CN102471264B

CN102471264B - 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof

Info

Publication number: CN102471264B
Application number: CN201180002959.3A
Authority: CN
Inventors: 吕贺军; 邓炳初; 陈一千; 王胜蓝; 王�华; 张蕾; 李军
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd; Shanghai Shengdi Pharmaceutical Co Ltd
Priority date: 2010-05-11
Filing date: 2011-04-29
Publication date: 2014-04-02
Anticipated expiration: 2031-04-29
Also published as: CN102241621A; CN102471264A; WO2011140936A1

Abstract

Disclosed are 5,5-disubstituted-2-imino-pyrrolidine derivatives of formula (I) and their pharmaceutically acceptable salts, preparation methods and uses thereof in medicine as thrombin receptor antagonists, wherein each substituents of formula (I) is defined as the description.

Description

Two replacement-2-lminopyrrolidine the analog derivatives of 5,5-, its preparation method and in application pharmaceutically

Technical field

The present invention relates to a kind of new 5, the two replacement-2-lminopyrrolidine analog derivatives of 5-, its preparation method and the pharmaceutical composition that contains this derivative using and as therapeutical agent particularly as the purposes of thrombin receptor antagonist.

Background technology

At present worldwide, thrombotic diseases is the major cause that causes cardiovascular disorder high incidence and high mortality.Arterial thrombus can cause various acute symptoms such as comprising acute coronary syndrome, ishemic stroke/transient ischemic attack and peripheral arterial disease.These symptoms are all to cause blood vessel injury due to atherosclerotic plaque breakage or vascular endothelial cell damage, and then bring out that to form arterial thrombus inaccessible, and then the blood supply insufficiency causing causes.Thrombocyte has very important effect in the forming process of arterial thrombus.In this pathologic process, the breakage of atherosclerotic plaque or the damage of vascular endothelial cell all can cause blood vessel injury, in multiple platelet activating factor as zymoplasm, thromboxane A ₂and under the effect of ADP, cause platelet activation mechanism out of control and then cause a large amount of platelet activations and assemble, under the mediation of platelet glycoprotein (GP) IIb/IIIa acceptor, form thrombus thereafter, finally blocking blood flow.In the exciting factor of these thrombocytes, zymoplasm (thrombin) is as the most potent platelet activating agent, by with g protein coupled receptor family in PAR family member's interaction activate thrombocyte and induce it to assemble, and then realize the biological actions such as blood coagulation.

(the proteinase-activated receptors of proteinase activated receptors family, PARs) be under the jurisdiction of g protein coupled receptor family, in the various kinds of cell of this family member in cardiovascular systems, all have widely and express, as thrombocyte, vascular endothelial cell and vascular smooth muscle cell.PARs family has participated in the blood coagulation under normal physiological conditions, maintains blood vessel homeostasis, and the inflammatory reaction under pathological conditions, the various physiological processes such as thrombus and atherogenesis, and bring into play therein keying action.This family receptors is realized reactivation process with distinctive mechanism: the zymoplasm of being combined with PARs (thrombin) passes through proteolyzing, original N end in the function of extracellular district of PARs acceptor is hydrolyzed and forms a new N end, the new N end forming can be induced receptor activation after being combined with PARs in the mode of " mooring part ", and then realizes signal transduction process.

Confirmed that at present PARs family comprises four kinds of receptor subtypes, comprises PAR1, PAR2, PAR3 and PAR4.Remove PAR2 as trypsin trypsin) and the acceptor of tryptase (tryptase) outside, all the other 3 hypotypes are activated after all can being combined with zymoplasm, thereby are considered to main thrombin receptor (thrombin receptors).Wherein PAR1 is the thrombin receptor of high-affinity, and it can be activated under the zymoplasm condition of low concentration (lower than nanomolar concentration).Relatively, PAR4 is the thrombin receptor of low-affinity, only under the zymoplasm condition of higher concentration, participates in activation and the transmittance process of zymoplasm signal.Similar with PAR1, although PAR3 is also high-affinity receptor, it does not activate separately transmission of signal conventionally, but the activity that acts synergistically to improve PAR4 as accessory receptor and PAR4 realizes corresponding biological function (referring to Ho-Sam et al; Current Pharmaceutical Design, 2003,9,2349-2365).

As topmost thrombin receptor, PAR1 is expressed in the various kinds of cell and tissue in human body widely, comprises thrombocyte, endotheliocyte, blood vessel or tracheal smooth muscle, inflammatory cell (scavenger cell, lymphocyte), fibroblast, neurocyte, cardiovascular and Skeletal Muscle Cell.Except relevant to cardiovascular disorder, in wound, inflammatory conditions, and the rising that can observe PAR1 expression level under the multiple pathological state such as kinds of tumor cells.In addition, PAR1 can also and affect corresponding signal cascade by the crosslinked activated receptor tyrosine kinase activity of G protein signal, thus realize on cell proliferation and transfer process adjusting (referring to Derian CK, et al; Expert Opin.Investig Drugs, 2003,12:209-21).These have all further indicated that PAR1 can be used as the potential of various diseases treatment target spot.

At present, a large amount of non-peptide class PAR1 inhibitor that is used for the treatment of arterial thrombus class disease be in clinical before or clinical trial in.Development in early days, oral antiplatelet drug is mainly to regulate the thromboxane A of thrombocyte building-up process ₂(as aspirin acetylsalicylic acid) or P2Y ₁₂the platelet activation process (as ticlopidine ticlopidine) of adp receptor mediation is action target spot.Yet both do not have direct restraining effect (Davi G, et al for the zymoplasm-platelet activation approach realizing via PAR1 acceptor; N Engl J Med., 2007,357:2482-2494)., because both can weaken or disturb the during platelet aggregation of collagen protein induction, thereby may exert an influence to normal hemostasis meanwhile, make, in therapeutic process, hemorrhage probability occurs and raise.By contrast, the antagonist that the PAR1 of usining develops as target spot is directly for this process of zymoplasm-platelet activation, can bring into play more comprehensive and direct platelet activation restraining effect, and then directly reduce the risk of thrombosis and the generation of acute ischemia symptom.In addition, because PAR1 in normal blood coagulation-hemostatic mechanism is non-essential, thereby suppress PAR1 and can reduce in treatment and hemorrhage danger occurs (referring to Coughlin SR.; J Thromb Haemost., 2005,3:1800-1814).What is more important, the antagonist that the PAR1 of take is target spot does not affect the normal blood coagulation activity of zymoplasm (Thrombin) self, under special emergency, zymoplasm still can and be assembled by PAR4 signal induction platelet activation, the coagulation function of bringing into normal play.Therefore, take and suppress the antiplatelet drug that PAR1 develops as target spot and compare with conventional medicament, not only improved effect and the specificity for the treatment of, also reduced contingent side effect, thereby become the ideal medicament for the treatment of arterial thrombus class disease simultaneously.

Disclose at present the patent application of a series of thrombin receptor antagonists, comprising PCT patent applications such as WO2002085855, WO2005084679, WO2004078721 and WO2006051623, disclose a series of 2-lminopyrrolidine analog derivatives.

The present invention's design has the compound shown in general formula (I), and finds that the compound with this class formation shows the activity that excellent thrombin receptor suppresses.

Summary of the invention

In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide the new phthalazone analog derivative shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug

Wherein:

Ar is selected from aryl or heteroaryl, and wherein said aryl or heteroaryl are optionally further by one or more R ^asubstituting group replace;

Be selected from-CR of Y ¹²-or N atom;

Be selected from-CR of L ¹³r ¹⁴-or-(CH ₂) _m-;

R ¹, R ²and R ³independently be selected from separately hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷or-C (O) NR ¹⁶r ¹⁷substituting group replace;

R ¹and R ²or R ²and R ³form aryl together with the carbon atom being connected, wherein said aryl is optionally further by one or more halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷substituting group replace;

R ⁴and R ⁵independently be selected from separately cyano group, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further by one or more halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷substituting group replace;

Or, R ⁴and R ⁵form cycloalkyl together with the carbon atom being connected, wherein said cycloalkyl optionally further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical or-NR ¹⁶r ¹⁷substituting group replace;

R ⁶be selected from hydrogen atom, hydroxyl, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl ,-C (O) OR ¹⁵,-C (O) R ¹⁵or-C (O) NR ¹⁶r ¹⁷, wherein said alkyl, alkoxyl group, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituting groups that are selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl or heterocyclic radical;

R ^acan be identical or different, be independently selected from separately hydrogen atom, hydroxyl, halogen, cyano group, nitro, silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷, wherein said silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷substituting group replace;

R ¹²be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷substituting group replace;

R ¹³and R ¹⁴independently be selected from separately alkyl or halogen, wherein said alkyl is optionally further replaced by one or more substituting groups that are selected from halogen, hydroxyl, cyano group or nitro;

R ¹⁵be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituting groups that are selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group or alkyl;

R ¹⁶and R ¹⁷independently be selected from separately hydrogen atom, halogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁸r ¹⁹,-OC (O) NR ¹⁸r ¹⁹,-C (O) NR ¹⁸r ¹⁹or-S (O) ONR ¹⁸r ¹⁹substituting group replace;

Or, R ¹⁶and R ¹⁷form heterocyclic radical with the nitrogen-atoms being connected, wherein said heterocyclic radical contains one or more N, O or S (O) _pheteroatoms, and described heterocyclic radical is optionally further by one or more halogens, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁸r ¹⁹,-OC (O) NR ¹⁸r ¹⁹,-C (O) NR ¹⁸r ¹⁹or-S (O) ONR ¹⁸r ¹⁹substituting group replace;

R ¹⁸and R ¹⁹independently be selected from separately hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl;

M is selected from 1,2 or 3;

N is selected from 1,2 or 3; And

P is selected from O, and 1 or 2.

