CN105593232B - Benzoxazoles and oxazines ketone compounds as coagulation factor xa inhibitors - Google Patents

Abstract

The present invention relates to new formulas（Ⅰ）Compound or its solvate, hydrate, tautomer or pharmaceutically acceptable salt, wherein R¹Represent substituted or unsubstituted aryl or heteroaryl；R²Represent optionally substituted 39 yuan of carbocyclic rings or heterocycle etc.；R³Represent H etc.；A is selected from O, NH, N CH₃、S、SO、SO₂And CH₂；X, Y and Z is separately selected from CH, C Br, C Cl, C F, C I and N.The compound of the present invention can be directed to the selectivity of blood coagulation Xa and the current demand of potent inhibitor by providing the potent inhibitor of factor Xa as the anti-coagulants for treating and preventing thrombus abnormal diseases, the present invention to meet.

Description

Benzoxazoles and oxazines ketone compounds as coagulation factor xa inhibitors

Technical field

The present invention relates to new benzoxazoles and oxazines ketone compound, compound, preparation side especially shown in formula (I) Method, pharmaceutical composition and its purposes as anti-coagulants in thrombotic disease is treated and prevented.

Background technology

Angiocardiopathy is the main reason for developed country's population causes a disease and is lethal, wherein most of cardiovascular event master It is attributed to thrombosis.Warfarin is the oral anticoagulation object of first granted listing, and application locks into slowly dimension life The interaction between interaction and drug and food between plain K dependent forms antagonism, drug and drug, this causes It needs to continuously monitor to obtain correct dose.Other anti-coagulants such as heparin, fondaparin etc. are suitable only for stomach External administration.The drawbacks described above of existing anti-coagulants has pushed the further investigation of new anticoagulation medicine.

In blood coagulation cascade system, factor Xa is can be by inner track (contact activation) and external path The common intersection that (tissue factor) is activated keeps balance, therefore be a kind of unique serine protease.It is contacted with grade A variety of effects that fibrin ferment is played in system are compared, and conversion of prothrombin is only fibrin ferment by factor Xa, but is not influenced existing Some cycle level of thrombin.In preclinical animal model, relative to thrombin inhibitor, coagulation factor xa inhibitors reduce Bleeding risk simultaneously improves safety/validity.Therefore, in the past ten years, find and develop selectivity and mouth The small molecule coagulation factor xa inhibitors for taking activity have taken as the anticoagulant for the treatment of vein or arterial thromboembolism aspect Huge progress was obtained, for example, prevention of postoperative Deep vain thrombosis (DVT) and pulmonary embolism (PE), prevent in auricular fibrillation Apoplexy, treatment acute coronary syndrome (ACS), razaxaban (US2003/153610) and formula especially shown in formula (II) (III) Eliquis shown in (WO2003/049681) was ratified to list respectively at 2011 and 2013 through FDA.

At present, in order to prevent to experienced select a time replacement of total hip or total knee replacement operation patient venous blood Bolt embolism (VTE), the standard dose of razaxaban is 10 milligrams, once a day.However, the higher curative effect of razaxaban along with Higher hemorrhagic tendency, great or fatal hemorrhage risk also should not be underestimated, especially in the case of patient's Long-term taking medicine. In addition, razaxaban poorly water-soluble, thus be difficult to develop intravenous formulations.Therefore, the extensive of coagulation factor xa inhibitors should With the linguistic term depended on regarding to the issue above.

In this respect, from the viewpoint of clinic, develop has high specific and potent inhibiting effect to factor Xa And with compared with highly-water-soluble, oral medication is more effective, be more suitable for intravenously administrable, the treatment window with bigger and less goes out The drug of blood tendency has caused the very big concern of people.

WO2011/147259 discloses compound shown in formula (IV), for treating infectious disease, especially multiple drug resistant bacteria Caused infectious disease：

Wherein,

U is H or F,

R¹It is acetamide or triazole：

But the compound does not have the inhibiting effect for factor Xa, and WO2011/147259 is also without this The relevant teachings of aspect.

Invention content

The purpose of the present invention is to provide formula (I) compound represented or its pharmaceutically acceptable salt, hydrate or Prodrug：

Wherein,

R¹Represent optionally substituted aryl or heteroaryl, substituent group independently selected from F, Cl, Br, I, cyano, amino, CF₃、C_1-8Alkoxy and C_1-8Alkyl, the number of substituent group are one or more, the C_1-8Alkyl optionally by F, Cl, Br, I, cyano, amino or CF₃Replaced；

R²It represents optionally substituted 3-9 members carbocyclic ring or 3-9 circle heterocyclic rings, substituent group be selected from=O, F, Cl, Br, I, OH, SH, PH₂, cyano, SO₂、COOCH₂CH₂OH、COOCH₂CH₃、CONH₂、COOCH₃、C_1-8Alkyl and amino, the number of the substituent group are One or more, the C_1-8Alkyl is optionally by F, Cl, Br, I, OH, NH₂、SH、PH₂、OCH₃、N(CH₃)₂Or NHCH₃Replaced, The amino is optionally by CH₃Or COCH₃Replaced；

R³Represent H,Or

A is selected from O, NH, N-CH₃、S、SO、SO₂And CH₂；

X, Y and Z is separately selected from CH, C-Br, C-Cl, C-F, C-I and N；With

Optionally the compound is stereoisomer.

In the preferred embodiment of the present invention：

R¹Represent optionally substituted phenyl, thienyl or pyridyl group, substituent group independently selected from F, Cl, Br, I, cyano, Amino, CF₃、C_1-8Alkoxy and C_1-8Alkyl, the number of substituent group are one or more, the C_1-8Alkyl optionally by F, Cl, Br, I, cyano, amino or CF₃Replaced；

R²Optionally substituted phenyl or optionally substituted 3-9 circle heterocyclic rings are represented, the 3-9 circle heterocyclic rings contain at most three Kind hetero atom/atomic group, the hetero atom/atomic group are selected from O, N, S, SO and SO₂, the heterocycle is that saturation or part are unsaturated , the heterocycle be it is monocyclic or bicyclic, the heterocycle be it is optionally benzo-fused, the substituent group separately selected from=O, F、Cl、Br、I、OH、SH、PH₂, cyano, SO₂、COOCH₂CH₂OH, optionally by F, Cl, Br, I, OH, NH₂、SH、PH₂、OCH₃、N (CH₃)₂、NHCH₃The C replaced_1-8Alkyl and optionally by CH₃、COCH₃Substituted amino, the number of the substituent group for 1 or It is multiple；

R³Selected from H,Or

A is selected from O, S, SO, SO₂And CH₂；

X, Y and Z is separately selected from CH, C-Br, C-Cl, C-F, C-I and N；With

Optionally the compound is stereoisomer.

In another preferred embodiment of the present invention：

R¹It is selected from：

R²Optionally substituted phenyl or optionally substituted 3-9 circle heterocyclic rings are represented, the 3-9 circle heterocyclic rings contain at most three Kind hetero atom/atomic group, the hetero atom/atomic group are selected from O, N, S, SO and SO₂, the heterocycle is that saturation or part are unsaturated , the heterocycle be it is monocyclic or bicyclic, the heterocycle be it is optionally benzo-fused, the substituent group separately selected from=O, F、Cl、Br、I、OH、SH、PH₂, cyano, SO₂、COOCH₂CH₂OH, optionally by F, Cl, Br, I, OH, NH₂、SH、PH₂、OCH₃、N (CH₃)₂、NHCH₃The C replaced_1-8Alkyl and optionally by CH₃、COCH₃Substituted amino, the number of the substituent group for 1 or Multiple, the number of the substituent group is one or more；

R³Selected from H,Or

A is selected from O, S, SO, SO₂And CH₂；

X, Y and Z is separately selected from CH, C-Br, C-Cl, C-F, C-I and N；With

Optionally the compound is stereoisomer.

In another preferred embodiment of the present invention：

R¹Represent optionally substituted phenyl, thienyl or pyridyl group, the substituent group separately selected from F, Cl, Br, I, cyano, amino, CF₃Optionally by F, Cl, Br, I, cyano, amino or CF₃Substituted C_1-8Alkyl, of the substituent group Number is one or more；

R²It is selected from：

A is selected from O, S, SO, SO₂And CH₂；

X, Y and Z is separately selected from CH, C-Cl, C-F and N；With

Optionally the compound is stereoisomer.

Further, acceptable salt is selected from Chinese pharmacology of the present invention：

1) base addition salts：Sodium, potassium, calcium, ammonium, organic amino or magnesium salts；Or

2) acid-addition salts：Hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, one hydrogen radical of phosphoric acid, dihydrogen phosphate, The organic acid of sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc. and relative nontoxic such as acetic acid, propionic acid, isobutyric acid, maleic acid, third Diacid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid, to toluene sulphur Acid, citric acid, tartaric acid, methanesulfonic acid, amino acid or glucuronic acid.

Further, the present invention has following preferred embodiment：

1) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

2) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxo-piperidine -1- bases) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

3) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (5- oxo-Isosorbide-5-Nitrae-oxazepine cycloheptane -4- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

4) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxygen piperazine -1- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

5) the chloro- N- of 5- (((3S, 3aS) -7- (4- methyl -2- oxygen piperazine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

6) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo -1,3- oxazepine hexamethylene -3- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

7) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo pyridines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

8) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo pyridines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

9) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- Oxopyrazines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

10) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- ((R) -3- oxos tetrahydro-1 H-pyrrolo [1,2-c] imidazoles -2 (3H)-yl) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

11) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- ((S) -3- oxos tetrahydro-1 H-pyrrolo [1,2-c] imidazoles -2 (3H)-yl) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

12) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo-pyrrolidine -1- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

13) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- hydroxyl -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

14) the chloro- N- of 5- (((3S, 3aS) -7- (2- methoxyl group-N- ethylmethylamidos) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

15) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (5- oxo-Isosorbide-5-Nitrae-oxazepine cycloheptane -4- bases) -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

16) 1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -2- oxo pyridine -3- Ethyl formates；

17) the chloro- N- of 5- (((3S, 3aS) -7- (3- (methylol) -2- oxo-piperidine -1- bases) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

18) the chloro- N- of 5- (((3S, 3aS) -7- (2- (methylol) -5- oxomorpholin generations) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

19) the chloro- N- of 5- (((3S, 3aS) -7- (2- methyl -3- oxomorpholin generations) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

20) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- methyl -5- oxomorpholin generations) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

21) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo -8- oxa- -3- azabicyclo [3.2.1] octyl-s 3- Base) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

22) 4- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxomorpholin -2- carbamoyl ethyls；

23) N- (((3S, 3aS) -7- ((S) -3- amino -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

24) the chloro- N- of 5- (((3S, 3aS) -7- (2- ((methylamino) methyl) -1H- imidazoles -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

25) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- methoxyl group -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

26) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxo -2- azabicyclos [2.2.2] octyl- 2- yls) -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

27) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- azabicyclos [2,2,1] hept- 3- ketone) -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

28) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxo thiomorpholine generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

29) the chloro- N- of 5- (((3S, 3aS) -7- (1,1- titanium dioxide -3- oxo thiomorpholine generations) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

30) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -2- (methoxyl methyl) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

31) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -2- (methoxyl methyl) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

32) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo-pyrrolidine -3- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

33) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- aminosulfonylphenyls) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

34) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (1H-1,2,4- triazol-1-yls) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

35) the chloro- N- of 5- (((3S, 3aS) -7- (2- ((dimethylamino) methyl) -1H- imidazoles -1- bases) -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

36) the chloro- N- of 5- (((3S, 3aS) -7- (2- ethyl -4,5- dihydro -1H- imidazoles -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

37) the chloro- N- of 5- (((3S, 3aS) -7- (2- cyclopropyl -4,5- dihydro -1H- imidazoles -1- bases) -1- oxygen -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

38) the chloro- N- of 5- (((3S, 3aS) -7- (- 1 (4H)-yl of 2- ethyls -5,6- dihydro-pyrimidin) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

39) the chloro- N- of 5- (((3S, 3aS) -7- (4,5- dihydro -1H- imidazoles -2- bases) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

40) the chloro- N- of 5- (((3S, 3aS) -7- (1- methyl -4,5- dihydro -1H- imidazoles -2- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

41) the chloro- N- of 5- (((3S, 3aS) -7- (1- methyl-1s, 4,5,6- tetrahydropyrimidine -2- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

42) N- (((3S, 3aS) -7- ((S) -3- amino-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

43) N- (((3S, 3aS) -7- ((R) -3- amino-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

44) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (methylamino) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

45) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

46) the chloro- N- of 5- (((3S, 3aS) -7- (3- hydroxy piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

47) (((3S, 3aS) -1- oxos -7- (3- oxomorpholins) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

48) N- ((dislike by (3S, 3aS) -7- ((S) -3- amino piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

49) N- ((dislike by (3S, 3aS) -7- ((R) -3- amino piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

50) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- (methylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

51) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (methylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

52) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- (dimethylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

53) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (dimethylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

54) (R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- methyl formates；

55) (S) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- methyl formates；

56) (R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- formamides；

57) (S) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- formamides；

58) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -2- (methylol) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

59) (R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- carboxylic acid -2- hydroxyethyl esters；

60) the chloro- N- of 5- (((3S, 3aS) -7- (Cyclopropylsulfonyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

61) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (pyrrolidin-1-yl) sulfonyl) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

62) the chloro- N- of 5- (((3S, 3aS) -7- ((4- methylpiperazine-1-yls) sulfonyl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

63) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxoimidazolinium -1- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

64) the chloro- N- of 5- (((3S, 3aS) -7- (3- hydroxyl pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

65) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- methoxypyrrolidin -1- bases) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

66) 4- methoxyl groups-N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) benzamide；

67) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) pyridine carboxamide；

68) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -1H- indole 2-carboxamides；

69) 5- methyl-N- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

70) 5- bromos-N- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

71) 5- cyano-N- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

72) the fluoro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

73) 4,5-, bis- fluoro- N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

74) the fluoro- N- of the chloro- 3- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

75) the chloro- N- of 4- amino -5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

76) 3- methoxyl groups-N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) benzamide；

77) 5- methoxyl groups-N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) pyridine carboxamide；

78) the chloro- N- of 5- ((the fluoro- 1- oxos -7- of (3S, 3aS) -9- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

79) the chloro- N- of 5- ((the fluoro- 1- oxos -7- of (3S, 3aS) -8- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

80) the chloro- N- of 5- ((the fluoro- 1- oxos -7- of (3S, 3aS) -6- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

81) the chloro- N- of 5- ((- 6,6a, 7,9- tetrahydrochysene oxazoles of (6aS, 7S) -9- oxos -3- (3- oxomorpholin generations) simultaneously [3,4- D] pyrido [3,2-b] [Isosorbide-5-Nitrae] oxazines -7- bases) methyl) thiophene-2-carboxamide derivatives；

82) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydrochysenes oxazoles simultaneously [3,4- D] pyrido [4,3-b] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

83) 2- (the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formamido groups) -2- oxoethyl 2- amion acetic acid hydrochlorides；

84) (R) -2- (the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formamido groups) -2- oxoethyl 2- amino -3- methyl Butyrate hydrochlorate；

85) ((1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously [3,4-d] by the chloro- N- of 5- [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives；

86) ((5- oxidation -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives；With

87) the chloro- N- of 5- ((dislike by 5,5- titanium dioxide -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives.Wherein, above compound is named as chemical combination respectively Object 1~87, structural formula and preparation method detailed in Example 1~87 successively.

Another object of the present invention is to provide formula (I) preparation method of compound, wherein R¹, X, Y and Z such as claim 1 is defined, A O, R³For H, R²For 3-9 member heterocyclic ring containing nitrogens, include the following steps：

Another object of the present invention is to provide a kind of pharmaceutical composition, formula (I) compound including therapeutically effective amount Or its pharmaceutically acceptable salt, hydrate or prodrug and pharmaceutically acceptable carrier.

Another object of the present invention is to provide above compound in the drug for preparing treatment thrombotic disease Using, wherein, the disease preferably is selected from artery cardiovascular thromboembolic disease, intravenous cardio thrombotic disease, brain Arterial thromboembolism disease, vein cerebral vessels embolism disease, further preferably from unstable angina pectoris, myocardial infarction, Myocardial infarction, ischemic sudden death, transient ischemic attack, apoplexy, atherosclerosis, venous thronbosis, lower limb are sent out again Deep vain thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis formation, cerebral artery thrombosis formation, cerebral embolism, Renal embolism, pulmonary embolism and thrombosis caused by following reasons：(a) heart valve prosthesis or other implantation materials；(b) indwelling is led Pipe；(c) stent；(d) cardiopulmonary bypass；(e) haemodialysis；And blood is exposed to artificial surface so as to promote thrombus by (f) Other programs formed or operation.

The present invention can be realized by not departing from other concrete modes of its invention essence, preferably square including the invention described above All combinations of case.All specific embodiments of the present invention can be combined to form more preferred embodiment party with other modes Formula, specified features therein can be combined to form new embodiment with any relevant other technical characteristics；Certainly, It is also assumed that each preferred embodiment is independent, specified features therein are only limitted to this preferred embodiment sheet Body.

The present invention relates to following definitions：

The compound of the present invention may be with asymmetric center, and the compound containing Asymmetrical substitute atom can in the present invention To be separated into optical activity or racemate form, those skilled in the art know how to prepare optical active forms, such as It is synthesized by mesotomy or by optically active starting material.The alkene of many geometric isomers, C=N double bonds etc. It can also exist in the compound of the present invention, the isomers of all these stabilizations belongs to the part of the present invention.The present invention Cis and trans geometric isomer is also illustrated, the mixture of isomers or individual isomer form can be separated into. Specific spatial chemistry or isomeric forms unless specifically stated otherwise, the present invention include all chiral, diastereoisomers, raceme With all geometric isomer forms.It prepares the method for the compounds of this invention and its intermediate belongs to the part of the present invention.This It is a part of the invention that all tautomers of invention compound, which also belong to,.

In a preferred embodiment, the molecular weight of the compounds of this invention is less than 500~800g/mol；Another preferred embodiment In, the molecular weight is less than 800g/mol；In another preferred embodiment, the molecular weight is less than 650g/mol；Another is preferably In scheme, the molecular weight is less than 550g/mol.

Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, including heavy hydrogen With the variant of hydrogen, as long as the valence state of specific atoms be it is normal and replace after compound be stable.When substituent group is ketone During base (i.e.=O), it is meant that two hydrogen atoms are substituted.Ketone substitution is not occurred on aromatic radical.Ring double bond refers at two The double bond formed on adjacent annular atom, such as C=C, C=N and N=N.It is of the invention general do not include as N- halogens, S (O) H with And SO₂Group as H.

The present invention includes all isotopes of atom in the compound of the present invention.Isotope include atomic number it is identical but The different atom of mass number.Such as, but not limited to, the isotope of hydrogen includes tritium and deuterium, and the isotope of carbon includes C-13 and C-14.

As any variable (such as R⁶) when occurring more than primary in the composition of compound or structure, in each situation Under definition be all independent.If thus, for example, a group is by 0-2 R⁶Replaced, then the group can be optionally At most by two R⁶Replaced, and R in each case⁶There is independent option.In addition, the group of substituent group and/or its variant Conjunction is just allowed in the case of stable compound can be only generated in such combination.

Two atomic time that can be cross connected to when the key of a substituent group on a ring, this substituent group can be with this Arbitrary atom on a ring is mutually bonded.When not indicating it is connected to chemical knot by which atom in cited substituent group During the compound that structure general formula includes but is not specifically mentioned, this substituent group can be mutually bonded by its any atom.Substituent group And/or the combination of its variant stable compound can be only generated in such combination in the case of be just allowed.Unless It states otherwise, term " alkyl " itself or the part as another substituent group represent straight chain, branch or cricoid hydrocarbon Atomic group or combination can be fully saturated, unit or polynary undersaturated, can include divalent or polyad group, Carbon atom (i.e. C with specified quantity₁-C₁₀Represent 1 to 10 carbon).In some embodiments, term " alkyl " represents straight chain Or branch atomic group or combination thereof, can be fully saturated, unit or polynary undersaturated, divalent can be included With polyad group.The example of saturated hydrocarbons atomic group includes but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, uncle Butyl, isobutyl group, sec-butyl, isobutyl group, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl and n-pentyl, n-hexyl, just The homologue or isomers of the atomic groups such as heptyl, n-octyl.Unsaturated alkyl has one or more double or triple bonds, the example Including but not limited to vinyl, 2- acrylic, cyclobutenyl, crotyl, 2- isopentene groups, 2- (butadienyl), 2,4- pentadienes Base, 3- (Isosorbide-5-Nitrae-pentadienyl), acetenyl, 1- and 3- propinyls, 3- butynyls and more advanced homologue and isomers.

Term " alkoxy ", " alkylamino " and " alkylthio group " (or thio alkoxy) belongs to idiomatic expression, refers to lead to respectively Cross those alkyl groups that an oxygen atom, amino or sulphur atom are connected to the rest part of molecule.

Unless otherwise prescribed, term " miscellaneous alkyl " itself or combine straight chain, the branch for representing stable with another term Or cricoid hydrocarbon atomic group or combination, be made of the carbon atom and at least one hetero atom of certain amount.In some implementations In example, term " miscellaneous alkyl " itself or straight chain, branch the hydrocarbon atomic group or its group for combining expression stabilization with another term Object is closed, is made of the carbon atom and at least one hetero atom of certain amount.In an exemplary embodiment, hetero atom be selected from B, O, N and S, wherein nitrogen and sulphur atom are optionally aoxidized, and nitrogen heteroatom is optionally quaternized.Hetero atom B, O, N and S can be located at Any interior location or the alkyl of miscellaneous alkyl are attached to the position of molecule rest part.Example includes but not limited to-CH₂- CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂、-S(O)-CH₃、- CH₂-CH₂-S(O)₂-CH₃,-CH=CH-O-CH₃、-CH₂- CH=N-OCH₃With-CH=CH-N (CH₃)-CH₃.At most two miscellaneous originals Son can be continuous, such as-CH₂-NH-OCH₃。

Unless otherwise prescribed, term " cycloalkyl " and " Heterocyclylalkyl " itself or combine with other terms and represent to be cyclized respectively " alkyl " and " miscellaneous alkyl ".In addition, for Heterocyclylalkyl, hetero atom can take up the heterocycle and be attached to molecule rest part Position.The example of cycloalkyl includes but not limited to cyclopenta, cyclohexyl, 1- cyclohexenyl groups, 3- cyclohexenyl groups, suberyl etc.. The non-limiting examples of heterocycle include 1- (1,2,5,6- tetrahydro pyridyl), 1- piperidyls, 2- piperidyls, 3- piperidyls, 4- Morpholinyl, morpholinyl, tetrahydrofuran -2- bases, tetrahydrofuran indol-3-yl, thiophane -2- bases, thiophane -3- bases, 1- piperazinyls and 2- piperazinyls.

Unless otherwise prescribed, term " halogenated element " or " halogen " itself or as another substituent group part expression fluorine, Chlorine, bromine or iodine atom.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl.For example, term " halogen Generation (C₁-C₄) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyls, 4- chlorobutyls and 3- bromopropyls etc. Deng.

Unless otherwise prescribed, term " aryl " represents the aromatics hydrocarbon substituent of how unsaturated, it can be monocyclic or polycyclic (preferably 1 to 3 ring), they are fused together or are covalently attached.Term " heteroaryl " refers to heteroatomic containing one to four Aryl (or ring).In an exemplary embodiment, hetero atom is selected from B, N, O and S, and wherein nitrogen and sulphur atom is optionally aoxidized, Nitrogen-atoms is optionally quaternized.Heteroaryl can be connected to the rest part of molecule by hetero atom.Aryl or heteroaryl it is non- Restricted embodiment includes phenyl, 1- naphthalenes, 2- naphthalenes, 4- xenyls, 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazoles Base, 2- imidazole radicals, 4- imidazole radicals, pyrazinyl, 2- oxazolyls, 4- oxazolyls, 2- phenyl -4- oxazolyls, 5- oxazolyls, the different evils of 3- Oxazolyl, 4- isoxazolyls, 5- isoxazolyls, 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, 2- furyls, 3- furyls, 2- thiophenes Fen base, 3- thienyls, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- benzothiazolyls, purine Base, 2- benzimidazolyls, 5- indyls, 1- isoquinolyls, 5- isoquinolyls, 2- quinoxalinyls, 5- quinoxalinyls, 3- quinolyls With 6- quinolyls.Any one above-mentioned aryl and the substituent group of heteroaryl ring system are selected from acceptable substituent group described below.

For simplicity, aryl when being used in combination with other terms (such as aryloxy group, arylthio, aralkyl) including such as The aryl and heteroaryl ring of upper definition.Therefore, term " aralkyl " is intended to include those atomic group (examples that aryl is attached to alkyl Such as benzyl, phenethyl, pyridylmethyl), including wherein carbon atom (such as methylene) by such as oxygen atom replace that A little alkyl, such as phenoxymethyl, 2- pyridine oxygen methyls 3- (1- naphthoxys) propyl etc..

Each above-mentioned term (such as " alkyl ", " miscellaneous alkyl ", " aryl " and " heteroaryl ") be intended to it is substituted or not by The atomic group of substitution.It can hereafter provide each atomic group institute preferred substituent group.

Alkyl and miscellaneous alkyl atomic group (including be commonly known as alkylidene, alkenyl, sub- miscellaneous alkyl, miscellaneous thiazolinyl, alkynyl, Cycloalkyl, Heterocyclylalkyl, cycloalkenyl group and heterocycloalkenyl those groups) substituent group be commonly referred to as " alkyl substituent ", it Can be selected from, but not limited to, one or more of following groups：- R ' ,-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R " ,- SR ', halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO₂R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、 NR’C(O)NR”R”’、-NR”C(O)₂R ' ,-NR " "-C (NR ' R " R " ')=NR " " ", NR " " C (NR ' R ")=NR " ' ,-S (O) R’、-S(O)₂R’、-S(O)₂NR’R”、NR”SO₂R’、-CN、-NO₂、-N₃、-CH(Ph)₂With fluoro (C₁-C₄) alkyl, substituent group Number is 0~(2m '+1), and wherein m ' is the sum of carbon atom in this kind of atomic group.R ', R ", R " ', R " " and R " " ' it is respectively independent The preferred hydrogen in ground, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted aryl (such as are replaced by 1~3 halogen Aryl), substituted or unsubstituted alkyl, alkoxy, thio alkoxy group or aralkyl.When the compound of the present invention packet When including more than one R group, for example, each R group is independently to be subject to selection, as when there are more than one R ', R ", R " ', R " " and R " " ' group when these each groups.When R ' and R " is attached to same nitrogen-atoms, they can be with The nitrogen-atoms combines and forms 5-, 6- or 7- round ringss.For example,-NR ' R " are intended to include but are not limited to 1- pyrrolidinyls and 4- morpholines Base.According in the above-mentioned discussion about substituent group, it will be understood by those skilled in the art that term " alkyl " is intended to include carbon atom The group that non-hydrogen group is formed is bonded to, such as halogenated alkyl (such as-CF₃、-CH₂CF₃) and acyl group (such as-C (O) CH₃、-C (O)CF₃、-C(O)CH₂OCH₃Deng).

Similar to substituent group described in alkyl radicals, aryl and heteroaryl substituent are commonly referred to collectively as " aryl substituent ", Selected from such as-R ' ,-OR ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO2R ' ,-CONR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ', NR ' C (O) NR " R " ' ,-NR " C (O) 2R ' ,-NR " " '-C (NR ' R " R " ')=NR " ", NR " " C (NR ' R ")=NR " ' ,-S (O) R ' ,-S (O)₂R’、-S(O)₂NR’R”、NR”SO₂R’、-CN、-NO₂、-N₃、-CH(Ph)₂、 Fluorine (C₁-C₄) alkoxy and fluorine (C₁-C₄) alkyl etc., the quantity of substituent group is the sum of open chemical valence on 0 to aromatic rings Between；Wherein R ', R ", R " ', R " " and R " " ' preferably independently be selected from hydrogen, substituted or unsubstituted alkyl, it is substituted or not by Substituted miscellaneous alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.When the chemical combination of the present invention When object includes more than one R group, for example, each R group is independently to be subject to selection, as when there are more than one R ', R ", R " ', R " " and R " " ' group when these each groups.Two substitutions on the adjacent atom of aryl or heteroaryl ring Base can optionally be replaced by substituent group of the general formula by-T-C (O)-(CRR ') q-U-, wherein T and U independently selected from-NR- ,- O-, CRR '-or singly-bound, q are 0 to 3 integers.

Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally by general formula Replaced by the substituent group of-A (CH2) r B-, wherein A and B independences selected from-CRR '-,-O- ,-NR- ,-S- ,-S (O)-, S (O)₂-、-S(O)₂NR '-or singly-bound, r are 1~4 integers.Optionally, a singly-bound on the new ring being consequently formed can be replaced For double bond.

Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally by general formula Being replaced by the substituent group of-(CRR ') s-X- (CR " R " ') d-, wherein s and d are independently selected from 0~3 integer, and X is- O-、-NR’、-S-、-S(O)-、-S(O)₂Or-S (O)₂NR’-.Substituent R, R ', R " and R " ' preferably separately be selected from hydrogen and Substituted or unsubstituted (C₁-C₆) alkyl.

" ring " used herein represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.So-called ring includes condensed ring.Ring atom Number be generally defined as first number of ring, for example, " 5~7 round rings " refers to surround 5~7 atoms of arrangement.Unless otherwise rule Fixed, which optionally includes 1~3 hetero atom.Therefore, " 5~7 round rings " includes such as phenyl, pyridine and piperidyl；The opposing party Face, term " 5~7 membered heterocycloalkyl ring " do not include phenyl including pyridyl group and piperidyl.Term " ring " is further included containing extremely The ring system of a few ring, each " ring " independently conform to above-mentioned definition.

Terms used herein " hetero atom " includes the atom other than carbon (C) and hydrogen (H), such as including oxygen (O), nitrogen (N), sulphur (S), silicon (Si), germanium (Ge), aluminium (Al) and boron (B) etc..

Term " leaving group " refers to can by substitution reaction, (such as affine substitution be anti-by another functional group or atom Should) functional group that is replaced or atom.For example, representative leaving group includes triflate；Chlorine, bromine, iodine；Sulphonic acid ester Base, such as methanesulfonates, tosylate, brosylate, p-methyl benzenesulfonic acid ester；Acyloxy, such as acetoxyl group, trifluoro second Acyloxy etc..

" R " is a general abbreviation, is represented selected from substituted or unsubstituted alkyl, substituted or unsubstituted Miscellaneous alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkanes The substituent groups such as base, substituted or unsubstituted Heterocyclylalkyl.

Drug, preparation or the penetrant of so-called " effective " amount are to refer to obtain required effect topically or systemically The activating agent of sufficient amount." topically effective ", " cosmetically effective ", " pharmaceutically effective " or " clinically effective " measures Refer to realize the drug dose of desired treatment results.

Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when containing relatively acid functional group in the compound of the present invention To pass through the side that the alkali of sufficient amount is used to be contacted with the neutral form of this kind of compound in pure solution or suitable atent solvent Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt. It, can be by pure solution or suitable atent solvent when containing relatively alkaline functional group in the compound of the present invention Acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.Pharmaceutically acceptable acid addition The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And the acylate of relative nontoxic, it is described Organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, breast Acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；It further includes The salt (referring to Berge et al., " of the salt of amino acid (such as arginine) and such as glucuronic acid organic acid Pharmaceutical Salts ", Journal of Pharmaceutical Science 66：1-19(1977)).The present invention Certain specific compounds contain alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.

Preferably, salt is made to be contacted with alkali or acid in a usual manner, then detaches parent compound, thus again in raw compounds Property form.The form of the parent fo of compound and its various salt is the difference lies in certain physical properties, such as in polarity Different solubility in solvent.

In addition to the form of salt, also there are prodrug forms for compound provided by the present invention.Compounds described herein Chemical change easily occurs in physiological conditions for prodrug so as to be converted to the compound of the present invention.In addition, pro-drug can be with The compound of the present invention is switched to by chemistry or biochemical method in environment in vivo.

Certain compounds of the present invention can exist with nonsolvated forms or solvation form, including hydrate shape Formula.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.The present invention's Certain compounds can exist with polycrystalline or amorphous form.

Certain compounds of the present invention have asymmetric carbon atom (optical centre) or double bond.Racemic modification, diastereomeric are different Structure body, geometric isomer and single isomers are included within the scope of the present invention.Herein raceme, The diagrammatic representation of the compound of ambiscalemic and scalemic or enantiomer-pure comes from Maehr, J.Chem.Ed.1985, 62：114-120.Unless otherwise indicated, the absolute configuration of a Stereocenter is represented with wedge key and dotted line key.When described herein Compound contains olefinic double bond or other geometry asymmetric centers, and unless otherwise prescribed, they include E, Z geometric isomer.Together Sample, all tautomeric forms are included within the scope of the present invention.

The compound of the present invention may have specific geometry or stereoisomer form.It is contemplated by the invention that all is this kind of Compound, including cis and trans isomer, (-)-and (+)-enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers and its racemic mixture and other mixtures, such as enantiomter or diastereomer richness The mixture of collection, all these mixtures are within the scope of the present invention.May be present in the substituent groups such as alkyl it is other not Symmetric carbon atom.All these isomers and their mixture, are included within the scope of the present invention.

