)

[0549] According to General Method B, compound 10 (80 mg, 0.22 mmol) and 4-methoxybenzenesulfonyl chloride (69.61 mg, 0.34 mmol) were used as starting materials, and DMAP (8.21 mg, 0.07 mmol) and triethylamine (68 mg, 0.67 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O118 (105 mg, 84.0% yield) as a white solid with a melting point of 148.0-149.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.55(s,1H),8.25(s,1H),7.81-7.75(m,2H),7.75-7.70(m,2H),7.62-7.56 (m,2H),7.10-7.05(m,2H),4.34(dd,J=5.2,3.8Hz,2H),4.18-4.05(m,5H),3.90(s,3H),3.84-3.78(m,2H); 13 C NMR (101MHz, Chloroform-d): δ164.61,149.76,147.07,144.58,137.83,132.29(2C),130.77(2C),130.29(2C), 125.16,124.74,121.54,118.70,114.86(2C),112.11,66.21,57.06,52.18(2C),49.36,43.91.HRMS(ESI):calcd for C 24 H 22 N4O6S2[M+H] + :526.5820,found:527.1054.

[0550] 3-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)methyl)benzonitrile (O120)

[0551] 3-((3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)methyl)benzonitrile(O120)

[0552] According to General Method F, compound 10 (60 mg, 0.17 mmol) and 3-cyanobenzyl bromide (49.41 mg, 0.25 mmol) were used as starting materials, and anhydrous potassium carbonate (46.44 mg, 0.34 mmol) was added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 2) to synthesize the target compound O120 (30 mg, 33% yield) as a white solid with a melting point of 158.0-159.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.72(s,1H),8.25(s,1H),7.74-7.70(m,2H), 7.62-7.58(m,2H),7.59-7.53(m,2H),7.50(dt,J=7.9,1.6Hz,1H),7.42(t,J =7.7Hz,1H),4.37(dd,J=5.2,3.9Hz,2H),4.22(p,J=7.5Hz,1H),3.87(dd,J= 5.2,3.9Hz,2H),3.72(s,2H),3.68(td,J=7.6,1.3Hz,2H),3.61-3.54(m,2H); 13 C NMR (101MHz, Chloroform-d): δ149.70,146.87,144.85,138.52,133.28,132.26(2C),131.87,131.39,130.27 (2C),129.52,124.58,121.94,118.71,112.84,112.00,66.85,62.51,56.17,51.00,43.01; HRMS(ESI):calcd for C 25 H 21 N5O3S[M+H] + :471.5350,found:472.1434.

[0553] 4-(4-((1-(4-cyanobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O121)

[0554] 4-(4-((1-(4-cyanobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O121)

[0555] According to General Method F, compound 10 (80 mg, 0.22 mmol) and 4-cyanobenzyl bromide (65.85 mg, 0.34 mmol) were used as starting materials, and anhydrous potassium carbonate (61.92 mg, 0.44 mmol) was added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O121 (40 mg, 38% yield) as a white solid with a melting point of 181.0-182.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.72(s,1H),8.25(s,1H),7.77-7.69(m,2H),7.60(dd,J=8.2,3.6Hz,4H),7.39(d,J=8.0Hz,2H) ,4.37(t,J=4.4Hz,2H),4.22(p,J=7.5Hz,1H),3.87(t,J=4.5Hz,2H),3.76(s,2H),3.69(t,J=7.9Hz,2H),3.59(t,J=7.7Hz,2H); 13 C NMR (101MHz, Chloroform-d): δ149.72,146.90,144.88,142.31,138.48,132.53

[0556] (2C),132.28(2C),130.27(2C),129.07(2C),124.29,121.90,118.78,118.7 0,112.06,111.63,68.25,63.28,55.82(2C),52.28,43.32; HRMS(ESI):calcd for C 25 H 21 N5O3S[M+H]+:471.5350,found:472.1438.

[0557] 4-(4-((1-(3-fluorobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O122)

[0558] 4-(4-((1-(3-fluorobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O122)

[0559] According to General Method F, compound 10 (80 mg, 0.22 mmol) and 3-fluorobenzyl chloride (48.58 mg, 0.34 mmol) were used as starting materials, and anhydrous potassium carbonate (61.92 mg, 0.44 mmol) was added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O122 (50 mg, 60% yield) as a white solid with a melting point of 164.0-165.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.73(s,1H),8.25(s,1H),7.72(d,J=8.0Hz,2H),7.60(d,J=8.0Hz,2H),7.30-7.24(m,1H),7.0 7-6.91(m,3H),4.42-4.32(m,2H),4.22(p,J=7.6Hz,1H),3.87(t,J=4.5Hz,2H),3.69(d,J=9.1Hz,4H),3.58(t,J=7.8Hz,2H); 13 C NMR (101MHz, Chloroform-d): δ162.33( 1 J CF =244.9Hz),149.69,146.90,144.90,139.08,138.55,132.27(2C),130.28( 3 J CF =8.3Hz),124.55,124.14,124.11,121.94,118.74,116.56,115.47,114.62( 2 J CF =21.1Hz),112.00,66.18,62.20,55.17,51.12,43.78; 19 F NMR (377MHz, Chloroform-d): δ-112.80; HRMS (ESI): calcd for C 24H 21 FN4O3S[M+H]+:464.5154,found:465.1393.

[0560] 4-(4-((1-(4-fluorobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O123)

[0561] 4-(4-((1-(4-fluorobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O123)

[0562] According to General Method F, compound 10 (80 mg, 0.22 mmol) and 4-fluorobenzyl chloride (48.58 mg, 0.34 mmol) were used as starting materials, and anhydrous potassium carbonate (61.92 mg, 0.44 mmol) was added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O123 (45 mg, 44% yield) as a white solid with a melting point of 120.0-121.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.73(s,1H),8.25(s,1H),7.76-7.69(m,2H),7.63-7.56(m,2H),7.22(dd,J=8.4,5.6Hz,2H), 6.99(t,J=8.6Hz,2H),4.40-4.33(m,2H),4.19(p,J=7.5Hz,1H),3.86(t,J=4.5Hz,2H),3.70-3.61(m,4H),3.58-3.51(m,2H); 13 C NMR (101MHz, Chloroform-d): δ161.19( 1 J CF =244.7Hz),149.68,146.88,144.93,138.56,133.25,132.71(2C),130.27( 3 J CF =8.7Hz),124.54,121.96,118.71,115.48( 2 J CF =21.2Hz),112.01,66.17,62.06,55.04,51.14,43.76; 19F NMR (377MHz, Chloroform-d): δ-114.67; HRMS (ESI): calcd for C 24 H 21 FN4O3S[M+H]+:464.5154,found:465.1386.

[0563] 4-(4-((1-(3-methoxybenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O124)

[0564] 4-(4-((1-(3-methoxybenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O124)

[0565] According to General Method F, compound 10 (60 mg, 0.17 mmol) and 3-methoxybenzyl chloride (40 mg, 0.25 mmol) were used as starting materials, and anhydrous potassium carbonate (46.44 mg, 0.37 mmol) was added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O124 (45 mg, 56% yield) as a white solid with a melting point of 123.0-124.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.73(s,1H),8.24(s,1H),7.72(d,J=8.1Hz,2H),7.60(d,J=8.0Hz,2H),7.22(td,J=7.4,1.6Hz,1H),6.86-6 .77(m,3H),4.36(t,J=4.5Hz,2H),4.21(p,J=7.6Hz,1H),3.86(t,J=4.5Hz,2H),3.79(s,3H),3.68(d,J=2.6Hz,4H),3.57(t,J=7.8Hz,2H); 13C NMR (101MHz, Chloroform-d): δ159.95,149.65,146.87,144.94,138.58,137.96,132.25(2C),130.28(2C),129.73,1 24.52,121.97,120.89,118.74,114.07,113.27,111.97,66.16,62.79,55.35,55.11,51.17,43.75; HRMS(ESI):calcd for C 25 H 24 N4O4S[M+H]+:476.5510,found:477.1583.

[0566] 4-(4-((1-(4-methoxybenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O125)

[0567] 4-(4-((1-(4-methoxybenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O125)

[0568] According to General Method F, compound 10 (60 mg, 0.17 mmol) and 4-methoxybenzyl chloride (40 mg, 0.25 mmol) were used as starting materials, and anhydrous potassium carbonate (46.44 mg, 0.37 mmol) was added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O125 (45 mg, 56% yield) as a white solid with a melting point of 130.0-131.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.73(s,1H),8.24(s,1H),7.75-7.70(m,2H),7.62-7.57(m,2H),7.19-7.13(m,2H),6.86-6.80(m,2H) ,4.35(dd,J=5.2,3.8Hz,2H),4.18(p,J=7.6Hz,1H),3.89-3.83(m,2H),3.78(s,3H),3.66-3.58(m,4H),3.52(dd,J=8.5,7.2Hz,2H); 13C NMR (101MHz, Chloroform-d): δ159.22,149.63,146.81,144.94,138.58,132.23(2C),130.27(2C),129.86,1 28.49,124.48,121.98,118.73,114.06,111.93,66.14,62.26,55.36,54.89,51.19,43.72; HRMS(ESI):calcd for C 25 H 24 N4O4S[M+H]+:476.5510,found:477.1582.

[0569] 4-(4-((1-(3-fluorophenyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O126)

[0570] 4-(4-((1-(3-fluorophenyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O126)

[0571] According to General Method F, compound 10 (80 mg, 0.22 mmol) and 3-fluorobromobenzene (78.4 mg, 0.45 mmol) were used as starting materials, and cesium carbonate (218.95 mg, 0.67 mmol), Xantphos (6.48 mg, 0.01 mmol), and Pd2(dba)3 (10.26 mg, 0.01 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O126 (40 mg, 40% yield) as a white solid with a melting point of 236.0-237.0°C. 1 H NMR (400MHz, Chloroform-d): δ8.76(s,1H),8.29(s,1H),7.74(d,J=7.9Hz,2H),7.61(d,J=7.9Hz,2H),7.19(q,J=7.8Hz,1H),6. 58-6.46(m,1H),6.22(d,J=8.2Hz,1H),6.15(d,J=10.9Hz,1H),4.51-4.37(m,3H),4.23(p,J=7.9Hz,4H),3.95(t,J=4.6Hz,2H); 13C NMR (101MHz, DMSO-d6): δ164.37( 1 J CF =239.9Hz),152.28,152.18,149.84,146.15,144.56,138.61,132.22(2C),130.44( 3 J CF =9.9Hz,2C),130.36,128.84,123.85,121.83,118.75,110.61,107.62,104.17( 2 J CF =21.3Hz),98.70,98.45,66.06,53.14(2C),49.27,3.02; 19 F NMR (377MHz, Chloroform-d): δ-121.89; HRMS (ESI): calcd for C 23 H 19 FN4O3S[M+H]+:450.4884,found:451.1236.