Preferred version of the present invention, the compound that a kind of general formula (I) is described or its be pharmaceutically useful salt pharmaceutically, comprising the compound a kind of general formula (II) Suo Shu or its pharmaceutically useful salt pharmaceutically:

Wherein:

Be selected from-CR of Y ¹²-or N atom;

Be selected from-CR of L ¹³r ¹⁴-or-(CH ₂) _m-;

R ¹and R ²or R ²and R ³form aryl together with the carbon being connected, wherein said aryl is optionally further by one or more halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷substituting group replace;

R ⁷, R ⁸, R ⁹, R ¹⁰and R ¹¹independently be selected from separately hydrogen atom, hydroxyl, halogen, cyano group, nitro, silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷, wherein said silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷substituting group replace;

Or, R ⁹and R ¹⁰form heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein said heterocyclic radical, aryl or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, nitro, silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR of being selected from ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷substituting group replace;

R ¹⁸and R ¹⁹independently be selected from separately hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.

M is selected from 1,2 or 3;

N is selected from 1,2 or 3; And

P is selected from 0,1 or 2.

Preferred version of the present invention, the compound that a kind of general formula (I) is described or its be pharmaceutically useful salt pharmaceutically, and wherein Ar is selected from 5 yuan or 6 yuan of heteroaryls, is preferably pyrryl or pyridyl.

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R ⁴and R ⁵be selected from alkyl or aryl.

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R ⁴and R ⁵form cyclopropyl together with the carbon atom being connected.

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R ⁶be selected from hydrogen atom.

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R ¹²be selected from hydrogen atom or halogen.

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, be wherein selected from-(CH of L ₂) _m-, m is 1.

Typical compound of the present invention includes, but are not limited to:

Typical compound of the present invention also includes, but are not limited to:

Or its pharmaceutically useful salt.

The present invention relates to a kind of general formula (I) described compound or its pharmaceutically useful salt, its formula of (I) compound exists with the form of free state or pharmaceutically useful acid salt, described pharmaceutically useful acid salt comprises hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, maleate, malate, Citrate trianion, acetate or trifluoroacetate, is preferably hydrobromate and hydrochloride.

The synthetic method that the present invention relates to compound shown in a kind of general formula (I), the method comprises:

By general formula (IA) compound or (IB) compound

React with general formula (IC) compound, obtain general formula (I) compound;

Wherein:

X is selected from halogen, is preferably chlorine atom or bromine atoms;

Wherein: L, Y, R ¹～R ¹¹definition described in general formula (I) compound.

The present invention relates to general formula (IA) or (IB) shown in compound, it is as the intermediate of preparing general formula (I) compound,

Wherein:

Be selected from-CR of Y ¹²-or N atom;

Or, R ¹⁶and R ¹⁷form heterocyclic radical with the nitrogen-atoms being connected, wherein said heterocyclic radical contains one or more N, O or S (O) _pheteroatoms, and described heterocyclic radical is optionally further by one or more halogens, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁸r ¹⁹,-OC (O) NR ¹⁸r ¹⁹,-C (O) NR ¹⁸r ¹⁹or-S (O) ONR ¹⁸r ¹⁹substituting group replace;

N is selected from 1,2 or 3; And

P is selected from 0,1 or 2.

Preferred version of the present invention, a kind of general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R ⁴and R ⁵be selected from alkyl or aryl.

Preferred version of the present invention, a kind of general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R ⁴and R ⁵form cyclopropyl together with the carbon atom being connected.

Preferred version of the present invention, a kind of general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R ⁶be selected from hydrogen atom.

Preferred version of the present invention, a kind of general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R ¹²be selected from hydrogen atom or halogen.

The Equivalent of considering---those skilled in the art will appreciate that into, also can there is the form of tautomer in compound (IA).The change form of compound (IA) can include but not limited to the structure being represented by following formula (IB):

All these change forms are included in the scope of the present invention and are included in inherently in compound (IA) definition.

General formula (IA) or (IB) typical compound of compound include, but are not limited to:

Or its pharmaceutically useful salt.

The present invention relates to a kind of general formula (IA) or (IB) preparation method of compound, the method comprises:

By the dimethyl sulfoxide solution of general formula (III) compound, under cuprous cyanide and cuprous iodide exist, reacting by heating, obtains general formula (IA) or (IB) compound;

Or, under ice bath, general formula (IV) compound being mixed with grignard reagent and titanic acid ester, stirring reaction under room temperature, obtains general formula (IA) or (IB) compound;

Or, will lead to formula V compound and strong aqua and tert.-butoxy hydroperoxidation, obtain general formula (IA) or (IB) compound;

Or under water and triphenylphosphine exist, stirring reaction under room temperature, obtains general formula (IA) or (IB) compound by the tetrahydrofuran solution of general formula (VI) compound.

Another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains general formula of the present invention (I) compound or its pharmaceutically useful salt and the pharmaceutically useful carrier for the treatment of effective dose.

Another aspect of the present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition that contains them purposes in preparation calcium ion transport inhibitor.

Another aspect of the present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition that contains them purposes in preparing thrombin receptor antagonist, and wherein said thrombin receptor antagonist is PAR1 receptor antagonist.

The present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or the purposes of the pharmaceutical composition that contains them in preparing anticoagulant.

The present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or the purposes of the pharmaceutical composition that contains them in inhibitors of smooth muscle cell proliferation.

The present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or the purposes of the pharmaceutical composition that contains them in the medicine of the preparation treatment disease relevant with thrombin receptor, the wherein said disease relevant with thrombin receptor is selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary infarction disease, cerebral infarction, heart disease, sowing vessel inner blood and solidifies syndromes, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.

The present invention relates to a kind of method that suppresses calcium ion transport, the method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or the pharmaceutical composition that contains them.

The present invention relates to a kind of method of anticoagulant enzyme acceptor, the method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or the pharmaceutical composition that contains them, wherein said thrombin receptor is PAR1 acceptor.

The present invention relates to a kind of method that suppresses platelet aggregation, the method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or the pharmaceutical composition that contains them.

The present invention relates to a kind of method that suppresses smooth muscle cell proliferation, the method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or the pharmaceutical composition that contains them.

The present invention relates to the method for a kind for the treatment of disease relevant with thrombin receptor, the method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or the pharmaceutical composition that contains them, the wherein said disease relevant with thrombin receptor is selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary infarction disease, cerebral infarction, heart disease, sowing vessel inner blood and solidifies syndromes, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.

The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition that contains them is as the medicine that suppresses calcium ion transport.

The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition that contains them is as the medicine of anticoagulant enzyme acceptor, wherein said thrombin receptor is PAR1 acceptor.

The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition that contains them is as the medicine that suppresses platelet aggregation.

The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition that contains them is as the medicine that suppresses smooth muscle cell proliferation.

The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition that contains them is as the medicine of the treatment disease relevant with thrombin receptor, the wherein said disease relevant with thrombin receptor is selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary infarction disease, cerebral infarction, heart disease, sowing vessel inner blood and solidifies syndromes, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.

the detailed description of invention

Unless there is phase counter-statement, the term using in specification sheets and claims has following implication.