Can by chiral synthesis or chiral reagent or other routine techniques prepare it is optically active（R)-and (S)- Isomers and D and L isomers.If expecting a kind of enantiomer of certain compound of the invention, asymmetric syntheses can be passed through Or it is prepared by the derivatization with chiral auxiliary, wherein gained non-enantiomer mixture is detached, and auxiliary group is split It opens to provide pure required enantiomter.Alternatively, when containing basic functionality (such as amino) or acidic functionality (such as in molecule Carboxyl) when, the salt of diastereoisomer is formed with appropriate optically active acid or alkali, then passes through known in the field point One step crystallizing or chromatography carry out diastereoisomer fractionation, and then recycling obtains pure enantiomer.In addition, enantiomter and The separation of diastereoisomer is typically what is completed by using chromatography, and the chromatography uses chiral stationary phase, and optionally Ground is combined (such as generating carbaminate by amine) with chemical derivatization.

The compound of the present invention can include the original of unnatural proportions on one or more atoms for forming the compound Daughter isotope.For example, radioisotope labeled compound can be used, such as tritium (³H), iodine-125 (¹²⁵I) or C-14 (¹⁴C).This The transformation of all isotopics of the compound of invention, no matter radioactivity whether, be included within the scope of the present invention.

Term " pharmaceutically acceptable carrier " is to refer to deliver effective quantity active material of the present invention, do not interfere active matter The bioactivity of the matter and any preparation or mounting medium having no toxic side effect to host or patient, representative carrier include Water, oil, vegetables and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal rush Into agent etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other letters about carrier Breath, can refer to Remington：The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams＆Wilkins (2005), the content of the document are incorporated herein by reference.

Term " excipient " typically refers to carrier, diluent and/or medium required for preparing drug composition effective.

For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to nontoxic but can reach To the drug of desired effect or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition " effective quantity " when referring to be combined with active material another in the composition for the required dosage that achieves the desired results.Have The determining of effect amount varies with each individual, and age and ordinary circumstance depending on receptor also depend on specific active material, closed in case Suitable effective quantity can be determined by those skilled in the art according to routine test.

Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refer to a kind of chemical entities, it can have The therapeutic purpose disorder of effect ground, disease or illness.

Term " pharmaceutically acceptable " adopted here is for those compounds, material, composition and/or agent For type, they contact use within the scope of reliable medical judgment, suitable for the tissue with human and animal, without Excessive toxicity, irritation, allergic reaction or other problems or complication match with rational interests/Hazard ratio.

" pharmaceutically acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein, by with acid into Salt modifies the parent compound with the mode of alkali into salt.The example of pharmaceutically acceptable salt includes but not limited to：Base Such as the inorganic acid or acylate of amine, the alkali metal of acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt packet Include the quaternary ammonium salt of conventional avirulent salt or parent compound, such as the salt that nontoxic inorganic acid or organic acid are formed.Often The avirulent salt of rule includes but not limited to those salt derived from inorganic acid and organic acid, the inorganic acid or organic acid choosing From Aspirin, 2- ethylenehydrinsulfonic acids, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, lemon Lemon acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, Glycollyarsanilic, hexylresorcinic hydrabamic, hydrobromic acid, hydrochloric acid, hydriodate, hydroxyl, hydroxyl naphthalene, Isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, Loprazolam, nitric acid, oxalic acid, double hydroxyls Naphthoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly galacturonic, propionic acid, salicylic acid, stearic acid, sub- acetic acid, succinic acid, sulfamic acid, P-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.

The pharmaceutically acceptable salt of the present invention can pass through conventional chemical side by the parent compound containing acid group or base Method synthesizes.Under normal circumstances, the preparation method of such salt is：In the mixture of water or organic solvent or both, via trip Appropriate alkali or acid from these compounds and the stoichiometry of acid or alkali form react to prepare.It is generally preferable that ether, acetic acid The non-aqueous medias such as ethyl ester, ethyl alcohol, isopropanol or acetonitrile.Remington ' s Pharmaceutical Sciences, 18th Ed., p.1445 Mack Publishing Company, Easton, PA, 1990 disclose the list of suitable salt, disclosure Content be incorporated by reference herein in their entirety.

Since prodrug can improve many qualities (such as solubility, bioavilability, industrialization) of drug, this hair Bright compound can be administered with prodrug forms.Therefore, the invention is intended to cover the prodrug of claimed compound Form, its administering mode and its pharmaceutical composition." prodrug " is intended to the carrier for including any covalent bonding, is fed when prodrug is given During newborn receptoroid, it will discharge active parent drug of the invention in vivo.The preparation method of prodrug of the present invention is to pass through modification What the functional group of parent compound of the present invention realized, parent compound after modification can be by way of routine operation or body Interior mode is cracked into parent compound.Prodrug includes the compound of the present invention, wherein, the group bonding of hydroxyl, amino or sulfydryl To any functional group, when the pro-drug of the present invention is given lactation receptoroid, it will respectively cracking formed free hydroxyl, Free amino acid or free sulfydryl.The example of pro-drug includes but not limited to the second of the compounds of this invention alcohol or amine functional group Acid, formic acid and benzoic acid derivative.

Term " peroral dosage form " refers to give arbitrary pharmaceutical composition by oral cavity.The example of peroral dosage form include tablet, Capsule, film, powder, sachet, granule, solution, solid, suspension or by multiple and different medicine unit (such as Granule, tablet and/or capsule containing different active constituents) it is packaged together drug combination and as is generally known in the art Other modes.Peroral dosage form can be one, two, three, four, five or six unit, when peroral dosage form has multiple units, own Unit be all packed in one packaging in (packaging of such as bottle or other forms, such as blister package)；When peroral dosage form is During one independent unit, it may may also be not present in unitary package.In a preferred embodiment, mouth Oral dosage form is one, two or three unit.In an especially preferred embodiment, peroral dosage form is a unit.

" inhibition " and " blocking ", is used interchangeably herein, refer to the part of enzyme such as serine protease a kind of or Whole blockings.

Term " leaving group " refers to that a functional group or atom can be by another functional group or originals in substitution reaction Son substitution, such as nucleophilic substitution reaction.For example, representative leaving group includes trifluoromethayl sulfonic acid, chlorine, bromine and iodo；Sulphur Perester radical is such as mesylate, toluene fulfonate, brosylate, dimethylformamide salt；And acyloxy, such as acetyl oxygen Base, trifluoroacetyl oxygroup etc..

Term " amino protecting group " refers to the blocking group for being suitable for preventing side reaction on ammonia nitrogen position.Representative ammonia Base protecting group includes but not limited to：Formoxyl；Acyl group, such as alkanoyl (such as acetyl group, tribromo-acetyl base or trifluoroacetyl Base)；Alkoxy carbonyl, such as tert-butoxycarbonyl (Boc)；Arylmethoxycarbonyl groups, such as benzyloxycarbonyl group (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc)；Aryl methyl, such as benzyl (Bn), trityl (Tr), 1,1- bis--(4 '-methoxyphenyl) methyl；Silicyl, Such as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS).

Term " hydroxyl protection base " refers to the protecting group for being suitable for preventing hydroxyl side reaction.Representative hydroxyl protection base packet It includes but is not limited to：Alkyl, such as methyl, ethyl and tertiary butyl；Acyl group, such as alkanoyl (such as acetyl group)；Aryl methyl, such as benzyl Base (Bn), to methoxy-benzyl (PMB), 9- fluorenyl methyls (Fm) and diphenyl methyl (benzhydryl, DPM)；Silicyl, such as Trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc..

The example of halogenated alkyl includes but are not limited to：Trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls. The abovementioned alkyl with given number carbon atom that " alkoxy " representative is connected by oxygen bridge.C_1-6Alkoxy includes C₁、C₂、C₃、 C₄、C₅And C₆Alkoxy.The example of alkoxy includes but not limited to：Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just Butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- amoxys." cycloalkyl " includes saturation ring group, such as cyclopropyl, ring Butyl or cyclopenta.3-7 cycloalkyl includes C₃、C₄、C₅、C₆And C₇Cycloalkyl.The hydrocarbon of " alkenyl " including straight chain or branched chain There is one or more carbon-to-carbon double bonds, such as vinyl and acrylic on chain, the wherein chain on any stabilization site.

C_2-6Alkenyl refers to include C₂、C₃、C₄、C₅And C₆Alkenyl." alkynyl " refers to include straight chain or branched chain hydrocarbon There are one or more carbon-carbon triple bonds on chain, the wherein chain on any stabilization site, such as acetenyl and propinyl.C_2~6Alkynyl Refer to include C₂、C₃、C₄、C₅And C₆Alkynyl.

" halogen " or " halogen " used herein refer to fluorine, chlorine, bromine and iodine；" counter ion counterionsl gegenions " be used to indicate that it is one small, Negatively charged substance, such as chloride, bromide, hydroxide, acetate and sulfate.

Specifically, C_1-8Can be C₁、C₂、C₃、C₄、C₅、C₆、C₇Or C₈, 3-9 members carbocyclic ring or heterocycle can be 3,4,5,6,7, 8th, 9 yuan of carbocyclic rings or heterocycle.

As used herein, " carbocyclic ring " or " carbocylic radical " refer to any stabilization 3,4,5,6 or 7 unit monocycles it is bicyclic or 7,8, 9th, 10,11,12 or 13 yuan of two rings or tricyclics, they can be that saturation, part are undersaturated or undersaturated (aromatics).This The example of the carbocyclic ring of sample includes but not limited to：Cyclopropyl, cyclobutyl, cyclobutane base, cyclopenta, cyclopentenyl, cyclohexyl, cycloheptyl Alkenyl, suberyl, cycloheptenyl, adamantyl, cyclooctyl, cyclo-octene, cyclo-octadiene base, [3,3,0] double-octane, [4,3, 0] bicyclic nonane, [4,4,0] bicyclic decane, [2,2,2] double-octane, fluorenyl, phenyl, naphthalene, 2,3- indanyls, Buddha's warrior attendant Alkyl and tetralyl.As it appears from the above, bridged ring is also contained in the definition of carbocyclic ring (such as [2,2,2] double-octane).When one Or multiple carbon atoms form bridged ring when connecting two non-conterminous carbon atoms.It is preferred that the bridge of one or two carbon atom.It is worth note Meaning, a bridge are always converted into tricyclic by monocyclic.In bridged ring, the substituent group on ring can also be appeared on bridge.

As used herein, term " heterocycle " or " heterocycle " mean 5,6 or 7 stable unit monocycles it is bicyclic or 7,8,9 or 10 membered bicyclic heterocycles, they can be that saturation, part are undersaturated or undersaturated (aromatics), they include carbon atom and 1st, 2,3 or 4 ring hetero atoms independently selected from N, O and S are formed wherein above-mentioned arbitrary heterocycle can be fused on a phenyl ring It is bicyclic.Nitrogen and sulfur heteroatom can be aoxidized optionally (i.e. NO and S (O) p).Nitrogen-atoms can be substituted or unsubstituted (i.e. N Or NR, wherein R are H or other substituent groups of defined mistake herein).The heterocycle can be attached to any hetero atom or carbon atom Side group on so as to form stable structure.If the compound generated is stable, carbon can occur for heterocycle as described herein Substitution on position or nitrogen position.Miscellaneous ring nitrogen is optionally quaternized.One preferred embodiment is, when S in heterocycle and O atom Sum be more than 1 when, these hetero atoms are not adjacent to each other.Another preferred embodiment is that the sum of S and O atom does not surpass in heterocycle Cross 1.As used herein, term " aromatic heterocyclic group " or " heteroaryl " mean 5,6,7 stable unit monocycles or bicyclic or 7,8,9 Or 10 membered bicyclic heterocycle aromatic rings, it include carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S. Nitrogen-atoms can be substituted or unsubstituted (i.e. N or NR, wherein R are H or other substituent groups of defined mistake herein). Nitrogen and sulfur heteroatom can be aoxidized optionally (i.e. NO and S (O) p).It is worth noting that, the sum of S and O atom is not on aromatic heterocycle More than 1.

Bridged ring is also contained in the definition of heterocycle.When one or more atoms (i.e. C, O, N or S) connection two is non-conterminous Bridged ring is formed when carbon atom or nitrogen-atoms.Preferred bridged ring includes but not limited to：One carbon atom, two carbon atoms, a nitrogen Atom, two nitrogen-atoms and a carbon-to-nitrogen base.It is worth noting that, a bridge is always converted into tricyclic by monocyclic.In bridged ring, Substituent group on ring can also be appeared on bridge.

The example of heterocyclic compound includes but not limited to：Acridinyl, azocine base, benzimidazolyl, benzofuranyl, benzene And sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo Tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzimidazoline base, carbazyl, 4aH- carbazyls, carboline base, benzo two Hydrogen pyranose, chromene, cinnoline base decahydroquinolyl, 2H, 6H-1,5,2- dithiazine base, dihydrofuran simultaneously [2,3-b] tetrahydrofuran Base, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazole radicals, 1H- indazolyls, indoles alkenyl, indolinyl, middle nitrogen Indenyl, indyl, 3H- indyls, isatinoyl, isobenzofuran-base, pyrans, isoindolyl, iso-dihydro-indole-group, different Yin Diindyl base, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridines base, octahydro isoquinoline Quinoline base, 1,2,3-oxadiazoles base, 1,2,4- oxadiazoles bases, 1,2,5- oxadiazoles bases, 1,3,4- oxadiazoles bases, is disliked at oxadiazoles base Oxazolidinyl, oxazolyl, isoxazolyl, hydroxyindole base, pyrimidine radicals, phenanthridinyl, phenanthroline, azophenlyene, phenthazine, benzo xanthine Base, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4- piperidone bases, piperonyl, pteridyl, purine radicals, pyrrole Mutter base, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole, Pyridyl group, pyrimidine radicals, pyrrolidinyl, pyrrolinyl, 2H- pyrrole radicals, pyrrole radicals, pyrazolyl, quinazolyl, quinolyl, 4H- quinolines Piperazine base, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, 6H-1,2,5- thiophenes Diazine, 1,2,3- thiadiazolyl groups, 1,2,4- thiadiazolyl groups, 1,2,5- thiadiazolyl groups, 1,3,4- thiadiazolyl groups, thianthrene group, thiophene Oxazolyl, isothiazolyl thienyl, thienyl, thieno oxazolyl, thiophene benzothiazolyl, Thienoimidazole base, thienyl, triazine Base, 1,2,3-triazoles base, 1,2,4- triazolyls, 1,2,5- triazolyls, 1,3,4- triazolyls and xanthyl.Further include condensed ring and spiral shell Cycle compound, such as above-mentioned heterocycle.

" stable compound " and " rock-steady structure " refer to such a compound, it can be detached from reaction mixture simultaneously Independently, steadily exist, and be formulated into effective medicine with certain effective purity.

It is (right herein that one or more hydrogen atoms that " substituted " refers to identify on " substituted " atom are substituted base These substituent groups did restriction) substitution, as long as the valence state of specific atoms be it is normal and replace after compound be stable. When substituent group is ketone group (i.e.=O), it is meant that two hydrogen atoms are substituted.

" treatment " used herein is the treatment to the morbid state of mammal, particularly people, including：(a) prevention hair The raw morbid state in mammal, especially when the mammal is susceptible to suffer from this disease but not yet make a definite diagnosis its suffered from it is this Disease；(b) inhibit the state of disease, that is, prevent its development；And/or (c) alleviates morbid state, that is, morbid state is caused to disappear It moves back.

" therapeutically effective amount " refers to that the compounds of this invention is administered alone or when drug combination can effectively inhibit coagulation factor The required dosages of Xa." therapeutically effective amount ", which also refers to, can effectively inhibit factor Xa institute when the compounds of this invention is applied in combination The dosage needed.The preferred synergistic combination that is applied in combination of the compounds of this invention uses.As Chou and Talalay, Adv.Enzyme Regul.1984,22：The text of 27-55 mono- is instructed, when the effect acquired by drug is applied in combination (i.e. to coagulating The inhibiting effect of blood factor Xa) better than be used alone when drug between synergistic effect occurs.Under normal circumstances, sub-optimal concentration Compound most can clearly show synergistic effect.Compared with independent medication, the synergistic effect of drug combination can show reduction Cytotoxicity improves anti-thrombogenic capacity or other advantageous effect aspects.

The preparation method of part of compounds of the present invention：

The compound of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including under The embodiment and art technology that the combination of specific embodiment that face is enumerated, itself and other chemical synthesis process is formed Equivalent replacement mode known to personnel, preferred embodiment include but not limited to the embodiment of the present invention.

The chemical reaction of the specific embodiment of the invention is completed in a suitable solvent, and the solvent must be suitable for The chemical change and its required reagent and material of the present invention.In order to obtain the compound of the present invention, it is sometimes desirable to this field skill Art personnel modify or select to synthesis step or reaction process on the basis of having embodiment.

An important consideration factor in any synthetic route planning in this field is to be reactive functional groups (in the present invention Amino) the suitable protecting group of selection.For trained practitioner, (the Protective of Greene and Wuts Groups In Organic Synthesis, Wiley and Sons, 1991) be this respect authority.The institute that the present invention quotes There is the bibliography incorporated herein on the whole.

Formula (I) compound (as A=O) provided by the present invention, can pass through reaction process 1 and people in the art Prepared by standard method known to member.By taking bromo-fluoro- nitrobenzene (1-1, X=Y=Z=CH) as an example, in the organic of sodium hydride It is reacted in the presence of solvent (such as THF) with cis--butyl -2- alkene-Isosorbide-5-Nitrae-glycol to replace fluorine, the substituted nitrobenzene of gained passes through Zinc and ammonium chloride reduction, obtain the i.e. substituted aniline of intermediate product, amino is protected by benzyl chloroformate, Ran Houjing Sharpless asymmetric epoxidation reactions obtain epoxide compound (1-2) (arbitrary spatial chemistry).Hydroxyl is protected, warp Cyclisation, LDA processing obtain benzoxazoles and oxazinone ring system, and centre is obtained with heterocyclic substituted bromide in the presence of cuprous iodide Product, that is, substituted benzoxazoles and oxazines ketone compound (1-3).By four-step reaction, silicyl (TBS) is by protection hydroxyl Base becomes protecting amino.Silyl-protecting groups are sloughed with the hydroxyl of tetrabutyl ammonium fluoride (TBAF) exposure, are become from methylsulfonyl Methanesulfonates is replaced to obtain azide with sodium azide, is restored to obtain intermediate product amine (1- with reducing agent such as triphenylphosphine 4).Through generating substituted benzoxazoles and oxazines ketone compound (1-5), i.e. blood coagulation of the invention with the acylation reaction of ring acyl chlorides Factor Xa inhibitor.

Reaction process 1

Specifically, formula (I) compound (as A=O) provided by the present invention, can pass through reaction process 1 and sheet Prepared by standard method known to field technology personnel.Since fluoro- 1- nitrobenzenes (1-1) derivatives of commercially available 4- bromos -2-, It can also be since other be with the close derivatives of different functional groups modification, for example, F- and Br- could alternatively be other halogen Element ,-OH ,-NH₂Or protected-NH₂, the NO on compound (1-1) ring₂It could alternatively be-NH2 or protected-NH₂ (such as CBzHN) etc., X, Y, Z are selected from CH, CF, CCl or N.All these variations are replaced and will be given in specific embodiment part It is described in detail.It will be recognized by those skilled in the art that in order to prepare the compounds of this invention, the sequence of reaction step can in reaction process 1 To be different, this also belongs to the scope of the present invention.

The present invention can be specifically described by embodiment below, these embodiments are not meant to any limit to the present invention System.

All solvents used in the present invention are commercially available, and can be used without being further purified.Reaction is usually lazy Under property nitrogen, carried out in anhydrous solvent.Hydrogen nuclear magnetic resonance modal data is by Bruker Avance III 400 (400MHz) nuclear-magnetism The instrument that resonates acquires, and chemical shift is represented with δ (ppm), is calibrated using tetramethylsilane.Liquid chromatograph-mass spectrometer device includes Have：1200 series HPLC of Agilent is equipped with 6110 or 1956A mass detectors；And Shimadzu LC20 liquid chromatograies are equipped with 2020 matter Compose detector.Mass spectrograph is equipped with the electric spray ion source (ESI) detected under positive or negative pattern.

The present invention uses following initialisms：Aq represents water；HATU represents O-7- azepine benzos triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphate；EDC represents N- (3- dimethylaminopropyls)-N '-ethyl-carbodiimide hydrochloride；m- CPBA represents 3- chloroperoxybenzoic acids；Eq represents equivalent, equivalent；CDI represents carbonyl dimidazoles；DCM represents dichloromethane；PE generations Table petroleum ether；DIAD represents diisopropyl azo-2-carboxylic acid；DMF represents n,N-Dimethylformamide；DMSO represents dimethyl sulfoxide； EtOAc represents ethyl acetate；EtOH represents ethyl alcohol；MeOH represents methanol；CBz represents benzyloxycarbonyl group, is a kind of amine protecting group group； It is a kind of amine protecting group group that BOC, which represents tert-butyl carbonyl,；HOAc represents acetic acid；NaCNBH₃Represent sodium cyanoborohydride；R.t. generation Table room temperature；O/N is represented overnight；THF represents tetrahydrofuran；Boc₂O represents two carbonic ester of di-t-butyl；TFA represents trifluoro second Acid；DIPEA represents diisopropyl ethyl amine；SOCl₂Represent thionyl chloride；CS₂Represent carbon disulfide；TsOH is represented to toluene sulphur Acid；NFSI represents N- fluoro- N- (benzenesulfonyl) benzsulfamide；NCS represents 1- chlorine pyrrolidines -2,5- diketone；n-Bu₄NF represents fluorine Change tetrabutylammonium；IPrOH represents 2- propyl alcohol；Mp represents fusing point.

Compound manually orSoftware is named, and commercial compound uses supplier's directory name.

With equipped with Shimadzu SIL-20A autosamplers and Japanese Shimadzu DAD：The Shimadzu of SPD-M20A detectors LC20AB systems carry out efficient liquid phase chromatographic analysis, using Xtimate C18 (3 μm of fillers, specification are 2.1x 300mm) chromatography Column.The method of 0-60AB_6 minutes：Using linear gradient, start to elute using 100%A (A is the aqueous solution of 0.0675%TFA), And terminate to elute using 60%B (B is MeCN solution of 0.0625%TFA), whole process is 4.2 minutes, is then eluted with 60%B 1 minute.Chromatographic column rebalancing is reached 100: 0 for 0.8 minute, total run time is 6 minutes.The method of 10-80AB_6 minutes：It should With linear gradient, start to elute, and (B is 0.0625%TFA's using 80%B using 90%A (A is the aqueous solution of 0.0675%TFA) Acetonitrile solution) terminate elution, whole process is 4.2 minutes, is then eluted 1 minute with 80%B.Chromatographic column rebalancing 0.8 is divided Clock reaches 90: 10, and total run time is 6 minutes.Column temperature is 50 DEG C, flow velocity 0.8mL/min.Diode array detector scans Wavelength is 200-400nm.

Thin-layer chromatographic analysis (TLC) is carried out on the silica GF254 of Sanpont-group, commonly uses ultraviolet lamp irradiation inspection Depending on spot, spot also is inspected using other methods in some cases, in these cases, (about 1g is added in 10g silica gel with iodine Iodine is simultaneously thoroughly mixed), vanillic aldehyde (dissolving about 1g vanillic aldehydes in 100mL 10%H₂SO₄In be made), ninhydrin (from Aldrich is bought) or special color developing agent (be thoroughly mixed 25g (NH₄)₆Mo₇O₂₄·4H₂O、5g(NH₄)₂Ce(IV)(NO₃)₆、 450mL H₂The dense H2SO of O and 50mL₄And be made) expansion lamellae, inspect compound.Using Still, W.C.；Kahn, M.；and Mitra, M.Journal of Organic Chemistry, the similar side of technology disclosed in 1978,43,2923-2925. Method carries out flash column chromatography on 40-63 μm of (230-400 mesh) silica gel of Silicycle.Flash column chromatography or thin-layer chromatography Common solvent is the mixture of methylene chloride/methanol, ethyl acetate/methanol and hexane/ethyl acetate.

Preparation chromatography is carried out using the gloomy UV/VIS-156 detectors of gill in 322 systems of Gilson-281 Prep LC Analysis, used chromatographic column is Agella Venusil ASB Prep C18,5 μm, 150x 21.2mm；Phenomenex Gemini C18、5μm、150x 30mm；Boston Symmetrix C18,5 μm, 150x30mm；Or Phenomenex Synergi C18、4μm、150x 30mm.When flow velocity is about 25mL/min, with the acetonitrile/water eluting compounds of low gradient, Contain 0.05%HCl, 0.25%HCOOH or 0.5%NH in middle water₃·H₂O, total run time are 8-15 minutes.

With with Agilent1260 autosamplers and Agilent DAD：The Agilent of 1260 detectors 1260Infinity SFC systems carry out SFC analyses.Chromatographic column is using Chiralcel OD-H 250x 4.6mm I.D., 5 μm Either 5 μm of Chiralpak AS-H 250x 4.6mm I.D. or Chiralpak AD-H 250x 4.6mm I.D., 5 μm. The chromatographic condition of OD-H_5_40_2.35ML：(specification is 250x 4.6mm I.D. to Chiralcel OD-H chromatographic columns, and 5 μm are filled out Material), mobile phase is 40% ethyl alcohol (0.05%DEA)-CO₂；Flow velocity is 2.35mL/min；Detection wavelength is 220nm.AS-H_3_ 40_2.35ML chromatographic conditions：Chiralpak AS-H chromatographic columns (specification be 250x 4.6mm I.D., 5 μm of fillers)；Mobile phase For 40% methanol (0.05%DEA)-CO₂；Flow velocity is 2.35mL/min, Detection wavelength 220nm.OD-H_3_40_2.35M colors Spectral condition：Chiralcel OD-H chromatographic columns (specification be 250x 4.6mm I.D, 5 μm of fillers), mobile phase are 40% methanol (0.05%DEA)-CO₂, flow velocity 2.35mL/min, Detection wavelength 220nm.AD-H_2_50_2.35ML chromatographic conditions： Chiralpak AD-H chromatographic columns (specification is 250x 4.6mm I.D, 5mm filler), mobile phase is 50% methanol (0.1% MEA)-CO₂, flow velocity 2.35mL/min, Detection wavelength 220nm.

Preparative SFC analyses are carried out in the Waters Thar 80Pre-SFC systems for use Gilson UV detectors, Used chromatographic column is Chiralcel OD-H (specification be 250x 4.6mm I.D, 5 μm of fillers) or Chiralpak AD- H (specification be 250x 4.6mm I.D, 5 μm of fillers).When flow velocity is about 40-80mL/min, with ethyl alcohol-titanium dioxide of low gradient Carbon or methanol-carbon dioxide eluting compounds, wherein methanol or ethyl alcohol contain 0.05%NH₃·H₂O, 0.05%DEA or 0.1%MEA, total run time are 20-30 minutes.

The compound of the present invention can be used as treating or preventing the coagulant of mammal thrombotic disease.Ordinary circumstance Under, thrombotic disease is that (i.e. platelet activation and/or platelet aggregation has for the disease of the circulatory system caused by blood clotting The disease of pass).The term as used herein " thrombotic disease " includes arterial cardiovascular thrombotic disease, vein painstaking effort Pipe thrombotic disease, artery cerebrovascular thrombotic disease and vein cerebrovascular thrombotic disease.It is used herein Term " thrombotic disease " include specific disease, be selected from, but not limited to,：Unstable angina pectoris, for the first time cardiac muscle stalk Extremely, Relapse myocardial infarction, ischemic sudden death, transient ischemic attack, apoplexy, atherosclerosis, venous thronbosis, Deep vain thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis formation, cerebral artery thrombosis formation, cerebral embolism, Renal embolism, pulmonary embolism and the thrombosis as caused by following reason：(a) heart valve prosthesis or other implantation materials；(b) indwelling is led Pipe；(c) stent；(d) cardiopulmonary bypass；(e) haemodialysis；And blood is exposed to artificial surface so as to promote thrombus by (f) Other programs formed or operation.It is worth noting that, thrombosis is including obstruction (such as obstruction after by-pass operation) and again Block (such as during percutaneous transluminal coronary angioplasty or later).The anticoagulant effect of the compound of the present invention is come Derived from its inhibiting effect to Xa factor or fibrin ferment.

A series of new benzoxazoles and oxazines ketone compound shown in the formula (I) of the present invention are the selections of factor Xa Property and potent inhibitor, therefore can be used as anticoagulant use.Compared with prior art, the compounds of this invention, which has, improves Water solubility, enhancing the effect of and lower hemorrhagic tendency.Therefore, the compound of formula (I) can become thromboembolia type disease The treatment or prevention drug of disease.

Formula (I) compound of the present invention is also different from the compound in WO2011/147259, not only exists in structure notable Difference, from effect, the compound in WO2011/147259 does not have the inhibiting effect to factor Xa, WO2011/ 147259 do not provide any introduction of this respect yet.

Specific embodiment

Below by embodiment, the present invention will be described in detail, but is not meant to any unfavorable limitation of the present invention. The present invention is described in detail herein, wherein its specific embodiment mode is also disclosed that, to those skilled in the art Speech, carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention will It is obvious.

Embodiment 1

(((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Reaction process：

Step A：Dry THF (300mL) solution of (Z)-but-2-ene-Isosorbide-5-Nitrae-glycol (39.7g, 450mmol) is cooled to 0 DEG C, sodium hydride (60% is dissolved in mineral oil, 9.0g, 225mmol) is added portionwise, it is fluoro- that the bromo- 2- of 4- are then added dropwise at 0 DEG C The dry THF solution (450mL) of 1- nitrobenzenes (33.0g, 150mmol).Reaction solution is stirred at room temperature two hours, pours into 600mL water, Mixture is extracted with EtOAc, the organic layer of merging is dried, filtered and concentrated with anhydrous sodium sulfate, and obtaining (Z) -4-, (5- is bromo- 2- nitro-phenoxies) but-2-ene -1- alcohol (45g), yellow solid.Crude product is used in next step, without further pure Change.

Step B：Zinc powder (49.0g, 750mmol) and ammonium chloride (40.0g, 750mmol) are added in methanol (450mL) and mixed It closes, the first of (Z) -4- (5- bromo -2- nitro-phenoxies) but-2-ene -1- alcohol (43.2g, 150mmol) is then added dropwise at room temperature Alcohol (300mL) solution.Reaction mixture is stirred at room temperature 24 hours, is then filtered.Filtrate is concentrated, obtains (Z) -4- (2- amino -5- bromobenzenes oxygroup) but-2-ene -1- alcohol is dark oil object.By crude product in next step, without into one Step purifying.

Step C：By crude product (Z) -4- (2- amino -5- bromobenzenes oxygroup) but-2-ene -1- alcohol be dissolved in THF (300mL) and In water (150mL), sodium bicarbonate (25.2g, 300mmol) and benzyl chloroformate (38.4g, 225mmol) are added at 0 DEG C, is risen It warms to room temperature, and is stirred at room temperature 16 hours.Mixture is extracted with EtOAc.The organic layer of merging is dried and concentrated.It is thick residual Excess is purified with silica gel chromatograph (PE: EtOAc=1: 10~1: 5), obtains (Z) -4- bromos -2- (4- hydroxyl but-2-enes oxygroup) Phenyl) benzyq carbamate (28.0g, 48%), pale solid.414,416 (M+Na) of LCMS (ESI) m/z

Step D：- 25 DEG C, molecular sieve (It 40g) is suspended in DCM (350mL).L- is added in into the mixture of cooling (+)-diethyl tartrate (11.3g, 54mmol), Ti (Oi-Pr)₄(14.1g, 49.5mmol) and tert-butyl hydroperoxide (5-6M in decane, 27mL, 135mmol).- 25 ° are stirred 1 hour, are added dropwise and are contained (Z) -4- bromos -2- (4- hydroxyl but-2-ene oxygen Base) phenyl) benzyq carbamate (17.6g, 45mmol) DCM (70mL) solution, it is small that reaction solution is stirred at -25 DEG C to 24 When.The aqueous solution (210mL) of 10% L- (+)-tartaric acid is poured into coolant, and is stirred 1 hour at 0 DEG C, is filtered, it will Organic solution detaches, and water phase is extracted with DCM.The organic layer of merging is washed with brine, anhydrous sodium sulfate drying, concentration.It is thick remaining Object is purified with silica gel chromatograph (PE: EtOAc=1: 5~1: 3), obtains (4- bromos -2- (((2R, 3S) -3- (methylol) epoxy second Alkane -2- bases) methoxyl group) phenyl) benzyq carbamate (9.4g, 51%, ee value ＞ 88%) is white solid.LCMS(ESI)m/ z：430,432 (M+Na)

Step E：At 0 DEG C, to tert-butyldimethylsilyl chloride ((5.2g, 34.5mmol), imidazoles (3.1g, 46mmol) and in the anhydrous DMF of 4-dimethylaminopyridine (280mg, 2.3mmol) (40mL) solution add in (4- bromos -2- (((2R, 3S) -3- (methylol) ethylene oxide -2- bases) methoxyl group) phenyl) benzyq carbamate (9.4g, 23mmol) it is anhydrous DMF (20mL) solution.The temperature of reaction solution is warmed to room temperature, and is stirred at room temperature 3 hours.Mixture is poured into ice water, It is extracted with EtOAc.The organic layer of merging is dried and concentrated with anhydrous sodium sulfate.By thick residue through silica gel chromatograph (PE: EtOAc=1: 20~1: 10), obtain (4- bromos -2- (((2R, 3S) -3- (((t-butyldimethylsilyl) oxygroup) first Base) ethylene oxide -2- bases) methoxyl group) phenyl) benzyq carbamate (10.5g, 87%) is colorless oil.LCMS(ESI) m/z：522,524 (M+1)

Step F：At -78 DEG C, to (the bromo- 2- of 4- (((2R, 3S) -3- (((t-butyldimethylsilyl) oxygroup) first Base) ethylene oxide -2- bases) methoxyl group) phenyl) amino methylbenzyl ester (10.5g, 20mmol) THF (200mL) solution in be added dropwise two Isopropylamino lithium (THF solution of 2.0M, 13mL, 26mmol).After being stirred 2 hours at -78 DEG C, acquired solution is heated up To room temperature, and it is stirred at room temperature 16 hours.At 0 DEG C, saturated ammonium chloride solution is added in.Mixture is extracted with EtOAc. The organic layer of merging is dried and concentrated with anhydrous sodium sulfate.By thick residue by silica gel chromatograph (PE: EtOAc=1: 30~1: 20) it purifies, obtains (3R, 3aS) -7- bromos -3- (((t-butyldimethylsilyl) oxygroup) methyl) -3a, 4- dihydrobenzenes And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (8.3g, 99%), it is white solid.MS(ESI)m/z：414,416 (M+1).