[0572] 4-(4-((1-(4-Fluorophenyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O127)

[0573] 4-(4-((1-(4-fluorophenyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O127)

[0574] According to General Method F, compound 10 (80 mg, 0.22 mmol) and 4-fluorobromobenzene (78.4 mg, 0.45 mmol) were used as starting materials, and cesium carbonate (218.95 mg, 0.67 mmol), Xantphos (6.48 mg, 0.01 mmol), and Pd2(dba)3 (10.26 mg, 0.01 mmol) were added. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to synthesize the target compound O127 (40 mg, 40% yield) as a white solid with a melting point of 224.0-225.0°C. 1H NMR (400MHz, Chloroform-d): δ8.75(s,1H),8.28(s,1H),7.74(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,2H),6.95(t,J=8. 4Hz, 2H), 6.40 (dd, J=8.8, 4.3Hz, 2H), 4.42 (q, J=5.4, 4.3Hz, 3H), 4.20 (h, J=7.9, 7.4Hz, 4H), 3.94 (t, J=4.5Hz, 2H); 13 C NMR (101MHz, Chloroform-d): δ155.84( 1 J CF =235.9Hz),149.74,146.98,146.80,144.79,138.52,132.31(2C),130.31(2C),129.31,124.67,121.97,118.73,116.05( 2 J CF =22.6Hz),112.92( 3 J CF =7.5Hz),112.09,111.86,66.37,53.87,53.50,51.03,44.00; 19 F NMR (377MHz, Chloroform-d): δ-125.52; HRMS (ESI): calcd for C 23 H 19 FN4O3S[M+H]+:450.4884,found:451.1232.

[0575] 4-((8-Bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (11)

[0576] 4-((8-bromo-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile(11)

[0577] Synthesized according to General Method F. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (V / V)=6:1) to give a white solid. 1H NMR (400MHz, Chloroform-d) δ8.85(s,1H),8.42(s,1H),7.94–7.72(m,4H),4.01(t,J=4.2Hz,2H),3.94(t,J=4.2Hz,2H).

[0578] 4-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O128)

[0579] 4-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile(O128)

[0580] According to General Method C, intermediate 11 (100 mg, 0.26 mmol) and 5-chloro-benzofuran-2-boronic acid (76 mg, 0.39 mmol), cesium carbonate (339 mg, 1.04 mmol), palladium acetate (3 mg, 0.013 mmol), dppf (14 mg, 0.026 mmol), and cuprous chloride (26 mg, 0.026 mmol) were synthesized. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to give compound O128 (32 mg, 26.8% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.93(s,1H),7.86(d,J=8.5Hz,2H),7.80(d,J=8.5Hz,2H),7.51(d, J=2.1Hz,1H),7.45(d,J=8.7Hz,1H),7.28(d,J=2.1Hz,1H),7.15(s,1H),4.17–4.10(m,2H),4.05–3.99(m,2H). 13 C NMR(101MHz,Chloroform-d) δ151.47,148.75,148.23,144.06,141.26,132.42,129.10,127.69,126.95,124.43, 119.69,116.68,115.73,111.15,106.89,76.27,76.01,75.70,63.50,42.50,28.68.

[0581] 2-(4-((4-Cyanophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyanobenzofuran (O129)

[0582] 2-(4-((4-cyanophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzofuran-5-carbonitril(O129)

[0583] Synthesized according to General Method C, starting with Intermediate 11 (100 mg, 0.26 mmol) and 5-cyano-benzofuran-2-boronic acid (73 mg, 0.39 mmol), cesium carbonate (339 mg, 1.04 mmol), palladium acetate (3 mg, 0.013 mmol), dppf (14 mg, 0.026 mmol), and cuprous chloride (26 mg, 0.026 mmol) were added. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to afford compound O129 (41 mg, 35.3% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.79(s,1H),8.19(s,1H),8.10(d,J=7.9Hz,2H),7.98(d ,J=7.9Hz,2H),7.84(d,J=8.2Hz,1H),7.77(d,J=8.2Hz,1H),7.45(s,1H),4.21–3.95(m,4H).

[0584] .

[0585] 4-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O130)

[0586] 4-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile(O130)

[0587] Synthesized according to General Method C, starting with Intermediate 11 (100 mg, 0.26 mmol) and 4-cyanophenylboronic acid (80 mg, 0.29 mmol), potassium phosphate (165 mg, 0.78 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (18 mg, 0.026 mmol) were added. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to afford compound O130 (42 mg, 39.6% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.91(s,1H),8.27(s,1H),7.87(d,J=8.3Hz,2H),7.8 1(d,J=8.3Hz,2H),7.38(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),4.04–3.84(m,4H).

[0588] 4-((8-(Benzo[d]oxazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O131)

[0589] 4-((8-(benzo[d]oxazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile(O131)

[0590] Synthesized according to General Method C, starting with Intermediate 11 (100 mg, 0.26 mmol) and benzoxazole-6-boronic acid pinacol ester (96 mg, 0.29 mmol), potassium phosphate (165 mg, 0.78 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (18 mg, 0.026 mmol) were added. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to afford compound O131 (36 mg, 32.7% yield) as a light yellow solid. 1 H NMR(400MHz,Chloroform-d)δ8.94(s,1H),8.35(s,1H),8.13(s,1H),7.88(d,J=8.4Hz ,2H),7.83–7.81(m,3H),7.66(s,1H),7.41(dd,J=8.3,1.2Hz,1H),4.05–3.87(m,4H).

[0591] 4-((8-(2-oxoindole-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O132)

[0592] 4-((8-(2-oxoindolin-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile(O132)

[0593] Synthesized according to General Method C, starting with intermediate 11 (100 mg, 0.26 mmol) and 2-oxoindolin-5-boronic acid pinacol ester (75 mg, 0.29 mmol), potassium carbonate (144 mg, 1.04 mmol), PdCl2(PPh3)2 (18 mg, 0.026 mmol), and Pcy3 (14 mg, 0.0052 mmol) were added. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to afford compound O132 (45 mg, 39.5% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.69(s,1H),8.19(s,1H),8.12(d,J=8.4Hz,2H),7.96(d,J=8.4Hz, 2H),7.29(s,1H),7.23(s,1H),6.85(d,J=8.0Hz,1H),4.02–3.96(m,2H),3.90–3.85(m,2H),3.48(s,2H).

[0594] 3-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-bicyclo[1.1.1]pentane (O133)

[0595] 3-(4-(1-(3-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)bicyclo[1.1.1]pentane-1-carbonitrile(O133)

[0596] Compound intermediate 7 (203 mg, 0.50 mmol), 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid-1,3-dioxoisoindolin-2-ester (0.75 mmol, 1.5 equiv), Hantzsch ester (253 mg, 1.0 mmol), NiBr2(dtbbpy) (48.7 mg, 0.01 mmol), and NaHCO3 (168 mg, 2.0 mmol) were suspended in anhydrous DMA. The reaction mixture was irradiated with UV light at 390 nm under a nitrogen atmosphere ( The reaction mixture was stirred for 12 hours with a PR160 lamp. After dilution with 20 mL of ether, the mixture was extracted with EA / 2.0 M hydrochloric acid. The combined organic phases were washed with saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography afforded O133 (40 mg, 19% yield). 1 H NMR (400MHz, CDCl3): δ8.36(s,1H),8.02(s,1H),7.32-7.27(m,1H),7.10-6.99(m,3H),4.46(t,J=4.8Hz,2H),4.10- 3.66(m,3H),3.58(s,2H),3.52-3.45(m,2H),3.37(t,J=7.0Hz,2H),2.29-2.25(m,3H),2.05-1.98(m,3H).HRMS(ESI):calcd for C 24 H 24 FN4O2[M+H] + :419.1878,found:419.1893.

[0597] 6-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-2-cyano-2,6-diazabicyclospiro[3.3]heptane (O134)

[0598] 6-(4-(1-(3-Fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-2,6-diazaspiro[3.3]heptane-2-carbonitrile(O134)

[0599] Compound Intermediate 7 (125 mg, 0.30 mmol), cesium carbonate (343.3 mg, 1.05 mmol), XANTPHOS (52.1 mg, 0.09 mmol), palladium acetate (7.2 mg, 0.03 mmol), and 2-cyano-2,6-diazabicyclospiro[3.3]heptane (37 mg, 0.30 mmol) were suspended in 1,4-dioxane (9 mL) and stirred at 100°C under N2 protection for 18 h. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, quenched with water (5 mL), and extracted with ethyl acetate (5 mL x 5). The combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate for 30 min, and concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane:methanol (v / v) = 100:1 to 10:1 as the eluent to afford compound O134 (16 mg, 12% yield). 1 H NMR (400MHz, CDCl3): δ8.17(s,1H),7.92(s,1H),7.29-7.22(m,1H),7.06-6.88(m,3H),4.48(t,J=4.8Hz,2H ),4.08-3.66(m,3H),3.61(s,2H),3.59-3.48(m,4H),3.41(s,2H),3.37(t,J=7.0Hz,2H).HRMS(ESI):calcd for C 24 H 26 FN6O2[M+H] + :449.2096,found:449.2103.

[0600] (8-(5,6-Dihydro-[1,2,4]triazolo[4,3-a]piperazin-7(8H)-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O135)

[0601] (8-(5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone(O135)

[0602] Compound intermediate 7 (125 mg, 0.30 mmol), cesium carbonate (343.3 mg, 1.05 mmol), XANTPHOS (52.1 mg, 0.09 mmol), palladium acetate (7.2 mg, 0.03 mmol) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]piperazine (37 mg, 0.30 mmol) were suspended in 1,4-dioxane (9 mL) and stirred at 100 ° C for 18 h under N2 protection. The reaction was monitored by TLC until completion, cooled to room temperature, quenched by the addition of water (5 mL), and extracted with ethyl acetate (5 mL×5). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate for 30 min, and concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 100:1-10:1 as eluent to obtain compound O135 (12 mg, yield 9%). 1 H NMR (400MHz, CDCl3): δ8.36(s,1H),8.15(s,1H),8.01(s,1H),7.26-7.21(m,1H),7.06-6.85( m,3H),4.52(t,J=4.8Hz,2H),4.32(s,2H),4.25(t,J=4.6Hz,2H),4.09-3.69(m,5H),3.61(s, 2H),3.50-3.38(m,2H),3.32(t,J=7.0Hz,2H).HRMS(ESI):calcd for C 23 H 25 FN7O2[M+H] + :450.2048,found:450.2039.

[0603] 4-(4-(3-(3-fluorobenzyl)azetidine-1-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O136)

[0604] 4-(4-(3-(3-fluorobenzyl)azetidine-1-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile(O136)

[0605] To a solution of compound 4 (100 mg, 0.42 mmol) and pyridine (79 mg, 0.63 mmol) in chloroform (10 mL) in an ice bath was slowly added dropwise a solution of triphosgene (623 mg, 2.1 mmol) in chloroform (3 mL). The mixture was stirred at 60°C under nitrogen for 12 hours. After completion of the reaction as monitored by TLC, 1N aqueous HCl (10 mL) was added dropwise. The mixture was extracted with chloroform, washed sequentially with saturated Na2CO3 solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil. This intermediate was dissolved in anhydrous dioxane (10 mL), and triethylamine (0.63 mmol) and 3-(3-fluorobenzyl)azetidine (105 mg, 0.63 mmol) were added. The mixture was stirred at room temperature under nitrogen for 12 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated to dryness under vacuum. The resulting oil was extracted with chloroform / water, and the organic phases were combined, washed sequentially with saturated Na2CO3 solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate) gave the product O136 (41 mg, 23% yield). 1 H NMR (400MHz, CDCl3): δ8.67(s,1H),8.18(s,1H),7.78(d,J=8.3Hz,2H),7.59(d,J=8.1Hz,2H),7.28-7.22(m,1H),7.12-6.99 (m,2H),6.95-6.88(m,1H),4.29(t,J=4.8Hz,2H),3.98-3.93(m,2H),3.65-3.59(m,4H),2.59-2.52(m,3H).HRMS(ESI):calcd for C 25 H 22 FN4O2[M+H] + :429.1721,found:429.1729.