" alkyl " refers to saturated aliphatic hydrocarbon group, comprises straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 12 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-trimethylammonium propyl group, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethyl hexyl, 2,4-dimethyl hexyl, 2,5-dimethyl hexyl, 2,2-dimethyl hexyl, 3,3-dimethyl hexyl, 4,4-dimethyl hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl group, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers etc.The low alkyl group that more preferably contains 1 to 6 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1, 1, 2-trimethylammonium propyl group, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2, 3-dimethylbutyl etc.Alkyl can be that replace or unsubstituted, when being substituted, substituting group can be substituted on any spendable tie point, be preferably one or more following groups, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, carbonyl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.

" cycloalkyl " refers to the unsaturated monocycle of saturated or part or encircles cyclic hydrocarbon substituting group more, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.Polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring.

" spiro cycloalkyl group " refers to 5 to 20 yuan, shares many cyclic groups of a carbon atom (title spiro atom) between monocycle, and these can contain one or more pairs of keys, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number that shares spiro atom between ring and ring, spiro cycloalkyl group is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises

" condensed ring alkyl " refers to 5 to 20 yuan, each ring in system and other rings in system are shared the many cyclic groups of full carbon of a pair of carbon atom adjoining, wherein one or more rings can contain one or more pairs of keys, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number of makeup ring, can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl, be preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of condensed ring alkyl comprises

" bridge ring alkyl " refers to 5 to 20 yuan, and any two rings share two not many cyclic groups of full carbon of direct-connected carbon atom, and these can contain one or more pairs of keys, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number of makeup ring, can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, being preferably dicyclo, three ring or Fourth Rings, more electing dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises

Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring wherein linking together with precursor structure is cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Cycloalkyl can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, carbonyl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.

" thiazolinyl " refers to the alkyl as defined above being comprised of at least two carbon atoms and at least one carbon-to-carbon double bond.For example vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Thiazolinyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.

" alkynyl " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond form.For example ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.

" heterocyclic radical " refers to the unsaturated monocycle of saturated or part or encircles cyclic hydrocarbon substituting group more, and it comprises 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _nthe heteroatoms of (wherein n is integer 0 to 2), but do not comprise-O-O-,-O-S-or-loop section of S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1～4 is heteroatoms, and more preferably cycloalkyl ring comprises 3 to 10 annular atomses.The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc.Polycyclic naphthene base comprises the heterocyclic radical of volution, condensed ring and bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, shares many rings heterocyclic group of an atom (title spiro atom) between monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _pthe heteroatoms of (wherein p is integer 0 to 2), all the other annular atomses are carbon.These can contain one or more pairs of keys, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number that shares spiro atom between ring and ring, spiro cycloalkyl group is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises

" fused heterocycle base " refers to 5 to 20 yuan, each ring in system and other rings in system are shared many rings heterocyclic group of a pair of atom adjoining, one or more rings can contain one or more pairs of keys, but neither one ring has the π-electron system of total conjugated, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _pthe heteroatoms of (wherein p is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number of makeup ring, can be divided into dicyclo, three rings, Fourth Ring or encircle fused heterocycle alkyl more, being preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises

" bridge heterocyclic radical " refers to 5 to 14 yuan, any two rings share two not many rings heterocyclic groups of direct-connected atom, these can contain one or more pairs of keys, but neither one ring has the π-electron system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _pthe heteroatoms of (wherein p is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.According to the number of makeup ring, can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, being preferably dicyclo, three ring or Fourth Rings, more electing dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:

Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring wherein linking together with precursor structure is heterocyclic radical, and non-limiting example comprises:

Deng.Heterocyclic radical can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, carbonyl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.

" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely share and adjoin the right ring of carbon atom) group, many rings (being that it is with the ring of phase adjacency pair carbon atom) group with the π-electron system of conjugation, be preferably 6 to 10 yuan, for example phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linking together with precursor structure is aryl rings, and non-limiting example comprises:

Aryl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.

" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 6 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl is preferably, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linking together with precursor structure is heteroaryl ring, and non-limiting example comprises:

Heteroaryl can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.

" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as mentioned above.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, independently selected from being alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.

" silylation " refers to silane (SiH ₄) in hydrogen by one or more alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, alkoxyl group, cycloalkyl, organosilane group that heterocyclic radical replaced, wherein alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, alkoxyl group, cycloalkyl, heterocyclic radical can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carbonyl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-O (CH ₂) _nc (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-C (O) NR ¹⁶r ¹⁷or-S (O) ONR ¹⁶r ¹⁷.That non-limiting example comprises is trimethyl silicon based, dimethyl ethyl is silica-based, tri-tert is silica-based, methyl diethoxy is silica-based, trimethoxy is silica-based, phenyl is silica-based etc.

" hydroxyl " refer to-OH group.

" halogen " refers to fluorine, chlorine, bromine or iodine.

" amino " refer to-NH ₂.

" cyano group " refer to-CN.

" nitro " refer to-NO ₂.

" urotropine " refers to vulkacit H.

" hydroxyalkyl " refers to that alkyl is replaced by hydroxyl.

" lawesson reagent " refers to

" optionally " or " optionally " mean describe subsequently ground event or environment can but needn't occur, this explanation comprises that this event or environment occur or spot occasion not.For example, " heterocyclic group optionally being replaced by alkyl " mean alkyl can but must not exist, this explanation comprises the situation that situation that heterocyclic group is replaced by alkyl and heterocyclic group are not replaced by alkyl.

The mixture of " pharmaceutical composition " represent to contain on one or more compounds described herein or its physiology/pharmaceutically useful salt or prodrug and other chemical compositions, and other components physiology/pharmaceutically useful carrier and vehicle for example.The object of pharmaceutical composition is the administration promoting organism, is beneficial to absorption and then the performance biological activity of activeconstituents.

M, n, p and R ¹⁵～R ¹⁷definition described in general formula (I) compound.

the synthetic method of the compounds of this invention

In order to complete object of the present invention, the present invention adopts following technical scheme:

The preparation method of general formula of the present invention (I) compound or its pharmaceutically useful salt, comprises the following steps:

Under room temperature, by general formula (IA) compound or (IB) tetrahydrofuran solution of compound react with general formula (IC) compound, under triethylamine condition, obtain general formula (I) compound;

The preparation method of general formula of the present invention (IA) or (IB) compound or its pharmaceutically useful salt, comprises the following steps:

By the dimethyl sulfoxide solution of general formula (II) compound, under cuprous cyanide and cuprous iodide exist, reacting by heating, obtains general formula (IA) or (IB) compound;

Or, under ice bath, general formula (III) compound being mixed with grignard reagent and titanic acid ester, stirring reaction under room temperature, obtains general formula (IA) or (IB) compound;

or,

By general formula (IV) compound and strong aqua and tert.-butoxy hydroperoxidation, obtain general formula (IA) or (IB) compound;

Or under water and triphenylphosphine exist, stirring reaction under room temperature, obtains general formula (IA) or (IB) compound by the tetrahydrofuran solution of logical formula V compound.

Wherein X is selected from halogen, is preferably chlorine atom or bromine atoms; L, Y and R ¹～R ¹¹definition described in general formula (I).

Embodiment

Below in conjunction with embodiment, be used for further describing the present invention, but these embodiment unrestricted scope of the present invention.

embodiment

The structure of compound by nucleus magnetic resonance (NMR) or/and mass spectrum (MS) determine.NMR displacement (δ) with 1,000,000/unit (ppm) provides.The mensuration of NMR is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆), deuterochloroform (CDC1 ₃), deuterated methanol (CH ₃oD), be inside designated as tetramethylsilane (TMS), chemical shift is with 10 ^-6(ppm) as unit, provide.

FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX) for the mensuration of MS.

The mensuration of HPLC is used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 * 4.6mm chromatographic column).

IC ₅₀novoStar microplate reader for the mensuration of value (German BMG company).

Tlc silica gel plate is used Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm.

It is carrier that column chromatography is generally used Yantai Huanghai Sea silica gel 200～300 order silica gel.

Known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy the Co.KG from ABCR GmbH &, Acros Organics, Aldrich Chemical Company, splendid chemistry science and technology far away (Accela ChemBio Inc), reaches the companies such as auspicious chemical.

In embodiment, without specified otherwise, all under nitrogen atmosphere or argon atmospher, carry out.

Argon atmospher or nitrogen atmosphere refer to that reaction flask connects argon gas or the nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.

Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument are used in pressure hydration reaction.

Hydrogenation vacuumizes conventionally, is filled with hydrogen, repeatable operation 3 times.

Microwave reaction is used CEM Discover-S 908860 type microwave reactors.

In embodiment, without specified otherwise, solution refers to the aqueous solution.

In embodiment, without specified otherwise, the temperature of reaction is room temperature.