Step G：By (3R, 3aS) -7- bromos -3- (((t-butyldimethylsilyl) oxygroup) methyl) -3 α, 4- bis- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (8.3g, 20mmol), morpholine -3- ketone (2.8g, 28mmol), K₂CO₃(3.3g, 24mmol) and DMSO (60mL) are mixed, and are stirred 1 hour at room temperature.At room temperature add in CuI (760mg, 4mmol) and 1,10- o-phenanthrolines (200mg).Obtained mixture is heated to 130 DEG C, keeps the temperature 24 hours.It is cooled to room temperature Afterwards, water (180mL) is added in.Mixture is extracted with EtOAc.The organic layer of merging is dried and concentrated with anhydrous sodium sulfate.It will be thick Residue through silica gel chromatograph (PE: EtOAc=1: 10~1: 1)), obtain (3R, 3aS) -3- (((t-butyl-dimethylsilyls Base) oxygroup) methyl) -7- (3- oxomorpholin generations) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) - Ketone (3.5g, 40%) is red oil.LCMS(ESI)m/z：435(M+1).

Step H：At 0 DEG C, to (3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- (3- oxygen For morpholino) -3a, the THF of 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (3.5g, 8mmol) N-Bu is added dropwise in (20mL) solution₄THF (10mL) solution of NF (2.5g, 9.6mmol).It is small that acquired solution is stirred at 0 DEG C to 2 When.Reaction is quenched, and extracted with EtOAc with saturated aqueous ammonium chloride.The organic layer of merging is dry and dense with anhydrous sodium sulfate Contracting.Thick residue by silica gel chromatograph (PE: EtOAc=1: 1~0: 1) is purified, obtains (3R, 3aS) -3- (methylol) -7- (3- oxomorpholins) -3a, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (2.4g, 94%) are nothing Color grease.LCMS(ESI)m/z：321(M+1).

Step I：At 0 DEG C, to (3R, 3aS) -3- (methylol) -7- (3- oxomorpholin generations) -3 α, 4- dihydrobenzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (2.4g, 7.5mmol) and Et₃The DCM of N (2.3mL, 16.5mmol) Mesyl chloride (1.0g, 9mmol) is added dropwise in (50mL) solution.The mixture was warmed to room temperature, and is stirred at room temperature 16 hours. Reaction is quenched, and extracted with DCM with water (20mL).The organic phase of merging is washed with brine, is dried with anhydrous sodium sulfate, and is dense Contracting, obtains (3S, 3aS) -3- (azido-methyl) -7- (3- oxomorpholin generations) -3a, 4- dihydrobenzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one is pale solid.By crude product for reacting in next step, without being further purified.

Step J：By crude product (3S, 3aS) -3- (azido-methyl) -7- (3- oxomorpholin generations) -3 α, 4- dihydrobenzos [b] The mixture of oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one, sodium azide (540mg, 8.3mmol) and DMF (20mL) exist It is stirred 6 hours at 80 DEG C, reaction mixture is cooled to room temperature, then adds in water, mixture is extracted with EtOAc.It will merge Organic phase be washed with brine, dried with anhydrous sodium sulfate, and concentrate, obtain (3S, 3aS) -3- (azido-methyl) -7- (3- oxygen For morpholino) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (2.2g), be brown oily Object.LCMS(ESI)M/Z：Crude product is used in next step by 346 (M+1), without being further purified.

Step K：At room temperature, to (3S, 3aS) -3- (azido-methyl) -7- (3- oxomorpholin generations) -3 α, 4- dihydrobenzos [b] oxazole simultaneously adds in triphenylphosphine in THF (20mL) solution of [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.9g, 5.5mmol) Acquired solution at 45 DEG C is stirred 2 hours, then adds in water (1mL), and stirring 16 is small at 45 DEG C by (1.7g, 6.6mmol) When.After being cooled to room temperature, mixture is concentrated.Thick residue is pure by silica gel chromatograph (MeOH: DCM=1: 30~1: 20) Change, obtain (3S, 3aS) -3- (amino methyl) -7- (3- oxomorpholin generations) -3 α, 4- dihydrobenzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.1g, 64%) is pale solid.LCMS(ESI)m/z：320(M+1).

Step L：At 0 DEG C, to (3S, 3aS) -3- (amino methyl) -7- (3- oxomorpholin generations) -3 α, 4- dihydrobenzos [b] oxazole simultaneously adds in triethylamine in DCM (30mL) solution of [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.1g, 3.5mmol) DCM (10mL) solution of (2.4mL, 17.5mmol) and 5- chlorothiophene -2- carbonyls chlorine (830mg, 4.6mmol) mixes reaction Object stirs 1 hour at 0 DEG C.It adds in water and extracts the mixture with DCM.The organic phase of merging anhydrous sodium sulfate is dried simultaneously Concentration.Thick residue through silica gel chromatograph (MeOH: DCM=1: 30to 1: 20) is purified, obtains the present embodiment title compound Object is white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J=5.6Hz, 1H), 7.85 (d, J=8.8Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 7.05 (d, J=2.0Hz, 1H), 7.05 (dd, J=8.8, 2.0Hz, 1H), 4.62-4.51 (m, 2H), 4.18 (s, 2H), 4.11-4.01 (m, 2H), 3.95 (t, J=5.2Hz, 2H), 3.73 (t, J=5.2Hz, 2H), 3.68 (t, J=5.2Hz, 2H) .LCMS (ESI) m/z：464(M+1).

Embodiment 2

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo-piperidine -1- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3R, 3aS) -3- ((t-butyldimethylsilyloxy base) methyl) -7- (2- are prepared according to embodiment 1 Oxo-piperidine -1- bases) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one, yield 7%, wherein Morpholine -3- ketone in step G is replaced with into piperidines -2- ketone.LCMS(ESI)m/z：433.2(M+1).

Step B：The title compound of embodiment 2 is prepared according to embodiment 1 step G, I, J, K and L sequence, it is solid for white Body.¹HNMR (400MHz, DMSO-d₆) δ 9.01 (t, J=5.6Hz, 1H), 7.83 (d, J=8.8Hz, 1H), 7.72 (d, J= 4.0Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 6.87-6.93 (m, 2H), 4.50-4.64 (m, 2H), 3.99-4.13 (m, 2H), 3.73 (t, J=5.6Hz, 2H), 3.52-3.60 (m, 2H), 2.37 (t, J=6.0Hz, 2H), 1.77-1.90 (m, 4H)； LCMS(ESI)m/z：462.1(M+1).

Embodiment 3

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (5- oxo-Isosorbide-5-Nitrae-oxazepine cycloheptane -4- bases) -1,3,3a, 4- Tetrahydro benzo [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- is prepared according to embodiment 1 (5- oxo-Isosorbide-5-Nitrae-oxazepine cycloheptane -4- bases) -3a, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one the, wherein morpholine -3- ketone in step G is replaced with Isosorbide-5-Nitrae-oxazepine cycloheptane -5- ketone, yield 35%.LCMS (ESI)m/z：449.2(M+1).

Step B：The title compound of embodiment 3 is prepared according to embodiment 1 step G, I, J, K and L sequence, it is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.01 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 6.87-6.83 (m, 2H), 4.60-4.54 (m, 2H), 4.10-4.00 (m, 2H), 3.80-3.65 (m, 8H), 2.78 (t, J=4.8Hz, 2H)；LCMS(ESI)m/z：478.1(M+1).

Embodiment 4

((- 1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by (3S, 3aS) -1- oxos -7- (2- oxygen piperazine -1- bases) by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：To the EtOAc/H of piperazine -2- ketone (3.00g, 30.0mmol)₂K is added in O (30mL/6mL) solution₂CO₃ (4.32g, 31.5mmol) and benzyl chloroformate (5.10g, 30.0mmol).The mixture is stirred at room temperature 12 hours, then Reaction solution is poured into water (50mL), and is extracted with ethyl acetate (40mL x 2), is dried with anhydrous sodium sulfate, and concentrate.Slightly Residue is purified with silica gel chromatograph (PE: EtOAc=50: 1), is obtained 3- oxypiperazin -1- benzyl formates (6.3 grams, 88%), is White solid.¹H NMR (400MHz, CDCl₃) δ 7.34-7.33 (m, 5H), 6.87-6.76 (m, 1H), 5.17 (s, 2H), 4.17 (s, 2H), 3.71 (t, J=5.2Hz, 2H), 3.39 (s, 2H) .LCMS (ESI) m/z：235.1(M+1).

Step B：4- ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) first is prepared according to embodiment 1 Base) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxypiperazin -1- formic acid Benzyl ester, wherein morpholine -3- ketone in step G is replaced with 3- oxypiperazin -1- benzyl formates, yield 22%.LCMS(ESI)m/ z：568.2(M+1).

Step C：To 4- ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxypiperazin -1- benzyl formates (200mg, In methanol (4mL) solution of 0.352mmol add in two carbonic ester of di-t-butyl (115mg, 0.529mmol) and Pd/C (10%, 20mg), it is then handled with hydrogen balloon.Reaction solution is stirred at room temperature 16 hours.LCMS display reactions are completed, and are then filtered to remove Pd/ C concentrates filtrate.Thick residue by silica gel column chromatography (PE: EA=5: 1~1: 1) is purified, obtains 4- ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxypiperazin -1- t-butyl formates (160mg, 85%) are white solid.LCMS(ESI)m/z： 534.1(M+1).

Step D：4- ((3S, 3aS) -3- ((5- chlorothiophene -2- first is prepared according to the sequence of embodiment 1 step G, I, J, K, L Acylamino-) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxo piperazines Piperazine -1- t-butyl formates.LCMS(ESI)m/z：563.1(M+1).

Step E：To 4- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxypiperazin -1- t-butyl formates (425mg, 2,2,2- trifluoroacetic acids (259mg, 2.27mmol) are added in DCM (8mL) solution 0.756mmol), at room temperature stir mixture It is poured into after mixing 4 hours in water (30mL), is extracted with DCM, the organic phase of merging is dried and concentrated with anhydrous sodium sulfate, it will be remaining Object crude product is purified through preparation HPLC, obtain the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxygen piperazine -1- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (38mg, 14%), for white Solid.¹H NMR (400MHz, DMSO-d₆) δ 9.63 (s, 2H), 9.07 (t, J=6.0Hz, 1H), 7.88 (d, J=8.8Hz, 1H), 7.74 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.95-6.93 (m, 2H), 4.61-4.55 (m, 2H), 4.13-4.03 (m, 2H), 3.85-3.81 (m, 2H), 3.72 (t, J=4.2Hz, 2H), 3.50 (s, 2H) .LCMS (ESI) m/z： 463.1(M+1).

Embodiment 5

The chloro- N- of 5- (((3S, 3aS) -7- (4- methyl -2- oxygen piperazine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxypiperazin -1- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (100mg, 0.216mmol) DMF (2mL) K is added in solution₂CO₃(29.8mg, 0.216mmol) and iodomethane (35mg, 0.216mmol), after stirring 16 hours at room temperature, Mixture is poured into water (15mL), is washed with EtOAc (20mL x 2), is dried and concentrated with anhydrous sodium sulfate, it will be thick remaining Object preparative TLC (ethyl acetate) is purified, and preparation HPLC (formic acid) purifies again, obtains the present embodiment title compound (5.7mg, 5%), white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J=5.6Hz, 1H), 8.23 (s, 1H), 7.83 (d, J=8.8Hz, 1H), 7.71 (d, J=4.4Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.97-6.92 (m, 2H), 4.61-4.53 (m, 2H), 4.07-4.03 (m, 2H), 3.72 (t, J=4.4Hz, 2H), 3.61-3.58 (m, 2H), 3.07 (s, 2H), 2.69 (t, J=5.2Hz, 2H), 2.26 (s, 3H) .LCMS (ESI) m/z：477.1(M+1).

Embodiment 6

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo -1,3- oxazepine hexamethylene -3- bases) -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：Under a nitrogen, to the bromo- 3- of (3R, 3aS) -7- (((t-butyldimethylsilyl) oxygroup) methyl) - 3a, 4- dihydrobenzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.5g, 3.6mmol), Cs₂CO₃(2.4g, 7.2mmol) and add in Pd in the toluene of 1,3- oxazepine hexamethylene -2- ketone (550mg, 5.4mmol) (20mL) solution₂ (dba)₃(916mg, 0.66mmol) and Xantphos (420mg, 0.7mmol) flows back 16 hours, reaction solution is cooled to room Temperature is subsequently poured into water (30mL), is extracted with EtOAc (30mL x 2).The organic layer of merging is dry and dense with anhydrous sodium sulfate Contracting.Thick residue through silica gel chromatograph (PE: EtOAc=20: 1~3: 1) is purified, obtains (3R, 3aS) -3- (((tertiary butyls two Methyl silicane base) oxygroup) methyl) -7- (2- oxo -1,3- oxazepine hexamethylene -3- bases) -3 α, 4- dihydrobenzos [b] evil Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (250mg, 16%).LCMS(ESI)m/z：435.1(M+1).

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K, L, wherein by step Morpholine -3- ketone in G replaces with the own ring -2- ketone of 1,3- oxygen azepines, obtains white solid.¹H NMR (400MHz, DMSO-d₆)δ 9.00 (t, J=5.6Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.22 (d, J=4.4Hz, 1H), 7.01-6.97 (m, 2H), 4.61-4.55 (m, 2H), 4.32 (t, J=5.6Hz, 2H), 4.07-4.04 (m, 2H), 3.73 (t, J=5.6Hz, 2H), 3.63-3.60 (m, 2H), 2.11-2.05 (m, 2H)；LCMS(ESI)m/z：464.1(M+1).

Embodiment 7

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo pyridines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- is prepared according to embodiment 1 (- 1 (2H)-yl of 2- oxos tetrahydropyrimidine) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one, Morpholine -3- ketone in the middle G by step replaces with tetrahydropyrimidine -2 (1H) -one, yield 7%.LCMS(ESI)m/z：434.2(M+ 1).

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K, L, it is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J=6.0Hz, 1H), 7.69-7.75 (m, 2H), 7.20 (d, J=4.0Hz, 1H), 6.85-6.95 (m, 2H), 6.55 (s, 1H), 4.47-4.62 (m, 2H), 3.94-4.10 (m, 2H), 3.71 (t, J= 5.6Hz, 2H), 3.56 (t, J=5.6Hz, 2H), 3.20 (td, J=5.2,2.0Hz, 2H), 1.91 (t, J=6.0Hz, 2H)； LCMS(ESI)m/z：463.0(M+1).

Embodiment 8

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo pyridines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- is prepared according to embodiment 1 (2- oxo pyridines -1 (2H)-yl) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one, wherein will Morpholine -3- ketone in step G replaces with pyridine -2 (1H) -one, yield 22%.LCMS(ESI)m/z：429.1(M+1).

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K, L, it is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J=5.6Hz, 1H), 7.95 (d, J=8.8Hz, 1H), 7.72 (d, J= 4.0Hz, 1H), 7.59 (dd, J=6.8,1.6Hz, 1H), 7.49 (ddd, J=9.2,6.8,2.0Hz, 1H), 7.21 (d, J= 4.0Hz, 1H), 7.06 (d, J=2.4Hz, 1H), 7.01 (dd, J=8.8,2.4Hz, 1H), 6.45 (d, J=9.2Hz, 1H), 6.29 (td, J=6.8,1.2Hz, 1H), 4.56-4.69 (m, 2H), 4.03-4.16 (m, 2H), 3.75 (t, J=5.6Hz, 2H)； LCMS(ESI)m/z：458.1(M+1).

Embodiment 9

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- Oxopyrazines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- is prepared according to embodiment 1 (2- Oxopyrazines -1 (2H)-yl) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one, wherein will Morpholine -3- ketone in step G replaces with pyrazine -2 (1H) -one, yield 30%.LCMS(ESI)m/z：430.2(M+1).

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K, L.¹H NMR (400MHz, DMSO-d₆) δ 9.02 (t, J=6.0Hz, 1H), 8.10 (d, J=1.2Hz, 1H), 7.98 (d, J=8.4Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.61 (dd, J=4.4,1.0Hz, 1H), 7.37 (d, J=4.4Hz, 1H), 7.17-7.24 (m, 2H), 7.11 (dd, J=8.8,2.4Hz, 1H), 4.54-4.71 (m, 2H), 4.04-4.18 (m, 2H), 3.74 (t, J=5.6Hz, 2H)；LCMS(ESI)m/z：459.0(M+1).

Embodiment 10

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- ((R) -3- oxo tetrahydrochysenes -1H- [pyrroles [1,2-c] imidazoles -2 (3H) - Base) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, divide into THF (150mL) solution of (R)-pyrrolidines -2- formamides (5.0g, 49.9mmol) It criticizes and adds in lithium aluminium hydride reduction (9.5mg, 0.25mol), stirred 1 hour at 0 DEG C, and flow back 48 hours.Mixture is cooled to 0 DEG C, and be quenched with water (12mL).Mixture is filtered, filter cake is washed with hot THF (150mL x 3).The filtrate of merging is concentrated, Vacuum distillation, obtains (R)-pyrrolidin-2-yl methylamine (1.6g, 25%), is colorless oil.¹H NMR (400MHz, DMSO- d₆) δ 2.90-2.87 (m, 1H), 2.76-2.68 (m, 2H), 2.44-2.36 (m, 2H), 1.69-1.55 (m, 3H), 1.26-1.21 (m, 1H)

Step B：At 0 DEG C, added in into DCM (50mL) solution of (R)-pyrrolidin-2-yl methylamine (1.0g, 1.0mmol) DCM (20mL) solution of two (1H- imidazoles -1- bases) ketones (1.6g, 1.0mmol) is stirred 16 hours at 7 DEG C, is then concentrated.It will Thick residue is purified through silica gel chromatograph (PE: EtOAc=1: 1to DCM), obtains (R)-tetrahydro-1 H-pyrrolo simultaneously [1,2-c] miaow Azoles -3 (2H) -one (300mg, 24%) is white solid.¹H NMR (400MHz, CDCl₃) δ 5.35-5.32 (brs, 1H), 3.64-3.76 (m, 1H), 3.63-3.62 (m, 2H), 3.32-3.30 (m, 1H), 3.07-3.05 (m, 1H), 1.98-1.94 (m, 3H), 1.48-1.42 (m, 1H)

Step C：(3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- is prepared according to embodiment 6 ((R) -3- oxos tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -2 (3H)-yl) -3 α, 4- dihydrobenzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one, wherein 1, the 3- oxazepine hexamethylene -2- ketone in step A is replaced with (R)-tetrahydrochysene -1H- pyrroles Simultaneously [1,2-c] imidazoles -3 (2H) -one is coughed up, obtains white solid, yield 59%.LCMS(ESI)m/z：460.2(M+1).

Step D：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K, L, it is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J=6.0Hz, 1H), 7.76 (d, J=9.2Hz, 1H), 7.72 (d, J= 4.4Hz, 1H), 7.33 (d, J=2.4Hz, 1H), 7.22 (d, J=2.4Hz, 1H), 7.16 (dd, J=8.8,2.4Hz, 1H), 4.58-4.52 (m, 2H), 4.05-4.02 (m, 2H), 3.92-3.90 (m, 1H), 3.76-3.70 (m, 4H), 3.51-3.50 (m, 1H), 3.02-3.01 (m, 1H), 2.03-2.00 (m, 1H), 1.92-1.79 (m, 2H), 1.37-1.31 (m, 1H)；LCMS(ESI) m/z：489.2(M+1).

Embodiment 11

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- ((S) -3- oxos tetrahydro-1 H-pyrrolo [1,2-c] imidazoles -2 (3H) - Base) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the sequence of embodiment 10 step A, B, C, D, wherein by step A In -1 hydrogen of (S)-tetrahydrochysene-pyrroles [1,2-c] imidazoles -3 (2 hydrogen) -one replace with -1 hydrogen of (R)-tetrahydrochysene-pyrroles [1,2-c] imidazoles - 3 (2 hydrogen) -one, obtain white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J=5.6Hz, 1H), 7.76 (d, J= 8.8Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.36 (d, J=2.4Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 7.15 (dd, J=9.2,2.4Hz, 1H), 4.58-4.52 (m, 2H), 4.05-4.02 (m, 2H), 3.92-3.90 (m, 1H), 3.75- 3.72 (m, 4H), 3.51-3.49 (m, 1H), 3.02-2.98 (m, 1H), 2.03-1.99 (m, 1H), 1.95-1.75 (m, 2H), 1.37-1.31 (m, 1H)；LCMS(ESI)m/z：489.2(M+1).

Embodiment 12

The chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxo-pyrrolidine -1- bases) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- is prepared according to embodiment 1 (2- oxo-pyrrolidine -1- bases) -3a, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one, wherein will step Morpholine -3- ketone in rapid G replaces with pyrrolidin-2-one, yield 32%.LCMS(ESI)m/z：419.1(M+1).

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K, L.¹H NMR (400MHz, DMSO-d₆) δ 8.98 (t, J=5.6,1H), 7.80 (d, J=9.2Hz, 1H), 7.70 (d, J=4.4Hz, 1H), 7.40 (d, J=2.4Hz, 1H), 7.22-7.19 (m, 2H), 4.58-4.52 (m, 2H), 4.05-4.02 (m, 2H), 3.79-3.69 (m, 4H), 2.48-2.47 (m, 2H), 2.06-1.99 (m, 2H)；LCMS(ESI)m/z：448.1(M+1).

Embodiment 13

The chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- hydroxyl -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Reaction process：

Step A：It is molten to the MeOH (100mL) for (the S) -4- amino -2- hydroxybutyric acids (15.0g, 0.126mol) that stirred The concentrated sulfuric acid (14.8mL, 0.151mol) is added dropwise in liquid, is added dropwise more than 5 minutes, flows back 4 hours, reaction solution can be cooled to 18 DEG C, It is diluted with water (15mL), excessive K is added portionwise₂CO₃, stir 15 minutes, reaction mixture is diluted with DCM (150mL), diatomite Filtering.Filtrate is evaporated to dryness, obtains thick liquid residue.Residue is beaten with the DCM solution of 1-2%MeOH, And it filters.Merge organic layer, concentration obtains (S) -3- hydroxyl pyrrolidine -2- ketone (11g, 86%), is white solid.¹H NMR (400MHz, CDCl₃) δ 6.74 (brs, 1H), 4.35 (t, J=8.8,1H), 3.49-3.39 (m, 1H), 3.36-3.30 (m, 1H), 2.52-2.47 (m, 1H), 2.11-2.05 (m, 1H)

Step B：Imidazoles is added in into DMF (20mL) solution of (S) -3- hydroxyl pyrrolidine -2- ketone (2g, 19.7mmol) TBDPSCl (9.24g, 33.6mmol) is then added dropwise in (3.37g, 49.4mmol).Gained mixture is heated to 90 DEG C, and stir It mixes 15 hours.Mixture is poured into NaHCO₃In aqueous solution (100mL), extracted with EtOAc (50mL).The organic phase of merging is used Salt water washing, is dried with anhydrous sodium sulfate, concentration.Thick residue is pure by silica gel column chromatography (PE: EA=10: 1~1: 1) Change, obtain (S) -3- ((t-butyldiphenylsilyl) oxygroup) pyrrolidin-2-one (5g, 74%), be white solid.LCMS (ESI)m/z：340.2(M+1).

Step C：To the bromo- 3- of (3R, 3aS) -7- (((t-butyldimethylsilyl) oxygroup) methyl) -3a, 4- dihydros Benzo [b] oxazole simultaneously add in toluene (30mL) solution of [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (2g, 4.83mmol) (S) - 3- ((t-butyldiphenylsilyl) oxygroup) pyrrolidin-2-one (2.5g, 7.24mmol), Cs₂CO₃(3.15g, 9.66mmol)、Pd₂(dba)₃(440mg, 0.483mmol) and Ruphos (224mg, 0.483mmol).Heat the mixture to 80 DEG C continue 16 hours.Mixture is poured into water (50mL), is extracted with EtOAc (50mL x 2).Organic matter Na₂SO4 is dried, Concentration.Thick residue is passed through into silica gel column chromatographyPurifying, obtains (3R, 3aS) -3- (((tertiary fourths Base dimetylsilyl) oxygroup) methyl) -7- ((S) -3- ((t-butyldiphenylsilyl) oxygroup) -2- oxo pyrroles Alkane -1- bases) -3a, 4- dihydrobenzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.15g, 35%) consolidates for yellow Body.LCMS(ESI)m/z：673.3(M+1).

Step D：The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- are prepared according to the sequence of embodiment 1 step G, I, J, K, L (2- oxo-pyrrolidine -3- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene Fen -2- formamides the, wherein morpholine -3- ketone in step G is replaced with (S) -3- ((t-butyldiphenylsilyl) oxygroup) Pyrrolidin-2-one.LCMS(ESI)m/z：702.2(M+1).

Step E：At 0 DEG C, to N- (((3S, 3aS) -7- ((S) -3- ((t-butyldiphenylsilyl) oxygroup) -2- Oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) - In THF (10mL) solution of 5- chloro thiophene -2- formamides (500mg, 0.713mmol) be added dropwise TBAF (3.72g, 1.43mmol), mixture at 20 DEG C is stirred 1 hour, solvent is removed under reduced pressure, crude product is passed through into preparation HPLC (formic acid) Purifying, obtains the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- hydroxyl -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (115mg, 35%), for white Solid.¹H NMR (400MHz, DMSO-d₆) δ 8.99 (t, J=6.0Hz, 1H), 7.82 (d, J=8.8Hz, 1H), 7.71 (d, J= 4.0Hz, 1H), 7.45 (d, J=2.8Hz, 1H), 7.26-7.20 (m, 2H), 5.74 (d, J=5.4Hz, 1H), 4.58-4.53 (m, 2H), 4.28-4.27 (m, 1H), 4.06-4.04 (m, 2H), 3.73-3.63 (m, 4H), 2.39-2.34 (m, 1H), 1.84- 1.79 (m, 1H)；LCMS(ESI)m/z：464.1(M+1).

Embodiment 14

The chloro- N- of 5- (((3S, 3aS) -7- (2- methoxyl group-N- ethylmethylamidos) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, to ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -1- oxos - 1,3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) t-butyl carbamate (991mg, 2.2mmol) DMF (10mL) solution in NaH (123mg, 3.1mmol) is added dropwise, and stirred 20 minutes at 0 DEG C.Then it is added at 0 DEG C MeI (624mg, 4.4mmol) is simultaneously stirred 1 hour at 0 DEG C.Add in saturation NH₄Cl aqueous solutions (30mL) and with EtOAc (30mL X 2) extraction mixture.Merge organic phase to be dried over anhydrous sodium sulfate, filter and be concentrated to give ((3R, 3aS) -3- (((tertiary butyls Dimetylsilyl) oxygroup) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines - 7- yls) (methyl) t-butyl carbamate (1.00g), brown oil is directly used in and reacts in next step, without further pure Change.LCMS(ESI)m/z：409(M+1).

Step B：((3S, 3aS) -3- ((5- chloro thiophenes -2- are prepared according to the sequence of embodiment 1 step H, I, J, K and L Formamido group) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) (methyl) T-butyl carbamate wherein the morpholine -3- ketone in step H is replaced with methylamino t-butyl formate, obtains yellow solid. LCMS(ESI)m/z：438(M+1).

Step C：At room temperature, to ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) (methyl) t-butyl carbamate (741mg, HCl/ dioxane (5mL, 4M) is added in DCM (5mL) solution 1.5mmol) and is stirred at room temperature 1 hour.Mixture is evaporated, Thick residue is purified through silica gel chromatograph (MeOH: DCM=1: 100~1: 50), obtains the chloro- N- of 5- (((3S, 3aS) -7- (first ammonia Base) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (450mg, 76%), yellow solid.LCMS(ESI)m/z：394(M+1).

Step D：To the chloro- N- of 5- (((3S, 3aS) -7- (methylamino) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (158mg, 0.4mmol) DCM (4mL) solution in add in Et₃DCM (1mL) solution of 2- methoxyacetyl chlorides (56mg, 0.5mmol) is then added dropwise in N (202mg, 2.0mmol) at 0 DEG C And it is stirred two hours at 0 DEG C.Add in saturation NaHCO₃Aqueous solution (10mL) then with DCM (10mL x 3) extract mixture. Merge organic phase anhydrous Na₂SO₄It is dried, filtered and concentrated.Crude product is purified through preparation HPLC (formic acid), obtains this implementation Example title compound (60mg, 32%), yellow solid.¹H NMR (400MHz, DMSO-d₆) δ 9.03 (t, J=6.0Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 7.73 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 7.04 (s, 1H), 6.96 (d, J=8.4Hz, 1H), 4.61-4.55 (m, 2H), 4.09-4.06 (m, 2H), 3.74-3.71 (m, 4H), 3.18 (s, 3H), 3.11 (s, 3H)；LCMS(ESI)m/z：466(M+1).

Embodiment 15

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (5- oxo-Isosorbide-5-Nitrae-oxazepine cycloheptane -4- bases) -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, it is added portionwise into THF (50mL) solution of 3- aminopropan-1-ols (5.0g, 66.6mmol) Na₂CO₃Water (10mL) solution of (8.5g, 80.0mmol).Then at 0 DEG C be added dropwise di-tert-butyl dicarbonate ((14.8g, 67.9mmol), it is added dropwise 30 minutes.It is stirred two hours at 16 DEG C.Water is added in, mixture is extracted with dichloromethane (200mL x 2). Merge organic layer and washed with anhydrous sodium bicarbonate aqueous solution, be dried and concentrated with anhydrous sodium sulfate, obtain (3- hydroxypropyls) ammonia Base t-butyl formate (11.7g, yield 99%) is directly used in and reacts in next step, without being further purified.

Step B：At -10 DEG C, to (3- hydroxypropyls) t-butyl carbamate (8.0g, 45.7mmol), NaOH aqueous solutions (20mL, 457mmol, 50%) and n-Bu₄2- bromoacetic acid uncles are added dropwise in toluene (80mL) solution of NBr (736mg, 2.3mmol) Toluene (20mL) solution of butyl ester (9.8g, 50.2mmol).Mixture is stirred 16 hours at 22 DEG C.Isolate organic layer, Water layer (25mL x 1) is extracted with ethyl acetate, then adjust water layer to pH=2 and is extracted with toluene (100mL x 2).It will The organic phase of merging is washed with brine, and anhydrous sodium sulfate is dried and concentrated, and obtains crude product 2- (3- ((tert-butoxycarbonyl) ammonia Base) propoxyl group) acetic acid (7.4g, yield 56%), it is directly used in next step, without being further purified.

Step C：To 2- (3- ((tert-butoxycarbonyl) amino) propoxyl group) acetic acid (7.0g, 30.0mmol) at 0 DEG C Thionyl chloride (10mL) is added dropwise in MeOH (50mL) solution.Gained mixture stirs 2 hours at 16 DEG C, is then concentrated to give 2- (3- amino propoxyl group) acetate hydrochloride (5.5g, yield 99%) is directly used in next step, without being further purified.