[0606] (8-(5,6-Dihydro-[1,2,4]imidazo[4,3-a]piperazin-7(8H)-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O137)

[0607] (8-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone(O137)

[0608] Compound intermediate 7 (125 mg, 0.30 mmol), cesium carbonate (343.3 mg, 1.05 mmol), XANTPHOS (52.1 mg, 0.09 mmol), palladium acetate (7.2 mg, 0.03 mmol) and 5,6,7,8-tetrahydro-[1,2,4]imidazo[4,3-a]piperazine (36 mg, 0.30 mmol) were suspended in 1,4-dioxane (9 mL) and stirred at 100 ° C for 18 h under N2 protection. The reaction was monitored by TLC until completion, cooled to room temperature, quenched by the addition of water (5 mL), and extracted with ethyl acetate (5 mL×5). The organic phases were combined and washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate for 30 min, and concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane:methanol (V / V) = 100:1-10:1 as eluent to obtain compound O137 (12 mg, yield 9%). 1 H NMR (400MHz, CDCl3): δ8.13(s,1H),8.04(s,1H),7.25-7.21(m,1H),7.06-6.92(m,3H),6.9 7(d,J=4.2Hz,2H),6.75(d,J=4.2Hz,2H),4.55(t,J=4.8Hz,2H),4.32(s,2H),4.28(t,J=4.6 Hz,2H),4.07-3.89(m,5H),3.61(s,2H),3.52-3.39(m,2H),3.30(t,J=7.0Hz,2H).HRMS(ESI):calcd for C 24 H 26 FN6O2[M+H] + :449.2096,found:449.2110.

[0609] Example 2

[0610] This example provides the preparation method and structural characterization data of the compound.

[0611] General methods for compound synthesis

[0612] General Method A: Dissolve the corresponding amine (0.30 mmol), benzyl chloride (0.45 mmol) or benzyl bromide (0.45 mmol), and potassium carbonate (0.59 mmol) in dry DMF and stir at room temperature for 2 h. After completion of the reaction as monitored by TLC, dilute with water (10 mL) and extract with ethyl acetate (3 x 10 mL). The combined organic layers are washed sequentially with water (2 x 10 mL) and saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by column chromatography using dichloromethane / methanol as the eluent to yield the desired compound.

[0613] General Method B: Dissolve the corresponding amine (1 mmol), DMAP (0.3 mmol), and triethylamine (3 mmol) in anhydrous dichloromethane (5 mL). Add the corresponding acid chloride (1.5 mmol) dropwise to the reaction mixture in an ice bath. The reaction mixture is then warmed to room temperature and stirred under N2 for 12 hours. After TLC, the reaction mixture is diluted with water (6 mL) and extracted with DCM (3 x 6 mL). The combined organic phases are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated under reduced pressure to remove the solvent. The crude product is purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0614] General Method C: Dissolve the corresponding amine (1 mmol) and the corresponding sulfonyl chloride (2 mmol) in pyridine (4 mL). The reaction system is protected with N2, heated to 120°C, and stirred for 12 hours. After TLC, the reaction mixture is cooled to room temperature, diluted with water (6 mL), and extracted with ethyl acetate (3 x 12 mL). The organic phase is washed with saturated copper sulfate (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product is then purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0615] General Method D: Add the corresponding bromide (1 mmol), potassium carbonate (4 mmol), and the corresponding boronic acid (1.5 mmol) to a mixed solution of 1,4-dioxane (3 mL) and water (1 mL). The mixture is ventilated and, under a nitrogen purge, PdCl2(PPh3)2 (0.1 mmol) and tricyclohexylphosphine (0.2 mmol) are added. The mixture is then heated and stirred at 90°C for 24 hours. After completion of the reaction as determined by TLC, the reaction mixture is cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (3 x 5 mL). The combined organic phases are washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0616] General Procedure E: Dissolve the corresponding amine (0.2 mmol), DMAP (7.2 mg, 0.06 mmol) and triethylamine (0.6 mmol) in anhydrous dichloromethane (5 mL) and add the corresponding arylsulfonyl chloride (0.3 mmol) dropwise at 0°C. Warm to room temperature and stir for 8 hours. After the reaction is complete as monitored by TLC, dilute with water (5 mL) and extract three times with dichloromethane (5 mL). The combined organic layer is washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the pure product.

[0617] General Procedure F: Dissolve the corresponding amine (1 mmol) in anhydrous dichloromethane (5 mL). Slowly add triethylamine (1.1 mmol) and the corresponding anhydride (1.1 mmol) at 0°C, then warm to room temperature and stir overnight. After TLC, dilute with water (6 mL) and extract with dichloromethane (2 x 6 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0618] General Method G: Dissolve the corresponding amine (1 mmol), carboxylic acid (1.1 mmol), and N,N-diisopropylethylamine (3 mmol) in anhydrous dichloromethane (5 mL). Add HATU (1.05 mmol) at 0°C, then warm to room temperature and stir overnight. After the reaction is complete as determined by TLC, dilute with water (6 mL) and extract with dichloromethane (2 x 6 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (PE / EA) to yield the title compound.

[0619] General Procedure H: The corresponding amine (0.30 mmol) and cesium carbonate (0.89 mmol) were dissolved in toluene (5 mL) by sonication as much as possible. The corresponding bromide (0.59 mmol) was then added and the atmosphere was replaced with N2 three times. After stirring for 5 min, XantPhos (0.02 mmol) and Pd2(dba)3 (0.02 mmol) were added. The atmosphere was replaced with N2 three times and stirred at 90°C for 3 h. After completion of the reaction as monitored by TLC, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed sequentially with water (2 × 10 mL) and saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography using petroleum ether / ethyl acetate as the eluent to afford the desired compound.

[0620] General Method I: Bromide (1 eq), Pd(OAc)2 (0.05 eq), dppf (0.1 eq), cesium carbonate (1.5 eq), CuCl (1 eq), and the corresponding boronic acid (1.5 eq) were suspended in anhydrous DMF (4 mL) and reacted at 100°C for 4 h under nitrogen. After completion of the reaction, monitored by TLC, the mixture was cooled to room temperature, quenched with water (5 mL), and extracted with ethyl acetate (5 mL x 5). The combined organic phases were washed sequentially with water (5 mL x 5) and saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate for 30 min, and concentrated under reduced pressure. The crude product was eluted with petroleum ether:ethyl acetate (v / v) = 20:1 to 1:1 to afford the target compound.

[0621] General Method G: The corresponding amine (100 mg, 1 eq) was dissolved in anhydrous dichloromethane (2 mL), and NaOH (2 eq) and tetrabutylammonium hydrogen sulfate (TBAHS, 0.05 eq) were added. After the mixture was stirred at 0°C for 5 minutes, the corresponding arylsulfonyl chloride (4 eq) was added dropwise, the temperature was raised to 40°C, and stirred for 12 hours. After the reaction was completed by TLC monitoring, it was cooled to room temperature, diluted with water (5 mL), and extracted with dichloromethane (5 mL) three times. The combined organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the pure product.

[0622] Synthesis steps and structural characterization of compounds

[0623] 3-Nitro-4-chloro-5-bromopyridine (1)

[0624] 3-bromo-4-chloro-5-nitropyridine(1)

[0625] 4-Chloro-5-nitropyridine (100 mg, 0.63 mmol) was dissolved in 50% aqueous AcOH (8.0 mL) at 0°C, and bromine (0.03 mL, 0.63 mmol) was slowly added dropwise to the reaction mixture. After stirring at 0°C for 0.5 h, the mixture was slowly warmed to room temperature and stirred for 12 h. The resulting solid was filtered, washed with water, and dried at 60°C to obtain Compound 1 (97.2 mg, 65.0% yield) as a white solid, which was used in the next step without further purification or characterization.

[0626] 3-Bromo-4-chloro-5-aminopyridine (2)

[0627] 5-bromo-4-chloropyridin-3-amine(2)

[0628] Compound 1 (2.002 g, 8.4 mmol) was dissolved in a mixed solution of ethanol (24.0 mL) and water (8.0 mL), followed by the addition of iron powder (2.815 g, 50.4 mmol) and ammonium chloride (898.5 mg, 16.8 mmol). The mixture was stirred at 80 ° C for 0.5 hours under nitrogen protection. After TLC monitoring, the reaction was completed, cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was diluted with water (50 mL), extracted with ethyl acetate (50 mL) 3 times, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow solid compound 2 (1.640 g, yield 94.0%), which was used directly in the next step without further purification.

[0629] 8-Bromo-2H-pyrido[4,3-b][1,4]thiazin-3(4H)-one (3)

[0630] 8-bromo-2H-pyrido[4,3-b][1,4]thiazin-3(4H)-one(3)

[0631] Compound 2 (1.003 g, 4.82 mmol) and triethylamine (0.67 mL, 4.82 mmol) were dissolved in DMF (15.0 mL). Methyl thioglycolate (0.43 mL, 4.821 mmol) was slowly added dropwise under nitrogen protection. The mixture was then heated to 90°C and stirred for 24 hours. After TLC monitoring, the reaction was complete, cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with water (3×10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 3 as a yellow solid (682.4 mg, 57.8% yield). 1 H NMR (400MHz, DMSO-d6) δ = 10.99 (s, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 3.68 (s, 2H).

[0632] 8-Bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (4)

[0633] 8-bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine(4)

[0634] Compound 3 (100.0 mg, 0.4 mmol) was dissolved in anhydrous THF (12.0 mL), and lithium aluminum hydride (52.6 mg, 1.4 mmol) was added in batches at 0°C, and bubbles were observed. The mixture was then stirred at 0°C for 0.5 h, then warmed to room temperature and stirred overnight. After completion of the reaction by TLC, water (10 mL) was added to the reaction solution at 0°C to quench the reaction. The mixture was then filtered through celite, the filter cake was washed with ethyl acetate, the filtrate was collected and extracted with ethyl acetate (3 × 10 mL), then washed with saturated brine (10 mL), and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 30 / 1) to give compound 4 (56.0 mg, 59.4% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 7.94 (s, 1H), 7.69 (s, 1H), 4.26 (s, 1H), 3.65-3.57 (m, 2H), 3.19-3.09 (m, 2H).