Room temperature is optimum temperature of reaction, is 20 ℃～30 ℃.

The monitoring of the reaction process in embodiment adopts tlc (TLC), the system of the developping agent that reaction is used has: methylene dichloride and methanol system, normal hexane and ethyl acetate system, sherwood oil and ethyl acetate system, acetone, the volume ratio of solvent regulates according to the polarity of compound is different.

The system of eluent of column chromatography and the system of the developping agent of tlc that purifying compounds adopts comprise: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: ethyl acetate and methanol system, D: normal hexane, E: ethyl acetate, the volume ratio of solvent regulates according to the polarity of compound is different, also can add the acid reagents such as the alkalescence such as a small amount of triethylamine or acetic acid to regulate.

Embodiment 1

1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

4,5-dimethoxy phthalic nitrile

1,2-bis-is bromo-4, and 5-dimethoxy benzene 1a (20.01g, 68mmol) is dissolved in 100mL DMF, adds cuprous cyanide (24.00g, 272mmol), and stirring reaction is 1 hour at 150 ℃, continues stirring reaction 5 hours at 170 ℃.Reaction solution is poured in 100mL ammoniacal liquor, added 400mL ethyl acetate, filter, ethyl acetate washing (100mL * 6) for filter cake.Filtrate is extracted with ethyl acetate (200mL * 2), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, thick product recrystallization (methyl alcohol: ethyl acetate=10mL: 20mL) purifying, obtain title product 4,5-dimethoxy phthalic nitrile 1b (4.50g, white solid), productive rate: 35.0%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.20(s，2H)，4.01(s，6H)

Second step

5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate

Under ice bath, 4,5-dimethoxy phthalic nitrile 1b (0.94g, 5mmol) is dissolved in 50mL ether, adds titanium isopropylate (1.65mL, 5.58mmol) and ethylmagnesium bromide (3.70mL, 11.10mmol), stirring reaction 2.5 hours.In reaction solution, add 55mL methyl alcohol, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (407mg, brown solid), productive rate: 37.3%.

MS?m/z(ESI)：219[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ10.37(br.s，1H)，9.39(br.s，1H)，9.15(br.s，1H)，7.88(s，1H)，7.06(s，1H)，4.96(m，3H)，3.83(s，3H)，1.78(m，2H)，1.64(m，2H)

The 3rd step

The bromo-1-of 2-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone

Dry ice-propanone is dissolved in aluminum chloride (16.00g, 0.12mol) in 150mL methylene dichloride under bathing, add successively bromoacetyl chloride 1e (10mL, 0.12mol) and 70mL 2,6-di-t-butyl-phenol 1d (24.50g, dichloromethane solution 0.12mol), stirring reaction 1 hour.In reaction solution, add 300mL frozen water, filter, washed with dichloromethane for water (200mL * 3), merge organic phase, use successively saturated sodium bicarbonate solution (200mL * 3) and saturated nacl aqueous solution washing (200mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the bromo-1-of title product 2-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (28g, yellow solid), productive rate: 72.0%.

MS?m/z(ESI)：326[M-1]

¹H?NMR(400MHz，CDC1 ₃，ppm)：δ7.89(s，2H)，5.84(br.s，1H)，4.40(s，2H)，1.48(s，18H)

The 4th step

By 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (223mg, 1.02mmol) be dissolved in 3mL tetrahydrofuran (THF), add the bromo-1-of 2-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (398mg, 1.22mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction is 12 hours.Filter, filter cake is used normal hexane (5mL * 2) successively, water (3mL * 2) and ethyl acetate washing (0.5mL * 2), vacuum-drying, obtain title product 1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 1 (138mg, yellow solid), 29.1%.

MS?m/z(ESI)：465[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.64(br.s，1H)，9.08(br.s，1H)，7.86(br.s，1H)，7.85(s，1H)，7.82(s，2H)，7.02(s，1H)，5.17(s，2H)，3.92(s，3H)，3.83(s，3H)，1.66(m，4H)，1.44(s，18H)

Embodiment 2

1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(3-tert-butyl-hydroxy phenyl) ethyl ketone

Dry ice-propanone is dissolved in aluminum chloride (71.0g, 0.53mol) in 250mL methylene dichloride under bathing, add the 2-tertiary butyl-phenol 2a (81.6mL, 0.53mol), stirring reaction 2 hours, drip Acetyl Chloride 98Min. 2b (37.9mL, 0.53mol), continue stirring reaction 1 hour.In reaction solution, add 300mL frozen water, filter, solid vacuum-drying, obtains title product 1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (32g, white solid), productive rate: 31.3%.

MS?m/z(ESI)：191[M-1]

Second step

1-(the iodo-phenyl of 3-tertiary butyl-4-hydroxy-5-) ethyl ketone

1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (16.2g, 84.3mmol) is dissolved in 200mL acetonitrile, adds N-N-iodosuccinimide (20.9g, 92.8mmol), stirring reaction 4 hours.Concentrating under reduced pressure, adds 50mL water and 50mL ethyl acetate, separatory, water is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the iodo-phenyl of 3-tertiary butyl-4-hydroxy-5-) ethyl ketone 2d (16.1g, yellow solid), productive rate: 60.0%.

MS?m/z(ESI)：317[M-1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.17(s，1H)，7.90(d，J＝1.6Hz，1H)，5.98(br.s，1H)，2.55(s，3H)，1.48(s，9H)

The 3rd step

1-(the iodo-4-p-methoxy-phenyl of the 3-tertiary butyl-5-) ethyl ketone

At 25 ℃, 1-(the iodo-phenyl of 3-tertiary butyl-4-hydroxy-5-) ethyl ketone 2d (16.1g, 51mmol) is dissolved in 200mL acetone, add salt of wormwood (21.14g, 153mmol) and methyl iodide (18g, 127mmol), stirring reaction 12 hours.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the iodo-4-p-methoxy-phenyl of the 3-tertiary butyl-5-) ethyl ketone 2e (14.2g, faint yellow oily matter), productive rate: 84.5%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.25(d，J＝2.0Hz，1H)，7.94(d，J＝2.0Hz，1H)，3.93(s，3H)，2.54(s，3H)，1.39(s，9H)

The 4th step

The iodo-2-anisole of the 1-tertiary butyl-5-(1,1-dimethoxy-ethyl)-3-

By 1-(the iodo-4-p-methoxy-phenyl of the 3-tertiary butyl-5-) ethyl ketone 2e (2.6g, 7.83mmol) and trimethyl orthoformate (2.49g, 23.5mol) be dissolved in 2.6mL methyl alcohol, add D (+)-10-camphorsulfonic acid (91mg, 0.39mmol), stirring reaction is 12 hours.In reaction solution, add 217mg salt of wormwood, stir 0.5 hour, add 10mL water and 10mL normal hexane, n-hexane extraction for water (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains the iodo-2-anisole of the title product 1-tertiary butyl-5-(1,1-dimethoxy-ethyl)-3-2f (2.3g, faint yellow oily matter), productive rate: 79.3%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.82(d，J＝2.0Hz，1H)，7.41(d，J＝2.0Hz，1H)，3.89(s，3H)，3.18(s，6H)，1.51(s，3H)，1.40(s，9H)

The 5th step

The 4-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl]-morpholine

By the 1-tertiary butyl-5-(1,1-dimethoxy-ethyl) the iodo-2-anisole of-3-2f (3.3g, 8.73mmol) be dissolved in 33mL toluene with 2-bis-hexamethylene phosphino--2 '-(N, N dimethylamine)-biphenyl (172mg, 0.44mmol), add palladium/carbon (330mg, 10%), sodium tert-butoxide (1.68g, 17.46mmo1) and morpholine (1.52g, 17.46mmol), stirring reaction 3 hours at 60 ℃.In reaction solution, add 100mL water, water is extracted with ethyl acetate (50mL * 3), merges organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtain the title product 4-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl]-morpholine 2g (1.5g, brown oil), productive rate: 51.0%.

MS?m/z(ESI)：338[M+1]

The 6th step

The bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone

By the 4-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl]-morpholine 2g (1.5g, 4.45mmol) is dissolved in 18mL acetic acid, adds pyridinium tribromide salt (1.57g, 4.90mmol), stirring reaction 2 hours.In reaction solution, add 30mL water, water is extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (930mg, faint yellow solid), productive rate: 56.4%.