Step D：At 0 DEG C, to the MeOH of 2- (3- amino propoxyl group) acetate hydrochloride (6.0g, 38.1mmol) K is added in (100mL) solution₂CO₃(23g, 163.0mmol) flows back 3 hours, then concentration adds water.Gained mixture acetic acid Ethyl ester (20mL x 3) extracts.Be washed with brine organic phase, dried with anhydrous sodium sulfate, concentrate, then through column chromatography (PE: EtOAc=5: 1~1: 1) purify, obtain Isosorbide-5-Nitrae-oxazepine cycloheptane -3- ketone, white solid (300mg, yield 10%)

Step E：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, H, I, J, K and L, wherein will Morpholine -3- ketone in step G replaces with Isosorbide-5-Nitrae-oxazepine cycloheptane -3- ketone, obtains white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.03-9.00 (m, 1H), 7.82 (d, J=9.2Hz, 1H), 7.73 (d, J=4.0Hz, 1H), 7.22 (d, J= 4.0Hz, 1H), 6.85-6.80 (m, 2H), 4.61-4.55 (m, 2H), 4.26 (s, 2H), 4.10-4.00 (m, 2H), 3.85- 3.75 (m, 4H), 3.74-3.72 (m, 2H), 1.96-1.93 (m, 2H)；LCMS(ESI)m/z：479.1(M+1).

Embodiment 16

1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -2- oxo pyridine -3- Ethyl formates

Step A：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, H, I, J, K and L, wherein will Morpholine -3- ketone replaces with 2- oxo-piperidine -3- Ethyl formates.Obtain white solid.¹H NMR (400MHz, DMSO-d₆)δ9.01 (t, J=6.0Hz, 1H), 7.83 (d, J=9.2Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 4.59-4.53 (m, 2H), 4.12-4.06 (m, 4H), 3.73-3.52 (m, 6H), 2.12-2.01 (m, 3H), 1.19 (t, J= 6.8Hz, 3H)；LCMS(ESI)m/z：534.1(M+1).

Embodiment 17

The chloro- N- of 5- (((3S, 3aS) -7- (3- (methylol) -2- oxo-piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, to 1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -2- oxo-piperidine -3- Ethyl formates (350mg, CaCl2 (72.8mg, 0.656mmol) and NaBH is added in MeOH (5mL) solution 0.656mmol)₄(75mg, 1.96mmol), It is stirred 16 hours at 20 DEG C.Mixture is poured into water (30mL), is extracted with EtOAc (30mL x 2), anhydrous sodium sulfate drying, It filters and concentrates.Thick residue through silica gel chromatograph (EtOAc) purify, obtain the chloro- N- of 5- (((3S, 3aS) -7- (3- hydroxy piperidines - 1- yls) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formyls Amine (120mg, 42%) is light yellow solid isomer, is further purified to obtain two through preparative SFC and preparation HPLC A component, one is 10mg, another is also 10mg.Component 1：¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J=6.0Hz, 1H), 7.81 (d, J=8.4Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.89-6.86 (m, 2H), 4.67-4.53 (m, 3H), 4.07-4.01 (m, 2H), 3.55-3.51 (m, 6H), 2.43-2.42 (m, 1H), 1.93-1.78 (m, 4H) .MS (ESI) m/z：492 (M+1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J=6.0Hz, 1H), 7.81 (d, J=8.4Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.89-6.86 (m, 2H), 4.67-4.53 (m, 3H), 4.07-3.99 (m, 2H), 3.55-3.53 (m, 6H), 2.43-2.42 (m, 1H), 1.93-1.77 (m, 4H).MS(ESI)m/z：492(M+1).

Embodiment 18

The chloro- N- of 5- (((3S, 3aS) -7- (2- (methylol) -5- oxomorpholin generations) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At -10 DEG C, to the CH of 3- aminopropanes -1,2- glycol (7.5g, 82.3mmol)₃CN (270mL) and Triethylamine (9.98g, 98.8mmol) is added in MeOH (45mL) solution, chloracetyl chloride then is added dropwise under -10 DEG C, nitrogen (10.2g, 90.5mmol).Reaction mixture is warmed to room temperature and is stirred 16 hours.It is concentrated in vacuo, thick residue is through silica gel chromatograph (MeOH: EtOAc=1: 11) it purifies, obtains the chloro- N- of 2- (2,3- dihydroxypropyl) acetamide (10.2g, 74.2%), sticky oil Shape object..

Step B：Under room temperature and nitrogen, to the 40mL tert-amyl alcohol solutions of potassium tert-butoxide (5.61g, 5.0mmol) that stirred The middle 70mL tert-amyl alcohol solutions for adding in 2- chloro- N- (2,3- dihydroxypropyl) acetamides (3.35g, 2.0mmol), add for 2 hours.It stirs After mixing no less than 1 hour, MeOH (20mL) and H is added in₂O (1mL) is then stirred for 20 minutes.It is concentrated in vacuo, thick residue warp Silica gel chromatograph (MeOH: EA=1: 4) purifies, and obtains 6- (methylol) morpholine -3- ketone (1.4g, 53%), yellow oil.

Step C：Pyridine (9mL) and THF (17mL) solution to 6- (methylol) morpholine -3- ketone (1.4g, 10.7mmol) Middle addition TBDPSCl (4.4g, 16.0mmol) and AgNO₃Mixture is stirred 15 by (3.93g, 23.5mmol) at 5~15 DEG C Hour.THF and pyridine is removed in vacuum.Thick residue is purified through silica gel chromatograph (PE: EtOAc=1: 10~1: 1), obtains 6- (((t-butyldiphenylsilyl) oxygroup) methyl) morpholine -3- ketone (2.8g, 71%), yellow solid.

Step D：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, H, I, J, K and L, wherein will Morpholine -3- ketone replaces with 6- (methylol)-morpholine -3- ketone.The product is white solid isomer, through preparative SFC and Preparation HPLC is further purified, and obtains two components, and one is 8mg, the other is 9mg.Component 1：¹H NMR (400MHz, DMSO-d₆) δ 9.03 (t, J=6.0Hz, 1H), 7.87 (d, J=6.0Hz, 1H), 7.73 (d, J=4.0Hz, 1H), 7.22 (d, J =4.0Hz, 1H), 7.05 (d, J=0.6Hz, 1H), 7.01 (dd, J=5.2,2.0Hz, 1H), 4.55-4.62 (m, 2H), 4.23 (s, 2H), 4.03-4.12 (m, 2H), 3.93-3.99 (m, 1H), 3.73 (t, J=6.0Hz, 2H), 3.65 (t, J=12.0Hz, 1H), 3.50-3.58 (m, 4H) .LCMS (ESI) m/z：494 (M+1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 9.02 (t, J=5.6Hz, 1H), 7.86 (d, J=8.8Hz, 1H), 7.73 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.99-7.05 (m, 2H), 4.54-4.60 (m, 2H), 4.22 (s, 2H), 4.05-4.09 (m, 2H), 3.95-3.97 (m, 1H), 3.72 (t, J=6.0Hz, 2H), 3.65 (m, 1H), 3.45-3.51 (m, 4H) .LCMS (ESI) m/z：494(M+1).

Embodiment 19

The chloro- N- of 5- (((3S, 3aS) -7- (2- methyl -3- oxomorpholin generations) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, 2- ethanol amines are added dropwise into toluene (80mL) solution of sodium hydride (3.27g, 81.9mmol) Toluene (30mL) the solution of (2.5g, 40.9mmol) stirs 0.5 hour at 25 DEG C, 2- chloropropionic acid second is then added dropwise at 25 DEG C Toluene (30mL) solution of ester (6.15g, 45.0mmol).Gained mixture flows back 16 hours.Add in solid NH₄Cl (6.0g), It is stirred for 0.5 hour.Mixture is filtered, concentrates filtrate, thick residue is purified through silica gel chromatograph (PE: EtOAc=5: 1~1: 1), Obtain 2- methyl morpholine -3- ketone (2.0g, 43%), colorless oil.

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, H, I, J, K and L, wherein will Morpholine -3- ketone replaces with the 2- methyl morpholine -3- ketone product as white solid isomer, through preparative SFC and preparative HPLC is further purified, and obtains two components, and one is 20mg, the other is 17mg.Component 1：¹H NMR (400MHz, DMSO- d₆) δ 9.04-8.96 (m, 1H), 7.50 (d, J=8.8Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 7.03-6.98 (m, 2H), 4.57-4.55 (m, 2H), 4.30-4.28 (m, 1H), 4.07-3.95 (m, 3H), 3.92-3.76 (m, 2H), 3.74-3.70 (m, 2H), 3.57-3.52 (m, 1H), 1.36 (d, J=6.8Hz, 3H) .LCMS (ESI) m/z：478(M + 1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 9.04-8.96 (m, 1H), 7.50 (d, J=8.8Hz, 1H), 7.72 (d, J =4.0Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 7.03-6.98 (m, 2H), 4.57-4.55 (m, 2H), 4.30-4.28 (m, 1H), 4.07-3.95 (m, 3H), 3.92-3.76 (m, 2H), 3.74-3.70 (m, 2H), 3.57-3.52 (m, 1H), 1.36 (d, J =6.8Hz, 3H) .LCMS (ESI) m/z：478(M+1).

Embodiment 20

The chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- methyl -5- oxomorpholin generations) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, (R) -2- aminopropans are added dropwise into toluene (150mL) solution of sodium hydride (6.2g, 145mmol) Toluene (60mL) solution of alkane -1- alcohol (5.0g, 67.0mmol).Mixture is stirred 0.5 hour at 25 DEG C.Then at 25 DEG C Lower toluene (60mL) solution that 2- ethyl chloroacetates (8.0mL g, 73.8mmol) are added dropwise, mixture is flowed back 16 hours.It adds in Solid NH₄Cl (6.0g) is stirred 0.5 hour.Filter mixture, concentrate filtrate, through silica gel chromatograph (PE: EtOAc=5: 1~0: 1) it purifies, obtains (R) -5- methyl morpholine -3- ketone (3.5g, 46%), colorless oil.

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, H, I, J, K and L, wherein will Morpholine -3- ketone replaces with (R) -5- methyl morpholine -3- ketone, which is white solid.¹H NMR (400MHz, DMSO-d₆)δ 9.02 (dd, J=12.0,6.0Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.22 (d, J= 4.0Hz, 1H), 6.95-6.90 (m, 2H), 4.61-4.55 (m, 2H), 4.50-4.01 (m, 4H), 4.00-3.80 (m, 2H), 3.75-3.65 (m, 3H), 1.03 (d, J=6.8Hz, 3H) .LCMS (ESI) m/z：478(M+1).

Embodiment 21

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxos -8- oxa- -3- azabicyclos [3.2.1] oct-3-yl) - 1,3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：Nothing is added in into dichloromethane (100mL) solution of furans -2- methyl formates (10.0g, 71.4mmol) Mixture is warmed to 40 DEG C, anhydrous chlorination by water zinc chloride (2.9g, 21.4mmol) and paraformaldehyde (3.2g, 107.0mmol) Hydrogen bubbling 1 hour.Add water, mixture is extracted with dichloromethane (100mL x 2).Merge organic layer to be washed with brine, nothing Aqueous sodium persulfate is dried, filtered and concentrated, and obtains 5- (chloromethyl) furans -2- methyl formates (13.5g, 99%), colorless oil.

Step B：5- (chloromethyl) furans -2- methyl formates (3.5g, 18.6mmol) and sodium azide (2.2g, It is stirred 5 hours at 70 DEG C of DMF (20mL) solution 33.4mmol).Add water, mixture is extracted with ethyl acetate (100mL x 2). Merge organic layer to be washed with brine, be dried over anhydrous sodium sulfate, filter and concentrate, obtain 5- (azido-methyl) furans -2- formic acid Methyl esters (3.6g, 99%) is directly used in and reacts in next step, without being further purified.

Step C：The first of 5- (azido-methyl) furans -2- methyl formates (3.6g, 18.6mmol) and Pd/C (0.5g, 10%) 60 DEG C of alcohol (50mL) solution and the pressure of 30psi hydrogen are stirred 48 hours, and mixture is filtered, filtrate is concentrated, through silica gel chromatograph (PE : EtOAc=5: 1~1: 1) purify, obtain 8- oxa- -3- azabicyclos [3.2.1] octyl- 2- ketone (1.9g, 75%), white is solid Body.

Step D：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, H, I, J, K and L, wherein will Morpholine -3- ketone replaces with 8- oxa- -3- azabicyclos [3.2.1] the octyl- 2- ketone product as white solid isomer, through system Standby type SFC and preparation HPLC are further purified, and obtain two components, one is 29mg, the other is 28mg.Component 1：¹H NMR (400MHz, DMSO-d₆) δ 9.01 (m, 1H), 7.83 (d, J=8.8Hz, 1H), 7.71 (d, J=4.4Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 7.02-6.97 (m, 2H), 4.72-4.70 (m, 1H), 4.60-4.54 (m, 2H), 4.45 (d, J= 6.0Hz, 1H), 4.10-4.00 (m, 2H), 3.85-3.80 (m, 1H), 3.74-3.72 (m, 2H), 3.55-3.50 (m, 1H), 2.09-2.00 (m, 4H) .LCMS (ESI) m/z：490 (M+1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 9.01 (m, 1H), 7.83 (d, J=8.8Hz, 1H), 7.71 (d, J=4.4Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 7.02-6.97 (m, 2H), 4.72-4.70 (m, 1H), 4.60-4.54 (m, 2H), 4.45 (d, J=6.0Hz, 1H), 4.10-4.00 (m, 2H), 3.85-3.80 (m, 1H), 3.74-3.72 (m, 2H), 3.55-3.50 (m, 1H), 2.09-2.00 (m, 4H) .LCMS (ESI) m/z：490(M+1).

Embodiment 22

4- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxomorpholin -2- carbamoyl ethyls

Step A：At -78 DEG C, to (3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- (3- oxygen For morpholino) -3a, the THF of 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (300mg, 0.7mmol) LDA (THF solution of 0.4mL, 0.8mmol, 2M) is added dropwise in (2mL) solution, is stirred 1 hour at -78 DEG C, second is then added portionwise THF (1mL) solution of base chloro-formate (67mg, 0.6mmol).Mixture is stirred 2 hours at -78 DEG C.It adds in anhydrous NH₄Cl solution, mixture are extracted with ethyl acetate (20mL x 2).Merge organic layer to be washed with brine, anhydrous sodium sulfate drying, Concentration purifies through silica gel chromatograph (PE: EtOAc=1: 1~0: 1), obtains 4- ((3R, 3aS) -3- (((tertbutyldimethylsilyl chloride silicon Alkyl) oxygroup) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxygen For morpholine -2-Ethyl formate (100mg, 29%), white solid.LCMS(ESI)m/z：507(M+1).

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step H, I, J, K and L, wherein will Quinoline -3- ketone replaces with 3- oxomorpholin -2- Ethyl formates.The product is white solid.¹H NMR (400MHz, DMSO-d₆)δ 9.03-9.01 (m, 1H), 7.87 (d, J=8.8Hz, 1H), 7.73 (d, J=4.0Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 7.04-7.00 (m, 2H), 4.78 (s, 1H), 4.58-4.50 (m, 2H), 4.12-4.09 (m, 1H), 4.08-3.80 (m, 3H), 3.76-3.71 (m, 4H) .LCMS (ESI) m/z：509(M+1).

Embodiment 23

N- (((3S, 3aS) -7- ((S) -3- amino -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides

Preparation flow：

Step A：By N-, (((3S, 3aS) -7- amino -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides (950mg, 2.5mmol), (S) -2- ((tertbutyloxycarbonyl) ammonia Base) -4- (methyl mercapto) butyric acid (623mg, 2.5mmol), EDC (959mg, 5mmol), HOBT (766mg, 5mmol), DIPEA (969mg, 7.5mmol) and DMF (10mL) mixture is stirred at room temperature 16 hours.60mL water is added in, and with EtOAc (60mL X 2) extraction.Organic layer drying will be merged and be concentrated in vacuo, thick residue is pure through silica gel chromatograph (PE: EtOAc=3: 1~1: 2) Change, obtain ((S) -1- (((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) amino) -4- (methyl mercapto) -1- oxo-butanes -2- bases) carbamic acid The tert-butyl ester (1.10g, 71%), yellow solid.LCMS(ESI)m/z：555(M-55).

Step B：Will ((S) -1- (((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) amino) -4- (methyl mercapto) -1- oxo-butanes -2- bases) T-butyl carbamate (880mg, 1.4mmol), Me₃SI (881mg, 4.3mmol) and K₂CO₃The DMSO of (299mg, 2.2mmol) (10mL) solution stirs 16 hours at 80 DEG C.Mixture is cooled to room temperature and is then poured into water (60mL), and uses EtOAc (60mL x 2) is extracted.Merge organic layer to be washed with brine (30mL), be dried over anhydrous sodium sulfate, filter and concentrate.It is thick remaining Object is purified through preparation HPLC (hydrochloric acid), obtain ((S) -1- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) - 1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -2- oxo-pyrrolidine -3- bases) ammonia Base t-butyl formate (300mg, 37%), yellow solid.LCMS(ESI)m/z：507(M-55).

Step C：At room temperature, to ((S) -1- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos - 1,3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -2- oxo-pyrrolidine -3- bases) carbamic acid uncle HCl/ dioxane solutions (3mL, 4M) are added in DCM (3mL) solution of butyl ester (282mg, 0.5mmol), and are stirred at room temperature It mixes 1 hour.It is concentrated in vacuo, thick residue is purified through preparative SFC and preparation HPLC, obtains the present embodiment title compound (10mg, 4%), white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.12 (t, J=6.0Hz, 1H), 8.61 (brs, 3H), 7.88 (d, J=8.8Hz, 1H), 7.78 (d, J=4.0Hz, 1H), 7.45 (d, J=2.4Hz, 1H), 7.28 (dd, J=8.8, 2.4Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 4.63-4.55 (m, 2H), 4.25-4.20 (m, 1H), 4.10-4.03 (m, 2H), 3.87-3.79 (m, 2H), 3.73 (t, J=5.6Hz, 2H), 2.55-2.45 (m, 1H), 2.13-2.02 (m, 1H) .LCMS (ESI)m/z：463(M+1).

Embodiment 24

The chloro- N- of 5- (((3S, 3aS) -7- (2- ((methylamino) methyl) -1H- imidazoles -1- bases) -1- oxos -1,3,3a, 4- Four oxygen benzo [b] oxazoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：It is at 25 DEG C, the MeOH (20mL) of 1H- imidazoles -2- formaldehyde (500mg, 5.2mmol) and methylamine (2mL) is molten Liquid stirs 30 minutes.Then aliquot is divided to add in NaBH₄(400mg, 10.4mmol) is then stirred 15 hours at 60 DEG C.Vacuum is removed Remove solvent.With DCM (3x 25mL) debris.Merge organic phase to be dried, filtered and concentrated with anhydrous sodium sulfate, obtain thick Product 1- (1H- imidazoles -2- bases)-N- methyl methylamine (600mg) is directly used in next step.

Step B：By 1- (1H- imidazoles -2- bases)-N- methyl methylamine (600mg, 5.38mmol), triethylamine (654mg, 6.46mmol) stirred 2 hours at 18 DEG C with THF (15mL) solution of di-tert-butyl dicarbonate (1.18g, 5.38mmol).Solvent With vacuum concentration.Thick residue is purified with silica gel chromatograph (PE: EtOAc=10: 1~3: 1), obtains ((1H- imidazoles -2- bases) first Base) (methyl) t-butyl carbamate (712mg, 65%), colorless oil.LCMS(ESI)m/z：212(M+1).

Step C：((1- ((3S, 3aS) -3- ((5- chloro thiophenes are prepared according to the sequence of embodiment 1 step G, H, I, J, K and L Fen -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) - 1H- imidazoles -2- bases) methyl) (methyl) t-butyl carbamate, wherein morpholine -3- ketone is replaced with ((1H- imidazoles -2- bases) first Base) (methyl) t-butyl carbamate.The product is yellow solid.LCMS(ESI)m/z：574(M+1).

Step D：To ((1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -1H- imidazoles -2- bases) methyl) (methyl) carbamic acid uncle HCl/MeOH solution (4M, 2mL) is added dropwise in DCM (5mL) solution of butyl ester (350mg, 0.61mmol).Mixture is stirred at 20 DEG C It mixes two hours.Solvent is removed in vacuum, thick residue is purified through preparation HPLC (hydrochloric acid), obtains the present embodiment title compound (140mg, 50%), yellow solid.¹H NMR (400MHz, DMSO-d₆) δ 9.30 (brs, 1H), 9.15 (t, J=5.6Hz, 1H), 8.01 (d, J=8.4Hz, 1H), 7.78 (d, J=4.0Hz, 1H), 7.58 (s, 1H), 7.29 (s, 1H), 7.21-7.22 (m, 2H), 7.15 (dd, J=8.2,2.4Hz, 1H), 4.63-4.68 (m, 2H), 4.25 (brs, 2H), 4.07-4.16 (m, 2H), 3.75-3.77 (m, 2H), 2.62 (s, 3H)；LCMS(ESI)m/z：474(M+1).

Embodiment 25

The chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- methoxyl group -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：To (3R, 3aS) -7- bromos -3- (((t-butyldimethylsilyl) oxygroup) methyl) -3a, 4- bis- Hydrogen benzo [b] oxazole is simultaneously added in toluene (10mL) solution of [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1g, 2.42mmol) (S) -3- ((t-butyldiphenylsilyl) oxygroup) pyrrolidin-2-one (1.23g, 3.62mmol), Cs₂CO₃(1.58g, 4.84mmol)、Pd₂(dba)₃(222mg, 0.242mmol) and Ruphos (113mg, 0.242mmol).It under nitrogen atmosphere, will be mixed It closes object and is heated to 80 DEG C, heat 16 hours.It pours the mixture into water (50mL), is extracted with EA (50mL x 2), anhydrous slufuric acid Sodium is dried, filtered and concentrated.Thick residue is purified through silica gel chromatograph (PE: EA=10: 1~1: 1), obtains (3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- ((S) -3- ((t-butyldiphenylsilyl) oxygroup) -2- oxygen For pyrrolidin-1-yl) -3a, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (600mg, 38%), in vain Color solid.

Step B：To (3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- ((S) -3- ((tertiary fourths Base diphenylsilyl group) oxygroup) -2- oxo-pyrrolidine -1- bases) -3a, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] Aqueous hydrochloric acid solution (10mL, 4M) is added in dioxane (15mL) solution of oxazines -1 (3H) -one (600mg, 0.892mmol), Mixture is stirred 3 hours at 25 DEG C.It pours the mixture into water (50mL), is extracted with EA (50mL x 2), salt water washing, Anhydrous sodium sulfate is dried, filtered and concentrated, obtain (3R, 3aS) -7- ((S) -3- ((t-butyldiphenylsilyl) oxygroup) - 2- oxo-pyrrolidine -1- bases) -3- (methylol) -3a, 4- dihydrobenzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (400mg, 86%), yellow solid.

Step C：At 0 DEG C, to (3R, 3aS) -7- ((S) -3- ((t-butyldiphenylsilyl) oxygroup) -2- oxo pyrroles Cough up alkane -1- bases) -3- (methylol) -3a, 4- dihydrobenzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (400mg, NaH (31mg, 0.788mmol) and BnBr (145mg, 0.86mmol) is added in DMF (5mL) solution 0.717mmol).It will be mixed It closes object to stir 3 hours at 25 DEG C, pour into water (30mL), extracted with EA (30mL x 2), anhydrous sodium sulfate drying is filtered and dense Contracting.Thick residue is purified through silica gel chromatograph (PE: EA=5: 1~1: 1), obtains (3R, 3aS) -3- ((benzyloxy) methyl) -7- ((S) -3- ((t-butyldiphenylsilyl) oxygroup) -2- oxo-pyrrolidine -1- bases) -3a, 4- dihydrobenzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (300mg, 64%), white solid.

Step D：To (3R, 3aS) -3- ((benzyloxy) methyl) -7- ((S) -3- ((t-butyldiphenylsilyl) oxygen Base) -2- oxo-pyrrolidine -1- bases) -3a, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (300mg, TBAF (242mg, 0.925mmol) is added in THF (8mL) solution 0.462mmol).Mixture is stirred 16 hours at 25 DEG C, It is then poured into water (20mL), EA (30mL x 2) extractions, anhydrous sodium sulfate is dried, filtered and concentrated, and obtains (3R, 3aS) -3- ((benzyloxy) methyl) -7- ((S) -3- hydroxyl -2- oxo-pyrrolidine -1- bases) -3a, 4- dihydrobenzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (200mg, 90%), yellow solid.LCMS(ESI)m/z：411(M+1).

Step E：At 0 DEG C, to (3R, 3aS) -3- ((benzyloxy) methyl) -7- ((S) -3- hydroxyl -2- oxo-pyrrolidines -1- Base) -3a, the DMF of 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (200mg, 0.487mmol) NaH (23mg, 0.584mmol) and MeI (344mg, 2.44mmol) is added in (3mL) solution.Mixture is stirred 3 at 25 DEG C Hour.Then mixture being poured into water (20mL), EA (30mL x 2) extractions merge organic phase and are dried over anhydrous sodium sulfate, Filter and concentrate, obtain (3R, 3aS) -3- ((benzyloxy) methyl) -7- ((S) -3- methoxyl group -2- oxomorpholins generation -1- bases) - 3a, 4- dihydrobenzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (180mg, 87%), yellow solid.LCMS (ESI)m/z：425(M+1).

Step F：To (3R, 3aS) -3- ((benzyloxy) methyl) -7- ((S) -3- methoxyl group -2- oxomorpholins generation -1- bases) - The MeOH (5mL) of 3a, 4- dihydrobenzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (180mg, 0.425mmol) is molten Pd (OH) is added in liquid₂(50mg), 50 DEG C, stir 16 hours under nitrogen (50psi).After being cooled to room temperature, mixture is filtered, it is dense Contracting filtrate obtains (3R, 3aS) -3- (methylol) -7- ((S) -3- methoxyl group -2- oxo-pyrrolidine -1- bases) -3a, 4- dihydrobenzenes And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (100mg, 60%), yellow solid.LCMS(ESI)m/z：335(M+ 1).

Step G：The present embodiment title compound is prepared according to the sequence of embodiment 1 step I, J, K and L, wherein by morpholine- 3- ketone replaces with (S) -3- methoxypyrrolidin -2- ketone.The product is white solid.¹H NMR (400MHz, DMSO-d₆)δ8.99 (t, J=6.0Hz, 1H), 7.83 (d, J=8.8Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.41 (d, J=2.4Hz, 1H), 7.26-7.21 (m, 2H), 4.59-4.53 (m, 2H), 4.13-4.04 (m, 3H), 3.74-3.69 (m, 4H), 3.45 (s, 3H), 3.31-3.30 (m, 1H), 2.43-2.41 (m, 1H), 1.92-1.87 (m, 1H)；LCMS(ESI)m/z：478(M+1).

Embodiment 26

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxo -2- azabicyclos [2.2.2] octyl- 2- yls) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, into MeOH (250mL) solution of 4- oxocyclohex alkane carboxylic acid, ethyl esters (5.0g, 29.4mmol) NH3 is passed through, Pd/C (1.0g, 10%) is then added in, hydrogen is introduced by balloon.Agitating and heating 16 hours at 40 DEG C.Filtering Reaction mixture, the filtrate was concentrated to dryness.Thick residue is purified through silica gel chromatograph (PE: EtOAc=40: 1~10: 1), obtains 4- ammonia Butylcyclohexane carboxylic acid, ethyl ester (1.9g, 38.2%), brown solid.

Step B：4- cyclohexanecarboxylic acids ethyl ester (1.9g, 11.1mmol) is dissolved in PhMe (10mL) and is heated to 170 DEG C continue 3 hours, after being cooled to room temperature, thick residue is purified through silica gel chromatograph (PE: EtOAc=80: 1~30: 1), obtains 2- Azabicyclo [2.2.2] octyl- 3- ketone (0.51g, 28.2%), brown solid.

Step C：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, H, I, J, K and L, wherein will Morpholine -3- ketone replaces with 2- azabicyclos [2.2.2] octyl- 3- ketone.The product is white solid.¹H NMR (400MHz, DMSO- d₆) δ 8.17 (t, J=5.6Hz, 1H), 6.96 (d, J=8.8Hz, 1H), 6.87 (d, J=4.0Hz, 1H), 6.16 (d, J= 2.4Hz, 1H), 6.11 (d, J=8.8Hz, 1H), 3.76-3.68 (m, 2H), 3.24-3.17 (m, 3H), 2.89-2.86 (m, 2H), 1.63 (s, 1H), 1.93-1.87 (m, 3H), 1.01-0.86 (m, 8H.LCMS (ESI) m/z：488(M+1).

Embodiment 27

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- azabicyclos [2,2,1] hept- 3- ketone) -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：By 2- azabicyclos [2.2.1] hept- 5- alkene -3- ketone (2.0g, 18.3mmol) and dry Pd/C (0.2g, 10%) is added in MeOH (40mL), is introduced hydrogen with balloon, is then stirred mixture 16 hours at 45 DEG C. Reaction mixture is filtered, filtrate is concentrated to dryness, and obtains 2- azabicyclos [2.2.1] hept- 3- ketone (1.6g, 78.8%), and white is solid Body.

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, H, I, J, K and L, wherein will Morpholine -3- ketone replaces with 2- azabicyclos [2.2.1] hept- 3- ketone.The product is white solid isomer, through preparative SFC and preparation HPLC are further purified, and obtain two components, and one is 28.5mg, another 3.6mg.Component 1：¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J=5.6Hz, 1H), 7.76 (d, J=8.8Hz, 1H), 7.70 (d, J=4.0Hz, 1H), 7.26 (d, J=4.0Hz, 1H), 7.20 (d, J=2.0Hz, 1H), 7.13 (dd, J=8.8,2.0Hz, 1H), 4.57-4.52 (m, 3H), 4.02 (m, 2H), 3.69-3.72 (m, 2H), 2.78 (s, 1H), 1.93-1.87 (m, 3H), 1.65-1.60 (m, 1H), 1.50-1.48 (m, 2H) .MS (ESI) m/z：474 (M+1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J= 5.6Hz, 1H), 7.76 (d, J=8.8Hz, 1H), 7.70 (d, J=4.0Hz, 1H), 7.27 (d, J=4.0Hz, 1H), 7.20 (d, J=2.4Hz, 1H), 7.13 (m, 1H), 4.57-4.53 (m, 3H), 4.07-3.98 (m, 2H), 3.72-3.69 (m, 2H), 2.78 (s, 1H), 1.95-1.87 (m, 3H), 1.65-1.60 (m, 1H), 1.50-1.48 (m, 2H) .MS (ESI) m/z：474(M+1).

Embodiment 28

The chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxo thiomorpholine generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：After Na (1.06g, 46mmol) is dissolved in PrOH (100mL), 2- thioacetic acid second is added at room temperature Ester (8.29g, 69mmol) is simultaneously stirred at room temperature 0.5 hour.Then add at room temperature oxazolidine -2- ketone (2.00g, 23mmol) and at 100 DEG C stir 16 hours.Solvent is removed in vacuum, adds in water (20mL), EtOAc (20mL x 3) extractions.Merge Organic layer is purified with silica gel chromatograph (PE: EtOAc=1: 1~1: 3) after drying, filtering, concentration, obtains thiomorpholine -3- ketone (1.10g, 40%), light yellow solid.

Step B：By thiomorpholine -3- ketone (350mg, 3mmol), (3R, 3aS) -7- bromo -3- ((tertbutyldimethylsilyl chlorides Silylation) methyl) -3a, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.04g, 2.5mmol), Cs₂CO₃(1.63g, 5mmol), Pd₂(dba)₃(230mg), Isosorbide-5-Nitrae-dioxane (30mL) solution of Xantphos (430mg) Mixture stirs 16 hours at 90 DEG C.Mixture is cooled to room temperature, filter and is concentrated.Thick residue through silica gel chromatograph (PE: EtOAc=5: 1~2: 1) purify, obtain (3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- (3- Oxo thiomorpholine generation) -3a, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (640mg, 56%), Yellow solid.MS(ESI)m/z：451(M+1).

Step C：The present embodiment title compound is prepared according to the sequence of embodiment 1 step H, I, J, K and L, wherein will Quinoline -3- ketone replaces with thiomorpholine -3- ketone.The product is white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J= 6.0Hz, 1H), 7.83 (d, J=8.8Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.93- 6.90 (m, 2H), 4.60-4.53 (m, 2H), 4.10-4.01 (m, 2H), 3.91 (t, J=5.6Hz, 2H), 3.72 (t, J= 5.6Hz, 2H), 3.39 (s, 2H), 3.01 (t, J=5.6Hz, 2H) .MS (ESI) m/z：480(M+1).

Embodiment 29

The chloro- N- of 5- (((3S, 3aS) -7- (1,1- titanium dioxide -3- oxo thiomorpholine generations) -1- oxos -1,3,3^a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, to the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxo thiomorpholine generations) -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (48mg, 0.1mmol) DCM M-CPBA (41mg, 0.24mmol) is added portionwise in (3mL) solution and is stirred 2 hours at 0 DEG C.Add in saturation NaHCO₃Solution (10mL), DCM (10mL x 3) extractions.Merge organic relevant dry, concentration.Thick residue is through preparative TLC and preparation HPLC (hydrochloric acid) purifies, and obtains the present embodiment title compound (20mg, 50%), white solid.¹H NMR (400MHz, DMSO-d₆)δ 9.00 (t, J=6.0Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.20 (d, J=4.0Hz, 1H), 6.94-6.91 (m, 2H), 4.62-4.55 (m, 2H), 4.41 (s, 2H), 4.11-4.02 (m, 4H), 3.74-3.68 (m, 4H).MS(ESI)m/z：512(M+1).