[0635] 4-(3,4-Dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (5)

[0636] 4-(3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(5)

[0637] Synthesized according to General Method D, using compound 4 (50.1 mg, 0.2 mmol), 4-cyanophenylboronic acid (47.6 mg, 0.32 mmol), PdCl2(PPh3)2 (15.2 mg, 0.02 mmol), tricyclohexylphosphine (12.1 mg, 0.04 mmol) and potassium carbonate (119.4 mg, 0.86 mmol) in a mixture of dioxane (3.0 mL) and water (1.0 mL). The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 5 (45.9 mg, 83.9% yield) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δ = 7.89 (s, 1H), 7.73 (d, J = 8.4Hz, 2H), 7.68 (s, 1H), 7.53 (d, J = 8.4Hz, 2H), 4.61 (s, 1H), 3.72-3.65 (m, 2H), 3.06-3.00 (m, 2H).

[0638] 4-(4-(3-Fluorobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S1)

[0639] 4-(4-(3-fluorobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S1)

[0640] According to general method A, compound 5 (30.3 mg, 0.12 mmol), 1-(bromomethyl)-4-fluorobenzene (45.4 mg, 0.24 mmol) and N, N-diisopropylethylamine (0.06 mL, 0.36 mmol) in acetonitrile (3 mL) were used for synthesis. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give S1 (77.2 mg, 90.1% yield) as a yellow solid with a melting point of 83-84 ° C. The molecular formula is C 21 H 16 FN3S, HRMS (ESI): [M+H] + :362.1122, theoretical molecular weight:361.1049; 1 H NMR (400MHz, DMSO-d6) δ=8.32(d,J=1.2Hz,1H),8.11-8.05(m,2H),8.02(s,1H),7.76-7.70(m,2H),7.66(s,1H),7.51(td,J=8.0,6.1 Hz,1H),7.44(d,J=9.6Hz,1H),7.38(d,J=7.7Hz,1H),7.28(td,J=8.3,2.2Hz,1H),5.60(s,2H),3.62-3.54(m,2H),3.16-3.09(m,2H). 13 C NMR(100MHz,DMSO-d6)δ=162.19( 1 J CF =245.1Hz),142.03,138.12,136.97( 3 J CF =7.8Hz),135.44,135.41,132.83(2C),131.28( 3 J CF =8.4Hz),130.27(2C),129.73, 124.93( 4 J CF =2.8Hz),124.80,118.31,116.14( 2 J CF =20.8Hz),115.76( 2 J CF=22.1Hz),112.36,61.41,54.92,24.62.

[0641] 4-(4-(4-Fluorobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S2)

[0642] 4-(4-(4-fluorobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S2)

[0643] According to general method A, compound 5 (30.3 mg, 0.12 mmol), 1-(bromomethyl)-4-fluorobenzene (45.4 mg, 0.24 mmol) and N, N-diisopropylethylamine (0.06 mL, 0.36 mmol) in acetonitrile (3 mL) were used for synthesis. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give S2 (32.5 mg, 74.9% yield) as a yellow solid with a melting point of 203-204 ° C. The molecular formula is C 21 H 16 FN3S, HRMS (ESI): [M+H] + :362.1119, theoretical molecular weight:361.1049; 1 H NMR (400MHz, DMSO-d6) δ = 8.32 (d, J = 1.3Hz, 1H), 8.06 (d, J = 8.5Hz, 2H), 8.00 (d, J = 1.4Hz, 1H), 7.71 (d, J = 8.5Hz, 2H), 7 .67(s,1H),7.62(dd,J=8.7,5.4Hz,2H),7.30(t,J=8.9Hz,2H),5.58(s,2H),3.58(d,J=2.8Hz,2H),3.16-3.06(m,2H). 13 C NMR(100MHz,DMSO-d6)δ=160.08( 1 J CF =246.0Hz),142.01,138.12,135.41,135.26,132.84(2C),131.29( 3 J CF =8.8Hz,2C),130.78( 4 J CF =3.0Hz),130.25(2C),129.55,124.69,118.31,116.06( 2 JCF =21.8Hz,2C),112.38,61.35,33,78,24.61.

[0644] 4-(4-(3-Nitrobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S3)

[0645] 4-(4-(3-nitrobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S3)

[0646] According to general method A, compound 5 (200.0 mg, 0.8 mmol), 1-(bromomethyl)-3-nitrobenzene (345.7 mg, 1.6 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.4 mmol) in acetonitrile (3 mL) were used. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give S3 (291.1 mg, 94.8% yield) as a yellow solid with a melting point of 239-240°C. The molecular formula is C 21 H 16 N4O2S, HRMS(ESI):[M+H] + :389.1054, theoretical molecular weight:388.0994; 1 H NMR (400MHz, CDCl3) δ = 9.67 (s, 1H), 8.30 (d, J = 6.6Hz, 2H), 8.16 (d, J = 7.7Hz, 1H), 7.81 (d, J = 8.2Hz, 2H), 7. 72(t,J=7.6Hz,1H),7.53(d,J=8.3Hz,2H),7.46(s,1H),5.67(s,2H),3.85-3.75(m,2H),3.09-3.03(m,2H). 13 C NMR (100MHz, DMSO-d6) δ = 147.99, 142.05, 138.08, 136.28, 135.61, 135.52, 135.43, 132.83 (2C ),130.78,130.25(2C),129.74,124.79,124.15,124.09,118.30,112.36,60.91,45.68,24.63.

[0647] 4-(4-(3-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S4)

[0648] 4-(4-(3-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S4)

[0649] According to general method B, compound 5 (100.0 mg, 0.4 mmol), 3-fluorobenzoyl chloride (0.07 mL, 0.60 mmol), DMAP (DMAP) (14.5 mg, 0.12 mmol) and triethylamine (0.16 mL, 1.2 mmol) and anhydrous dichloromethane (DCM) (6 mL) were used to synthesize. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give S4 (101.1 mg, 68.2% yield) as a white solid with a melting point of 178-179 ° C. The molecular formula is C 21 H 14 FN3OS, HRMS(ESI):[M+H] + :376.0920, theoretical molecular weight:375.0842; 1 H NMR (400MHz, DMSO-d6) δ=8.04(s,1H),7.99(d,J=8.3Hz,3H),7.70(d,J=8.3Hz,2H),7.44(dd,J= 15.0,7.3Hz,1H),7.31(dd,J=8.7,5.6Hz,2H),7.18(d,J=7.9Hz,1H),4.06(s,2H),3.33(s,2H). 13 C NMR(100MHz,DMSO-d6)δ=167.43,161.66( 1 J CF =245.1Hz),145.80,144.10,140.35,137.41,137.34,132.57(2C),130.70,130.61,130.40(2C),124.17,124.15,118.53,117.40( 2 J CF =21.0Hz),115.20( 2 J CF =23.2Hz),111.40,41.35,28.69.

[0650] 4-(4-(4-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S5)

[0651] 4-(4-(4-fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S5)

[0652] According to general method B, compound 5 (100.0 mg, 0.4 mmol), 4-fluorobenzoyl chloride (0.07 mL, 0.60 mmol), DMAP (14.5 mg, 0.12 mmol), triethylamine (0.16 mL, 1.2 mmol) and dry dichloromethane (3 mL) were used to synthesize the product. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain S5 (119.1 mg, 80.3% yield) as a white solid with a melting point of 174-175°C. The molecular formula is: C 21 H 14 FN3OS,HRMS(ESI):[M+H] + :376.0911, theoretical molecular weight:375.0842; 1 H NMR (400MHz, CDCl3) δ = 8.04 (s, 1H), 7.79 (d, J = 8.4Hz, 3H), 7.59 (d, J = 8.3Hz, 2H), 7. 40(dd,J=8.7,5.2Hz,2H),7.04(t,J=8.6Hz,2H),4.23(s,2H),3.30(t,J=5.5Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ=168.24,163.45( 1 J CF =248.5Hz),146.73,144.86,140.97,137.21,134.54,133.20,133.02(2C),131.99( 4 J CF =3.3Hz),131.50( 3 J CF =9.0Hz,2C),130.88(2C),119.02,115.92( 2 J CF =21.9Hz,2C),111.81,41.76,29.33.

[0653] 4-(4-(4-Methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S6)

[0654] 4-(4-(4-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S6)

[0655] According to general method B, compound 5 (100.0 mg, 0.4 mmol), 4-methoxybenzoyl chloride (0.08 mL, 0.6 mmol), DMAP (14.5 mg, 0.12 mmol), triethylamine (0.16 mL, 1.2 mmol) and dichloromethane (3 mL) were used to synthesize the product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain S6 (115.3 mg, 74.4% yield) as a white solid with a melting point of 187-188 ° C. The molecular formula is C 22 H 17 N3O2S, HRMS(ESI):[M+H] + :388.1115, theoretical molecular weight:387.1041; 1 H NMR (400MHz, CDCl3) δ = 8.01 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 8.2Hz, 2H), 7.59 (d, J = 8.2Hz, 2H), 7.35(d,J=8.7Hz,2H),6.83(d,J=8.7Hz,2H),4.23(s,2H),3.81(s,3H),3.29(t,J=5.4Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ= 168.36,160.92,146.15,144.04,140.57,136.31,134.66,132.71(2C),132.53,131.33,13 0.55(2C),130.40(2C),126.86,118.55,113.80,113.66(2C),111.30,55.27,41.17,29.01.

[0656] 4-(4-nicotinoyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S7)

[0657] 4-(4-nicotinoyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S7)

[0658] According to general method B, compound 5 (100.0 mg, 0.4 mmol), 3-nicotinoyl chloride hydrochloride (105.5 mg, 0.6 mmol), DMAP (14.5 mg, 0.12 mmol), triethylamine (0.16 mL, 1.2 mmol) and dichloromethane (3 mL) were used to synthesize the product. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain S7 (98.4 mg, 69.5% yield) as a white solid with a melting point of 218-219°C. The molecular formula is C 20 H 14 N4OS, HRMS(ESI):[M+H] + :359.1057, theoretical molecular weight:358.0888; 1 H NMR (400MHz, CDCl3) δ = 8.68-8.61 (m, 1H), 8.52 (s, 1H), 8.05 (s, 1H), 7.85-7.76 (m, 4H), 7. 59(d,J=8.3Hz,2H),7.35(dd,J=7.8,4.9Hz,1H),4.32-4.17(m,2H),3.33(t,J=5.6Hz,2H). 13 C NMR (100MHz, DMSO-d6)δ=166.71,151.05,148.85,146.40,144.69,140.45,137.19,136.18 ,133.62,132.79,132.58(2C),131.10,130.44(2C),123.45,118.58,111.38,59.78,28.79.

[0659] 4-(4-(phenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S8)

[0660] 4-(4-(phenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S8)

[0661] According to the general method C, compound 5 (150.0 mg, 0.6 mmol), benzenesulfonyl chloride (0.15 mL, 0.12 mmol), and pyridine (6 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain S8 (132.4 mg, 57.1% yield) as a white solid with a melting point of 134-135°C. The molecular formula is C 20 H 15N3O2S2, HRMS(ESI):[M+H] + :394.0673, theoretical molecular weight:393.0606; 1 H NMR (400MHz, DMSO-d6) δ = 8.58 (s, 1H), 8.16 (s, 1H), 7.99-7.92 (m, 2H), 7.81-7.73 (m, 1H), 7.69 (t, J =4.3Hz,2H),7.66-7.60(m,2H),7.58-7.51(m,2H),3.92(dd,J=7.2,3.9Hz,2H),2.94-2.77(m,2H). 13 C NMR (100MHz, DMSO-d6)δ=146.83,145.37,140.20,138.84,137.73,134.02,132.73,132 .56(2C),130.44,130.31(2C),129.88(2C),127.07(2C),118.48,111.39,42.86,25.30.