MS?m/z(ESI)：370[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.70(d，J＝2.0Hz，1H)，7.52(d，J＝2.0Hz，1H)，4.41(s，2H)，4.01(s，3H)，3.90(m，4H)，3.09(m，4H)，1.40(s，9H)

The 7th step

By 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (229mg, 1.05mmo1) be dissolved in 4mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (440mg, 1.19mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) successively, water (3mL * 2) and ethyl acetate washing (0.5mL * 2), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 2 (168mg, buff powder), productive rate: 31.5%

MS?m/z(ESI)：508[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.71(br.s，1H)，9.13(br.s，1H)，7.91(s，1H)，7.62(d，J＝1.6Hz，1H)，7.55(d，J＝1.6Hz，1H)，7.08(s，1H)，5.34(s，2H)，4.01(s，3H)，3.97(s，3H)，3.91(s，3H)，3.88(m，4H)，3.03(m，4H)，1.66(m，4H)，1.39(s，9H)

Embodiment 3

1-(the 3-tertiary butyl-4-p-methoxy-phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone

1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (6.3g, 32.8mmol) is dissolved in 50mL acetone, adds salt of wormwood (13.6g, 98.4mmol) and methyl iodide (11.65g, 82mmol), stirring reaction is 2 hours at 50 ℃.Filter, filtrate decompression is concentrated, add 50mL water and 50mL methylene dichloride, separatory, saturated nacl aqueous solution washing (20mL * 3) for organic phase, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains title product 1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 3a (6.0g, white solid), productive rate: 88.6%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.99(d，J＝2.0Hz，1H)，7.87(dd，J ₁＝8.4Hz，J ₂＝2.0Hz，1H)，6.94(d，J＝8.4Hz，1H)，3.97(s，3H)，2.60(s，3H)，1.46(s，9H)

Second step

The bromo-1-of 2-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone

1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 3a (1.0g, 4.8mmol) is dissolved in 8mL acetic acid, adds pyridinium tribromide salt (1.6g, 5.04mmol), stirring reaction 3.5 hours.Concentrating under reduced pressure, adds 20mL water and 20mL ethyl acetate, separatory, water is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 3b (900mg, faint yellow oily matter), productive rate: 66.2%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.02(d，J＝2.0Hz，1H)，7.91(dd，J ₁＝8.8Hz，J ₂＝2.0Hz，1H)，6.97(d，J＝8.8Hz，1H)，4.44(s，2H)，3.97(s，3H)，1.44(s，9H)

The 3rd step

By 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (240mg, 1.1mmol) be dissolved in 3mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 3b (360mg, 1.26mmol) and triethylamine (0.3mL, 2.l6mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) successively, water (3mL * 2) and ethyl acetate washing (0.5mL * 2), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-p-methoxy-phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 3 (287mg, buff powder), productive rate: 61.7%

MS?m/z(ESI)：423[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.68(br.s，1H)，9.14(br.s，1H)，8.00(dd，J ₁＝8.8Hz，J ₂＝1.6Hz，1H)，7.88(s，1H)，7.86(d，J＝1.6Hz，1H)，7.21(d，J＝8.8Hz，1H)，7.08(s，1H)，5.18(s，2H)，3.92(s，3H)，3.91(s，3H)，3.87(s，3H)，1.73(m，4H)，1.39(s，9H)

Embodiment 4

1-(the bromo-5-tert-butyl-hydroxy phenyl of 3-)-2-(3 '-imino--5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the bromo-5-tert-butyl-hydroxy phenyl of 3-)-ethyl ketone

By 1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (6.3g, 32.8mmol) be dissolved in 50mL acetonitrile and DMF (V/V=10: 1) in mixed solvent, add N-bromo-succinimide (10.2g, 57mmol), stirring reaction is 0.5 hour.Concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 1-(the bromo-5-tert-butyl-hydroxy phenyl of 3-) ethyl ketone 4a (12.1g, white solid), productive rate: 85.8%.

MS?m/z(ESI)：269[M-1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.03(d，J＝2.0Hz，1H)，7.92(d，J＝2.0Hz，1H)，6.33(br.s，1H)，2.58(s，3H)，1.46(s，9H)

Second step

The bromo-1-of 2-(the bromo-5-tert-butyl-hydroxy phenyl of 3-) ethyl ketone

1-(the bromo-5-tert-butyl-hydroxy phenyl of 3-) ethyl ketone 4a (5.0g, 18.4mmol) is dissolved in 50mL acetic acid, adds pyridinium tribromide salt (6.2g, 19.4mmol), stirring reaction 12 hours.Concentrating under reduced pressure, adds 100mL water and 100mL ethyl acetate, separatory, water is extracted with ethyl acetate (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(the bromo-5-tert-butyl-hydroxy phenyl of 3-) ethyl ketone 4b (6.4g, grey oily matter), productive rate: 99.2%.

MS?m/z(ESI)：349[M-1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.07(d，J＝2.0Hz，1H)，7.57(d，J＝2.0Hz，1H)，6.41(br.s，1H)，4.40(s，2H)，1.48(s，9H)

The 3rd step

1-(the bromo-5-tert-butyl-hydroxy phenyl of 3-)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

By 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (228mg, 1.05mmol) be dissolved in 4mL tetrahydrofuran (THF), add the bromo-1-of 2-(the bromo-5-tert-butyl-hydroxy phenyl of 3-) ethyl ketone 4b (540mg, 1.54mmol) and triethylamine (0.3mL, 2.l6mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) successively, water (5mL * 4) and ethyl acetate washing (2mL * 2), vacuum-drying, obtain title product 1-(the bromo-5-tert-butyl-hydroxy phenyl of 3-)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 4 (166mg, buff powder), productive rate: 32.6%

MS?m/z(ESI)：487[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.63(br.s，1H)，9.12(br.s，1H)，7.92(s，1H)，7.86(s，1H)，7.55(s，1H)，7.05(s，1H)，4.95(s，2H)，3.90(s，3H)，3.84(s，3H)，1.65(m，4H)，1.33(s，9H)

Embodiment 5

The 2-[8-tertiary butyl-6-[2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-4-yl] ethyl acetate hydrobromate

The first step

1-(3-tertiary butyl-4-hydroxy-5-nitro-phenyl)-ethyl ketone

At 10 ℃, by 68% concentrated nitric acid (105mL, 1.6mol) be dissolved in 60mL methylene dichloride and water (V/V=2: in mixed solvent 1), add 1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (12.87g, 66.9mmol), stirring reaction 0.5 hour, adds 60mL ether, 0.6mL diacetyl oxide and 105mL concentrated hydrochloric acid, continues stirring reaction 1.5 hours.In reaction solution, add 200mL frozen water, be extracted with ethyl acetate (150mL * 3), merge organic phase, with saturated sodium bicarbonate, regulating pH is 5～6, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 1-(3-tertiary butyl-4-hydroxy-5-nitro-phenyl) ethyl ketone 5a (6.27g, yellow solid), productive rate: 39.6%.

MS?m/z(ESI)：236[M-1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ11.40(br.s，1H)，8.45(d，J＝2.0Hz，1H)，8.08(d，J＝2.0Hz，1H)，2.59(s，3H)，1.42(s，9H)

Second step

1-[4-(2-the bromine oxethyl)-3-tertiary butyl-5-nitro-phenyl] ethyl ketone

By 1-(3-tertiary butyl-4-hydroxy-5-nitro-phenyl) ethyl ketone 5a (6.26g, 26.4mmol) be dissolved in 80mLN, in dinethylformamide, add salt of wormwood (18.25g, 132mmol) He 1,2-ethylene dibromide (24.8g, 132mmol), stirring reaction is 10 hours at 100 ℃.Concentrating under reduced pressure, add 200mL water, be extracted with ethyl acetate (200mL * 3), merge organic phase, with saturated nacl aqueous solution washing (100mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 1-[4-(2-the bromine oxethyl)-3-tertiary butyl-5-nitro-phenyl] ethyl ketone 5b (5.74g, yellow oil), productive rate: 48.6%.

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ8.32(d，J＝2.0Hz，1H)，8.11(d，J＝2.0Hz，1H)，4.25(m，2H)，3.82(m，2H)，2.62(s，3H)，1.44(s，9H)

The 3rd step

1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone

By 1-[4-(2-the bromine oxethyl)-3-tertiary butyl-5-nitro-phenyl] ethyl ketone 5b (3.65g, 10.6mmol) is dissolved in 35mL toluene, adds palladium/carbon (0.5g, 10%), hydrogen exchange three times, stirring reaction 40 hours.In reaction solution, add 30mL ethyl acetate, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (400mg, yellow solid), productive rate: 14.8%.