Embodiment 30

The chloro- N- of 5- (((3S, 3aS) -7- ((R) -2- (methoxyl methyl) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) first is prepared according to the method for embodiment 6 Base) -7- ((R) -2- (methoxy) pyrrolidin-1-yl) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines - 1 (3H) -one, wherein 1, the 3- oxazepine hexamethylene -2- ketone in rapid A is replaced with into (R) -2- (methoxy) pyrrolidines, Yield 92%.LCMS(ESI)m/z：449.2(M+1).

Step B：The present embodiment title solid chemical compound is prepared according to the sequence of embodiment 1 step G, I, J, K, L.¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J=5.4Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.57 (d, J=9.2Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.27 (dd, J=9.2,2.8Hz, 1H), 6.16 (d, J=2.8Hz, 1H), 4.53-4.46 (m, 2H), 3.97-3.95 (m, 2H), 3.78-3.73 (m, 1H), 3.70 (t, J=5.6Hz, 2H), 3.33-3.31 (m, 2H), 3.27 (s, 3H), 3.21-3.17 (m, 1H), 3.01-2.95 (m, 1H), 1.99-1.87 (m, 4H)；LCMS(ESI)m/z：478.1(M+ 1).

Embodiment 31

The chloro- N- of 5- (((3S, 3aS) -7- ((S) -2- (methoxyl methyl) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Oxygen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title solid chemical compound is prepared according to the sequence of embodiment 30 step A and B, it is solid for white Body.(R) -2- (methoxy) pyrrolidines in step A is wherein replaced with into (S) -2- (methoxy) pyrrolidines.¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J=6.0Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.58 (d, J=8.8Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.27 (dd, J=9.2,2.4Hz, 1H), 6.15 (d, J=2.8Hz, 1H), 4.53- 4.46 (m, 2H), 3.98-3.96 (m, 2H), 3.71-3.68 (m, 3H), 3.36-3.32 (m, 2H), 3.27 (s, 3H), 3.21- 3.16 (m, 1H), 3.01-2.95 (m, 1H), 2.01-1.84 (m, 4H)；LCMS(ESI)m/z：478.1(M+1).

Embodiment 32

The chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxo-pyrrolidine -3- bases) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：To (3R, 3aS) -7- bromos -3- (((t-butyldimethylsilyl) oxygroup) methyl) -3a, 4- bis- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (4.0g, 9.65mmol), Pd (OAc)₂(0.22g, 0.97mmol) and in the THF of Xantphos (0.92g, 1.93mmol) (60mL) solution add in (2- ethyoxyl -2- oxoethyls) Zinc (II) bromine (1.12g, 48.27mmol).Mixture is refluxed 16 hours, cooling, concentration.Thick residue is passed through into silica gel Chromatography (petroleum ether: ethyl acetate=15: 1~10: 1) purifies, obtains 2- ((3R, 3aS) -3- (((t-butyl-dimethylsilyls Base) oxygroup) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) acetate (2.38 grams, 58%), light yellow oil.LCMS(ESI)m/z：422.2(M+1).

Step B：At -70 DEG C, to 2- ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -1- oxygen Generation -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) acetate (600mg, 1.42mmol) LiHMDS (1.56mL, 1M in THF) is added dropwise in THF (5mL) solution, gained mixture stirs 1 hour at -70 DEG C, then THF (2mL) solution of 2- bromoacetonitriles (307mg, 2.56mmol) is added dropwise at -70 DEG C.Gained mixture is stirred at -70 DEG C It 1 hour, is then heated to 15 DEG C and stirs 16 hours.Mixture is poured into saturation NH₄In Cl aqueous solutions (30mL), EtOAc is used (30mL x 3) is extracted.The organic phase of merging is dried, filtered and concentrated with anhydrous sodium sulfate.Thick residue is passed through into silica gel chromatograph It (petroleum ether: ethyl acetate=10: 1~5: 1) purifies, obtains 2- ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygen Base) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- cyanopropionic acid esters (366mg, 56%) is yellow oil.LCMS(ESI)m/z：461.2(M+1).

Step C：To 2- ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- cyanopropionic acids ester (366mg, 0.79mmol) MeOH (20mL) and NH₃·H₂Raney Nickel (100mg) are added in O (30% aqueous solution, 4mL).Gained mixture exists It is stirred at room temperature under the Hydrogen Vapor Pressure of 30psi 16 hours.Filtering mixture simultaneously concentrates filtrate, thick residue silica gel chromatographPurifying, obtains (3R, 3aS) -3- (((t-butyldimethylsilyl) oxygen Base) methyl) -7- (2- oxo-pyrrolidine -3- bases) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) - Ketone (160mg, 48%) is colorless oil.LCMS(ESI)m/z：419.2(M+1).

Step D：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K, L, wherein by step Morpholine -3- ketone in G replaces with 2- oxo-pyrrolidines, white solid isomer is obtained, through preparative SFC and preparation HPLC It is further purified, obtains two components, component 1 is 7.5mg, and component 2 is 3.5mg.Component 1：¹H NMR (400MHz, DMSO-d₆) δ 8.8 (t, J=5.6Hz, 1H), 7.68-7.84 (m, 3H), 7.20 (d, J=4.0Hz, 1H), 6.80-6.88 (m, 2H), 4.43- 4.66 (m, 2H), 3.93-4.13 (m, 2H), 3.72 (t, J=5.2Hz, 2H), 3.46 (t, J=8.8Hz, 1H), 3.20-3.30 (m, 2H), 2.38-2.48 (m, 1H), 2.02 (m, 1H)；MS(ESI)m/z：465 (M+1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 9.0 (t, J=5.6Hz, 1H), 7.70-7.80 (m, 3H), 7.20 (d, J=4.0Hz, 1H), 6.80-6.88 (m, 2H), 4.43-4.66 (m, 2H), 3.93-4.13 (m, 2H), 3.73 (t, J=5.2Hz, 2H), 3.47 (t, J=8.8Hz, 1H), 3.21-3.31 (m, 2H), 2.39-2.49 (m, 1H), 2.03 (dq, J=12.4,8.8Hz, 1H) .MS (ESI) m/z：465(M+ 1).

Embodiment 33

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- aminosulfonylphenyls) -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Preparation flow：

Step A：According to the sequence of embodiment 1 step G, I, J, K, L prepare N- (((3S, 3aS) 7- bromo -1- oxo -1, 3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chlorothiophene -2- formamides, wherein will Morpholine -3- ketone in step G replaces with bromine.LCMS(ESI)m/z：443,445 (M+1)

Step B：N- is added in flask, and ((the bromo- 1- oxos -1,3 of (3S, 3aS) -7-, 3a, 4- tetrahydro benzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chlorothiophene -2- formamides (500mg, 1.13mmol), Pd (dppf) Cl₂ (80mg, 0.113mmol), duplex Knit-the-brows alcohol borate (430mg, 1.70mmol), KOAc (332mg, 3.39mmol) and Isosorbide-5-Nitrae- Dioxanes (6mL), rapidly with the air in reaction system with nitrogen.Reaction is heated to 80 DEG C, continues 16 hours.Cooling It to room temperature, pours into water (25mL), is extracted with EtOAc (30mL x 2).Merge organic phase to be dried with anhydrous sodium sulfate, filter And it concentrates.Thick residue through silica gel chromatograph (PE: EA=5: 1 to 1: 1) is purified, obtains the chloro- N- of 5- (((3S, 3aS) -1- oxygen Generation -7- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4- D] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (430mg, 77%) are white solid.LCMS(ESI)m/z：491.2 (M+1).

Step C：To the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (4,4,5,5- tetramethyls -1,3, penta boron of 2- dioxas Alkane -2- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives 2- bromophenylsulfonyls amine (452mg, 1.74mmol), Pd (t- are added in Isosorbide-5-Nitrae-dioxanes (6mL) solution of (430mg, 0.87mmol) Bu₃P)₄(90mg, 0.174mmol), Cs₂CO₃(572mg, 1.74mmol) and H₂O(1mL).80 DEG C are heated the mixture to, and is held It is 16 hours continuous.Gained mixture is cooled down, is subsequently poured into water (30mL), is extracted with DCM (30mL x 3), uses anhydrous Na₂SO₄It is dry It is dry, it filters and concentrates.Thick residue is purified with silica gel chromatograph (PE: EA=1: 2), then pure again with preparation HPLC (formic acid) Change, obtain the present embodiment title compound (52mg, 11%), be white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.02 (t, J=6.0Hz, 1H), 8.01 (d, J=7.6Hz, 1H), 7.86 (d, J=8.8Hz, 1H), 7.73 (d, J=4.0Hz, 1H), 7.62-7.56 (m, 2H), 7.31-7.30 (m, 1H), 7.23-7.21 (m, 3H), 6.99 (d, J=7.6Hz, 2H), 4.62-4.55 (m, 2H), 4.12-4.04 (m, 2H), 3.75-3.74 (m, 2H)；LCMS(ESI)m/z：520.0(M+1).

Embodiment 34

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (1H-1,2,4- triazol-1-yls) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- is prepared according to embodiment 1 (1H-1,2,4- triazol-1-yls) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one, wherein will step Morpholine -3- ketone in rapid G replaces with 1H-1,2,4- triazoles, yield 30%.LCMS(ESI)m/z：403(M+1).

Step B：The title compound of embodiment 2 is prepared according to embodiment 1 step G, I, J, K and L sequence, it is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.05 (t, J=5.6Hz, 1H), 8.22 (s, 1H), 8.02 (d, J= 8.4Hz, 1H), 7.75 (d, J=4.0Hz, 3H), 7.52 (m, 2H), 7.22 (d, J=4.0Hz, 1H), 4.64 (m, 2H), 4.14 (m, 2H), 3.75 (t, J=5.6Hz, 2H)；LCMS(ESI)m/z：432(M+1).

Embodiment 35

The chloro- N- of 5- (((3S, 3aS) -7- (2- ((dimethylamino) methyl) -1H- imidazoles -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：To the bromo- 3- of (3R, 3aS) -7- (((t-butyldimethylsilyl) oxygroup) methyl) -3a, 4- dihydros Benzo [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) (2.0g, 4.38mmol), K₂CO₃(0.8g, 5.80mmol), 1- (1H- miaows Azoles -2- bases)-N, the DMSO of N- dimethyl methylamine (0.9g, 7.24mmol) and 8-hydroxyquinoline (140mg, 0.96mmol) (12mL) solution, is first deaerated with nitrogen, adds CuI (500mg, 2.2mmol).Mixture is stirred 16 hours at 130 DEG C. It after being cooled to room temperature, pours into water (25mL), is extracted, dried with anhydrous sodium sulfate, and concentrate with EtOAc (30mL x2).It will be thick Residue is purified by silica gel chromatograph (PE: EA=5: 1~1: 1), obtains (3R, 3aS) -3- (((t-butyl-dimethylsilyls Base) oxygroup) methyl) -7- (2- ((dimethylamino) methyl) -1H- imidazoles -1- bases) -3a, 4- dihydrobenzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one is yellow solid.LCMS(ESI)m/z：459(M+1).

Step B：The title compound of embodiment 35 is prepared according to embodiment 1 step G, I, J, K and L sequence, wherein will step Morpholine -3- ketone in rapid G replaces with 1- (1H- imidazoles -2- bases)-N, and N- dimethyl methylamines are white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.06 (t, J=5.6Hz, 1H), 8.7 (d, J=8.8Hz, 1H), 7.74 (d, J=4.0Hz, 1H), 7.53 (d, J=1.2Hz, 1H), 7.22 (m, 3H), 7.12 (dd, J=8.8,2.0Hz, 1H), 4.66 (m, 2H), 4.4 (s, 2H), 4.1 (m, 2H), 3.76 (m, 2H), 2.78 (s, 2H)；LCMS(ESI)m/z：488(M+1).

Embodiment 36

The chloro- N- of 5- (((3S, 3aS) -7- (2- ethyl -4,5- dihydro -1H- imidazoles -1- bases) -1- oxos -1,3,3a, 4- tetra- Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Preparation flow：

Step A：((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) is prepared according to the method for embodiment 6 Methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) t-butyl carbamate, 1, the 3- oxazepine hexamethylene -2- ketone in rapid A is wherein replaced with into t-butyl carbamate, yield 85%.LCMS(ESI) m/z：451.2(M+1).

Step B：((3S, 3aS) -3- ((5- chlorothiophene -2- first is prepared according to the sequence of embodiment 1 step G, I, J, K and L Acylamino-) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) carbamic acid The tert-butyl ester.LCMS(ESI)m/z：480.1(M+1).

Step C：((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) t-butyl carbamate (0.62g, 1.29mmol) 4MHCl methanol it is molten Liquid (10mL) stirs 16 hours at 15 DEG C.Mixture is filtered, filter cake is washed with DCM.Then saturation NaHCO is used₃Aqueous solution Adjust filtrate pH value beAnd it is extracted with DCM (50mL x 5).By the organic phase anhydrous Na of merging₂SO₄It is dry, mistake Filter, concentration, obtaining N-, (((3S, 3aS) -7- amino -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] are disliked Piperazine -3- bases) methyl) -5- chloro thiophene -2- formamides (340mg, 69%), yellow solid.LCMS(ESI)m/z：380,382 (M +1).

Step D：To N- (((3S, 3aS) -7- amino -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole [3,4-d] [1, 4] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides (380mg, 1mmol) methanol (8mL) and dimethylformamide (2- oxoethyls) t-butyl carbamate ((159mg, 1mmol)) is added in (8mL) solution, acetic acid is then added in and adjustsMixture is stirred at room temperature 1 hour, then adds in NaBH₃CN (126mg, 2mmol), and stir at room temperature It mixes 16 hours.Saturation NH is added in into gained mixture₄Cl (15mL) aqueous solution (15mL), and concentrate mixture.It will be thick remaining Object (PE: ethyl acetate=3: 1~1: 1) obtains (2- ((3S, 3aS) -3- ((5- chlorothiophene -2- formyl ammonia by silica gel chromatograph Base) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) the tertiary fourth of carbamic acid Ester (300mg, 57%) is white solid.LCMS(ESI)m/z：523,525 (M+1)

Step E：At room temperature, to (2- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) amino) ethyl) t-butyl carbamate (209mg, 0.4mmol), propionyl chloride is added in DCM (3mL) solution of pyridine (63mg, 0.8mmol) and DMAP (10mg, 0.08mmol) In DCM (1mL) solution of (56mg, 0.6mmol), mixture is stirred at room temperature 16 hours, is added into the mixture of gained Enter saturation NH₄In Cl aqueous solutions (20mL), and extracted with DCM (20mL x 3).The organic layer of merging is dried with anhydrous sodium sulfate, It filters and concentrates.By thick residue by silica gel chromatograph (PE: ethyl acetate=3: 1~1: 1) purify, obtain (2- (N- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) propionamido-) ethyl) t-butyl carbamate (200mg, 86%), white solid.LCMS(ESI)m/ z：579,581 (M+1)

Step F：At room temperature, to (2- (N- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos - 1,3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) propionamido-) ethyl) t-butyl carbamate Isosorbide-5-Nitrae-dioxane (3mL) of 4M HCl is added in DCM (3mL) solution of (232mg, 0.4mmol), and is stirred at room temperature 1 hour.Solvent is removed in vacuum, residue is dissolved in AcOH (4mL), and is stirred 16 hours at 120 DEG C, by reaction solution Concentration.Thick residue is passed through into thin-layered chromatography (DCM: methanol=10: 1) purifying obtains crude product, crude product is passed through preparation Type HPLC (formic acid) is further purified, and obtains the present embodiment title compound (27mg, 14%), is white solid¹H NMR (400MHz, DMSO-d₆) δ 9.05 (t, J=5.6Hz, 1H), 8.28 (brs, 1H), 7.83 (d, J=8.8Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.92-6.88 (m, 2H), 4.61-4.56 (m, 2H), 4.07-4.04 (m, 2H), 3.85-3.82 (m, 2H), 3.74-3.69 (m, 4H), 2.30 (q, J=7.2Hz, 2H), 1.01 (t, J=7.2Hz, 3H) .LCMS(ESI)m/z：461,463 (M+1)

Embodiment 37

The chloro- N- of 5- (((3S, 3aS) -7- (2- cyclopropyl -4,5- dihydro -1H- imidazoles -1- bases) -1- oxygen -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(2- (N- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) are prepared according to the method for embodiment 36 Methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) cyclopropanecarbonyl amino) Ethyl) t-butyl carbamate, wherein the propionyl chloride in step E is replaced with cyclopropane base formyl chloride, yield 76%.LCMS (ESI)m/z：591,593 (M+1)

Step B：The present embodiment title compound is prepared according to the method for step F in embodiment 36, obtains white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.04 (t, J=5.6Hz, 1H), 8.28 (brs, 1H), 7.83 (d, J=8.8Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.97-6.91 (m, 2H), 4.60-4.55 (m, 2H), 4.07-4.04 (m, 2H), 3.82-3.79 (m, 2H), 3.74-3.70 (m, 2H), 3.63-3.60 (m, 2H), 1.53-1.48 (m, 1H), 0.97- 0.86 (m, 4H)；LCMS(ESI)m/z：473,475 (M+1)

Embodiment 38

The chloro- N- of 5- (((3S, 3aS) -7- (- 1 (4H)-yl of 2- ethyls -5,6- dihydro-pyrimidin) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(3- (((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) first is prepared according to the method for embodiment 36 Base) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) amino) propyl) carbamic acid The tert-butyl ester, wherein (2- oxoethyls) t-butyl carbamate in step D is replaced with (3- oxopropyls) carbamic acid uncle Butyl ester, yield are 65%.LCMS (ESI) m/z：537,539 (M+1)

Step B：At room temperature, to (3- (((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos - 1,3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) amino) propyl) t-butyl carbamate Isosorbide-5-Nitrae-dioxane (3mL) of 4M HCl is added in DCM (3mL) solution of (215mg, 0.4mmol), by mixture in room temperature Lower stirring 1 hour.Solvent is removed under reduced pressure, by residue be dissolved in 1,1,1- triethoxy propane/acetic acid (in (6mL, 1: 1)), And it is stirred 2 hours at 120 DEG C.After being cooled to room temperature, reaction mixture is concentrated.Crude residue is through preparation HPLC (salt Acid) purifying, obtaining the present embodiment title compound, ((50mg, 26%) is yellow solid.¹H NMR (400MHz, DMSO-d₆)δ 10.10 (brs, 1H), 9.12 (brs, 1H), 7.99 (d, J=8.8Hz, 1H), 7.78-7.75 (m, 1H), 7.24 (d, J= 2.4Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 7.00 (dd, J=8.8,2.4Hz, 1H), 4.64-4.58 (m, 2H), 4.13- 4.09 (m, 2H), 3.75-3.71 (m, 2H), 3.66-3.64 (m, 2H), 3.36-3.33 (m, 2H), 2.30-2.23 (m, 2H), 2.10-2.05 (m, 2H), 0.99 (t, J=7.2Hz, 2H)；LCMS(ESI)m/z：475,477 (M+1)

Embodiment 39

The chloro- N- of 5- (((3S, 3aS) -7- (4,5- dihydro -1H- imidazoles -2- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Preparation flow：

Step A：N- (((3S, 3aS) -7- bromo -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [1, 4] oxazines -3- bases) methyl) -5- chlorothiophene -2- formamides (200mg, 0.45mmol), CuCN (161mg, 1.80mmol) and CuI NMP (15mL) solution of (9mg, 45umol), is stirred 8 hours at 180 DEG C.Mixture is filtered, by filtrate with EtOAc (5mL X 3) washing.Organic layer with water (25mL x 2) is washed, uses anhydrous Na₂SO₄It is dried, filtered and concentrated.Thick residue is passed through Silica gel chromatograph (PE: ethyl acetate=3: 1~1: 1) purify, obtain the chloro- N- of 5- (((3S, 3aS) -7- cyano -1- oxos -1,3, 3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (120mg, 68%), be Yellow solid.LCMS(ESI)m/z：390,392 (M+1)

Step B：At 0 DEG C, the chloro- N- of 5- (((3S, 3aS) -7- cyano -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (200mg, 0.513mmol) absolute methanol (5mL) it is molten In liquid, with hydrogen chloride gas bubbling 30 minutes.The reaction mixture is concentrated under reduced pressure, obtain (3S, 3aS) -3- ((- 5- chlorothiophenes - 2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- first imidic acids Methyl esters is yellow solid.Crude product is used in next step, without being further purified.

Step C：(3S, 3aS) -3- ((- 5- chlorothiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- first methyl ester imidate (85mg, 0.205mmol) and ethane -1,2- diamines (1mL) MeOH (10mL) solution, stirred 2 hours at 12 DEG C.Reaction mixture is concentrated, thick residue is through preparation HPLC (first Acid) purifying, the present embodiment title compound (20mg, 20%) is obtained, is white solid.¹H NMR (400MHz, DMSO-d₆)δ 9.06 (t, J=5.6Hz, 1H), 8.32 (s, 1H), 7.99 (d, J=7.2Hz, 1H), 7.73 (d, J=4.4Hz, 1H), 7.52- 7.49 (m 2H), 7.21 (d, J=4.4Hz, 1H), 4.64-4.58 (m, 2H), 4.16-4.07 (m, 2H), 3.73-3.71 (m, 6H)；LCMS(ESI)m/z：433,435 (M+1)

Embodiment 40

The chloro- N- of 5- (((3S, 3aS) -7- (1- methyl -4,5- dihydro -1H- imidazoles -2- bases) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the method for embodiment 39, wherein by ethane -1 in step C, 2- diamines replaces with N- Methylethyl -1,2- diamines, obtains white solid, yield 44%.¹H NMR (400MHz, DMSO-d₆)δ 9.08 (t, J=5.2Hz, 1H), 8.31 (s, 1H), 8.02 (d, J=8.4Hz, 1H), 7.74 (d, J=4.0Hz, 1H), 7.23- 7.20 (m, 3H), 4.65-4.59 (m, 2H), 4.14-4.07 (m, 2H), 3.75-3.74 (m, 3H), 3.67-3.65 (m, 3H), 2.87 (s, 3H)；LCMS(ESI)m/z：447,449 (M+1)

Embodiment 41

The chloro- N- of 5- (((3S, 3aS) -7- (1- methyl-1s, 4,5,6- tetrahydropyrimidine -2- bases) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the method for embodiment 39, wherein by ethane -1 in step C, 2- diamines replaces with N- methyl-propyl -1,3- bis aminomethyl ethane, obtains white solid, yield 44%.¹H NMR (400MHz, DMSO-d₆) δ 9.08 (t, J=5.2Hz, 1H), 8.31 (s, 1H), 8.02 (d, J=8.4Hz, 1H), 7.74 (d, J =4.0Hz, 1H), 7.23-7.20 (m 3H), 4.65-4.59 (m, 2H), 4.14-4.07 (m, 2H), 3.75-3.74 (m, 3H), 3.67-3.65 (m, 3H), 2.87 (s, 3H)；LCMS(ESI)m/z：461,463 (M+1)

Embodiment 42

N- ((dislike by (3S, 3aS) -7- ((S) -3- amino-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides

Step A：((S) -1- ((3R, 3aS) -3- (((t-butyl-dimethylsilyls are prepared according to the method for embodiment 6 Base) oxygroup) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3-1,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrroles Alkane -3- bases) t-butyl carbamate, wherein 1, the 3- oxazepine hexamethylene -2- ketone in step A is replaced with (S)-pyrroles Alkane -3- carbamates, yield 96%.LCMS(ESI)m/z：520.2(M+1).

Step B：((S) -1- ((3S, 3aS) -3- ((5- chlorine is prepared according to the sequence of step G, I, J, K and L in embodiment 1 Thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) Pyrrolidin-3-yl) t-butyl carbamate.LCMS(ESI)m/z：549.2(M+1).

Step C：((S) -1- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidin-3-yl) t-butyl carbamate (45mg, 4M HCl methanol solutions (2.0mL) 0.1mmol) stir 1 hour at 5 DEG C.Mixture is concentrated, and adds in water.It removes molten Residue is lyophilized for agent, obtains the present embodiment title compound (35mg, 94%), yellow solid.¹H NMR (400MHz, DMSO-d₆) δ 9.11 (t, J=5.6Hz, 1H), 8.27 (brs, 3H), 7.77 (d, J=4.0Hz, 1H), 7.64 (d, J= 9.2Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 6.26 (dd, J₁=2.4Hz, J₂=9.2Hz, 1H), 6.15 (d, J=2.8Hz, 1H), 4.55-4.48 (m, 2H), 4.01-3.97 (m, 3H), 3.71-3.68 (m, 2H), 3.46-3.44 (m, 2H), 3.27-3.22 (m, 2H), 2.32-2.29 (m, 1H), 2.08-2.05 (m, 1H)；LCMS(ESI)m/z：449,451 (M+1)

Embodiment 43

N- ((dislike by (3S, 3aS) -7- ((R) -3- amino-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides

Step A：The present embodiment title compound is prepared according to the sequence of embodiment 42 step A, B, C, wherein by (S)-pyrrole It coughs up alkane -3- carbamates and replaces with (R)-pyrrolidin-3-yl t-butyl carbamate, be white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.11 (t, J=5.6Hz, 1H), 8.27 (br s, 3H), 7.77 (d, J=4.0Hz, 1H), 7.64 (d, J=9.2Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 6.26 (dd, J₁=2.4Hz, J₂=9.2Hz, 1H), 6.15 (d, J= 2.8Hz, 1H), 4.55-4.48 (m, 2H), 4.01-3.97 (m, 3H), 3.71-3.68 (m, 2H), 3.46-3.44 (m, 2H), 3.27-3.22 (m, 2H), 2.32-2.29 (m, 1H), 2.08-2.05 (m, 1H)；LCMS(ESI)m/z：449,451 (M+1)

Embodiment 44

The chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (methylamino) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, to (R) -1- ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) - 1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidin-3-yl) carbamic acid uncle In DMF (10mL) solution of butyl ester (1.0g, 1.9mmol) add in sodium hydride (contain 60% sodium hydride mineral oil solution, 110mg, 2.7mmol), MeI (520mg, 3.6mmol) is then added at 0 DEG C, gained mixture stirs 1 hour at 5 DEG C, this is mixed Object is poured into saturated ammonium chloride solution, and is extracted with EtOAc (100mL x 3).Organic phase is washed with brine, and uses anhydrous sodium sulfate It is dry, concentration, obtain ((R) -1- ((3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -1- oxo -1, 3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidin-3-yl) the tertiary fourth of (methyl) carbamic acid Ester (1.0g, 99%) is yellow solid, is directly used in next step reaction.LCMS(ESI)m/z：534.3(M+1).

Step B：Sequentially prepared according to embodiment 1 step G, I, J, K and L ((R) -1- ((3S, 3aS) -3- ((5- chlorothiophenes - 2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrroles Alkane -3- bases) (methyl) t-butyl carbamate, wherein the morpholine -3- ketone in step G is replaced with pyrrolidin-3-yl (methyl) T-butyl carbamate.LCMS(ESI)m/z：563.2(M+1).

Step C：((R) -1- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidin-3-yl) (methyl) t-butyl carbamate (90mg, In 4M HCl methanol solutions (3mL) 0.2mmol), stirred 1 hour at 17 DEG C.Reaction mixture is concentrated, and uses preparative HPLC (hydrochloric acid) is purified, and obtains the present embodiment title compound (50mg, 67%), is white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.26 (brs, 2H), 9.12 (d, J=6.0Hz, 1H), 7.77 (d, J=4.4Hz, 1H), 7.63 (d, J= 8.8Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 6.28 (dd, J=8.8,2.4Hz, 1H), 6.18 (d, J=2.4Hz, 1H), 4.55-4.48 (m, 2H), 4.00-3.97 (m, 2H), 3.84-3.75 (m, 1H), 3.57-3.52 (m, 2H), 3.48-3.40 (m, 3H), 3.21-3.19 (m, 1H), 2.60-2.58 (m, 3H), 2.34-2.16 (m, 2H)；LCMS(ESI)m/z：463,465 (M+ 1).

Embodiment 45

The chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 10 DEG C, to the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (methylamino) pyrrolidin-1-yl) -1- Oxo -1,3,3a, 4- tetrahydro benzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (74mg, Aqueous formic acid (1.0mL, 33%) is added in MeOH (3.0mL) solution 0.2mmol), is stirred 30 minutes at 17 DEG C, Ran Houjia Enter NaBH₃CN (25mg, 1.0mmol), and stir at 40 DEG C the mixture 2 hours, reaction is quenched with water, with DCM (20mL x 3) it extracts.Merge organic phase to be dried with anhydrous sodium sulfate, concentrate, thick residue is purified by preparation HPLC (hydrochloric acid), is obtained The present embodiment title compound (25mg, 33%) is white solid¹H NMR (400MHz, DMSO-d₆) δ 11.09 (brs, 1H), 9.10 (t, J=6.4Hz, 1H), 7.77 (d, J=4.0Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 6.30 (dd, J=8.8,2.4Hz, 1H), 6.22 (d, J=2.4Hz, 1H), 4.55-4.48 (m, 2H), 4.00-3.80 (m, 3H), 3.71-3.68 (m, 2H), 3.56-3.55 (m, 1H), 3.48-3.46 (m, 2H), 3.21-3.19 (m, 1H), 2.80-2.78 (m, 6H), 2.40-2.20 (m, 2H)；LCMS(ESI)m/z：477,479 (M+1)

Embodiment 46

The chloro- N- of 5- (((3S, 3aS) -7- (3- hydroxy piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At room temperature, to piperidin-3-ol (1.01g, 10mmol), the THF/Py of TBDPSCl (3.30g, 12mmol) (21mL, 4: 3) AgNO is added in solution₃(3.57g, 21mmol), and be stirred at room temperature 16 hours.By mixture filtering simultaneously Concentration.Thick residue is passed through into silica gel chromatograph (methanol: DCM=1: 50~1: 20) purifying obtains 3- ((tert-butyl diphenyl first Silylation) oxygroup) piperidines (3.00g, 88%) is brown oil.LCMS(ESI)m/z：340(M+1).

Step B：N- (((3S, 3aS) -7- (3- ((tertiary butyls are prepared according to the sequence of embodiment 1 step F, G, I, J, K and L Diphenylsilyl group) oxygroup) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] evil Piperazine -3- bases) methyl) -5- chloro thiophene -2- formamides, wherein morpholine -3- ketone is replaced with 3- ((t-butyidiphenylsilyls Base) oxygroup) piperidines.LCMS(ESI)m/z：702(M+1).

Step C：At room temperature to N- (((3S, 3aS) -7- (3- ((t-butyldiphenylsilyl) oxygroup) piperidines -1- Base) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophenes -2- In THF (10mL) solution of formamide (913mg, 1.3mmol), n-Bu is added dropwise₄The THF of NF (1.23g, 4.7mmol) (10mL) solution stirs 16 hours at room temperature, concentrates mixture, thick residue is through silica gel chromatograph (methanol: DCM=1: 50~1 : 20) it purifies, obtains the present embodiment title compound (480mg, 79%), be light yellow solid form isomer.It is different with point Structure body is further purified to obtain two components through preparative SFC and preparation HPLC, and component 1 is 120mg, and component 2 is 120mg. Component 1：¹H NMR (400MHz, CD₃OD) δ 8.12 (d, J=8.8Hz, 1H), 7.58 (d, J=4.0Hz, 1H), 7.35 (d, J= 2.4Hz, 1H), 7.28 (dd, J=8.8,2.4Hz, 1H), 7.05 (d, J=4.0Hz, 1H), 4.68-4.63 (m, 2H), 4.08- 4.07 (m, 1H), 4.06-4.04 (m, 1H), 4.03-4.01 (m, 1H), 3.83-3.81 (m, 2H), 3.70-3.63 (m, 2H), 3.53-3.42 (m, 2H), 2.35-2.33 (m, 1H), 1.94-1.82 (m, 3H) .MS (ESI) m/z：464 (M+1) components 2：¹H NMR (400MHz, CD₃OD) δ 8.04 (d, J=8.4Hz, 1H), 7.57 (d, J=4.0Hz, 1H), 7.19-7.16 (m, 2H), 7.04 (d, J=4.0Hz, 1H), 4.65-4.60 (m, 2H), 4.10-4.08 (m, 2H), 4.03-4.01 (m, 1H), 3.82-3.80 (m, 2H), 3.65-3.61 (m, 2H), 3.43-3.35 (m, 2H), 2.27-2.24 (m, 1H), 1.92-1.75 (m, 3H) .MS (ESI)m/z：464(M+1).

Embodiment 47

The chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholins) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3, 4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At room temperature, Boc is added in into the acetonitrile solution (50mL) of piperidin-3-ol (1.01g, 10mmol)₂O (2.18g, 10mmol), and be stirred at room temperature 16 hours.Mixture is concentrated, obtains 3- hydroxy piperidine -1- t-butyl formates (2.01g, crude product) is colorless oil.The crude product is directly used in next step.