[0662] 4-(4-((3-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S9)

[0663] 4-(4-((3-fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S9)

[0664] According to the general method C, compound 5 (100.0 mg, 0.4 mmol), 3-fluorobenzenesulfonyl chloride (153.7 mg, 0.8 mmol), and pyridine (4 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain S9 (132.4 mg, 57.1% yield) as a white solid with a melting point of 138-139°C. The molecular formula is C 20 H 14 FN3O2S2, HRMS(ESI):[M+H] + :412.0577, theoretical molecular weight:411.0511; 1H NMR (400MHz, CDCl3) δ = 8.72 (s, 1H), 8.16 (s, 1H), 7.74 (d, J = 8.2Hz, 2H), 7.52 (d, J = 1.5Hz, 2H), 7 .44(d,J=8.2Hz,2H),7.39(d,J=7.6Hz,1H),7.35(s,1H),4.02-3.95(m,2H),2.96-2.89(m,2H). 13 C NMR (100MHz, CDCl3) δ = 162.65 ( 1 J CF =253.0Hz),147.17,145.68,141.68(J=6.7Hz),140.18,132.61(2C),131.52(J=7.8Hz),130 .29(2C),123.20(J=3.4Hz),121.22,121.01,118.45,114.93,114.69,112.91,43.52,26.32.

[0665] 4-(4-((4-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S10)

[0666] 4-(4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S10)

[0667] According to the general method C, compound 5 (100.0 mg, 0.4 mmol) 4-fluorobenzenesulfonyl chloride (153.7 mg, 0.8 mmol) and pyridine (4 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain S10 (132.4 mg, 57.1% yield) as a white solid with a melting point of 69-70°C. The molecular formula is C 20 H 14 FN3O2S2, HRMS(ESI):[M+H] + :412.0572, theoretical molecular weight:411.0511; 1 H NMR (400MHz, CDCl3) δ = 8.71 (s, 1H), 8.14 (s, 1H), 7.75-7.71 (m, 4H), 7.44 (d ,J=8.2Hz,2H),7.19(t,J=8.5Hz,2H),4.02-3.91(m,2H),2.97-2.86(m,2H).13 C NMR(100MHz,DMSO-d6)δ=165.02( 1 J CF =253.5Hz),146.91,145.45,140.15,138.03,135.20( 4 J CF =3.0Hz),132.82,132.58(2C),130.35( 3 J CF =9.4Hz,2C),130.33(3C),118.48,117.12( 2 J CF =22.85Hz,2C),111.42,42.92,25.49.

[0668] 4-(4-(m-Tolylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S11)

[0669] 4-(4-(m-tolylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S11)

[0670] According to the general method C, compound 5 (100.0 mg, 0.4 mmol) 3-methylbenzenesulfonyl chloride (150.6 mg, 0.8 mmol) and pyridine (4 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain S11 (93.1 mg, 57.1% yield) as a white solid with a melting point of 174-175°C. The molecular formula is C 21 H 17 N3O2S2, HRMS(ESI):[M+H] + :408.0826, theoretical molecular weight:407.0762; 1 H NMR (400MHz, CDCl3) δ = 8.72 (s, 1H), 8.14 (s, 1H), 7.73 (d, J = 8.2Hz, 2H), 7.52 (d, J = 8.8Hz, 2H), 7 .45(d,J=8.1Hz,3H),7.40(t,J=7.5Hz,1H),4.00-3.90(m,2H),2.95-2.84(m,2H),2.40(s,3H). 13C NMR (100MHz, DMSO-d6)δ=146.87,145.36,140.28,139.75,138.84,137.56,135.69,134.58 ,132.59(2C),130.28(2C),129.70,127.13,124.22,118.48,111.39,42.81,25.26,20.73.

[0671] 4-(4-Tolyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S12)

[0672] 4-(4-tosyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S12)

[0673] According to the general method C, compound 5 (10.0 mg, 0.04 mmol), 4-methylbenzenesulfonyl chloride (11.4 mg, 0.06 mmol), and pyridine (1.5 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain S12 (9.1 mg, 55.8% yield) as a white solid with a melting point of 141-142°C. The molecular formula is C 21 H 17 N3O2S2, HRMS(ESI):[M+H] + :408.0827, theoretical molecular weight:407.0762; 1 H NMR (400MHz, DMSO-d6) δ=8.56(s,1H),8.14(s,1H),7.95(d,J=8.1Hz,2H),7.57(dd,J=12 .3,8.2Hz,4H),7.43(d,J=8.2Hz,2H),3.94-3.87(m,2H),2.87-2.81(m,2H),2.41(s,3H). 13 C NMR (100MHz, DMSO-d6)δ=146.82,145.27,144.59,140.25,137.47,136.05,132.68,132.57 (2C),130.50,130.32(2C),130.28(2C),127.15(2C),118.49,111.38,42.73,25.25,21.08.

[0674] 4-(4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S13)

[0675] 4-(4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S13)

[0676] According to the general method C, compound 5 (100.0 mg, 0.4 mmol) 4-methoxybenzenesulfonyl chloride (163.3 mg, 0.8 mmol) and pyridine (4 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain S13 (101.9 mg, 60.1% yield) as a white solid with a melting point of 60-61°C. The molecular formula is C 21 H 17 N3O2S2, HRMS(ESI):[M+H] + :427.0782, theoretical molecular weight:423.0711; 1 H NMR (400MHz, CDCl3) δ = 8.71 (s, 1H), 8.12 (s, 1H), 7.74 (d, J = 7.9Hz, 2H), 7.65 (d, J = 8.7Hz, 2H), 7 .46(d,J=8.0Hz,2H),6.97(d,J=8.7Hz,2H),3.98-3.91(m,2H),3.89(s,3H),2.98-2.87(m,2H). 13 C NMR(100MHz,DMSO-d6)δ=163.32,146.92,145.17,140.25,132.70,132.57(2C),130.54,13 0.34(2C),130.19,129.43(2C),118.49,115.11,114.99(2C),111.38,55.88,42.65,25.12.

[0677] 4-(4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S14)

[0678] 4-(4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S14)

[0679] According to the general method C, compound 5 (100.0 mg, 0.4 mmol) 3-chlorobenzenesulfonyl chloride (166.7 mg, 0.8 mmol) and pyridine (4 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain S14 (98.3 mg, 57.4% yield) as a light yellow solid with a melting point of 126-127°C. The molecular formula is C 20 H 14 ClN3O2S2, HRMS(ESI):[M+H] + :428.0284, theoretical molecular weight:427.0216; 1 H NMR (400MHz, CDCl3) δ = 8.72 (s, 1H), 8.18 (s, 1H), 7.74 (d, J = 8.2Hz, 2H), 7.67-7.57 (m, 3H), 7.52-7.40 (m, 3H), 4.04-3.90 (m, 2H), 2.98-2.86 (m, 2H). 13 C NMR (100MHz, DMSO-d6)δ=147.01,145.72,140.63,140.10,138.18,134.35,133.97,132.83 ,132.61(2C),131.97,130.67,130.26(2C),126.57,125.79,118.46,111.45,43.13,25.66.

[0680] 4-(4-((4-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S15)

[0681] 4-(4-((4-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S15)

[0682] According to the general method C, compound 5 (100.0 mg, 0.4 mmol) 4-chlorobenzenesulfonyl chloride (166.7 mg, 0.8 mmol) and pyridine (4 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain S15 (94.5 mg, 55.9% yield) as a light yellow solid with a melting point of 171-172°C. The molecular formula is C 20 H 14 ClN3O2S2, HRMS(ESI):[M+H]+ :428.0282, theoretical molecular weight:427.0216; 1 H NMR (400MHz, CDCl3) δ = 8.71 (s, 1H), 8.15 (s, 1H), 7.75 (d, J = 8.2Hz, 2H), 7.66 (d, J = 8.6Hz ,2H),7.50(d,J=8.6Hz,2H),7.45(d,J=8.2Hz,2H),4.01-3.94(m,2H),2.97-2.91(m,2H). 13 C NMR (100MHz, DMSO-d6)δ=146.90,145.57,140.17,138.98,137.91 137.78,132.58(2C),132.09,130.33(2C),130.01(2C),129.08(2C),118.48,111.42(s),42.97,25.59.

[0683] 4-(4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S16)

[0684] 4-(4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S16)

[0685] According to the general method C, compound 5 (100.0 mg, 0.4 mmol), 3-trifluoromethylbenzenesulfonyl chloride (193.3 mg, 0.8 mmol), and pyridine (4 mL) were used to synthesize the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain S16 (101.6 mg, 55.0% yield) as a white solid with a melting point of 100-101°C. The molecular formula is C 21 H 14 F3N3O2S2, HRMS(ESI):[M+H] + :462.0537, theoretical molecular weight:461.0480; 1H NMR (400MHz, CDCl3) δ = 8.72 (s, 1H), 8.16 (s, 1H), 7.94 (d, J = 7.9Hz, 1H), 7.89 (d, J = 7.9Hz, 1H), 7.81 (s, 1H) ,7.71(d,J=8.4Hz,2H),7.67(d,J=7.9Hz,1H),7.40(d,J=8.4Hz,2H),4.04-3.94(m,2H),2.95-2.83(m,2H). 13 C NMR (100MHz, CDCl3)δ=147.67,146.23,140.91,140.10,138.16,132.52(2C),132.23( 2 J CF =33.5Hz),131.91( 1 J CF =266.9Hz),130.44,130.41,130.26( 3 J CF =7.0Hz),130.17(2C),124.40( 3 J CF =9.9Hz),124.34,121.64,118.40,112.76,43.62,26.21.

[0686] 4-(4-((4-trifluoromethylphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S17)

[0687] 4-(4-((4-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile(S17)

[0688] According to the general method C, compound 5 (100.0 mg, 0.4 mmol), 4-trifluoromethylbenzenesulfonyl c...