MS?m/z(ESI)：234[M+1]

The 4th step

2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl) ethyl acetate

By 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (4.8g, 20.5mmol) be dissolved in 80mLN, in dinethylformamide, add salt of wormwood (8.5g, 6l.7mmol) and ethyl bromoacetate (11.5mL, 102mmol), stirring reaction 3 hours at 100 ℃.Concentrating under reduced pressure, adds 200mL water, is extracted with ethyl acetate (100mL * 3); merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 2-(6-ethanoyl-8-tertiary butyl-2; 3-dihydro-1; 4-benzoxazine-4-yl) ethyl acetate 5d (4.7g, yellow solid), productive rate: 71.5%.

MS?m/z(ESI)：320[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.11(d，J＝2.0Hz，1H)，7.09(d，J＝2.0Hz，1H)，5.94(br.s，1H)，4.19(m，2H)，3.32(m，2H)，2.44(s，3H)，1.33(s，9H)

The 5th step

2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl] ethyl acetate

2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl) ethyl acetate 5d (6.68g, 20.9mmol) is dissolved in 80mL acetic acid, adds pyridinium tribromide salt (8.18g, 25.6mmol), stirring reaction 5 hours.Concentrating under reduced pressure; add 100mL saturated sodium bicarbonate solution; separatory; water is extracted with ethyl acetate (100mL * 3); merge organic phase; with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product 2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl] ethyl acetate 5e (3.3g; brownish black solid), productive rate: 39.0%.

MS?m/z(ESI)：400[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.42(d，J＝2.0Hz，1H)，7.13(d，J＝2.0Hz，1H)，4.43(s，2H)，4.36(m，2H)，4.21(m，2H)，4.10(s，2H)，3.58(m，2H)，1.42(s，9H)，1.35(m，3H)

The 6th step

By 5 '; 6 '-dimethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 1c (241mg; 1.11mmol) be dissolved in 4mL tetrahydrofuran (THF), add 2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate 5e (708mg; 1.77mmol) and triethylamine (0.4mL, 2.88mmol), stirring reaction 12 hours.Filter; filter cake is used normal hexane (10mL * 2) successively; water (5mL * 3) and ethyl acetate washing (1mL * 2), vacuum-drying, obtain the title product 2-[8-tertiary butyl-6-[2-(3 '-imino--5 '; 6 '-dimethoxy-spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl]-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-4-yl] ethyl acetate hydrobromate 5 (142mg; white powder), productive rate: 23.9%.

MS?m/z(ESI)：536[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.70(br.s，1H)，9.18(br.s，1H)，7.93(s，1H)，7.31(s，1H)，7.11(s，1H)，7.08(s，1H)，5.14(s，2H)，4.32(t，J＝4.4Hz，2H)，4.00(s，2H)，4.14(q，J＝7.2Hz，2H)，3.92(s，3H)，3.90(s，3H)，3.51(t，J＝4.4Hz，2H)，1.63(m，4H)，1.39(s，9H)，1.22(t，J＝7.2Hz，3H)

Embodiment 6

1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-6-yl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone

By 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (1.5g, 6.4mmol) be dissolved in 20mLN, in dinethylformamide, add salt of wormwood (2.66g, 19.3mmol) and iodoethane (2.6mL, 32.1mmol), stirring reaction 12 hours at 80 ℃.Concentrating under reduced pressure, adds 100mL water, is extracted with ethyl acetate (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6a (1.0g, yellow solid), productive rate: 59.5%.

MS?m/z(ESI)：262[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.35(d，J＝2.0Hz，1H)，7.29(d，J＝2.0Hz，1H)，4.33(t，J＝4.4Hz，2H)，3.45(q，J＝6.6Hz，2H)，3.40(t，J＝4.4Hz，2H)，2.58(s，3H)，1.42(s，9H)，1.22(t，J＝6.6Hz，3H)

Second step

The bromo-1-of 2-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone

1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone 6a (1.0g, 3.8mmol) is dissolved in 18mL acetic acid, adds pyridinium tribromide salt (1.28g, 4.0mmol), stirring reaction is 10 hours at 100 ℃.Concentrating under reduced pressure, adds 100mL saturated sodium bicarbonate solution, is extracted with ethyl acetate (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6b (194mg, yellow solid), productive rate: 29.2%.

MS?m/z(ESI)：340[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.38(d，J＝2.0Hz，1H)，7.30(d，J＝2.0Hz，1H)，4.45(s，2H)，4.35(t，J＝4.4Hz，2H)，3.45(m，2H)，3.41(t，J＝4.4Hz，2H)，1.42(s，9H)，1.22(m，3H)

The 3rd step

By 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (151mg, 0.69mmol) be dissolved in 3mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6b (253mg, 0.74mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 6 (139mg, white powder), productive rate: 35.9%

MS?m/z(ESI)：478[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.68(br.s，1H)，9.13(br.s，1H)，7.90(s，1H)，7.28(s，1H)，7.24(s，1H)，7.08(s，1H)，5.16(s，2H)，4.30(t，J＝4.4Hz，2H)，3.92(s，3H)，3.86(s，3H)，3.44(q，J＝7.2Hz，2H)，3.38(t，J＝4.4Hz，2H)，1.68(m，4H)，1.37(s，9H)，1.23(t，J＝7.2Hz，3H)

Embodiment 7

1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1,2-bis-is bromo-4,5-diethoxybenzene

Under ice bath, 1,2-diethoxybenzene 7a (16.6g, 100mmol) is dissolved in 200mL methylene dichloride, drips bromine (10mL, 200mmol), stirring at room reaction 4 hours.In reaction solution, add 100mL water and 1g S-WAT, separatory, saturated nacl aqueous solution washing (150mL) for organic phase, anhydrous sodium sulfate drying, filters, filtrate decompression is concentrated, obtain title product 1,2-bis-is bromo-4,5-diethoxybenzene 7b (29.8g, white solid), productive rate: 92.0%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.10(s，2H)，4.07(q，J＝7.2Hz，4H)，1.47(t，J＝7.2Hz，6H)

Second step

4,5-diethoxy phthalic nitrile

1,2-bis-is bromo-4, and 5-diethoxybenzene 7b (13.62g, 42mmol) is dissolved in 150mL methyl-sulphoxide, adds cuprous cyanide (14.97g, 167.2mmol) and cuprous iodide (7.18g, 37.7mmol), and stirring reaction is 4 hours at 160 ℃.Pour reaction solution into 250mL strong aqua and ethyl acetate (V/V=1: 1.5) in mixed solvent, filter, filter cake water (100mL) and ethyl acetate washing (100mL * 2), water is extracted with ethyl acetate (100mL), merge organic phase, use successively strong aqua (50mL), water (250mL) and saturated nacl aqueous solution washing (200mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 4, 5-diethoxy phthalic nitrile 7c (5.42g, pale solid), productive rate: 59.7%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.16(s，2H)，4.20(q，J＝4.1Hz，4H)，1.54(t，J＝4.1Hz，6H)

The 3rd step

5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate

Under ice bath, 4,5-diethoxy phthalic nitrile 7c (2.16g, 10mmol) is dissolved in 100mL ether, adds titanium isopropylate (3.3mL, 11.2mmol) and ethylmagnesium bromide (7.3mL, 21.9mmol), stirring at room reaction 2 hours.Add 55mL methyl alcohol, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (1.26g, orange powder), productive rate: 51.2%.

MS?m/z(ESI)：247[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ10.35(br.s，1H)，9.37(br.s，1H)，9.14(br.s，1H)，7.88(s，1H)，7.01(s，1H)，4.17(m，4H)，1.69(m，2H)，1.43(m，2H)，1.37(m，6H)

The 4th step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (195mg, 0.79mmol) be dissolved in 3mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (310mg, 0.84mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 7 (180mg, white powder), productive rate: 36.9%

MS?m/z(ESI)：536[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.69(br.s，1H)，9.13(br.s，1H)，7.91(s，1H)，7.65(d，J＝2.0Hz，1H)，7.56(d，J＝2.0Hz，1H)，7.06(s，1H)，5.23(s，2H)，4.18(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.97(s，3H)，3.83(m，4H)，3.03(m，4H)，1.64-1.61(m，4H)，1.41(m，15H)

Embodiment 8

1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the 3-tertiary butyl-4-methoxyl group-5-nitro-phenyl) ethyl ketone

By 1-(3-tertiary butyl-4-hydroxy-5-nitro-phenyl) ethyl ketone 5a (11.6g, 48.9mmol) be dissolved in 150mL acetone, add salt of wormwood (16.9g, 122mmol) and methyl iodide (23.2mL, 372mmol), stirring reaction 12 hours at 80 ℃.Concentrating under reduced pressure, add 200mL water, be extracted with ethyl acetate (200mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-nitro-phenyl) ethyl ketone 8a (8.94g, yellow oil), productive rate: 72.8%.