Step B：At 0 DEG C, to the solution of the THF (20mL) of 3- hydroxy piperidine -1- t-butyl formates (2.01g, 10mmol) It is middle to add in sodium hydride (containing the mineral oil solution of 60% sodium hydride, 400mg, 10mmol), room temperature is gradually increased to, and stir at room temperature It mixes 0.5 hour, room temperature is added dropwise MeI (1.42g, 10mmol) and stirs 16 hours.Mixture is concentrated in vacuo, crude residue warp Silica gel chromatography (PE: EtOAc=1: 50~1: 20) obtains 3- methoxy piperide -1- t-butyl formates (1.50g, 69%), For colorless oil.

Step C：At room temperature, into DCM (5mL) solution of 3- methoxy piperide -1- t-butyl formates (1.51g, 7mmol) The methanol solution (5mL) of 4M HCl is added in, is then stirred at room temperature 16 hours, is concentrated in vacuo, obtains 3- methoxy piperide salt Hydrochlorate (1.05g, crude product) is yellow oil.The crude product is directly used in react in next step.

Step D：The present embodiment title compound is prepared according to embodiment 1 step F, G, I, J, K and L sequence, wherein will step Morpholine -3- ketone in rapid F replaces with 3- methoxy piperides, obtains light yellow solid form isomer.Isomer passes through Preparative SFC and preparation HPLC are further purified to obtain two components, component 1 (60mg), component 2 (100mg).Component 1：¹H NMR (400MHz, CD₃OD) δ 8.11 (d, J=8.8Hz, 1H), 7.57 (d, J=4.0Hz, 1H), 7.31 (d, J=2.4Hz, 1H), 7.25 (dd, J=8.8,2.4Hz, 1H), 7.05 (d, J=4.0Hz, 1H), 4.68-4.63 (m, 2H), 4.12-4.10 (m, 1H), 4.02-3.99 (m, 1H), 3.83-3.80 (m, 3H), 3.67-3.53 (m, 3H), 3.49-3.45 (m, 4H), 2.25-2.20 (m, 1H), 2.05-2.01 (m, 1H), 1.93-1.87 (m, 2H) .MS (ESI) m/z：478 (M+1) components 2：¹H NMR (400MHz, CD₃OD) δ 8.13 (d, J=8.8Hz, 1H), 7.58 (d, J=4.4Hz, 1H), 7.36 (d, J=2.4Hz, 1H), 7.29 (dd, J=8.8,2.4Hz, 1H), 7.04 (d, J=4.4Hz, 1H), 4.68-4.64 (m, 2H), 4.06-4.02 (m, 1H), 4.00-3.97 (m, 1H), 3.84-3.81 (m, 3H), 3.69-3.58 (m, 3H), 3.53-3.50 (m, 1H), 3.46 (s, 3H), 2.25-2.23 (m, 1H), 1.95-1.92 (m, 1H), 1.90-1.84 (m, 2H) .MS (ESI) m/z：478(M+1).

Embodiment 48

N- (((3S, 3aS) -7- ((S) -3- amino piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides

Step A：The present embodiment title compound is prepared according to the sequence of step A, B, C in embodiment 42, wherein by (S)- Pyrrolidin-3-yl carbamate replaces with (S)-piperidines -3- ylcarbamates, and the product is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.19 (d, J=4.0Hz, 1H), 8.41 (br.s., 3H), 7.81 (t, J=2.8Hz, 1H), 7.74 (dd, J=8.4,3.2Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.79 (br.s., 2H), 4.53-4.57 (m, 2H), 3.98-4.09 (m, 2H), 3.70 (t, J=5.6Hz, 2H), 3.58 (d, J=11.2Hz, 1H), 3.35 (d, J= 11.6Hz, 2H), 2.92-3.12 (m, 2H), 1.80-2.01 (m, 2H), 1.51-1.77 (m, 2H)；LCMS(ESI)m/z：463, 465(M+1).

Embodiment 49

N- (((3S, 3aS) -7- ((R) -3- amino piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides

Step A：The present embodiment title compound is prepared according to the sequence of step A, B, C in embodiment 42, wherein by (S)- Pyrrolidin-3-yl carbamate replaces with (R)-piperidines -3- ylcarbamates, and the product is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.15 (t, J=5.6Hz, 1H), 8.31 (brs., 3H), 7.79 (d, J=4.0Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.74 (d, J=8.8Hz, 1H), 6.67 (brs., 1H), 4.49-4.59 (m, 2H), 3.96-4.05 (m, 2H), 3.70 (t, J=5.4Hz, 2H), 3.51-3.57 (m, 1H), 3.31 (d, J=12.4Hz, 2H), 2.99-3.08 (m, 1H), 2.92 (t, J=9.6Hz, 1H), 1.95 (d, J=9.2Hz, 1H), 1.82 (d, J=9.2Hz, 1H), 1.52-1.73 (m, 2H)；LCMS(ESI)m/z：463,465 (M+1)

Embodiment 50

The chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- (methylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the sequence of step A, B, C in embodiment 44, wherein by (S)- Pyrrolidin-3-yl carbamate replaces with (S)-piperidines -3- ylcarbamates, and the product is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.35-9.48 (m, 1H), 9.18 (t, J=5.6Hz, 2H), 7.80 (d, J=4.0Hz, 1H), 7.72 (d, J=8.8Hz, 1H), 7.20 (d, J=4.0Hz, 1H), 6.67-6.91 (m, 2H), 4.52-4.55 (m, 2H), 3.96-4.09 (m, 2H), 3.61-3.75 (m, 3H), 3.24-3.38 (m, 2H), 3.07-3.17 (m, 1H), 2.93 (t, J= 8.8Hz, 1H), 2.57 (t, J=5.6Hz, 3H), 2.03 (brs., 1H), 1.84 (brs., 1H), 1.65 (t, J=7.6Hz, 2H)；LCMS(ESI)m/z：477,479 (M+1)

Embodiment 51

The chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (methylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the sequence of step A, B, C in embodiment 44, wherein by (S)- Pyrrolidin-3-yl carbamate replaces with (R)-piperidines -3- ylcarbamates, and the product is solid for white Body.¹H NMR (400MHz, DMSO-d₆) δ 9.34 (d, J=4.8Hz, 1H), 9.15 (t, J=5.6Hz, 1H), 9.08 (d, J= 4.4Hz, 1H), 7.79 (d, J=4.0Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 7.20 (d, J=4.0Hz, 1H), 6.76 (dd, J=8.8,2.4Hz, 1H), 6.70 (s, 1H), 4.49-4.58 (m, 2H), 3.97-4.05 (m, 2H), 3.59-3.72 (m, 3H), 3.19-3.34 (m, 2H), 3.08 (dd, J=11.6,8.8Hz, 1H), 2.89 (t, J=8.8Hz, 1H), 2.57 (t, J= 5.2Hz, 3H), 2.00 (brs., 1H), 1.82 (d, J=9.2Hz, 1H), 1.56-1.70 (m, 2H)；LCMS(ESI)m/z：477, 479(M+1).

Embodiment 52

The chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- (dimethylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the method for step A in embodiment 45, wherein by step A (R) -3- (dimethylamino) pyrrolidines replaces with (S) -3- (dimethylamino) piperidines, yield 61%.¹H NMR (400MHz, DMSO-d₆) δ 10.91 (brs, 1H), 9.13 (t, J=5.6Hz, 1H), 7.78 (d, J=4.0Hz, 1H), 7.69 (d, J= 8.8Hz, 1H), 7.20 (d, J=4.0Hz, 1H), 6.66-6.82 (m, 2H), 4.49-4.58 (m, 2H), 3.88-4.04 (m, 2H), 3.66-3.74 (m, 2H), 3.53 (d, J=11.6Hz, 1H), 3.37 (d, J=13.2Hz, 1H), 2.97 (t, J= 11.2Hz, 1H), 2.68-2.80 (m, 7H), 2.12 (brs, 1H), 1.84 (d, J=5.6Hz, 1H), 1.56-1.70 (m, 2H)； LCMS(ESI)m/z：491,493 (M+1)

Embodiment 53

The chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (dimethylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the method for step A in embodiment 45, wherein by step A (R) -3- (dimethylamino) pyrrolidines replaces with (R) -3- (dimethylamino) piperidines, yield 55%.¹H NMR (400MHz, DMSO-d₆) δ 11.16 (brs, 1H), 9.21 (t, J=5.6Hz, 1H), 7.81 (d, J=4.0Hz, 1H), 7.73 (d, J= 8.4Hz, 1H), 7.20 (d, J=4.0Hz, 1H), 6.75-7.02 (m, 2H), 4.50-4.59 (m, 2H), 4.05-4.11 (m, 1H), 3.91-4.03 (m, 2H), 3.70 (brs, 2H), 3.53 (d, J=12.0Hz, 1H), 3.45 (brs, 1H), 3.12 (t, J= 11.2Hz, 1H), 2.80-2.89 (m, 1H), 2.75 (t, J=4.8Hz, 6H), 2.14 (d, J=9.2Hz, 1H), 1.81-1.93 (m, 1H), 1.60-1.79 (m, 2H)；LCMS(ESI)m/z：491,493 (M+1)

Embodiment 54

(R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- methyl formates

Step A：(R)-((3R, 3AS) -3- (((t-butyldimethylsilyl) oxygen is prepared according to the method for embodiment 6 Base) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- formic acid Methyl esters, wherein 1, the 3- oxazepine hexamethylene -2- ketone in rapid A is replaced with (R)-pyrrolidines -2- methyl formates, yield 72%.LCMS(ESI)m/z：463.2(M+1).

Step B：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K and L.¹H NMR (400MHz, DMSO-d₆) δ 8.99 (t, J=6.0Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.57 (d, J=9.2Hz, 1H), 7.21 (d, J=4.4Hz, 1H), 6.14 (dd, J=8.8,2.4Hz, 1H), 6.04 (d, J=2.8Hz, 1H), 4.55-4.50 (m, 1H), 4.47 (d, J=6.8Hz, 1H), 4.26-4.23 (m, 1H), 3.98-3.93 (m, 2H), 3.69 (t, J=5.6Hz, 2H), 3.63 (s, 3H), 3.21-3.17 (m, 1H), 3.01-2.95 (m, 1H), 1.99-1.87 (m, 4H)；LCMS(ESI)m/z：492.1 (M+1).

Embodiment 55

(S) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- methyl formates

Step A：The present embodiment title compound is prepared according to the method for embodiment 54 step A and B, wherein by step A (R)-pyrrolidines -2- methyl formates replace with (S)-pyrrolidines -2- methyl formates.¹H NMR (400MHz, DMSO-d₆)δ8.99 (t, J=6.0Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.58 (d, J=9.2Hz, 1H), 7.21 (d, J=4.4Hz, 1H), 6.17 (dd, J=8.8,2.4Hz, 1H), 6.04 (d, J=2.8Hz, 1H), 4.53-4.46 (m, 2H), 4.25-4.23 (m, 1H), 3.98-3.95 (m, 2H), 3.70 (t, J=5.6Hz, 2H), 3.63 (s, 3H), 3.21-3.17 (m, 1H), 3.01-2.95 (m, 1H), 2.04-1.87 (m, 4H)；LCMS(ESI)m/z：492.1(M+1).

Embodiment 56

(R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- formamides

Step A：(R) -1- ((3S, 3aS) -3- ((5- chlorothiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- methyl formates (100mg, 0.203mmol) it is full And NH_3-Ethylene glycol solution (20mL), 80 DEG C of sealings are stirred 2 hours.After being cooled to room temperature, water (100mL) is added in, and use EtOAc (30mLx3) is extracted, and the organic phase of merging is dried and concentrated with anhydrous sodium sulfate.By thick residue through preparation HPLC (first Acid) purifying, the present embodiment title compound (18mg, 18%) is obtained, is white solid.¹H NMR (400MHz, DMSO-d₆)δ 9.00 (t, J=6.0Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 7.33 (brs, 1H), 7.21 (d, J=4.0Hz, 1H), 7.21 (brs, 1H), 6.15 (dd, J=9.2,2.8Hz, 1H), 6.04 (d, J=2.4Hz, 1H), 4.55-4.51 (m, 1H), 4.48 (d, J=7.6Hz, 1H), 3.97-3.92 (m, 2H), 3.84-3.82 (m, 1H), 3.69 (t, J =5.2Hz, 2H), 3.51-3.48 (m, 1H), 3.16-3.13 (m, 1H), 2.20-2.16 (m, 1H), 1.98-1.87 (m, 3H)； LCMS(ESI)m/z：477,479 (M+1)

Embodiment 57

(S) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- formamides

Step A：The present embodiment title compound is prepared according to the method for 56 step A of embodiment, wherein by step A (R)-pyrrolidines -2- formamides replace with (S)-pyrrolidines -2- formamides, yield 16%.¹H NMR (400MHz, DMSO-d₆) δ 8.98 (t, J=6.0Hz, 1H), 7.70 (d, J=4.0Hz, 1H), 7.56 (d, J=8.8Hz, 1H), 7.32 (brs, 1H), 7.20 (d, J=4.0Hz, 1H), 7.01 (brs, 1H), 6.15 (dd, J=8.8,2.4Hz, 1H), 6.02 (d, J=2.4Hz, 1H), 4.52-4.45 (m, 2H), 3.97-3.93 (m, 2H), 3.84-3.79 (m, 1H), 3.69 (t, J=5.6Hz, 2H), 3.51- 3.48 (m, 1H), 3.14-3.12 (m, 1H), 2.17-2.15 (m, 1H), 1.98-1.90 (m, 3H)；LCMS(ESI)m/z：477, 479(M+1).

Embodiment 58

The chloro- N- of 5- (((3S, 3aS) -7- ((R) -2- (methylol) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：(R)-((3S, 3aS) -3- ((5- chlorothiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- methyl formates (50mg, 0.102mmol) THF LiBH is added in (6mL) solution₄(39mg, 1.02mmol), 15 DEG C are stirred 16 hours, and reaction then is quenched with MeOH (5mL), and Concentration.Crude residue through preparation HPLC (formic acid) purify, obtain the present embodiment title compound, be white solid (15mg, 32%).¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J=6.4Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.56 (d, J =8.8Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.26 (dd, J=8.8,2.4Hz, 1H), 6.17 (d, J=2.8Hz, 1H), 4.77-4.74 (m, 1H), 4.53-4.52 (m, 1H), 4.48-4.46 (m, 1H), 3.98-3.95 (m, 2H), 3.71-3.68 (m, 2H), 3.60-3.56 (m, 1H), 3.46-3.31 (m, 2H), 3.08-3.19 (m, 1H), 2.99-2.93 (m, 1H), 1.99-1.81 (m, 4H)；LCMS(ESI)m/z：464,466 (M+1)

Embodiment 59

(R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- carboxylic acid -2- hydroxyethyl esters

Step A：The present embodiment title compound is prepared according to the method for 56 step A of embodiment, wherein by step A (R) -2- (methylol) pyrrolidines replaces with (R)-pyrrolidines -2- carboxylic acid -2- hydroxyethyl esters, yield 35%.¹H NMR (400MHz, DMSO-d₆) δ 8.99 (t, J=6.0Hz, 1H), 7.71 (d, J=4.4Hz, 1H), 7.58 (d, J=8.8Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 6.16 (dd, J=9.2,2.8Hz, 1H), 6.06 (d, J=2.4Hz, 1H), 4.84 (t, J= 5.6Hz, 1H), 4.53-4.50 (m, 1H), 4.48-4.46 (m, 1H), 4.24-4.22 (m, 1H), 4.14-4.19 (m, 1H), 4.06-4.01 (m, 1H), 3.98-3.96 (m, 2H), 3.69 (t, J=6.0Hz, 2H), 3.58-3.54 (m, 2H), 3.36-3.41 (m, 1H), 3.29-3.21 (m, 1H), 2.34-2.22 (m, 1H), 2.08-1.96 (m, 3H)；LCMS(ESI)m/z：522,524 (M +1).

Embodiment 60

(((3S, 3aS) -7- (Cyclopropylsulfonyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：Water (8mL) solution of sodium sulfite (1.8g, 14.2mmol) is vigorously stirred 10 minutes at 20 DEG C.Add Enter NaHCO₃(2.4g, 28.5mmol), and stirred 1 hour at 50 DEG C.Be carefully added into the third sulfonic acid chloride of ring (2.0g, 14.2mmol).After adding, mixture is vigorously stirred 4 hours at 50 DEG C.It is after being cooled to 20 DEG C, mixture is dry with freezing Dry method drying, obtains residue.Then methanol (2mL) is added in, and is stirred 1 hour, filtering.Filtrate is concentrated, obtained ring third Alkane sulfinic acid sodium (1.0g, 55%) is white solid.¹H NMR (400MHz, methanol-d₄) δ 1.84-1.89 (m, 1H), 0.74- 0.77 (m, 2H), 0.61-0.64 (m, 2H)

Step B：Under nitrogen, to the bromo- 3- of (3R, 3aS) -7- (((t-butyldimethylsilyl) oxygroup) methyl) -3a, Simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (400mg, 0.97mmol) adds in cyclopropane sulfinic acid to 4- dihydrobenzos [b] oxazole Sodium (186mg, 1.5mmol), N, the anhydrous DMF (4mL) and CuI of N- dimethyl ethanes -1,2- diamines (17mg, 0.19mmol) (37mg, 0.19mmol) solution is stirred 20 minutes in the microwave tube of sealing at 50 DEG C.Water is added in, by mixture DCM (50mLx3) is extracted.The organic phase of merging is washed with brine, is dried with anhydrous sodium sulfate, is concentrated.By thick residue through silicon Glue chromatography Purifying, obtains (3R, 3aS) -3- (((t-butyldimethylsilyl) Oxygroup) methyl) -7- (Cyclopropylsulfonyl) -3a, 4- dihydrobenzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (300mg, 71%) is white solid.LCMS(ESI)m/z：440.1(M+1).

Step C：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K and L, wherein will step Morpholine -3- ketone in rapid G replaces with cyclopropanesulfonyl.¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J=11.6, 5.6Hz, 1H), 8.15 (d, J=8.4Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.52 (dd, J=8.4,2.0Hz, 1H), 7.44 (d, J=2.0Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 4.63-4.65 (m, 2H), 4.12-4.20 (m, 2H), 3.74- 3.76 (m, 2H), 2.82-2.88 (m, 1H), 1.01-1.10 (m, 4H)；LCMS(ESI)m/z：469(M+1).

Embodiment 61

The chloro- N- of 5- (tetra- oxygen benzos [b] of ((3S, 3aS) -1- oxos -7- (pyrrolidin-1-yl) sulfonyl) -1,3,3a, 4- Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：By the bromo- 3- of (3R, 3aS) -7- ((t-butyldimethylsilyl) oxygroup) methyl) -3a, 4- dihydrobenzenes And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (2.0g, 4.82mmol), beneze methane thiol (1.8g, 14.5mmol), Pd₂(dba)₃(440mg, 0.48mmol), Xantphos (560mg, 0.96mmol) and Cs₂CO₃(3.14g, 9.64mmol) and two The mixture of oxane (30mL) heats 8 hours under 100 DEG C, nitrogen atmosphere, is cooled to room temperature and adds in water, uses EtOAc (50mLx3) is extracted.The organic phase of merging is washed with brine, is dried with anhydrous sodium sulfate, is concentrated.Thick residue is passed through into silicon Glue chromatography Obtain (3R, 3aS) -7- (benzylthio) -3- (((tertbutyldimethylsilyl chloride silicon Alkyl) oxygroup) methyl) -3a, 4- dihydrobenzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.2g, 55%), for oil Shape object.LCMS(ESI)m/z：488(M+1).

Step B：By (3R, 3aS) -7- (benzylthio) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -3a, DCM (12mL) solution of 4- dihydrobenzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (600mg, 1.3mmol) is in room Temperature is lower to be stirred, and is then added in NCS (0.9g, 6.5mmol) and BnOH (650mg, 6.3mmol), is stirred at room temperature 14 hours.It adds in DIPEA (300mg, 2.33mmol), and pyrrolidines (150mg, 2.1mmol) is added dropwise.The mixture 12 is stirred at room temperature Hour, then it is concentrated in vacuo.Thick residue is purified by silica gel chromatograph (PE: EtOAc=10: 1~1: 1), obtain (3R, 3aS) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -7- (pyrrolidin-1-yl sulfonyl) -3a, 4- dihydrobenzos [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (280mg, 46%) is yellow solid.LCMS(ESI)m/z：469(M+ 1).

Step C：The present embodiment title compound is prepared according to the sequence of embodiment 1 step G, I, J, K and L, wherein will step Morpholine -3- ketone in rapid G replaces with pyrrolidin-1-yl sulfonyl.¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J= 5.6Hz, 1H), 8.14 (d, J=8.8Hz, 1H), 7.73 (d, J=4.0Hz, 1H), 7.45 (dd, J=9.4,2.0Hz, 1H), 7.33 (d, J=2.0Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 4.63 (m, 2H), 4.15 (m, 2H), 3.75 (t, J=5.2, 5.2Hz, 2H), 3.13 (t, J=6.4Hz, 4H), 1.65 (m, 4H)；LCMS(ESI)m/z：498(M+1).

Embodiment 62

The chloro- N- of 5- (((3S, 3aS) -7- ((4- methylpiperazine-1-yls) sulfonyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the sequence of embodiment 61 step A, B, C, wherein by step C Pyrrolidin-1-yl sulfonic acid replace with (4- methylpiperazine-1-yls) sulfonyl.¹H NMR (400MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.18 (d, J=8.4Hz, 1H), 7.72 (d, J=4.0Hz, 1H), 7.43 (dd, J=8.4,2.0Hz, 1H), 7.35 (d, J =2.0Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 4.68 (m, 2H), 4.12 (m, 2H), 3.76 (t, J=5.2Hz, 2H), 3.74 (s, 2H), 3.16 (s, 2H), 2.79 (s, 3H), 2.51 (s, 2H)；LCMS(ESI)m/z：528(M+1).

Embodiment 63

The chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxoimidazolinium -1- bases) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：0 DEG C, to N- (((3S, 3aS) -7- amino -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3, 4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chlorothiophene -2- formamides (80mg, 0.21mmol) and triethylamine (43mg, The THF (0.5mL) that the chloro- 2- ethyl isocyanates (33mg, 0.32mmol) of 1- are added dropwise in THF (3mL) solution 0.42mmol) is molten Liquid.Reaction mixture is stirred 16 hours at 15 DEG C, solvent is removed in vacuum.Thick residue silica gel chromatograph (EtOAc: PE=1 : 1) it purifies, obtains the chloro- N- of 5- (((3S, 3aS) -7- (3- (2- chloroethyls) urea groups) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (100mg, 98%), light yellow solid.LCMS (ESI)m/z：485(M+1).

Step B：At 0 DEG C, to the THF of sodium hydride (containing the mineral oil solution of 60% sodium hydride, 12mg, 0.31mmol) 5- chloro- N- (((3S, 3aS) -7- (3- (2- chloroethyls) urea groups) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene are added in (3mL) solution And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives (100mg, 0.21mmol) DMF (1.5mL).Reaction mixture is stirred 1 hour at 15 DEG C.Reaction mixture is poured into saturation NH₄Cl aqueous solutions (20mL) In, and extracted with DCM (20mLx5).The organic matter of merging is dried, filtered and concentrated with anhydrous sodium sulfate.Thick residue is passed through Preparation HPLC (formic acid) purifies, and obtains the present embodiment title compound (30mg, 32%), is light yellow solid.¹H NMR (400MHz, DMSO-d₆) δ 9.01 (t, J=5.6Hz, 1H), 7.67-7.78 (m, 2H), 7.29 (d, J=2.4Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 7.10 (dd, J=9.2,2.4Hz, 1H), 6.95 (s, 1H), 4.46-4.61 (m, 2H), 3.97-4.08 (m, 2H), 3.76-3.83 (m, 2H), 3.71 (t, J=5.6Hz, 2H), 3.37 (t, J=8.0Hz, 2H)；LCMS(ESI)m/z： 449(M+1).

Embodiment 64

The chloro- N- of 5- ((dislike by (3S, 3aS) -7- (3- hydroxyl pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the sequence of step A, B, C in embodiment 46, wherein by piperidines- 3- alcohol replaces with (S)-pyrrolidines -3- alcohol.¹HNMR (400MHz, DMSO-d₆) δ 7.71 (d, J=4.0Hz, 1H), 7.59 (d, J= 8.8Hz, 1H), 7.19 (d, J=4.0Hz, 1H), 6.29 (d, J=8.8Hz, 1H), 6.18 (s, 1H), 4.5 (m, 2H), 4.38 (m, 1H), 3.97 (m, 2H), 3.38 (dd, J=10.4,4.8Hz, 1H), 3.26 (m, 2H), 3.04 (d, J=10.4Hz, 2H), 2.03 (m, 1H), 1.93-1.87 (m, 1H)；LCMS(ESI)m/z：450(M+1).

Embodiment 65

The chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- methoxypyrrolidin -1- bases) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the sequence of step A, B, C and D in embodiment 47, wherein by 3- Methoxy piperide replaces with (S) -3- methoxypyrrolidins.¹H NMR (400MHz, DMSO-d₆) δ 9.02 (s, 1H) 7.73 (d, J= 4.0Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.22 (d, J=4.0Hz, 1H), 6.22 (dd, J=8.82.4Hz, 1H), 6.11 (d, J=2.4Hz, 1H), 4.54-4.43 (m, 2H), 4.06-3.94 (m, 3H), 3.69 (t, J=5.2Hz, 1H), 3.36 (dd, J=10.8,5.2Hz, 1H), 3.19 (m, 2H), 2.25-2.20 (m, 1H), 2.04-2.01 (m, 2H)；LCMS(ESI)m/ z：464(M+1).

Embodiment 66

4- methoxyl groups-N- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) benzamide

Step A：At room temperature, to (3S, 3aS) -3- (amino methyl) -7- (3- oxomorpholin generations) -3 α, 4- dihydrobenzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (80mg, 0.25mmol), 4- methoxy benzoic acids (43mg, 0.28mmol) and the DMF of DIPEA (48mg, 0.38mmol) (1mL) solution in add in HATU (110mg, 0.28mmol), and It stirs 16 hours at room temperature.The mixture by preparation HPLC (formic acid) is purified, obtains the present embodiment title compound (81mg, 71%), white solid.¹H NMR (400MHz, DMSO-d₆) δ 8.73 (t, J=5.6Hz, 1H), 7.87-7.83 (m, 3H), 7.05-7.00 (m, 4H), 4.64-4.59 (m, 1H), 4.55-4.51 (m, 1H), 4.17 (s, 2H), 4.15-4.02 (m, 2H), 3.95 (t, J=5.2Hz, 2H), 3.81 (s, 3H), 3.76-3.71 (m, 2H), 3.70-3.66 (m, 2H)；LCMS(ESI) m/z：454(M+1).

Embodiment 67

(((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) pyridine carboxamide

Step A：The present embodiment title compound is prepared according to the method for embodiment 66, wherein by 4- methoxyl groups in step A Benzoic acid replaces with 5- chloropyridine formic acid.¹H NMR (400MHz, DMSO-d₆) δ 9.18 (t, J=6.0Hz, 1H), 8.74 (d, J= 2.4Hz, 1H), 8.14 (dd, J=8.4,2.4Hz, 1H), 8.06 (d, J=8.4Hz, 1H), 7.84 (d, J=8.8Hz, 1H), 7.04 (d, J=2.0Hz, 1H), 7.05 (dd, J=8.8,2.0Hz, 1H), 4.66-4.63 (m, 1H), 4.53-4.48 (m, 1H), 4.19-4.16 (m, 3H), 4.06-4.03 (m, 1H), 3.95 (t, J=5.2Hz, 2H), 3.79-3.75 (m, 2H), 3.70-3.66 (m, 2H)；LCMS(ESI)m/z：459(M+1).

Embodiment 68

(((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -1H- indole 2-carboxamides

Step A：At room temperature, in ethyl alcohol (3mL) solution of the chloro- 1H- indole -2-carboxylic ethyl esters (45mg, 0.2mmol) of 5- Add in the H of NaOH (16mg, 0.4mmol)₂In O (3mL) solution, it is stirred at room temperature 16 hours.It is mixed that this is adjusted with 1N aqueous hydrochloric acid solutions Object pH=5 is closed, is extracted with EtOAc (3x 10mL).Merge organic layer to be washed with brine, be dried with anhydrous sodium sulfate, filtered and dense Contracting, obtains the chloro- 1H- indole-2-carboxylic acids of 5- (30mg, 90%), is shallow white solid.LCMS(ESI)m/z：220(M+1).

Step B：Method according to embodiment 66 prepares the present embodiment title compound, wherein by 4- methoxyl groups in step A Benzoic acid replaces with the chloro- 1H- indole-2-carboxylic acids of 5-.¹H NMR (400MHz, DMSO-d₆) δ 11.86 (brs, 1H), 8.97 (t, J =5.2Hz, 1H), 7.85 (d, J=8.8Hz, 1H), 7.72 (s, 1H), 7.43 (d, J=4.4Hz, 1H), 7.20-7.18 (m, 2H), 7.05 (s, 1H), 7.01 (d, J=8.8Hz, 1H), 4.66-4.61 (m, 1H), 4.59-4.56 (m, 1H), 4.17-4.13 (m, 3H), 4.10-4.04 (m, 1H), 3.94 (t, J=5.2Hz, 2H), 3.83-3.75 (m, 2H), 3.70-3.68 (m, 2H)； LCMS(ESI)m/z：497(M+1).

Embodiment 69

5- methyl-N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：Method according to embodiment 66 prepares the present embodiment title compound, wherein by 4- methoxyl groups in step A Benzoic acid replaces with 5- methylthiophene -2- carboxylic acids.¹H NMR (400MHz, DMSO-d₆) δ 8.77 (t, J=5.6Hz, 1H), 7.84 (d, J=8.8Hz, 1H), 7.62 (d, J=7.6Hz, 1H), 7.05-6.99 (m, 2H), 6.85 (d, J=3.6Hz, 1H), 4.59- 5.20 (m, 2H), 4.17 (s, 2H), 4.08-4.04 (s, 2H), 3.96-3.93 (m, 2H), 3.71-3.67 (m, 4H), 2.45 (s, 3H)；LCMS(ESI)m/z：444(M+1).

Embodiment 70

5- bromos-N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：Method according to embodiment 66 prepares the present embodiment title compound, wherein by the 4- methoxies in step A Yl benzoic acid replaces with 5- bromothiophene -2- carboxylic acids.¹H NMR (400MHz, DMSO-d₆) δ 8.99 (t, J=5.2Hz, 1H), 7.85 (d, J=8.8Hz, 1H), 7.66 (d, J=4.0Hz, 1H), 7.31 (d, J=4.0Hz, 1H), 7.06 (d, J=2.0Hz, 1H), 7.02 (dd, J=8.4,2.0Hz, 2H), 4.62-4.54 (m, 2H), 4.18 (s, 2H), 4.07-4.02 (m, 2H), 3.95 (t, J =4.8Hz, 2H), 3.74-3.68 (m, 4H)；LCMS(ESI)m/z：508(M+1).

Embodiment 71

5- cyano-N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Reaction process：

Step A：It is cooled down with ice-water bath, to methanol (20mL) solution of 5- bromothiophene -2- carboxylic acids (500mg, 2.42mmol) Middle dropwise addition SOCl₂(575mg, 4.83mmol).Reaction mixture is heated to flowing back, and is stirred 12 hours.By mixture vacuum Concentration, residue NaHCO₃Solution (50mL) is quenched, and is extracted with DCM (20mL x 2).By the organic phase of merging with anhydrous Sodium sulphate is dry and filters.Filtrate is concentrated, obtains 5- bromothiophene -2- carboxylic acid, ethyl esters (500mg, 94%), is yellow solid LCMS(ESI)m/z：221(M+1).

Step B：By 5- bromothiophene -2- carboxylic acid, ethyl esters (450mg, 2.04mmol) and CuCN (550mg, 6.11mmol) DMF (20mL) solution flows back 2 hours under a nitrogen.After cooling, water (100mL) and EtOAc (50mL) solution is added in, and filter. By the drying of organic layer anhydrous sodium sulfate and filter.Filtrate is concentrated, thick residue is through silica gel chromatograph (PE: EtOAc=20: 1 ~10: 1) purify, obtain 5- cyano thiophene -2- carboxylate methyl esters (320mg, 94%), be yellow solid.LCMS(ESI)m/z：168 (M+1).

Step C：By 5- cyano thiophene -2- carboxylate methyl esters (100mg, 0.60mmol) and NaOH (72mg, 1.80mmol) Water (5mL)-THF (5mL) solution stirs 16 hours at 25 DEG C.Mixture is concentrated and removes THF, with 1N hydrochloric acid solutions by pH tune Section is filtered to 5.Residue is washed, and dried with anhydrous sodium sulfate with water (3mL), is then concentrated, obtain 5 carbamyl thiophene- 2- carboxylic acids (60mg, 58%) are yellow solid.LCMS(ESI)m/z：172(M+1).

Step D：Thionyl chloride (20mL) solution of 5- carbamyls thiophene-2-carboxylic acid (40mg, 0.234mmol), reflux 2 Hour.Then reaction mixture is concentrated, obtains crude product 5- cyano thiophene -2- carbonyl chlorine.Crude product residue is directly used It is reacted in next step.