Claims

A compound of formula (I), in n is selected from 0, 1 and 2; m is selected from 0 and 1; X is selected from C, N, O and S; L1 is selected from hydrogen, -SO2-, -CO- and -CH2-; is a single bond or a double bond; Indicates that one or more ring carbon atoms are or are not carbonylated; R 11 R is selected from the group consisting of aryl, heteroaryl, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, bicyclic hydrocarbon, azaheterocyclic hydrocarbon and azaheterocyclic ketone; the aryl, heteroaryl, spirocyclic hydrocarbon, bicyclic alkyl, azaheterocyclic hydrocarbon and azaheterocyclic ketone are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, cyclic ether and alkyl optionally substituted with one to three halogens; or R 11 Has the following structure: R 12 is selected from hydrogen, alkyl, azacycloalkyl, bicycloalkyl, spirocycloalkyl, azaspirocycloalkyl, oxaspirocycloalkyl, aryl, heteroaryl and absent, wherein the alkyl, aryl and heteroaryl are optionally substituted with one or more selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, cyclic ether and optionally substituted with one to three halogens. alkyl, wherein the nitrogen heterocyclic hydrocarbon group, bicyclic hydrocarbon group, spirocyclic hydrocarbon group is optionally substituted by cyano, fluorophenyl, fluorophenylalkyl or fluorophenylamino; or, R 12 Selected from the following structures: wherein q1 and q2 are selected from 1, 2 and 3, R 13 Selected from hydrogen, cyano, cyclic ether and -L2-R 14 , wherein L2 is selected from -SO2-, -CO-, hydrocarbon group and does not exist, R 14 Selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one to three substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate ester. The compound of claim 1, wherein the aryl group is selected from phenyl and naphthyl, and the heteroaryl group is selected from quinolinyl, thienyl, thiazolyl, indolinyl, pyridinyl, furanyl, indazolyl, imidazopyridinyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridinyl, thienopyridinyl, benzoxazolyl, indolonyl, quinolinonyl, triazolopiperazine, imidazopiperazine, and benzoxazinonyl. The compound according to claim 1 or 2, wherein R 11 is an aryl or heteroaryl group, which is optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens; preferably, R 11 is cyano-substituted phenyl, halogen-substituted benzofuranyl and cyano-substituted benzofuranyl; more preferably, R 11 are p-cyanophenyl, 5-chlorobenzofuran-2-yl and 5-cyanobenzofuran-2-yl. The compound according to any one of claims 1 to 3, wherein R 12 is selected from phenyl, naphthyl, quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridinyl, thienopyridinyl, triazolopiperazine, imidazopiperazine, azetidinyl, azepanyl, azabicyclospiro[3.3]heptane, oxabicyclospiro[3.3]heptane and bicyclo[1.1.1]pentane, which are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, cyclic ether and alkyl optionally substituted with one to three halogens. The compound according to any one of claims 1 to 4, wherein the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl. The compound according to any one of claims 1 to 5, wherein: n is selected from 0, 1 and 2; m is 1; X is O; L1 is selected from -SO2- and -CO-; is a single bond; R 11 is an aryl, heteroaryl, spirocyclic hydrocarbon group, azaspirocyclic hydrocarbon group, oxaspirocyclic hydrocarbon group, bicyclic hydrocarbon group, azaheterocyclic hydrocarbon group and azaheterocyclic keto group, which is optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximino, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate ester group and alkyl group optionally substituted by one to three halogens; preferably, R 11 is a cyano-substituted phenyl, a cyano-substituted bicyclic hydrocarbon group, a cyano-substituted azaspirocyclic hydrocarbon group, or a cyano-substituted azaheterocyclic hydrocarbon group; more preferably, R 11 is p-cyanophenyl, 1-cyano-bicyclo[1.1.1]pentane, 1-cyanopiperazinyl and 1-cyanodihydropyridinyl; R 12 The alkyl group is selected from the group consisting of alkyl, azacycloalkyl, bicyclic alkyl, spirocycloalkyl, azaspirocycloalkyl, oxaspirocycloalkyl, aryl and heteroaryl, wherein the alkyl, azacycloalkyl, bicyclic alkyl, spirocycloalkyl, azaspirocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, cyclic ether, sulfonyl fluoride, borate ester and alkyl optionally substituted with one to three halogens. The compound according to any one of claims 1 to 6, which is a compound of formula (II): in: n is selected from 0, 1 and 2; L1 is selected from -SO2- and -CO-; R 15 is selected from alkyl, azacycloalkyl, bicyclic hydrocarbon, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, aryl and heteroaryl, wherein the alkyl, azacycloalkyl, bicyclic hydrocarbon, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted with one to three halogens; preferably, the alkyl is selected from methyl and ethyl, The aryl group is selected from phenyl and naphthyl, the heteroaryl group is selected from quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl, thienopyridinyl, the azacycloalkyl group is selected from azetidinyl, the bicycloalkyl group is selected from bicyclo[1.1.1]pentanyl and bicyclo[2.2.2]octanyl, and the azaspirocycloalkyl group is selected from 2,6-diazabicyclospiro[3.3]heptyl. The compound according to any one of claims 1 to 7, which is a compound of formula (III): in, R 16 Has the following structure: Among them, q1, q2, R 13 and R 14 As defined in claim 1. The compound according to any one of claims 1 to 8, wherein: n is 0; m is 1; X is S; L1 is selected from -SO2-, -CO- and -CH2-; is a single bond; R 11 is selected from aryl, heteroaryl, spirocyclic hydrocarbon, azaspirocyclic hydrocarbon, oxaspirocyclic hydrocarbon, bicyclic hydrocarbon, azaheterocyclic hydrocarbon and azaheterocyclic keto, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, cyclic ether and alkyl optionally substituted with one to three halogens; preferably, R 11 is cyano-substituted phenyl, halogen-substituted benzofuranyl and cyano-substituted benzofuranyl; More preferably, R 11 are p-cyanophenyl, 5-chlorobenzofuran-2-yl and 5-cyanobenzofuran-2-yl; R 12 The alkyl radicals are selected from aryl, heteroaryl, azacycloalkyl, bicyclic alkyl, spirocycloalkyl, azaspirocycloalkyl and oxaspirocycloalkyl, wherein the aryl, heteroaryl, azacycloalkyl, bicyclic alkyl, spirocycloalkyl, azaspirocycloalkyl and oxaspirocycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, thioether, sulfonyl fluoride, borate ester and alkyl optionally substituted with one to three halogens. The compound according to any one of claims 1 to 9, which is a compound of formula (IV): in: L1 is selected from -SO2-, -CO- and -CH2-; R 17 is selected from aryl and heteroaryl; the aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogen; preferably, the aryl is phenyl, and the heteroaryl is selected from quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl, thienopyridinyl, indolonyl, quinolinonyl; more preferably, R 17 are p-cyanophenyl, 5-chlorobenzofuran-2-yl and 5-cyanobenzofuran-2-yl; R 18 substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted with one to three halogens; preferably, the aryl is phenyl and naphthyl, and the heteroaryl is selected from quinolyl, thienyl, pyrazolyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, Pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridinyl, thienopyridinyl, triazolopiperazine, imidazopiperazine, the azacycloalkyl is selected from azetidinyl, the bicycloalkyl is selected from bicyclo[1.1.1]pentanyl and bicyclo[2.2.2]octanyl, the azaspirocycloalkyl is selected from 2-azabicyclospiro[3.3]heptyl. The compound according to any one of claims 1 to 10, which is a compound of formula (XI): wherein L1 is selected from -SO2-, -CO-, -CH2- or none; R 17 As defined in claim 10, R 29 is cyano, cyclic ether, or phenyl which is optionally substituted by one to three substituents selected from halogen, cyano, and alkoxy. The compound according to any one of claims 1 to 11, which is a compound of formula (XII): where R 30 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or two substituents selected from halogen, cyano and alkyl; preferably, the aryl is phenyl, and the heteroaryl is selected from pyridyl, indazolyl, benzothiazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyrazolyl, indolonyl, imidazopyridinyl, pyrazolopyridinyl, quinolinonyl, pyrrolopyridinyl; R 31 is selected from the group consisting of phenyl and pyridyl, said phenyl being optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, alkoxy, nitro, amino, hydroxy, acetamido, and alkyl optionally substituted with one to three halogens. The compound according to any one of claims 1 to 12, which is a compound of formula (XIII): where R 32 is selected from phenyl and quinolinone, wherein the phenyl and quinolinone are optionally substituted with one or two substituents selected from halogen, cyano and alkyl; L4 is selected from -SO2- and -CH2-; R 32 is selected from aryl and heteroaryl, the phenyl and heteroaryl groups are optionally substituted with substituents selected from cyano, nitro and hydroxy; preferably, the heteroaryl group is selected from thienyl and pyridyl. The compound according to any one of claims 1 to 12, which is a compound of formula (XIV): where R 13 As defined in claim 1. The compound according to any one of claims 1 to 14, wherein: n is selected from 0, 1 and 2; m is 0; X is C; L1 is selected from -SO2- and -CO-; is a single bond; R 11 is selected from aryl, heteroaryl, bicyclic hydrocarbon, azacycloalkyl, azaspirocyclic hydrocarbon and azacycloketone; the aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, R 11 is phenyl substituted by cyano, 1-cyano-piperidinyl, 1(2H)-cyano-3,6-dihydropyridinyl; more preferably, R 11 is p-cyanophenyl; R 12 is selected from alkyl, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted with one to three halogens. The compound according to any one of claims 1 to 15, which is a compound of formula (V): in, R 19 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, the aryl is selected from phenyl and naphthyl, and the heteroaryl is selected from quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl and thienopyridinyl. The compound according to any one of claims 1 to 16, which is a compound of formula (VI): in, R11 is as defined in claim 15; R 20 is selected from alkyl, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, the aryl is phenyl, and the heteroaryl is selected from quinolyl, thienyl, pyridyl, furyl, indazolyl, imidazopyridyl, benzothiazolyl, indolyl, benzofuranyl, benzothienyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopiperidinyl, imidazopyrimidinyl, imidazopiperidinyl, furopyridyl and thienopyridinyl. The compound according to any one of claims 1 to 17, which is a compound of formula (VII): in, R 21 Selected from aryl and heteroaryl, the aryl and heteroaryl are optionally substituted by one or more selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, The substituents are hydroxy, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl groups optionally substituted with one to three halogens. The compound according to any one of claims 1 to 18, which is a compound of formula (VIII): in, R 22 is an aryl group, which is optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amino, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, the aryl group is phenyl. The compound according to any one of claims 1 to 19, wherein: n is 0; m is 0; X is C; L1 is selected from -SO2- and -CO-; is a double bond; R 11 is selected from aryl and heteroaryl; the aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate and alkyl optionally substituted by one to three halogens; preferably, R 11 is a phenyl group substituted with a cyano group; more preferably, R 11 is p-cyanophenyl; R 12 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens. The compound according to any one of claims 1 to 20, which is a compound of formula (IX): in, L1 is selected from -SO2- and -CO-; R 23 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens. The compound according to any one of claims 1 to 21, which is a compound of formula (X): where R 24 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, acyl, nitro, alkoxy, alkoxyacyl, amine, sulfonyl, carboxyl, sulfoximinyl, trifluoromethyl, hydroxyl, amide, urea, thioether, sulfonyl fluoride, borate, and alkyl optionally substituted with one to three halogens. The compound according to any one of claims 1 to 22, which is a compound of formula (XV): where R 33 Selected from hydrocarbon groups and cycloalkyl groups. The compound according to any one of claims 1 to 23, which is a compound of formula (XVI): where R 34 is selected from cyano and halogen, R 13 As defined in claim 1, Indicates that one or more ring carbon atoms are or are not carbonylated. The compound according to any one of claims 1 to 24, which is selected from: 4-(4-(Benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O1); 4-(4-((4-Fluorophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O2); 4-(4-((3-Fluorophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O3); 4-(4-Methylbenzenesulfonyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O4); 4-(4-(3-Methylphenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O5); 4-(4-(4-chlorophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O6); 4-(4-(3-chlorophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O7); 4-(4-(4-Methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O8); 4-(4-(4-Nitrophenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O9); 4-(4-(3-nitrobenzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O10); 4-(4-(4-Trifluoromethyl)benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O11); 4-(4-(3-Trifluoromethyl)benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O12); 4-(4-(Pyridine-3-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O13); 4-(4-(Methylphenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O14); 4-(4-(Quinoline-8-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O15); 4-(4-(Thiophene-2-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O16); 4-(4-(naphthalene-1-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O17); 4-(4-(naphthalene-2-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O18); 4-(4-(4-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O19); 4-(4-(3-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O20); 4-(4-(2-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O21); 4-(4-(4-Methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O22); 4-(4-(3-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O23); 4-(4-(4-Trifluoromethylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O24); 4-(4-(3-Trifluoromethylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O25); 4-(4-(4-nitrobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O26); 4-(4-(3-nitrobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O27); 4-(4-(4-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O28); 4-(4-(3-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O29); 4-(4-nicotinoyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O30); 