MS?m/z(ESI)：252[M+1]

Second step

1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone

By 1-(the 3-tertiary butyl-4-methoxyl group-5-nitro-phenyl) ethyl ketone 8a (4.8g, 19mmol) be dissolved in 50mL second alcohol and water (V/V=4: in mixed solvent 1), add ammonium chloride (4.1g, 75mmol) and iron powder (2.1g, 38mmol), stirring reaction 1 hour at 80 ℃.Filter, filtrate decompression is concentrated, adds 100mL water and 100mL ethyl acetate, water is extracted with ethyl acetate (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system D, purifies gained resistates, obtains title product 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (3.6g, gray solid), productive rate: 81.0%.

MS?m/z(ESI)：222[M+1]

The 3rd step

1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone

By 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (2.0g, 9.05mmol) He 1,4-dibromobutane (2.54g, 11.77mmol) be dissolved in 20mLN, in dinethylformamide, add salt of wormwood (3.1g, 22.63mmol) and potassiumiodide (0.15g, 0.91mmol), stirring reaction 48 hours at 80 ℃.Filter, filtrate decompression is concentrated, adds 50mL water, with extracted with diethyl ether (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8c (1.1g, white solid), productive rate: 44.2%.

MS?m/z(ESI)：276[M+1]

The 4th step

The bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone

1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8c (900mg, 3.27mmol) is dissolved in 10mL acetic acid, adds pyridinium tribromide salt (1.1g, 3.43mmol), stirring reaction 12 hours.Concentrating under reduced pressure, add 30mL water and 30mL ethyl acetate, water is extracted with ethyl acetate (50mL * 3), merges organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the bromo-1-of title product 2-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8d (560mg, yellow solid), productive rate: 48.3%.

MS?m/z(ESI)：356[M+1]

The 5th step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (250mg, 1.02mmol) be dissolved in 4mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8d (360mg, 1.02mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 8 (232mg, white powder), productive rate: 38.0%.

MS?m/z(ESI)：520[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.65(br.s，1H)，9.08(br.s，1H)，7.88(s，1H)，7.77(b，J＝2.0Hz，1H)，7.41(b，J＝2.0Hz，1H)，7.05(s，1H)，5.19(s，2H)，4.17(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.66(s，3H)，3.10(m，4H)，1.93(m，4H)，1.74-1.60(m，4H)，1.39(m，15H)

Embodiment 9

1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate

The first step

1-(6-methyl-3-pyridine)-1-phenyl-ethanol

Under dry ice-propanone is bathed, by the bromo-2-methyl-pyridine of 5-9a (1.72g, 10mmol) be dissolved in 10mL ether, drip 2.5M n-Butyl Lithium (4.4mL, hexane solution 11mmol), stirring reaction 1 hour, adds methyl phenyl ketone (1.29mL, 11mmol), continue stirring reaction 1 hour.In reaction solution, add 10mL saturated ammonium chloride solution, water is extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(6-methyl-3-pyridine)-1-phenyl-ethanol 9b (1.8g, yellow solid), productive rate: 84.5%.

MS?m/z(ESI)：214[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.55(s，1H)，7.65(d，J＝8.4Hz，1H)，7.35(m，5H)，7.11(d，J＝8.4Hz，1H)，2.56(s，3H)，1.98(s，3H)

Second step

5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine

Under ice bath, 1-(6-methyl-3-pyridine)-1-phenyl-ethanol 9b (1.75g, 8.2mmol) and sodiumazide (1.6g, 24.6mmol) are dissolved in 10mL water, drip 9mL concentrated hydrochloric acid, stirring reaction 12 hours.To adding in reaction solution 200mL saturated sodium bicarbonate solution to regulate pH, be 7～8, be extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtain title product 5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 9c (1.8g, light yellow oil), productive rate: 92.3%.

MS?m/z(ESI)：239[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.53(s，1H)，7.57(d，J＝8.0Hz，1H)，7.37(m，5H)，7.16(d，J＝8.0Hz，1H)，2.62(s，3H)，2.07(s，3H)

The 3rd step

5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 1-oxide compound

5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 9c (1.8g, 7.6mmol) is dissolved in 30mL methylene dichloride, adds metachloroperbenzoic acid (2.6g, 15.1mmol), stirring reaction 12 hours.In reaction solution, add 20mL methylene dichloride, with saturated sodium bicarbonate solution washing (30mL * 3), water is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 1-oxide compound 9d (1.42g, light yellow oil), productive rate: 74.0%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.31(s，1H)，7.36(m，7H)，2.58(s，3H)，2.04(s，3H)

The 4th step

3-(1-nitrine-1-phenyl-ethyl)-6-methyl-pyridine-2-nitrile

By 5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 1-oxide compound 9d (1.3g, 5.1mmol) be dissolved in 15mL acetonitrile, add cyano group trimethyl silane (1.16mL, 8.7mmol) and dimethylaminoethyl chloride (0.70mL, 7.7mmol), stirring reaction 2 hours at 80 ℃.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 3-(1-nitrine-1-phenyl-ethyl)-6-methyl-pyridine-2-nitrile 9e (1.6g, light yellow oil) crude product.

MS?m/z(ESI)：264[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.04(d，J＝8.4Hz，1H)，7.47(m，6H)，2.63(s，3H)，2.28(s，3H)

The 5th step

2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines

3-(1-nitrine-1-phenyl-ethyl)-6-methyl-pyridine-2-nitrile 9e (1.68g, 6.39mmol) is dissolved in 35mL tetrahydrofuran (THF), adds 1mL water and triphenylphosphine (3.35g, 12.8mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system A, obtains title product 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (0.44g, light yellow solid), productive rate: 29.1%.

MS?m/z(ESI)：238[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.91(d，J＝7.6Hz，1H)，7.50(d，J＝7.6Hz，1H)，7.17(m，5H)，6.61(s，2H)，2.55(s，3H)，1.69(s，3H)

The 6th step

By 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (237mg, 1mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (444mg, 1.2mmol) be dissolved in 3mL N, in dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, be extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 9 (120mg, light yellow solid), productive rate: 19.8%.

MS?m/z(ESI)：527[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.97(d，J＝8.0Hz，1H)，7.68(d，J＝8.0Hz，1H)，7.52(s，1H)，7.47(s，1H)，7.38(m，5H)，5.50(d，J＝18.8Hz，1H)，5.16(d，J＝18.8Hz，1H)，4.03(s，3H)，3.80(m，4H)，2.98(m，4H)，2.74(s，3H)，1.99(s，3H)，1.33(s，9H)

Embodiment 10

1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (247mg, 1mmol) be dissolved in 4mL tetrahydrofuran (THF), add the bromo-1-of 2-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (393mg, 1.27mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction is 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 10 (233mg, white powder), productive rate: 41.8%.

MS?m/z(ESI)：493[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.65(br.s，1H)，9.10(br.s，1H)，8.06(br.s，1H)，7.91(s，1H)，7.85(s，2H)，7.06(s，1H)，5.30(s，2H)，4.18(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，1.76-1.66(m，2H)，1.35(m，24H)

Embodiment 11

1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone

1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (9.8g, 44mmol) is dissolved in to 50mLN, in dinethylformamide, add salt of wormwood (18.35g, 133mmol) and iodoethane (20.7g, 133mmol), stirring reaction 12 hours.In reaction solution, add 100mL water, with extracted with diethyl ether (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone 11a (2.4g, yellow oil), productive rate: 19.5%.

MS?m/z(ESI)：278[M+1]

Second step

The bromo-1-of 2-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone

1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone 11a (2.4g, 8.66mmol) is dissolved in 10mL acetic acid, adds pyridinium tribromide salt (3.6g, 11.25mmol), stirring reaction 12 hours.Concentrating under reduced pressure, add 20mL water, be extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the bromo-1-of title product 2-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone 11b (850mg, yellow solid), productive rate: 27.5%.

MS?m/z(ESI)：358[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.67(m，1H)，7.56(m，1H)，4.46(s，2H)，3.96(s，3H)，3.21(m，4H)，1.45(s，9H)，1.11(m，6H)

The 3rd step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (246mg, 1mmol) be dissolved in 5mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone 11b (368mg, 1.03mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake is used tetrahydrofuran (THF) (1mL) successively, normal hexane (10mL * 2) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 11 (314mg, white powder), productive rate: 52.2%.