Step E：The present embodiment title compound is prepared according to the method for embodiment 1, wherein by the 5- diurils in step K Fen -2- carbonyl chlorine replaces with 5- cyano thiophene -2- carbonyl chlorine.¹H NMR (400MHz, DMSO-d₆) δ 9.32 (t, J=5.6Hz, 1H), 8.00 (d, J=4.0Hz, 1H), 7.92 (d, J=4.0Hz, 1H), 7.85 (d, J=8.4Hz, 1H), 7.05 (d, J= 2.0Hz, 1H), 7.02 (dd, J=8.4,2.0Hz, 2H), 4.65-4.57 (m, 2H), 4.18 (s, 2H), 4.13-4.03 (m, 2H), 3.95 (t, J=4.4Hz, 2H), 3.79-3.76 (m, 2H), 3.69 (t, J=5.6Hz, 2H)；LCMS(ESI)m/z：455 (M+1).

Embodiment 72

(((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the fluoro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The present embodiment title compound is prepared according to the method for embodiment 66, wherein by the 4- methoxies in step A Yl benzoic acid replaces with 5- fluorine thiophene-2-carboxylic acids.¹H NMR (400MHz, DMSO-d₆) δ 8.97 (t, J=11.6,6.4Hz, 1H), 7.86 (d, J=8.8Hz, 1H), 7.61 (t, J=8.0,4.0Hz, 1H), 7.06-7.01 (m, 12H), 6.84 (dd, J=8.4, 2.0Hz, 1H), 4.57-4.55 (m, 2H), 4.18 (s, 2H), 4.08-4.03 (m, 2H), 3.96-3.92 (m, 2H), 3.73- 3.69 (m, 4H)；LCMS(ESI)m/z：448(M+1).

Embodiment 73

4,5- bis- fluoro- N- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Reaction process：

Step A：Under nitrogen, to the CS of 2,3- dibromo thiophenes (2g, 8.27mmol)₂Trichlorine is once added in (20mL) solution Change aluminium (1.65g, 12.4mmol), mixture is cooled to 0 DEG C, chloroacetic chloride (0.974g, 12.4mmol) is added dropwise.Then, by institute Mixture is obtained to stir 16 hours at 18 DEG C.Mixture is poured into ice water, is extracted with DCM (50mL x 2), with water (50mL) It is washed with brine (50mL), anhydrous sodium sulfate is dried, filtered and concentrated, and obtains 1- (4,5- dibromo thiophene -2- bases) ethyl ketone (1.9g, 81%) is orange solids.

Step B：Add into toluene (150mL) solution of 1- (4,5- dibromo thiophene -2- bases) ethyl ketone (14.3g, 0.05mol) Enter ethane -1,2- glycol (12.5g, 0.2mol) and TsOHH₂O (451mg, 0.0025mol).It is filled equipped with Dean-Stank In the flask put, under a nitrogen the mixture is heated to reflux 16 hours.Mixture is poured into water (100mL), uses EtOAc (150mL x 2) is extracted, and uses NaHCO₃Aqueous solution and salt water washing, are dried, filtered and concentrated with anhydrous sodium sulfate.It will be thick residual Excess is through silica gel chromatograph (PE: ethyl acetate=50: 1) purifying obtains 2- (4,5- dibromo thiophene -2- bases) -2- methyl-1s, 3- dioxies Penta ring (12g, 72%) is yellow solid.

Step C：At -78 DEG C, to 2- (4- bromo -5- fluoro thiophene -2- bases) -2- methyl-1s, 3- dioxolanes In THF (60mL) solution of (6.2g, 0.023mol), n-BuLi (12.1mL, 0.03mol) is added in, it is small to stir the mixture for 1 When, NFSI is then added dropwise (in 0.03mmol, 100mL THF).It then heats to 18 DEG C and stirs 16 hours.Reaction is mixed It closes object and is poured into NH₄It in Cl solution (80mL), is extracted with EtOAc (80mL x 2), anhydrous sodium sulfate is dried, filtered and concentrated.It will Thick residue is purified through silica gel chromatograph (PE: EA=100: 1~50: 1), obtains 2- (4,5- difluoro thiophene -2- bases) -2- first Base -1,3-dioxolane (3.5g, 73%) is yellow oil.

Step D：To 2- (4,5- difluoro thiophene -2- bases) -2- methyl-1s, the third of 3- dioxolanes (3.4g, 16.5mmol) TsOH (1.42g, 8.25mmol) is added in ketone (30mL)-water (3mL) solution, reaction mixture is stirred 3 hours at 18 DEG C. Then mixture is poured into water (80mL), EtOAc (80mL x 2) extractions, NaHCO₃(aq) it washs, anhydrous sodium sulfate drying, It filters and concentrates, obtain 1- (4,5- difluoro thiophene -2- bases) ethyl ketone (2.4g, 89%), yellow solid.

Step E：By the dioxanes of the 1- that stirred (4,5- difluoro thiophene -2- bases) ethyl ketone (200mg, 1.23mmol) (3mL) suspension is heated to 50 DEG C.It is meanwhile molten by the water (3mL) to NaOH (861mg, 21.5mmol) under agitation Br2 (969mg, 6.17mmol) is added dropwise in liquid to prepare the solution of sodium hypobromite.It is molten that sodium hypobromite solution is added drop-wise to dioxanes In liquid, stir 3 hours, the mixture is then cooled to 18 DEG C.Mixture is poured into water (30mL), it is molten with 12M HCl/waters Liquid is acidified to pH=1, EtOAc (30mL x 2) extractions.The organic matter of merging is dried, filtered and concentrated with anhydrous sodium sulfate, is obtained To 4,5- difluoros thiophene-2-carboxylic acid (180mg, 89%), yellow solid.

Step F：Method according to embodiment 66 prepares the present embodiment title compound, wherein by the 4- methoxies in step A Yl benzoic acid replaces with 4,5- difluoro thiophene-2-carboxylic acids.¹H NMR (400MHz, DMSO-d₆) δ 9.06 (t, J=4.2Hz, 1H), 7.85 (d, J=8.8Hz, 1H), 7.79 (d, J=3.6Hz, 1H), 7.05-7.00 (m, 2H), 4.59-4.55 (m, 2H), 4.17 (s, 2H), 4.06-4.04 (m, 2H), 3.96-3.93 (m, 2H), 3.74-3.66 (m, 4H)；LCMS(ESI)m/z：466(M+1).

Embodiment 74

The fluoro- N- of the chloro- 3- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：The hydrochloric acid solution (6M, 14.0mL) of 3- aminothiophene -2- methyl formates (7.0g, 50.3mmol), cooling To 0 DEG C, NaNO is added in₂(3.5g, 50.7mmol), and be stirred at room temperature 2 hours.Then, HBF is added in₄(7.0mL), and in room The lower stirring of temperature 15 minutes.Filter solid diazol is crossed, uses HBF₄(35.0mL), MeOH (50.0mL) and ether (50mL) washing are solid Body, it is dry under vacuum, obtain bis- azothiazole -2- methyl formates tetrafluoroborates (8.0g, 62%) of 3-, white solid.

Step B：By bis- azothiazole -2- methyl formates tetrafluoroborates (5.0g, 19.54mmol) of 3- and sand (26.0g) is uniformly mixed in the round-bottomed flask with vacuum distillation apparatus, heating in vacuum.Vacuum (0.1Torr) is heated to 160 DEG C, continue 2 hours, be then increased to 200 DEG C, continue 2 hours, crude product is weak yellow liquid, and silica gel chromatograph (PE) purifying obtains 3- fluorine thiophene-2-carboxylic acids methyl esters (1.0g, 32%), white solid.

Step C：DMF (10mL) solution of 3- fluorine thiophene-2-carboxylic acid methyl esters in DMF (10mL) (1.0g, 6.24mmol) exists It stirs 10 minutes at room temperature, adds in NCS (2.5g, 18.8mmol), then heat to 70 DEG C, continue 24 hours.Mixture is true Sky concentration, thick residue by silica gel chromatograph (PE: EA=100: 1~PE: EA=50: 1) purify, obtain the chloro- 3- fluorine thiophene of 5-- 2- carboxylate methyl esters (200mg, 17%), pale solid.

Step D：It is added in into MeOH (4mL) solution of the chloro- 3- fluorine thiophene-2-carboxylic acid methyl esters (150mg, 0.77mmol) of 5- Water (2mL) solution of lithium hydroxide (80mg, 1.90mmol).It heats the mixture to 40 DEG C, continue 3 hours.It is molten with 1M HCl Liquid adjusts reaction mixture to pH=2.0, is then extracted with EtOAc (3 × 10mL).The organic layer of merging is done with anhydrous sodium sulfate Dry, then filtering concentrates, obtains the chloro- 3- fluorine thiophene-2-carboxylic acids of 5- (100mg, 78%), pale solid.

Step E：Method according to embodiment 66 prepares this title compound, wherein by the 4- methoxybenzene first in step A Acid replaces with the chloro- 3- fluorine thiophene-2-carboxylic acids of 5-.¹H NMR (400MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.86 (d, J= 8.8Hz, 1H), 7.36 (s, 1H), 7.02 (m, 2H), 4.57 (m, 2H), 4.18 (s, 2H), 4.08 (m, 2H), 3.96 (t, J= 5.2Hz, 2H), 3.72 (m, 4H)；LCMS(ESI)m/z：482(M+1).

Embodiment 75

The chloro- N- of 4- amino -5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Preparation flow：

Step A：Under ice-water bath cooling condition, by SOCl₂(2.93g, 24.6mmol) is added drop-wise to 5- chloro thiophene -2- carboxylics In EtOH (20mL) solution of sour (2.00g, 12.3mmol).Reaction mixture is heated to flowing back and is stirred 16 hours.Then Solvent is removed in vacuum, uses NaHCO₃Residue is quenched in aqueous solution (50mL), and is extracted with DCM (20mL x 2).Merge organic layer It with anhydrous sodium sulfate drying and filters, concentrates filtrate, obtain 5- chloro thiophene -2- carboxylic acid, ethyl esters (2.10g, 89%), yellow oil Shape object.

Step B：By 5- chloro thiophene -2- carboxylic acid, ethyl esters (2.10g, 11.0mmol) and the mixture (8mL) of fuming nitric aicd It is stirred 2 hours at 20 DEG C.Then water (50mL) and EtOAc (20mL) are added in, water layer is extracted with EtOAc (20mL x 2).It closes And organic layer NaHCO₃Aqueous solution (50mL) washs, and with anhydrous sodium sulfate drying and filters, and concentrates filtrate, obtains 5- chlorine Generation -4- nitrothiophene -2- carboxylic acid, ethyl esters (1.6g, 61%), yellow oil.

Step C：By 5- chloro -4- nitrothiophene -2- carboxylic acid, ethyl esters (1.00g, 4.24mmol), iron powder (118g, 21.2mmol)、NH₄Cl (1.14g, 21.2mmol), EtOH (9mL) and H₂The mixture of O (3mL) stirs 16 hours at 60 DEG C. Then reaction mixture is filtered, concentration filtrate obtains crude product.Water (50mL) and EtOAc (20mL) are added in into crude product, With EtOAc (20mL x 2) aqueous layer extracted.Merge organic layer to be dried over anhydrous sodium sulfate, filter, concentrate filtrate, obtain 4- ammonia Base -5- chloro thiophene -2- carboxylic acid, ethyl esters (600mg, 68%), yellow oil.

Step D：By 4- amino -5- chloro thiophene -2- carboxylic acid, ethyl esters (0.30g, 1.46mmol), LiOH (70mg, 2.92mmol), the mixture of water (5mL) and THF (5mL) stir 16 hours at 25 DEG C.Then mixture is concentrated and removed THF adjusts pH value to 5 with 1N HCl (aq), filters.Thick residue is washed with water (3mL), anhydrous sodium sulfate drying obtains 4- Amino -5- chloro thiophene -2- carboxylic acids (150mg, 58%), yellow solid.

Step E：By Boc₂O (147mg, 0.675mmol) be added to 4- amino -5- chloro thiophene -2- carboxylic acids (100mg, 0.56mmol) and in the mixture of DMF (7mL), stirred 16 hours at 25 DEG C.It concentrates mixture and removes DMF, residue is through preparing Type TLC (DCM: MeOH=10: 1) purify, obtain 4- ((tertbutyloxycarbonyl) amino) -5- chloro thiophene -2- carboxylic acids (80mg, 51%), yellow solid.

Step F：By (3S, 3aS) -3- (amino methyl) -7- (3- oxomorpholin generations) -3a, 4- dihydrobenzo [b] oxazole [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one (46mg, 0.144mmol), 4- ((tertbutyloxycarbonyl) amino) -5- chloro thiophenes -2- Carboxylic acid (40mg, 0.144mmol), HATU (66mg, 0.172mmol), Et₃N's (0.44mg, 0.432mmol) and DMF (5mL) Mixture stirs 16 hours at 25 DEG C.Then mixture is concentrated.Thick residue is pure through preparative TLC (DCM: MeOH=30: 1) Change, obtain (2- chloros -5- ((((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) carbamyl) thiene-3-yl) t-butyl carbamate (30mg, 36%), in vain Color solid.

Step G：By (2- chloros -5- ((((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) carbamyl) thiene-3-yl) t-butyl carbamate (30mg, HCl/MeOH (4N, 5mL) solution 0.051mmol) stirs 1 hour at 25 DEG C.Concentration mixture obtains thick residue, through system Standby type HPLC (formic acid) is purified, and obtains the present embodiment title compound (10mg, 40%), white solid.¹H NMR (400MHz, DMSO-d₆) δ 8.88 (t, J=6.0Hz, 1H), 7.86 (d, J=8.8Hz, 1H), 7.28 (s, 1H), 7.05 (s, 1H), 7.02 (d, J=8.8Hz, 1H), 5.23 (s, 2H), 4.59-4.52 (m, 2H), 4.18 (s, 2H), 4.06-4.04 (m, 2H), 3.96- 3.94 (m, 2H), 3.70-3.67 (m, 4H) .LCMS (ESI) m/z：479(M+1).

Embodiment 76

3- methoxyl groups-N- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) benzamide

Step A：The present embodiment title compound is prepared according to the method for embodiment 66, wherein by the 4- methoxies in step A Yl benzoic acid replaces with 3- methoxy benzoic acids.¹H NMR (400MHz, DMSO-d₆) δ 8.89 (t, J=6.0Hz, 1H), 7.85 (d, J=8.8Hz, 1H), 7.45-7.38 (m, 3H), 7.06 (d, J=2.4Hz, 1H), 7.03 (d, J=2.4Hz, 1H), 7.01 (d, J=2.4Hz, 1H), 4.64-4.62 (m, 1H), 4.57-4.54 (m, 1H), 4.18 (s, 2H), 4.08-4.06 (m, 2H), 3.95 (t, J=4.8Hz, 2H), 3.81 (s, 3H), 3.75-3.74 (m, 2H), 3.70-3.69 (m, 2H)；LCMS(ESI)m/z： 454(M+1).

Embodiment 77

5- methoxyl groups-N- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) pyridine carboxamide

Step A：The present embodiment title compound is prepared according to the method for embodiment 66, wherein by the 4- methoxies in step A Yl benzoic acid replaces with 5- methoxypyridine formic acid.¹H NMR (400MHz, DMSO-d₆) δ 8.98-8.90 (m, 1H), 8.34 (d, J =2.8Hz, 1H), 8.04 (d, J=8.8Hz, 1H), 7.84 (d, J=8.8Hz, 1H), 7.57 (dd, J=8.8,2.8Hz, 1H), 7.05-7.00 (m, 2H), 4.65-4.60 (m, 1H), 4.50-4.45 (m, 1H), 4.18-4.12 (m, 3H), 4.10-4.00 (m, 1H), 3.98-3.88 (m, 5H), 3.80-3.75 (m, 2H), 3.70-3.65 (m, 2H)；LCMS(ESI)m/z：455(M+1).

Embodiment 78

The chloro- N- of 5- ((dislike by the fluoro- 1- oxos -7- of (3S, 3aS) -9- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, suspend to the acetic acid (500mL) for the sodium perborate tetrahydrate (150g, 0.96mol) that stirred Acetic acid (200mL) solution of bromo- 2, the 6- difluoroanilines (20.0g, 0.096mol) of 4- is slowly added in liquid.Stirring 4 is small at 60 DEG C Solution is cooled to room temperature by Shi Hou, and is poured into ice water, and is extracted with EtOAc (500mL x 3).The organic extract liquid of merging Be washed with brine, and dried with anhydrous sodium sulfate successively, be concentrated in vacuo, obtain bromo- 1,3-, the bis- fluoro- 2- nitrobenzenes of 5- (17g, 74%), white solid.

Step B：Method according to 1 step A-L of embodiment prepares the present embodiment title compound, wherein by step A The fluoro- 1- nitrobenzenes of the bromo- 2- of 4- replace with bromo- 1,3-, the bis- fluoro- 2- nitrobenzenes of 5-.¹H NMR (400MHz, DMSO-d₆)δ8.96- 8.93 (m, 1H), 7.67-7.65 (m, 1H), 7.21 (d, J=4.0Hz, 1H), 7.04 (dd, J=11.6,2.0Hz, 1H), 6.94-6.92 (m, 1H), 4.62-4.58 (m, 2H), 4.19 (s, 2H), 4.05-3.92 (m, 4H), 3.72-3.58 (m, 4H)； LCMS(ESI)m/z：482(M+1).

Embodiment 79

The chloro- N- of 5- ((dislike by the fluoro- 1- oxos -7- of (3S, 3aS) -8- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：To 1, the 2- dichloros for the fluoro- benzene of the bromo- Isosorbide-5-Nitraes-two of 2- (32.0g, 0.17mol) for stirring and cooling down (- 10 DEG C) In ethane (320mL) solution, HNO is added in₃The H of (15.7g, 0.25mol)₂SO₄(81.3g, 0.83mol) solution, mixture is existed 29 DEG C are stirred 2 hours, are poured into ice water (1500g), are then extracted with DCM (300mL x3).Organic liquor is concentrated to dryness, and obtains 1- Bromo- 2,5-, bis- fluoro- 4- nitrobenzenes (36.3g, 92%), yellow solid.

Step B：Method according to 1 step A-L of embodiment prepares the present embodiment title compound, wherein by 4- in step A The bromo- fluoro- 1- nitrobenzenes of 2- replace with bromo- 2,5-, the bis- fluoro- 4- nitrobenzenes of 1-.¹H NMR (400MHz, DMSO-d₆) δ 9.02 (t, J= 5.6Hz, 1H), 7.80-7.72 (m, 2H), 7.22-7.14 (m, 2H), 4.64-4.56 (m, 2H), 4.21 (s, 2H), 4.05- 3.95 (m, 4H), 3.76-3.74 (m, 2H), 3.64 (t, J=4.8Hz, 2H)；LCMS(ESI)m/z：482(M+1)

Embodiment 80

The chloro- N- of 5- ((dislike by the fluoro- 1- oxos -7- of (3S, 3aS) -6- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Reaction process：

Step A：At room temperature, add in batches into DMF (125mL) solution of the fluoro- 6- nitrophenols (47.1g, 300mmol) of 2- Enter K₂CO₃(62.2g, 450mmol) and MeI (65.7g, 450mmol) is added dropwise.Mixture is stirred at room temperature 16 hours, Water (350 milliliters) is added in, and is extracted with EtOAc (350mL).Organic layer with anhydrous sodium sulfate is dried, filtered and concentrated, is obtained The fluoro- 2- methoxyl groups -3- nitrobenzenes of crude product 1-, brown oil.The crude product need not be further purified, and be directly used in anti-in next step It should.

Step B：At room temperature, to EtOH (125mL) solution of the fluoro- 2- methoxyl groups -3- nitrobenzenes (51.3g, 300mmol) of 1- Middle to add in 10%wt.Pd/C (10.0g), (1 atmospheric pressure) is stirred at room temperature 16 hours under a hydrogen atmosphere.It filters and concentrates, it is thick remaining Object silica gel chromatograph (PE: ethyl acetate=1: 40) purifying obtains the fluoro- 2- aminoanisoles of 3- (40g, 94%), brown oil Object.

Step C：At room temperature, it is added dropwise into AcOH (50mL) solution of the fluoro- 2- aminoanisoles (9.33g, 66mmol) of 3- Br₂AcOH (50mL) solution of (2.7mL, 52mmol), is stirred at room temperature 1 hour.Mixture is filtered, solid is dissolved in water In (30mL), with saturation NaHCO₃Solution is adjusted to pH=8-9, EtOAc (30mL) and is extracted.Organic layer is done with anhydrous sodium sulfate It is dry, it filters and concentrates.The fluoro- 2- aminoanisoles (7.5g) of the bromo- 3- of crude residue 4-, can be used to down without being further purified The reaction in face.LCMS(ESI)m/z：220,222 (M+1)

Step D：At room temperature, into DCM (100mL) solution of the fluoro- 2- aminoanisoles (7.26g, 33mmol) of the bromo- 3- of 4- BBr is added dropwise₃DCM (50mL) solution of (33.07g, 132mmol), and be stirred at room temperature 1 hour.With saturation NaHCO₃Solution tune Whole mixture to pH=8~9, EtOAc (30mL) extract.Organic layer is dried, filtered and concentrated with anhydrous sodium sulfate.It will be remaining The bromo- 2- fluorophenols (6.0g) of object crude product 6- amino -3- are directly used in be reacted in next step, without being further purified.LCMS(ESI)m/ z：206,208 (M+1)

Step E：At 0 DEG C, add into THF (100mL) solution of the bromo- 2- fluorophenols (5.77g, 28mmol) of 6- amino -3- Enter NEt₃(5.9mL, 42mmol) is then added dropwise CbzCl (5.25g, 30.8mmol), and is stirred 2 hours at 0 DEG C.Add in ice Water (100mL), and extracted with EtOAc (100mL).Organic layer with anhydrous sodium sulfate is dried, filtered and concentrated, obtains crude product (the bromo- 3- fluoro-2-hydroxyphenyls of 4-) benzyq carbamate (7.0g), shallow white solid.Crude product is directly used in next step Reaction, without being further purified.LCMS(ESI)m/z：340,342 (M+1)

Step F：At room temperature, to the DMF of (the bromo- 3- fluoro-2-hydroxyphenyls of 4-) benzyq carbamate (3.40g, 10mmol) In (40mL) solution, K is added in₂CO₃(Z) -4- bromine but-2-enes oxygroup is then added dropwise in (2.76g, 20mmol)) (tertiary butyl) diformazan DMF (10mL) solution of base silane (2.65g, 10mmol), and be stirred at room temperature 2 hours.Water (150mL) is added in, is used in combination EtOAc (150mL) is extracted.Organic layer is dried, filtered and concentrated with anhydrous sodium sulfate.By thick residue through silica gel chromatograph It (PE: ethyl acetate=50: 1~20: 1) purifies, obtains (Z)-(the bromo- 2- of 4- ((4- ((t-butyldimethylsilyl) oxygen Base) butyl -2- alkene -1- bases) oxygroup) -3- fluorophenyls) benzyq carbamate (4.50g, 86%), yellow oil.LCMS (ESI)m/z：524, S26 (M+1)

Step G：At 0 DEG C, to (Z)-(the bromo- 2- of 4- ((4- ((t-butyldimethylsilyl) oxygroup) butyl -2- alkene - 1- yls) oxygroup) -3- fluorophenyls) and benzyq carbamate (4.40g, 8.4mmol) THF (40mL) solution in n-Bu is added dropwise₄NF THF (20mL) solution of (2.63g, 10.1mmol), acquired solution is warmed to room temperature, and is stirred at room temperature 2 hours.It will be mixed Object concentration is closed, and passes through silica gel chromatograph Purifying obtains (Z)-(the bromo- 3- of 4- are fluoro- 2- ((4- hydroxyl but-2-ene -1- bases) oxygroup) phenyl) benzyq carbamate (3.10g, 90%), white oil object.LCMS (ESI)m/z：410,412 (M+1)

Step H：Method according to 1 step D-L of embodiment prepares the present embodiment title compound, white solid.¹H NMR (400MHz, DMSO-d₆) δ 9.03 (t, J=5.6Hz, 1H), 7.73-7.71 (m, 2H), 7.21 (d, J=4.0Hz, 1H), 7.05 (dd, J=8.8,2.0Hz, 1H), 4.69-4.62 (m, 2H), 4.22 (s, 2H), 4.15-4.12 (m, 2H), 3.96 (t, J= 5.2Hz, 2H), 3.74 (t, J=5.2Hz, 2H), 3.64 (t, J=5.2Hz, 2H)；LCMS(ESI)m/z：482(M+1).

Embodiment 81

((- 6,6a, 7,9- tetrahydrochysene oxazoles of (6aS, 7S) -9- oxos -3- (3- oxomorpholin generations) are simultaneously [3,4-d] by the chloro- N- of 5- Pyrido [3,2-b] [Isosorbide-5-Nitrae] oxazines -7- bases) methyl) thiophene-2-carboxamide derivatives

Reaction process：

Step A：CDI is added in into THF (40mL) solution of 2- amino -3- pyridones (2.60g, 23.6mmol) Gained reaction mixture at 70 DEG C is stirred 14 hours, is cooled to room temperature, and be concentrated under reduced pressure by (5.74g, 35.4mmol).It will Residue is dissolved in DCM (50mL), is washed with 2N sodium hydroxides (3 × 10mL).The water layer of merging is cooled to 0 DEG C, is used in combination It is 6 that 6N hydrochloric acid, which is acidified to pH,.The sediment formed used in porous collection funnel, is washed with cold water (10mL), dry under vacuum, is obtained To oxazole simultaneously [4,5-b] pyridine -2 (3H) -one ((2.6g, 81%)), yellow solid.

Step B：Bromine (1.08mL, 21.0mmol) was added dropwise to the oxazole that stirred simultaneously [4,5-b] pyrrole through 20 minutes In DMF (20mL) solution of pyridine -2 (3H) -one.Reaction mixture is stirred at room temperature 14 hours.Mixture is poured into trash ice In, the sediment that is formed with porous collection funnel.Wash solid with water (20mL), be dried in vacuo, obtain 6- bromos oxazole simultaneously- [4,5-b] pyridine -2 (3H) -one (3.7g, 91%), light yellow solid.

Step C：With 10%NaOH aqueous solutions dilution 6- bromines oxazole simultaneously [4,5-b] pyridine -2 (3H) -one (3.4g, 15.8mmol), and by obtained mixture it is stirred 6 hours at 100 DEG C.The reaction is cooled to 5 DEG C, 6N HCl are added in until shape Into precipitation.It with cellular glass collection funnel solid, is washed with water (20mL), is dried in vacuo, obtains 2- amino -5- bromopyridines -3- Alcohol (2.4g, 80%), brown solid.

Step D：, to 2- amino -5- bromopyridine -3- alcohol (4.32g, 0.023mol), NaOH (5.49g, CbzCl (14.04g, 0.081mol) is added in THF (45mL)-H2O (45mL) solution 0.138mol), and mixture is existedLower stirring 16 hours.Reaction mixture EtOAc (100mL x 3) is extracted.The organic layer of merging is concentrated to give slightly Product.Residue is washed with water (50mL), is then dried in vacuo, and obtains (the bromo- 3- pyridones -2- bases of 5-) benzyq carbamate (5.5 grams, 75%), gray solid.LCMS(ESI)m/z：189,191 (M+1)

Step E：Method according to 80 step F, G of embodiment prepares the bromo- 3- of (Z) -5- (4- hydroxyl but-2-enes oxygroup) pyrrole Pyridine -2- aminocarbamic acid benzyl esters, wherein the bromo- 2- fluorobenzene of 6- amidos -3- in step E is replaced with 2- amido -3- hydroxyl -5- bromine pyrroles Pyridine.LCMS(ESI)m/z：189,191 (M+1)

Step F：Method according to 1 step D-L of embodiment prepares the present embodiment title compound.¹H NMR (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.09 (d, J=2.4Hz, 1H), 7.71 (d, J=4.0Hz, 1H), 7.53 (d, J=2.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 4.57 (d, J=6.8Hz, 2H), 4.22 (s, 2H), 4.06-4.17 (m, 2H), 3.97 (t, J=4.8Hz, 2H), 3.66-3.79 (m, 4H)；LCMS(ESI)m/z：465(M+1).

Embodiment 82

(((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydrochysenes oxazole is simultaneously [3,4-d] by the chloro- N- of 5- Pyrido [4,3-b] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：THF (125mL) is cooled to -78 DEG C, then passes to anhydrous NH₃(100mL).The chloro- 3- of 4- are added at 0 DEG C Nitropyridine (20.0g, 126mmol) then added in TBHP through 5 minutes (5M is dissolved in decane, 25mL, 125mmol).By uncle THF (100mL) solution of butanol potassium (35.7g, 318mmol) is heated to -35 DEG C, and acquired solution then is added drop-wise to above-mentioned tertiary fourth In potassium alkoxide solution, then 1 hour used time stirred 2 hours at -35 DEG C, then carefully with 25 milliliters of saturation NH₄Cl aqueous solutions Reaction is quenched.Mixture is warming up to and is placed at room temperature for 16 hours, then detaches organic layer, is concentrated, filtration residue.It is washed with ice water Solid is washed, is dried in vacuo, obtains 4- chloro-5-nitropyridines -2 (1H) -one (15.0g, 69%), black solid

Step B：At room temperature, phosphoryl bromide (54.0g, 189mmol) is added to 4- chloro-5-nitropyridines -2 (1H) -one In acetonitrile (200mL) suspension of (15.0g, 85.94mmol), and it is heated to reflux 3 hours.By reaction mixture cooling and it is careful Ground is poured into ice and saturation K₂CO₃In aqueous solution, then extracted with EtOAc (200mL x 3).Merge organic layer, washed with water and salt It washs, is dried, filtered and concentrated with anhydrous sodium sulfate, obtain 2,4-, bis- bromo- 5- nitropyridines ((9.0g, 38%)), yellow solid. LCMS(ESI)m/z：283(M+1).

Step C：It is added in into anhydrous DMF (120mL) solution of 2,4-, bis- bromo- 5- nitropyridines (9.0g, 31.9mmol) Cs₂CO₃(12.5g, 38.37mmol), (Z)-butyl -2- alkene-Isosorbide-5-Nitrae-glycol (3.1g, 31.9mmol) is then added in, will be obtained Mixture be stirred at room temperature 16 hours.Mixture is filtered, filter vacuum is concentrated.By thick residue by silica gel chromatograph (PE: EA=8: 1) purify, obtain (Z) -4- ((the bromo- 5- nitropyridines -4- bases of 2-) oxygroup) but-2-ene -1- alcohol (4.5g, 50%), light Yellow solid.LCMS(ESI)m/z：289(M+1).

Step D：The present embodiment title compound is prepared according to the method for 1 step B-L of embodiment, wherein by 4- in step B The bromo- fluoro- 1- nitrobenzenes of 2- replace with 2,4-, bis- bromo- 5- nitropyridines.¹H NMR (400MHz, DMSO-d₆) δ 9.00 (t, J= 6.0Hz, 1H), 8.76 (s, 1H), 7.71 (d, J=4.0Hz, 1H), 7.60 (s, 1H), 7.21 (d, J=4.0Hz, 1H), 4.67- 4.63 (m, 2H), 4.22-4.17 (m, 1H), 4.15-4.10 (m, 1H), 3.98-3.96 (m, 2H), 3.92-3.89 (m, 2H), 3.74 (d, J=5.6Hz, 2H)；LCMS(ESI)m/z：465(M+1).

Embodiment 83

2- (the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formamido groups) -2- oxoethyl 2- amion acetic acid hydrochlorides

Preparation flow：

Step A：At room temperature, the chloro- N- of 5- are added in into the mixture of NaH powder (112mg, 2.8mmol) and DMF (2mL) (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously dislike by [3,4-d] [Isosorbide-5-Nitrae] Piperazine -3- bases) methyl) thiophene-2-carboxamide derivatives (649mg, 1.4mmol) DMF (6mL) solution, stir 20 minutes, add at room temperature DMF (2mL) solution ＆ stir of 2- chloracetyl chlorides (474mg, 4.2mmol) 3 hours.Then 2- ((tertiary fourth oxygen is added at room temperature Base carbonyl) amino) acetic acid (1.96g, 11.2mmol) and CsCO₃It (1.37g, 4.2mmol) and stirs 16 hours.Gained is mixed Object is added to the NH of saturation₄It is extracted in Cl solution (30mL) and with EtOAc (30mL x 3).By the organic phase of merging with anhydrous Na₂SO₄It is dry, it filters and concentrates in vacuo.Thick residue through silica gel chromatograph (PE: EtOAc=1: 2~4: 1) is purified, obtains 2- ((((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously [3,4-d] by the chloro- N- of 5- [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formamido groups) -2- oxoethyls -2- ((tertbutyloxycarbonyl) amino) acetate (55mg, 6%yield), faint yellow solid.LCMS(ESI)m/z：579,191 (M+1-100)

Step B：At room temperature, to 2- (the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formamido groups) -2- oxoethyls -2- TFA (0.8mL) and stirring 30 are added in DCM (4mL) solution of ((tertbutyloxycarbonyl) amino) acetate (41mg, 0.06mmol) Minute.Concentrated reaction mixture at room temperature, thick residue are purified through preparation HPLC, obtain the present embodiment title compound (7mg, 20%), yellow solid.¹H NMR (400MHz, DMSO) δ 8.42 (brs, 3H), 7.82 (d, J=8.8Hz, 1H), 7.74 (d, J=4.4Hz, 1H), 7.36 (d, J=4.0Hz, 1H), 7.05 (d, J=2.0Hz, 1H), 7.05 (dd, J=8.8,2.4Hz, 1H), 5.23-5.18 (m, 2H), 4.67-4.64 (m, 1H), 4.64-4.61 (m, 1H), 4.39-4.34 (m, 2H), 4.17 (s, 2H), 4.05-4.02 (m, 2H), 3.96-3.93 (m, 4H), 3.68 (t, J=4.8Hz, 2H) .LCMS (ESI) m/z：579(M+ 1).