4-(4-(Furan-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O31); 4-(4-(2-cyanoacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O32); 4-(4-(2-chloroacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O33); 4-(4-(2-bromoacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O34); 4-(4-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O35); 4-(4-(2-(4-fluorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O36); 4-(4-(2-(3-fluorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O37); 4-(4-(2-(4-chlorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O38); 4-(4-(2-(3-chlorophenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O39); 4-(4-(2-(4-methoxyphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O40); 4-(4-(2-(3-methoxyphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O41); 4-(4-(2-(4-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O42); 4-(4-(2-(3-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O43); 4-(4-(2-(2-methylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O44); 4-(4-(2-(4-trifluoromethylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O45); 4-(4-(2-(3-trifluoromethylphenyl)acetyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O46); 4-(4-(3-(4-Fluorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O47); 4-(4-(3-(3-fluorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O48); 4-(4-(3-(4-chlorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O49); 4-(4-(3-(3-chlorophenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O50); 4-(4-(3-(4-methoxyphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O51); 4-(4-(3-(4-trifluoromethylphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O53); 4-(4-(3-(3-(trifluoromethylphenyl)propionyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O54); 4-(4-(1-((3-fluorophenyl)sulfonyl)piperidine-4-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O55); 4-(4-(azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O56); 4-(4-(1-(4-Fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O57); 4-(4-(1-(3-Fluorobenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O58); N-(2-(8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-2-oxoethyl)-4-fluorobenzamide (O59); 4-(4-(1-((4-fluorophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O60); 4-(4-(1-((3-fluorophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O61); 4-(4-(1-((4-nitrophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O62); 4-(4-(1-((3-nitrophenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O63); 4-(4-1-(thiophen-2-ylsulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O64); 4-(4-(1-Tosylazetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O65); 4-(4-(1-((3-methoxyphenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O66); 4-(4-(1-((4-methoxyphenyl)sulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O67); 3-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O68); 4-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O69); 4-(4-(1-(m-Toluenesulfonyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O70); 4-(4-(3-((3-fluorophenyl)amino)bicyclo[1.1.1]pentane-1-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O71); 4-(4-(5-(4-Fluorophenoxy)thiophene-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O72); 4-(4-(6-(3-fluorobenzyl))-2,6-diazabicyclospiro[3.3]heptane-2-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O73); 3-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O74); 4-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)sulfonyl)benzonitrile (O75); 4-(4-(1-(3-methoxybenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O76); 4-(4-(1-(4-methoxybenzoyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O77); 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O78); 4-(4-(1-(4-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O79); 3-((3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)methyl)benzonitrile (O80); 4-(4-(1-(4-cyanophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O81); 4-(4-(1-(3-methoxybenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O82); 4-(4-(1-(4-methoxybenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O83); 4-(4-(1-(3-fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O84); 4-(4-(1-(4-Fluorophenyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O85); 3-(3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)benzonitrile (O86); 4-(3-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-4-carbonyl)azetidin-1-yl)benzonitrile (O87); (8-(Benzo[d]thiazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O88); 5-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)indol-2-one (O89); (1-(3-Fluorobenzyl)azetidin-3-yl)(8-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone (O90); (8-(6-Chloro-1H-indol-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O91); 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-6-cyano-1H-indole (O92); (8-(6-Fluoro-1H-indol-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O93); 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-1H-indole (O94); (8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O95); 2-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyanobenzofuran (O96); 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-3,6-1(2H)-cyano-dihydropyridine (O97); 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-piperazine (O98); 4-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-3-oxopiperazine (O99); 4-(4-((3-(3-methoxyphenyl)-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O100); 3-(5-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)-4,5-dihydroisoxazol-3-yl)benzonitrile (O101); 4-(4-((3-phenyl-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O102); 4-(4-((3-Benzyl-4,5-dihydroisoxazol-5-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O103); (S)-4-(4-(1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O104); (R)-4-(4-(1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O105); 2-(4-((S)-1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-2,3-dihydro-benzofuran (O106); 2-(4-((R)-1-(3-fluorobenzyl)pyrrolidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-2,3-dihydrobenzofuran (O107); 8-(5-chlorobenzofuran-2-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (O108); 2-(3,4-Dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyano-benzofuran (O109); 4-(4-((1-(3-cyanobenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O110); 4-(4-((1-(4-cyanobenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O111); 4-(4-((1-(3-methoxybenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O112); 4-(4-((1-(4-methoxybenzoyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O113); 4-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)sulfonyl)benzonitrile (O114); 3-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)sulfonyl)benzonitrile (O115); 4-(4-((1-((4-fluorophenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O116); 4-(4-((1-((3-fluorophenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O117); 4-(4-((1-((3-methoxyphenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O119); 4-(4-((1-((4-methoxyphenyl)sulfonyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O118); 3-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)azetidin-1-yl)methyl)benzonitrile (O120); 4-(4-((1-(4-cyanobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O121); 4-(4-((1-(3-fluorobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O122); 4-(4-((1-(4-fluorobenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O123); 4-(4-((1-(3-methoxybenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O124); 4-(4-((1-(4-methoxybenzyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O125); 4-(4-((1-(3-Fluorophenyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O126); 4-(4-((1-(4-Fluorophenyl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O127); 4-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O128); 2-(4-((4-Cyanophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5-cyanobenzofuran (O129); 4-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O130); 4-((8-(Benzo[d]oxazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O131); 4-((8-(2-oxoindole-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)sulfonyl)benzonitrile (O132); 3-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-1-cyano-bicyclo[1.1.1]pentane (O133); 6-(4-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-2-cyano-2,6-diazabicyclospiro[3.3]heptane (O134); (8-(5,6-Dihydro-[1,2,4]triazolo[4,3-a]piperazin-7(8H)-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O135); 4-(4-(3-(3-fluorobenzyl)azetidine-1-carbonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)benzonitrile (O136); (8-(5,6-dihydro-[1,2,4]imidazo[4,3-a]piperazin-7(8H)-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (O137); 4-(4-(3-Fluorobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S1); 4-(4-(4-Fluorobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S2); 4-(4-(3-nitrobenzyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S3); 4-(4-(3-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S4); 4-(4-(4-Fluorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S5); 4-(4-(4-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S6); 4-(4-nicotinoyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S7); 4-(4-(phenylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S8); 4-(4-((3-fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyridyl[4,3-b][1,4]thiazin-8-yl)benzonitrile (S9); 4-(4-((4-Fluorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S10); 4-(4-(m-Tolylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S11); 4-(4-Tolyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S12); 4-(4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S13); 4-(4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S14); 4-(4-((4-chlorophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S15); 4-(4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S16); 4-(4-((4-trifluoromethylphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S17); 4-(4-((3-nitrophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S18); 4-(4-((4-nitrophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S19); 3-(((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S20); 4-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S21); 4-(4-(naphthalen-1-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S22); 4-(4-(naphthalen-2-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S23); 4-(4-(Thiophen-2-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S24); 4-(4-(pyridin-3-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S25); 4-(4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S26); 3-(4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S27); 8-(4-chlorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S28); 8-(3-chlorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S29); 8-(4-Fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S30); 8-(3-Fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S31); 4-((4-methoxyphenyl)sulfonyl)-8-(4-trifluoromethylphenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S32); 8-(4-Fluoro-3-methylphenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S33); 8-(3-chloro-4-fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S34); 2-Fluoro-4-(4-(((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S35); 4-((4-methoxyphenyl)sulfonyl)-8-(thiophen-3-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S36); 4-((4-methoxyphenyl)sulfonyl)-8-(thiophen-2-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S37); 8-(Furan-2-yl)-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S38); 4-((4-Methoxyphenyl)sulfonyl)-8-(1H-pyrazol-4-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S39); 4-((8-(Benzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S40); 4-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S41); 2-(4-((4-Cyanophenyl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)-5-cyano-benzofuran (S42); 4-((8-(Benzo[b]thiophen-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S43); 4-((8-(Benzofuran-5-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S44); 4-((8-(1-methyl-1H-indol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S45); 4-((8-(Benzo[d]thiazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S46); 4-((8-(Benzoxazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S47); 4-((8-(1H-indazol-5-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S48); 4-((8-(1H-benzo[d]imidazol-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S49); 4-((8-(imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S50); 4-((8-(2-Indolin-5-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S51); 4-((8-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)benzonitrile (S52); 8-(5-chlorobenzofuran-2-yl)-4-((6-methoxypyridin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S53); 5-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)pyridin-2-ol (S54); 8-(5-chlorobenzofuran-2-yl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S55); 8-(5-chlorobenzofuran-2-yl)-4-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S56); N-(5-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-4-methylthiazol-2-yl)acetamide (S57); 1-(5-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)indol-1-yl)ethan-1-one (S58); 6-((8-(5-Chloro-benzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (S59); 8-(5-chlorobenzofuran-2-yl)-4-((5-chlorothien-2-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S60); 8-(5-chlorobenzofuran-2-yl)-4-(piperidin-4-ylsulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S61); 4-(azetidin-3-ylsulfonyl)-8-(5-chlorobenzofuran-2-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S62); 4-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyano-piperidine (S63); 3-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyano-azetidine (S64); 3-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyano-bicyclo[1.1.1]pentane (S65); 4-((2-oxabicyclospiro[3.3]heptane-6-yl)sulfonyl)-8-(5-chlorobenzofuran-2-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S66); 6-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-2-cyano-2-azabicyclospiro[3.3]pentane (S67); 4-(4-(3-cyclobutylamino-sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (11); 4-(4-((1-(4-fluorophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S68); 4-(4-((1-(3-fluorophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S69); 4-(4-((1-(4-cyanophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S70); 3-(3-((8-(4-cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyclobutylaminocarbonyl)benzonitrile (S71); 4-(4-((1-(4-methoxyphenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S72); 4-(4-((1-(3-methoxyphenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S73); 4-(4-((1-((4-fluorophenyl)sulfonyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S74); 4-(4-((1-((3-fluorophenyl)sulfonyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S75); 4-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyclobutylamino)sulfonyl)benzonitrile (S76); 3-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyclobutylamino)sulfonyl)benzonitrile (S77); 4-(4-((1-((4-methoxyphenyl)sulfonyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S78); 4-(4-((1-((3-methoxyphenyl)sulfonyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S79); 4-(4-((1-(4-cyanophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S80); 3-((3-((8-(4-Cyanophenyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-1-cyclobutylamino)methyl)benzonitrile (S81); 4-(4-((1-(4-Fluorophenyl)3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S82) 4-(4-((1-(3-fluorophenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S83); 4-(4-((1-(4-methoxyphenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S84); 4-(4-((1-(3-methoxyphenyl)-3-cyclobutylamino)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S85); N-(2-(8-(4-cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine-4-carbonyl)phenyl)acetamide (S86); 4-(4-(3-(trifluoromethyl)benzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S87); 4-(4-(4-(trifluoromethyl)benzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S88); 4-(4-(4-Methylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S89); 4-(4-(2-methylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S90); 4-(4-(3-Methylbenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S91); 4-(4-(4-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S92); 4-(4-(3-chlorobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S93); 4-(4-(4-cyanobenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S94); 3-(8-(4-Cyanophenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine-4-carbonyl)benzonitrile (S95); 4-(4-(3-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S96); 4-(4-(4-methoxybenzoyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S97); 2-(4-(4-Methoxyphenyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)-5-carbonitrile-benzofuran (S98); 4-(3-Oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S99); 4-(4-(4-chlorobenzoyl)-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazin-8-yl)benzonitrile (S100); 1-((8-(5-chlorobenzofuran-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]thiazin-4-yl)sulfonyl)-3-cyano-azetidine (S101); 8-(5-chlorobenzofuran-2-yl)-4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]piperazin-7(8H)-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S102); 8-(5-chlorobenzofuran-2-yl)-4-((1-(oxetan-3-yl)azetidin-3-yl)sulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]thiazine (S103); 4-(1-Tosyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C1); 4-{1-[(4-nitrophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C2); 4-{1-[(4-methoxyphenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C3); 4-(1-{[4-(trifluoromethyl)phenyl]sulfonyl}-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C4); 4-{1-[(6-chloropyridin-3-yl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C5); 4-{1-[(3-Fluorophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C6); 4-{1-[(4-Fluorophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C7); 4-[1-(m-Toluenesulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C8); 4-{1-[(3-nitrophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C9); 4-[1-(Pyridin-3-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C10); 4-[1-(Quinolin-8-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C11); 4-[1-(naphthalen-2-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C12); 4-{1-[(4-chlorophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C13); 4-{1-[(3-chlorophenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C14); 4-{[4-(4-Cyanophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]sulfonyl}benzonitrile (C15); 3-{[4-(4-Cyanophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]sulfonyl}benzonitrile (C16); 4-[1-(Thiophen-2-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C17); 4-[1-(Naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C18); 4-{1-[(3-methoxyphenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C19); 4-{1-[(3-[Trifluoromethyl]phenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C20); 4-[1-(phenylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C21); 4-[1-(4-(Trifluoromethyl)benzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C22); 4-[1-(3-(Trifluoromethyl)benzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C23); 4-[1-(4-Methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C24); 4-[1-(4-Fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C25); 4-[1-(3-methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C26); 4-[1-(3-Nitrobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C27); 4-[1-(3-Fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C28); 4-(1-nicotinoyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C29); 4-[1-(4-Nitrobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C30); 4-[1-(2-Fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C31); 4-[1-(2-(Trifluoromethyl)benzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C32); 4-[1-(4-Methylbenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C33); 4-[1-(2-Methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C34); 4-[1-(2-Nitrobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C35); 4-[1-(2-Methylbenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C36); 3-[4-(4-Cyanophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carbonyl]benzonitrile (C37); 4-[1-(4-Chlorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C38); 4-[1-(3-Chlorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C39); 4-[1-(3-Methylbenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C40); 4-(1-Benzoyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C41); 4-(1-pivaloyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C42); 4-[1-(2-Chloroacetyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C43); 4-[1-(Furan-2-carbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C44); 4-[1-(3-Methylthiophene-2-carbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C45); 4-[1-(Thiophene-2-carbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C46); Methyl 4-[4-(4-cyanophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carbonyl]benzoate (C47); 4-[1-(4-Cyanobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C48); 4-{1-[4-(Bromomethyl)benzoyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C49); [4-(1H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C50); (2-Fluorophenyl)[4-(1-methyl-1H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (C51); (2-Fluorophenyl)(4-(3-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)methanone (C52); (2-Fluorophenyl)[4-(3-nitrophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (C53); [4-(4-Chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C54); 3-[1-(2-Fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (C55); (2-Fluorophenyl)[4-(furan-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (C56); (2-Fluorophenyl){4-[imidazo[1,2-a]pyridin-6-yl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl}methanone (C57); {4-(Benzo[d]thiazol-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl}(2-fluorophenyl)methanone (C58); [4-(1H-Indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C59); [4-(Benzofuran-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C60); [4-(Benzo[b]thiophen-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C61); [4-(1H-Indol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C62); [4-(Benzofuran-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl](2-fluorophenyl)methanone (C63); 4-{1-(2-[o-Tolyl]acetyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C64); 4-{1-[2-(2-bromophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C65); 4-{1-[2-(m-tolyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C66); 4-{1-[2-(2-Fluorophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C67); 4-{1-[2-(3-methoxyphenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C68); 4-{1-[2-(4-Fluorophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C69); 4-{1-[2-(2-nitrophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C70); 4-{1-[2-(3-chlorophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C71); 4-{1-[2-(p-Tolyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C72); 4-{1-[2-(4-bromophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C73); 4-(1-{2-[3-(Trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C74); 4-(1-{2-[4-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (C75); 4-{1-[2-(4-methoxyphenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C76); 4-{1-[2-(4-chlorophenyl)acetyl]-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (C77); 4-(4-(5-chlorobenzofuran-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)benzonitrile (C78); 2-(1-(4-Methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-cyano-benzofuran (C79); (4-(5-Chloro-1H-indol-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)(1-(3-fluorobenzyl)azetidin-3-yl)methanone (C80); 2-(1-(1-(3-fluorobenzyl)azetidine-3-carbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-cyano-1H-indole (C81); 4-(1-(3-methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1(2H)-cyano-3,6-dihydropyridine (C82); 4-(1-(3-methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-cyanopiperazine (C83); 4-{1-[(4-nitrophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E1); 4-(1-p-Toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (E2); 4-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E3); 4-[1-(m-Toluenesulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E4); 4-{1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E5); 4-{1-[(4-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E6); 4-{1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E7); 4-{1-[(4-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E8); 4-{1-[(4-methoxyphenyl)sulfonyl]1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E9); 3-{[4-(4-Cyanophenyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]sulfonyl}benzonitrile (E10); 4-{1-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E11); 4-{1-[(3-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E12); 4-{1-[(3-nitrophenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E13); 4-{[4-(4-Cyanophenyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]sulfonyl}benzonitrile (E14); 4-[1-(Naphthalen-1-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E15); 4-[1-(naphthalen-2-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E16); 4-[1-(Thiophen-2-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E17); 4-{1-[(6-chloropyridin-3-yl)sulfonyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E18); 4-[1-(Perfluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E19); 4-{1-[4-(Trifluoromethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E20); 4-[1-(2-iodobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E21); 4-[1-(3-Nitrobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E22); 4-{1-[3-(Trifluoromethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E23); 4-[1-(3-Methoxybenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E24); 4-[1-(2-Methoxybenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E25); 4-{1-[2-(Trifluoromethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-4-yl}benzonitrile (E26); 4-[1-(2-Methylbenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E27); 4-[1-(2-Fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E28); 4-[1-(2-Nitrobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E29); 4-[1-(4-Fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]benzonitrile (E30); [4-(Benzo[b]thiophen-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E31); [4-(Benzofuran-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E32); [4-(Benzofuran-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E33); [4-(1H-Indol-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E34); (4-Fluorophenyl)[4-(1-methyl-1H-indazol-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (E35); [4-(Benzo[d]thiazol-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl](4-fluorophenyl)methanone (E36); (4-Fluorophenyl)[4-(imidazo[1,2-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]methanone (E37); (4-(Benzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)(4-fluorophenyl)methanone (E38); (4-Fluorophenyl)(4-(imidazo[1,2-a]pyridin-7-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methanone (E39); 4-(1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-b]piperazin-8-yl)benzonitrile (N1); 8-(4-Fluorophenyl)-1-methyl-1,4-dihydropyrido[3,4-b]piperazine-2,3-dione (N2); 4-(1-methyl-1,2,3,4-tetrahydropyrido[3,4-b]piperazin-8-yl)benzonitrile (N3); 4-((8-(4-cyanophenyl)-1-methyl-2,3-dihydropyrido[3,4-b]piperazin-4(1H)-yl)sulfonyl)benzonitrile (N4); 4-(4-(4-Fluorobenzoyl)-1-methyl-1,2,3,4-tetrahydropyrido[3,4-b]piperazin-8-yl)benzonitrile (N5); 4-(1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)benzonitrile (N6); and 4-(1-Cyclopropyl-1H-imidazo[4,5-c]pyridin-7-yl)benzonitrile (N7). A pharmaceutical composition comprising the compound according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier. Use of the compound according to any one of claims 1 to 25 in the preparation of a medicament for treating diseases related to the synthesis of steroid compounds. A method for treating a disease associated with endogenous steroid compounds in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 25 or the pharmaceutical composition of claim 26. The use according to claim 27 or the method according to claim 28, wherein the steroid compound is selected from aldosterone, cortisol and / or bile acid. The method or use of claim 29, wherein the aldosterone-related disease is selected from primary aldosteronism, secondary aldosteronism, heart failure, renal failure, hypertension, obesity, renal fibrosis, coronary heart disease, cardiac hypertrophy, cardiac fibrosis, arrhythmia, edema, hypokalemia and the resulting muscle weakness, cardiac fibrillation, weak myocardial contraction, congestive heart failure, chronic kidney disease, diabetic nephropathy, cardiorenal syndrome, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, and cirrhosis. The method or use of claim 29, wherein the disease associated with cortisol synthesis is selected from Cushing's syndrome, metabolic syndrome, insulin resistance, obesity and type 2 diabetes, breast cancer, prostate cancer, tumor metastasis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, substance addiction, behavioral addiction, substance use disorder, mood disorder, anxiety disorder, bipolar disorder, sleep disorder, insomnia, post-traumatic stress syndrome, borderline personality disorder, disruptive behavior disorder, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, eating disorders, obesity, depression, premenstrual syndrome (PMS), obsessive-compulsive disorder (OCD), social anxiety disorder, generalized anxiety disorder. The method of claim 29, wherein the disease related to bile acid synthesis is selected from cardiovascular disease, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fatty liver, cirrhosis, liver fibrosis, hepatocellular carcinoma, chronic colitis, and ulcerative colitis. Any of the following compounds: A method for preparing the compound according to any one of claims 1 to 25.