Embodiment 84

(R) -2- (the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formamido groups) -2- oxoethyls 2- amino -3 Methylbutanoic acid Hydrochloride

Step A：The present embodiment title compound is prepared according to the sequence of embodiment 83 step A and B, wherein by step A 2- ((tert-butoxycarbonyl) amino) acetic acid replaces with 2- ((tert-butoxycarbonyl) amino) -3 Methylbutanoic acid, obtains white solid¹H NMR (400MHz, DMSO-d₆) δ 8.29 (brs, 3H), 7.81 (d, J=8.8Hz, 1H), 7.74 (d, J=4.4Hz, 1H), 7.36 (d, J=4.4Hz, 1H), 7.05 (d, J=2.0Hz, 1H), 7.01 (dd, J=8.82.4Hz, 1H), 5.27-5.11 (m, 2H), 4.65-4.55 (m, 2H), 4.40-4.35 (m, 2H), 4.17 (s, 2H), 4.05-4.01 (m, 2H), 3.96-3.92 (m, 4H), 3.68 (t, J=4.8Hz, 2H)；LCMS(ESI)m/z：621.1(M+1).

Embodiment 85

The chloro- N- of 5- ((tetra- oxygen benzo [b] oxazoles of 1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- simultaneously [3,4-d] [1, 4] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives

Preparation flow：

Step A：By 6- bromos benzo [d] thiazole -2 (3H) -one (10.0g, 43.5mmol) and NaOH solution (26gNaOH It is dissolved in 80mLH₂In O) mixture stirred 16 hours at 105 DEG C, mixture is cooled to room temperature, and at 0~10 DEG C Addition acetic acid adjusts the mixture to pH=8.Mixture is filtered, washes filter cake, vacuum drying obtains 2,2 '-disulphanes diyl Bis- (4- bromoanilines) (9.9g, 100%), yellow solid react in next step without being further purified to be directly used in.LCMS (ESI)m/z：405(M+1).

Step B：At 0 DEG C, to 2,2 '-disulphanes diyl bis- (4- bromoanilines) (10.0g, 24.6mmol) and NaHCO₃ The THF/H of (20.7g, 0.25mol)₂Benzyl chloroformate (21.0g, 0.12mol) is added dropwise in O (150mL/50mL) solution, by institute Mixture is obtained to stir 16 hours at 37 DEG C.Mixture is filtered, washes filter cake, vacuum drying obtains the (bis- (4- of disulphanes diyl Bromo- 2,1- phenylenes)) diamino acid dibenzyl ester (10.0g, 60%), white solid.LCMS(ESI)m/z：673(M+1).

Step C：By (disulphanes diyl is bis- (4- bromo- 2,1- phenylene)) diamino acid dibenzyl ester (6.5g, 9.6mmol), ((3- (bromomethyl) ethylene oxide -2- bases) methoxyl group) (tertiary butyl) dimethylsilane (2.0g, 7.1mmol) and The mixture of DMF (70mL) solution of N- ethyl-N-iospropyl propyl- 2- amine (12mL) stirs 8 hours at 110 DEG C, adds in water (200mL), and (100mL x 2) is extracted with ethyl acetate.Merge organic layer to be washed with brine, anhydrous sodium sulfate drying, filtering And it concentrates.Thick residue is purified through column chromatography (PE: EtOAc=100: 1), obtains (4- bromos -2- (((3- (((tertiary butyl diformazans Base silicyl) oxygroup) methyl) ethylene oxide -2- bases) methyl) sulfenyl) phenyl) benzyq carbamate (0.93g, 24%), in vain Color solid.LCMS(ESI)m/z：538(M+1).

Step F：According to the method for 1 step F-L of embodiment prepare 5- chloro- N- ((1- oxos -7- (3- oxomorpholin generations) -1, 3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives, wherein by (4- bromines Generation -2- (((2R, 3S) -3- (((t-butyldimethylsilyl) oxygroup) methyl) ethylene oxide -2- bases) methoxyl group) phenyl) Benzyq carbamate replace with (4- bromos -2- (((3- (((t-butyldimethylsilyl) oxygroup) methyl) ethylene oxide - 2- yls) methyl) sulfenyl) phenyl) benzyq carbamate.Title compound is white solid isomer, through preparative SFC and Preparation HPLC is further purified, and obtains two components, and component 1 is 360mg, and component 2 is 380mg.Component 1：¹H NMR (400MHz, DMSO-d₆) δ 9.00-8.93 (m, 1H), 7.96 (d, J=8.8Hz, 1H), 7.70 (d, J=4.0Hz, 1H), 7.29 (d, J=2.4Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 7.16-7.14 (m, 1H), 4.56-4.52 (m, 1H), 4.15 (s, 2H), 4.12-4.08 (m, 1H), 3.96-3.94 (m, 2H), 3.71-3.68 (m, 4H), 3.32-3.27 (m, 2H) .MS (ESI) m/ z：480 (M+1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 9.00-8.93 (m, 1H), 7.96 (d, J=8.8Hz, 1H), 7.70 (d, J=4.0Hz, 1H), 7.29 (d, J=2.4Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 7.16-7.14 (m, 1H), 4.56-4.52 (m, 1H), 4.15 (s, 2H), 4.12-4.08 (m, 1H), 3.96-3.94 (m, 2H), 3.71-3.68 (m, 4H), 3.32-3.27 (m, 2H) .MS (ESI) m/z：480(M+1).

Embodiment 86

The chloro- N- of 5- ((5- oxidation -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3, 4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, to the chloro- N- of 5-, ((1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] are disliked Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives (200mg, 0.4mmol) DCM (10mL) solution in M-CPBA (85mg, 0.4mmol) is added in, gained mixture is stirred 16 hours at 37 DEG C, adds in water (30mL), DCM (20mL X 2) extraction.Organic layer will be merged to be washed with brine, anhydrous sodium sulfate drying filters and concentrates in vacuo, and thick residue is through preparing Type HPLC is purified, and obtains the present embodiment title compound, is white solid isomer, through preparative SFC and preparative HPLC is further purified, and obtains two components, and component 1 is 35mg, and component 2 is 32mg.Component 1：¹H NMR (400MHz, DMSO- d₆) δ 9.08-9.03 (m, 1H), 8.42 (d, J=9.2Hz, 1H), 7.96 (d, J=2.4Hz, 1H), 7.73-7.67 (m, 2H), 7.21 (d, J=4.0Hz, 1H), 4.75-4.71 (m, 1H), 4.58-4.52 (m, 1H), 4.23 (s, 2H), 4.00-3.98 (m, 2H), 3.77-3.74 (m, 4H), 3.52-3.50 (m, 1H), 3.41-3.38 (m, 1H) .MS (ESI) m/z：496 (M+1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 9.08-9.03 (m, 1H), 8.42 (d, J=9.2Hz, 1H), 7.96 (d, J=2.4Hz, 1H), 7.73-7.67 (m, 2H), 7.21 (d, J=4.0Hz, 1H), 4.75-4.71 (m, 1H), 4.58-4.52 (m, 1H), 4.23 (s, 2H), 4.00-3.98 (m, 2H), 3.77-3.74 (m, 4H), 3.52-3.50 (m, 1H), 3.41-3.38 (m, 1H) .MS (ESI)m/z：496(M+1).

Embodiment 87

The chloro- N- of 5- ((5,5- titanium dioxide -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives

Step A：At 0 DEG C, to the chloro- N- of 5-, ((1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] are disliked Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives (200mg, 0.4mmol) THF/MeOH/H₂O (2.0mL/2.0mL/2.0mL) solution adds in potassium hydrogen persulfate (780mg, 1.2mmol), and gained mixture is stirred at 37 DEG C 16 hours.Water (10mL), EA (20mL x 2) extractions are added in into reaction mixture.Merge organic layer to do through anhydrous sodium sulfate It is dry, it is concentrated in vacuo.Thick residue is purified through preparation HPLC, obtains title compound, is white solid isomer, through preparing Type SFC and preparation HPLC are further purified, and obtain two components, and component 1 is 33mg, and component 2 is 31mg.Component 1：¹H NMR (400MHz, DMSO-d₆) δ 9.02-8.95 (m, 1H), 8.32 (d, J=9.2Hz, 1H), 7.96 (d, J=2.8Hz, 1H), 7.72-7.71 (m, 2H), 7.21 (d, J=4.0Hz, 1H), 4.75-4.68 (m, 2H), 4.23 (s, 2H), 4.15-4.05 (m, 2H), 3.95-3.90 (m, 2H), 3.77-3.72 (m, 4H) .MS (ESI) m/z：512 (M+1) components 2：¹H NMR (400MHz, DMSO-d₆) δ 8.99 (t, J₁=6.0Hz, J₂=12.0Hz, 1H), 8.32 (d, J=9.2Hz, 1H), 7.96 (d, J=2.8Hz, 1H), 7.72-7.71 (m, 2H), 7.21 (d, J=4.0Hz, 1H), 4.75-4.69 (m, 2H), 4.23 (s, 2H), 4.17-4.05 (m, 2H), 3.99-3.98 (m, 2H), 3.79-3.77 (m, 4H) .MS (ESI) m/z：512(M+1).

Experimental example 1：In-vitro evaluation

By measuring IC₅₀Value evaluates test-compound to the Xa factor of people or rat or other enzymes such as fibrin ferment or pancreas egg The rejection ability of white enzyme, wherein IC₅₀Value and inhibition constant K_iIt is associated.The enzyme of purifying is used in chromogenic assay.It uses FlexStation III (molecule instrument company of the U.S.) measure time course linear parts at 37 DEG C and (typically add in substrate 2 ~after ten minutes) variation of absorbance at 405nm measures the initial velocity of chromogenic substrate hydrolysis.By drawing hydrolysis After relative velocity (compared with untamed control group) is to the logarithmic curve of Test compound concentrations, pass through linear regression meter It calculates, measures the concentration of the inhibitor for the rate reduction by 50% for leading to substrate hydrolysis.According to Cheng-Prusoff equation：K_i =IC₅₀/(1+[S]/K_m) calculate enzyme inhibition constant (K_i), wherein [S] is concentration of substrate, K_mTo be determined by double-reciprocal plot method Michaelis-Menten constant.The IC of test-compound is obtained by GraphPad Prism softwares₅₀Value.Use " shape dosage effect (variable slope) " matched curve.

People/rat factor Xa experiment：

The factor Xa that people or rat are measured using Tris-HCl buffer solutions (50mM, pH 8.3,150mM NaCl) is lived Property inhibiting effect.By by 50 μ L human blood coagulations Xa (Enzyme Research Laboratories, Inc；It is final concentration of 8.36nM) or 50 μ L rats factor Xa (Enzyme Research Laboratories, Inc；Final concentration of 57.5nM) Buffer solution be added drop-wise to method in the appropriate bore of 384 microtiter plates of Greiner and measure IC₅₀.Containing 2 μ L2% (V/V) DMSO Measure buffer solution (untamed control group) or the untested compounds of various concentration be diluted in containing 2% (V/V) DMSO's It measures in buffer solution, and adds -2222 (Chromogenix of 48 μ L substrate Ss；Chemical formula：Bz-IIe-Glu(γ-OR)-Gly- Arg-pNAHCl R=H (50%), wherein R=CH₃(50%)) measure buffer solution, final concentration of 0.172mM.The experiment It is middle by test-compound and enzyme preculture 10 minutes, then add in substrate S-2222 and obtain 100 μ L final volumes to start to test.

K_iThe test-compound that 10 μM of ＜ is considered as positive, the preferred K of the present invention_iThe compound that 1 μM of ＜, more preferable K_i The compound that 0.1 μM of ＜, more preferable K_iThe compound that 0.01 μM of ＜, further preferred K_iThe compound that 0.001 μM of ＜.Through above-mentioned Test method measures, some compound Ks of the invention_i0.1 μM of ＜, therefore the compound of the present invention can be used as effective Xa factor Inhibitor.

Human thrombin is tested：

Using buffer solution (HEPES buffer solution of 10mM, pH 7.4,2mM CaCl₂) measure human thrombin activity suppression work With.Suitable hole in 384 microtiter plates of Greiner is selected to measure IC₅₀, contain 50 μ L human thrombins (Sigma companies； T8885 buffer solution), final concentration of 0.05NIH units/mL, the measure buffer solution containing 2 μ L2% (V/V) DMSO be not (suppressed Control group) or the untested compound of various concentration be diluted in the measure buffer solution containing 2% (V/V) DMSO；Addition contains 48 μ L substrate S-2238 (Chromogenix；Chemical formula：H-D-Phe-Pip-Arg-pNA2HCl buffer solution), it is final concentration of 30μM.By test-compound and enzyme preculture 10 minutes in the experiment, then add in substrate and obtain 100 μ L final volumes to start to try It tests.

People's trypsin test：

Using buffer solution (50mM Tris, pH 8.2, and 20mM CaCl₂) measure people's tryptic activity inhibition work With.Suitable hole in 384 microtiter plates of Greiner is selected to measure IC₅₀, contain 50 μ L people trypsase (Sigma companies； T6424 buffer solution), final concentration of 0.39BAEE units/mL, the measure buffer solution containing 2 μ L2% (V/V) DMSO be not (suppressed Control group) or the untested compound of various concentration be diluted in the measure buffer solution containing 2% (V/V) DMSO；Contain substrate The buffer solution of S-2222 (Chromogenix), final concentration of 30 μM.Test-compound and enzyme preculture 10 are divided in the experiment Then clock adds in 48 μ L of substrate, obtains 100 μ L of final volume to start to test.

Prothrombin test：

Activity of the test-compound to prothrombinase is measured by the generation of fibrin ferment.Briefly, in 10mM HEPES buffer solution and pH 7.4,2mM CaCl₂12.5 μ L people's factors Xa, final concentration of 0.5nM of middle incubation, and in 37 DEG C of additions 12.5 μ L human blood platelets (1 × 10⁷mL^-1) 10 minutes.25 μ L factors are added in start to react, final concentration of 0.5 μM, containing 2 μ The measure buffer solution (untamed control group) of L2% (V/V) DMSO or the untested compound of various concentration be diluted in containing In the measure buffer solution of 2% (V/V) DMSO.After twenty minutes, it is extremely final concentration of that 48 μ L substrates S-2238 (Chromogenix) are added in 50 μM to measure thrombin activity.

Table 1：The compounds of this invention body outer screening test result

" a " represents the component 1 after SFC is detached and component 2 respectively with " b "

Conclusion：Compared with known anti-coagulants razaxaban, the compounds of this invention is lived by its specific anticoagulin Xa Sex expression goes out very strong anticoagulant active.

The prothrombin time (PT) of test-compound is measured to determine its anticoagulant active in vitro.

Prothrombin time (PT) is tested：

Rat aorta blood drawing under from narcosis.With the plastic tube of the 0.11M sodium citrates containing 1/10 volume Blood is collected, is immediately centrifuged 10 minutes in 2500g, 4 DEG C, obtains blood plasma, and preserved at -80 DEG C.By using city The kit (Wuhan Thalys Biotechnology Co., Ltd., China) sold temperature controlled automatic thermal coaglation analyzer (Compact-X, Behnk-Elektronik (BE), Germany) measure prothrombin time (PT).Test-compound (profit is prepared with DMSO (10 μM) Cut down Sha Ban and invention compound 1) stoste, it (is respectively 0,0.3125,0.625,1.25,2.5,5 to be serially diluted in blood plasma μM).By 0.2mL PT reagents (at 37 DEG C incubate 3 minutes) be added to 0.1mL tested blood plasma and normal control blood plasma (37 It is incubated 3 minutes at DEG C).The clotting time is measured, and is compared with compareing blood plasma.Result of the test is with forming initial fibrin chain The inhibitor concentration of DT Doubling Time (2 × PT) represents.

Table 2

Compound	2xPT(μM)
		Razaxaban	0.54
Compound 1	0.99

As shown in table 2, razaxaban and the compounds of this invention 1 are when the concentration less than 1 μM reaches double factor Between.

Experimental example 2：In vivo study

Arteriovenous shunt rat model：

With the anti thrombotic action of rat arteriovenous (AV) shunting thrombotic model verification the compounds of this invention, test method With Journal of Thrombosis and Haemostasis 2005；3：Method disclosed in 514-521 is essentially identical. In this model, rat group gives the test-compound of 2mpk, 3mpk, 6mpk and 10mpk dosage respectively.By razaxaban and The compounds of this invention 1 is dissolved in solutol/ ethyl alcohol/H₂In [40%/10%/50% (v/v/v)] of O, and take orally and give male (Shanghai Slac Experimental Animal Co., Ltd., the animal subject number of each dosage group is 8) SD rats weight 350-450 to SD rats Gram, it is first anaesthetized 90 minutes with yellow Jackets (i.p., 50mg/Kg2.5mL/kg), then opens current divider 15 minutes.

Detach left neck vein and right carotid.6 centimeter lengths that jugular vein and opposing carotid are filled with a physiological saline Intubation catheter, pass through connect one comprising 6 centimeter lengths thick nylon wire (60 × 0.24mm) 8 centimeter lengths the poly- second of PE-160 Alkene pipe (American Health＆Medical Supply International Corp) is assembled into a physiological saline filling Current divider.Oral medication opens current divider after 90 minutes, and blood is allowed to flow through current divider 15 minutes.It takes out and carries from current divider The line of related thrombus subtracts the average weight of the operation suture thread of 6 centimeter lengths in the thrombus weight formed on calculating line.It removes Take out blood sample (2mL) after thrombus from carotid duct immediately.With the modeling of 3.8% trisodium citrate containing 1/10 volume Expects pipe collects blood (1.8mL), is immediately centrifuged 15 minutes in 2000g, 4 DEG C, collects blood plasma, and be stored in -80 DEG C It is lower to use (PT measure) for follow-up.With EDTA-K containing 0.5M₂Plastic tube collect blood (0.2mL), immediately in 7000rpm It (5204g), centrifuges 10 minutes at 4 DEG C and obtains blood plasma, plasma sample is stored in the measure that concentration is used at -80 DEG C. Then make animal euthanasia with carbon dioxide.

Table 3

As shown in table 3, it takes orally and gives the compounds of this invention 1 and show significant thrombosis inhibition, compound 1 3mpk antithrombotic effect it is suitable with the effect of razaxaban 6mpk.

Rat-tail Hemorrhage Model：

Test-compound (razaxaban and the compounds of this invention 1) or excipient 90 minutes is administered orally, then from anesthesia The crosscutting 1mm in tail portion front end of rat, and be dipped vertically into 37 DEG C of brine.The time that continuous blood flow stops 30 seconds or more is measured, most Long observing time is 15 minutes (belonging to the longer bleeding time in 15 minutes).

Table 4

* P ＜ 0.05；* P ＜ 0.01 are relative to excipient control group

As shown in table 4, effective antithrombotic oral dose (in the arteriovenous shunt model minimum of antithrombotic Dosage) be 3mg/kg when, the bleeding time is identical with baseline (0.8-1.2 times).Higher doses (10mg/kg) shows that moderate extends Bleeding time (about 2 times).The result shows that compared with razaxaban, the compound of the present invention 1 does not show significant bleeding Tendency.

Experimental example 3：The measure of dynamic solubility

Test-compound is dissolved in DMSO, to prepare the stoste of 10mmol/L.With pipette (Eppendorf Research companies) 980 μ L dissolution mediums are added to 2mL the glass vial of screw lid in.By each tested chemical combination of 20 μ L The stoste and QC samples of object are added in the buffer solution for the kinetic measurement solution for being equivalent to pH 6.5.Test-compound and The final concentration of DMSO solution is for 200 μM and 2% respectively.Medicine bottle gland.200 μM of the theoretical value of maximum concentration.At room temperature with 880 turns per minute of speed rotation shakes the mixture 24 hours.Bottle is centrifuged 30 minutes, 13000 turns per minute.With number 200 μ L supernatants are added in 96- orifice plates by pipette.With the dissolving of the spectrometric test-compound of high performance liquid chromatography Degree.

Table 5

Compound	Solubility (μM) pH 6.5
		Razaxaban	11.02
Compound 1	17.85

As shown in table 5, compared with razaxaban, the compounds of this invention 1 shows excellent water solubility (in pH= 6.5).Therefore, the compound of the present invention is more obvious than the prior art is more soluble in water.

Claims (20)

1. compound or its pharmaceutically acceptable salt shown in formula (I),

Wherein,

R¹Optionally substituted phenyl, thiophene or pyridine are represented, substituent group is independently selected from F, Cl, Br, cyano, amino, C_1-8Alkane Oxygroup and C_1-8Alkyl, the number of substituent group is 1；

R²It represents

R³Represent H；

A is selected from S, SO, SO₂；

X, Y and Z is separately selected from CH；And

Optionally the compound is stereoisomer.

2. compound or its pharmaceutically acceptable salt shown in formula (I),

Wherein,

R¹Optionally substituted phenyl, thiophene or pyridine are represented, substituent group is independently selected from F, Cl, Br, cyano, amino, C_1-8Alkane Oxygroup and C_1-8Alkyl, the number of substituent group is 1；

R²It represents

R³It represents

A is selected from O；

X, Y and Z is separately selected from CH；And

Optionally the compound is stereoisomer.

3. compound or its pharmaceutically acceptable salt shown in formula (I),

Wherein,

R¹Optionally substituted phenyl, thiophene or pyridine are represented, substituent group is independently selected from F, Cl, Br, cyano, amino, C_1-8Alkane Oxygroup and C_1-8Alkyl, the number of substituent group is 1；

R²It represents

R³Represent H；

A is selected from O；

X is selected from C-Br, C-Cl, C-F and N, and Y and Z are CH；Or

Y is selected from C-Br, C-Cl, C-F and N, and X and Z are CH；Or

Z is selected from C-Br, C-Cl, C-F and N, and X and Y are CH；

Optionally the compound is stereoisomer.

4. compound or its pharmaceutically acceptable salt shown in formula (I),

Wherein, R¹It represents：

R²It represents

R³Represent H；

A is selected from O；

X, Y and Z is separately selected from CH；

And optionally the compound is stereoisomer.

5. compound or its pharmaceutically acceptable salt shown in formula (I),

Wherein,

R¹Optionally substituted phenyl, thiophene or pyridine are represented, substituent group is independently selected from F, Cl, Br, cyano, amino, C_1-8Alkane Oxygroup and C_1-8Alkyl, the number of substituent group is 1；

R²It represents

R³Represent H；

A is selected from O；

X, Y and Z is separately selected from CH；And

Optionally the compound is stereoisomer.

6. according to compound and its pharmaceutically acceptable salt shown in the formula (I) described in claim 1,2,3,4 or 5, wherein Pharmaceutically acceptable salt is selected from：

1) base addition salts：Sodium, potassium, calcium, ammonium, organic amino or magnesium salts；Or

2) acid-addition salts：Hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, one hydrogen radical of phosphoric acid, dihydrogen phosphate, sulphur Acid, bisulfate ion, hydroiodic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, pungent two Acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, Amino acid or glucuronic acid.

7. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, the wherein compound select From：

85) the chloro- N- of 5- ((1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [1, 4] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives；

86) the chloro- N- of 5- ((5- oxidation -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3, 4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives；With

87) ((5,5- titanium dioxide -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles are simultaneously by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] thiazine -3- bases) methyl) thiophene-2-carboxamide derivatives.

8. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 2, the wherein compound select From：

83) 2- (the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formamido groups) -2- oxoethyl 2- amion acetic acid hydrochlorides；With

84) (R) -2- (the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene -2- formamido groups) -2- oxoethyls 2- amino -3 Methylbutanoic acid Hydrochloride.

9. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 3, the wherein compound select From：

78) the chloro- N- of 5- ((dislike by the fluoro- 1- oxos -7- of (3S, 3aS) -9- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

79) the chloro- N- of 5- ((dislike by the fluoro- 1- oxos -7- of (3S, 3aS) -8- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

80) the chloro- N- of 5- ((dislike by the fluoro- 1- oxos -7- of (3S, 3aS) -6- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

81) the chloro- N- of 5- ((- 6,6a, 7,9- tetrahydrochysene oxazoles of (6aS, 7S) -9- oxos -3- (3- oxomorpholin generations) simultaneously [3,4-d] pyrroles Pyridine simultaneously [3,2-b] [Isosorbide-5-Nitrae] oxazines -7- bases) methyl) thiophene-2-carboxamide derivatives；And

82) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydrochysenes oxazole simultaneously [3,4-d] pyrroles Pyridine simultaneously [4,3-b] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives.

10. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 4, the wherein compound select From：

66) 4- methoxyl groups-N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) benzamide；

69) (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by 5- methyl-N- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

70) (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [d] oxazole is simultaneously by 5- bromos-N- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

71) (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by 5- cyano-N- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

72) (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the fluoro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

73) 4,5-, bis- fluoro- N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

74) the fluoro- N- of the chloro- 3- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

75) the chloro- N- of 4- amino -5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；And

77) 5- methoxyl groups-N- (((3S, 3aS) -1- oxos -7- (3- oxomorpholin generations) -1,3,3a, 4- tetrahydro benzos [b] oxazoles And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) pyridine carboxamide.

11. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 5, the wherein compound select From：

3) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (5- oxo-Isosorbide-5-Nitrae-oxazepine cycloheptane -4- bases) -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

6) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxo -1,3- oxazepine hexamethylene -3- bases) -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

7) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxo pyridines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

8) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxo pyridines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

9) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- Oxopyrazines -1 (2H)-yl) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

10) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- ((R) -3- oxos tetrahydro-1 H-pyrrolo [1,2-c] imidazoles -2 (3H) - Base) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

11) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- ((S) -3- oxos tetrahydro-1 H-pyrrolo [1,2-c] imidazoles -2 (3H) - Base) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

12) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxo-pyrrolidine -1- bases) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

13) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- hydroxyl -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

14) the chloro- N- of 5- (((3S, 3aS) -7- (2- methoxyl group-N- ethylmethylamidos) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

15) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (5- oxo-Isosorbide-5-Nitrae-oxazepine cycloheptane -4- bases) -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

16) 1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -2- oxo pyridine -3- Ethyl formates；

17) the chloro- N- of 5- (((3S, 3aS) -7- (3- (methylol) -2- oxo-piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

18) the chloro- N- of 5- (((3S, 3aS) -7- (2- (methylol) -5- oxomorpholin generations) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

19) the chloro- N- of 5- (((3S, 3aS) -7- (2- methyl -3- oxomorpholin generations) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

21) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (2- oxos -8- oxa- -3- azabicyclos [3.2.1] oct-3-yl) -1, 3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

22) 4- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamido groups) methyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) -3- oxomorpholin -2- carbamoyl ethyls；

23) N- (((3S, 3aS) -7- ((S) -3- amino -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

24) the chloro- N- of 5- (((3S, 3aS) -7- (2- ((methylamino) methyl) -1H- imidazoles -1- bases) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

25) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- methoxyl group -2- oxo-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

26) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxo -2- azabicyclos [2.2.2] octyl- 2- yls) -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

28) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxo thiomorpholine generations) -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

29) the chloro- N- of 5- (((3S, 3aS) -7- (1,1- titanium dioxide -3- oxo thiomorpholine generations) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

30) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -2- (methoxyl methyl) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

31) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -2- (methoxyl methyl) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

32) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxo-pyrrolidine -3- bases) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

34) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (1H-1,2,4- triazol-1-yls) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

35) the chloro- N- of 5- (((3S, 3aS) -7- (2- ((dimethylamino) methyl) -1H- imidazoles -1- bases) -1- oxos -1,3,3a, 4- Tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

36) the chloro- N- of 5- (((3S, 3aS) -7- (2- ethyl -4,5- dihydro -1H- imidazoles -1- bases) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

37) the chloro- N- of 5- (((3S, 3aS) -7- (2- cyclopropyl -4,5- dihydro -1H- imidazoles -1- bases) -1- oxygen -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

38) the chloro- N- of 5- (((3S, 3aS) -7- (- 1 (4H)-yl of 2- ethyls -5,6- dihydro-pyrimidin) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

39) the chloro- N- of 5- (((3S, 3aS) -7- (4,5- dihydro -1H- imidazoles -2- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

40) the chloro- N- of 5- (((3S, 3aS) -7- (1- methyl -4,5- dihydro -1H- imidazoles -2- bases) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

41) the chloro- N- of 5- (((3S, 3aS) -7- (1- methyl-1s, 4,5,6- tetrahydropyrimidine -2- bases) -1- oxos -1,3,3a, 4- tetra- Hydrogen benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

42) N- (((3S, 3aS) -7- ((S) -3- amino-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

43) N- (((3S, 3aS) -7- ((R) -3- amino-pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

44) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (methylamino) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

45) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysenes Benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

46) the chloro- N- of 5- (((3S, 3aS) -7- (3- hydroxy piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole And [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

47) the chloro- N- of 5- (((3S, 3aS) -1- oxos -7- (3- oxomorpholins) -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3, 4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

48) (((3S, 3aS) -7- ((S) -3- amino piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by N- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

49) (((3S, 3aS) -7- ((R) -3- amino piperidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by N- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) -5- chloro thiophene -2- formamides；

50) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- (methylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

51) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (methylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

52) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- (dimethylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

53) the chloro- N- of 5- (((3S, 3aS) -7- ((R) -3- (dimethylamino) piperidin-1-yl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

54) (R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- methyl formates；

55) (S) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- methyl formates；

56) (R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- formamides；

57) (S) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- formamides；

59) (R) -1- ((3S, 3aS) -3- ((5- chloro thiophene -2- formamidos) methyl) -1- oxos -1,3,3a, 4- tetrahydrochysene benzene And [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -7- bases) pyrrolidines -2- carboxylic acid -2- hydroxyethyl esters；

60) (((3S, 3aS) -7- (Cyclopropylsulfonyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole is simultaneously by the chloro- N- of 5- [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

61) the chloro- N- of 5- (dislike by ((3S, 3aS) -1- oxos -7- (pyrrolidin-1-yl) sulfonyl) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

62) the chloro- N- of 5- (((3S, 3aS) -7- ((4- methylpiperazine-1-yls) sulfonyl) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

63) the chloro- N- of 5- ((dislike by (3S, 3aS) -1- oxos -7- (2- oxoimidazolinium -1- bases) -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；

64) the chloro- N- of 5- ((dislike by (3S, 3aS) -7- (3- hydroxyl pyrrolidine -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] Azoles simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives；And

65) the chloro- N- of 5- (((3S, 3aS) -7- ((S) -3- methoxypyrrolidin -1- bases) -1- oxos -1,3,3a, 4- tetrahydro benzos [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- bases) methyl) thiophene-2-carboxamide derivatives.

12. the preparation method of formula (I) compound according to claim 3, wherein R¹、R², X, Y and Z such as claim 3 institute Definition, includes the following steps：

13. the preparation method of formula (I) compound according to claim 4, wherein R¹、R², X, Y and Z such as claim 4 institute Definition, includes the following steps：

14. the preparation method of formula (I) compound according to claim 5, wherein R¹、R², X, Y and Z such as claim 5 institute Definition, includes the following steps：

15. a kind of pharmaceutical composition, formula (I) chemical combination including the therapeutically effective amount described in claim 1~11 any one Object or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

16. formula (I) compound or its pharmaceutically acceptable salt according to claim 1~11 any one or according to power Profit requires application of the pharmaceutical composition in the drug for preparing prevention or treatment thrombotic disease described in 15.

17. application according to claim 16, wherein the thrombotic disease is selected from arterial cardiovascular thrombus bolt Plug property disease, intravenous cardio thrombotic disease, cerebral artery thrombosis embolism class diseases and vein cerebral vessels embolism disease.

18. application according to claim 17, wherein the thrombotic disease is selected from unstable angina pectoris, the heart Flesh infarct, ischemic sudden death, transient ischemic attack, apoplexy, atherosclerosis, venous thronbosis, thrombotic vein Inflammation, arterial embolism, coronary artery thrombosis formation, cerebral artery thrombosis formation, cerebral embolism, renal embolism, pulmonary embolism and following reasons Caused by thrombosis：(a) heart valve prosthesis or other implantation materials；(b) inlying catheter；(c) stent；(d) cardiopulmonary bypass； (e) haemodialysis；And blood is exposed to artificial surface so as to promote other programs of thrombosis or operation by (f).

19. application according to claim 18, wherein the myocardial infarction is sends out myocardial infarction again.

20. application according to claim 18, wherein the venous thronbosis is Lower limb deep venous thrombosis.