MS?m/z(ESI)：523[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.69(br.s，1H)，9.15(br.s，1H)，7.93(s，1H)，7.59(d，J＝1.6Hz，1H)，7.54(d，J＝1.6Hz，1H)，7.06(s，1H)，5.20(s，2H)，4.18(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.88(s，3H)，3.17(q，J＝7.2Hz，4H)，1.76-1.61(m，4H)，1.40(m，15H)，1.20(t，J＝7.2Hz，6H)

Embodiment 12

The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone

By 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (2.21g, 10mmol) He 1, pentamethylene bromide (4.6g, 20mmol) be dissolved in 20mLN, in dinethylformamide, add salt of wormwood (4.14g, 30mmol) and potassiumiodide (0.17g, 1.0mmol), stirring reaction 12 hours at 50 ℃.In reaction solution, add 20mL water, with extracted with diethyl ether (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12a (1.8g, gray solid), productive rate: 62.3%.

MS?m/z(ESI)：290[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.66(d，J＝2.0Hz，1H)，7.55(d，J＝2.0Hz，1H)，4.03(s，3H)，3.03(m，4H)，2.60(s，3H)，1.79(m，4H)，1.62(m，2H)，1.45(s，9H)

Second step

The bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone

By the 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12a (1.8g, 6.2mmol) is dissolved in 20mL acetic acid, adds pyridinium tribromide salt (2.29g, 7.15mmol), stirring reaction 12 hours.Concentrating under reduced pressure, add 20mL water, be extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the bromo-1-[3-tertiary butyl-4-of title product 2-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (850mg, yellow solid), productive rate: 37.3%.

MS?m/z(ESI)：370[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.68(d，J＝2.0Hz，1H)，7.58(d，J＝2.0Hz，1H)，4.54(s，2H)，4.04(s，3H)，3.03(m，4H)，1.80(m，4H)，1.66(m，2H)，1.47(s，9H)

The 3rd step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (247mg, 1mmol) be dissolved in 5mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (424mg, 1.15mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) and water washing (5mL * 2) successively, vacuum-drying, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 12 (246mg, white powder), productive rate: 39.9%.

MS?m/z(ESI)：523[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.70(br.s，1H)，9.13(br.s，1H)，7.93(s，1H)，7.62(d，J＝1.8Hz，1H)，7.56(d，J＝1.8Hz，1H)，7.06(s，1H)，5.22(s，2H)，4.18(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.97(s，3H)，2.98(m，4H)，1.74(m，6H)，1.57(m，4H)，1.39(m，15H)

Embodiment 13

The N-[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2-p-methoxy-phenyl] ethanamide hydrobromate

The first step

N-(the 5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) ethanamide

Under ice bath, by 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (12.0g, 54mmol) be dissolved in 100mL tetrahydrofuran (THF), add triethylamine (15mL, 109mmol), stirring reaction 0.5 hour, drips Acetyl Chloride 98Min. 2b (6.14mL, 81mmol), continue stirring reaction 2 hours.Concentrating under reduced pressure; add 200mL frozen water, be extracted with ethyl acetate (100mL * 3), merge organic phase; with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product N-(the 5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) ethanamide 13a (13.4g, white solid), productive rate: 94.4%.

MS?m/z(ESI)：264[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.54(d，J＝2.0Hz，1H)，7.71(d，J＝2.0Hz，1H)，7.38(br.s，1H)，3.74(s，3H)，2.50(s，3H)，2.20(s，3H)，1.33(s，9H)

Second step

N-[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide

N-(the 5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) ethanamide 13a (3.7g, 14.1mmol) is dissolved in 20mL acetic acid, adds pyridinium tribromide salt (4.5g, 14.1mmol), stirring reaction 12 hours.Concentrating under reduced pressure; add 100mL water, be extracted with ethyl acetate (100mL * 3), merge organic phase; with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product N-[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide 13b (3.2g, white solid), productive rate: 66.0%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.68(d，J＝2.0Hz，1H)，7.85(d，J＝2.0Hz，1H)，7.30(br.s，1H)，4.48(s，2H)，3.86(s，3H)，2.31(s，3H)，1.43(s，9H)

The 3rd step

By 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (243mg; 0.99mmol) be dissolved in 5mL tetrahydrofuran (THF); add N-[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide 13b (395mg; 1.15mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter; filter cake is used normal hexane (5mL * 2) and water washing (10mL * 3) successively; vacuum-drying; obtain the title product N-[3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl]-2-p-methoxy-phenyl] ethanamide hydrobromate 13 (193mg, white powder), productive rate: 33.2%.

MS?m/z(ESI)：508[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.76(br.s，1H)，9.68(br.s，1H)，9.18(br.s，1H)，8.23(s，1H)，7.91(s，1H)，7.73(s，1H)，7.06(s，1H)，5.18(s，2H)，4.18(q，J＝7.2Hz，2H)，4.16(q，J＝7.2Hz，2H)，3.80(s，3H)，2.15(s，3H)，1.74-1.60(m，4H)，1.39(m，15H)

Embodiment 14

The 2-[[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2-p-methoxy-phenyl] amino] acetonitrile hydrobromate

The first step

2-[(5-ethanoyl-3-the tertiary butyl-2-p-methoxy-phenyl) amino] acetonitrile

1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (14.4g, 65.2mmol) is dissolved in to 100mLN, in dinethylformamide, add salt of wormwood (9.9g, 72mmol) and bromoacetonitrile (26.4g, 220mmol), stirring reaction 12 hours at 70 ℃.Filter, filtrate decompression is concentrated, adds 300mL water; with extracted with diethyl ether (200mL * 3); merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 2-[(5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) amino] acetonitrile 14a (15.3g; yellow solid), productive rate: 88.0%.

MS?m/z(ESI)：261[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.56(d，J＝2.0Hz，1H)，7.30(d，J＝2.0Hz，1H)，4.49(br.s，1H)，4.24(d，J＝6.8Hz，2H)，3.82(s，3H)，2.62(s，3H)，1.45(s，9H)

Second step

2-[[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] amino] acetonitrile

By the 2-[(5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) amino] acetonitrile 14a (14.24g, 54.7mmol) is dissolved in 80mL acetic acid, adds pyridinium tribromide salt (18.37g, 57.4mmol), stirring reaction 24 hours.In reaction solution, add 300mL water; water is extracted with ethyl acetate (200mL * 3); merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 2-[[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] amino] acetonitrile 14b (1.26g; yellow oil), productive rate: 7.0%.MS?m/z(ESI)：339[M+1]

The 3rd step

By 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (249mg; 1.03mmol) be dissolved in 5mL tetrahydrofuran (THF); add 2-[[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] amino] acetonitrile 14b (408mg; 1.19mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter; filter cake is used normal hexane (5mL * 2) and water washing (10mL * 3) successively; vacuum-drying; obtain the title product 2-[[3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl]-2-p-methoxy-phenyl] amino] acetonitrile hydrobromate 14 (262mg, white powder), productive rate: 43.6%.

MS?m/z(ESI)：504[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.66(br.s，1H)，9.17(br.s，1H)，7.87(s，1H)，7.43(d，J＝1.6Hz，1H)，7.36(d，J＝1.6Hz，1H)，7.07(s，1H)，6.16(t，J＝6.8Hz，1H)，5.20(s，2H)，4.40(d，J＝6.8Hz，2H)，4.18(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.74(s，3H)，1.73-1.62(m，4H)，1.40(m，15H)

Embodiment 15

1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (250mg, 1.02mmol) be dissolved in 5mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-ethyl ketone 6b (408mg, 1.19mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) and water washing (10mL * 2) successively, vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 15 (224mg, white powder), productive rate: 37.6%.

MS?m/z(ESI)：506[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.70(br.s，1H)，9.14(br.s，1H)，7.89(s，1H)，7.27(m，2H)，7.04(s，1H)，5.l6(s，2H)，4.29(t，J＝4.4Hz，2H)，4.17(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.10(m，4H)，1.75(m，4H)，1.36(m，15H)，1.19(t，J＝7.2Hz，3H)

Embodiment 16

The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-4-yl] acetonitrile hydrobromate

The first step

2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl)-acetonitrile

By 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (12g, 51.4mmol) be dissolved in 60mLN, in dinethylformamide, add salt of wormwood (7.82g, 56.6mmol) and bromoacetonitrile (12.33g, 103mmol), stirring reaction 4 hours at 70 ℃.In reaction solution, add 200mL water, by extracted with diethyl ether (200mL * 3), merge organic phase; with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product 2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl) acetonitrile 16a (9.4g; white solid), productive rate: 67.3%.

MS?m/z(ESI)：273[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.52(d，J＝2.0Hz，1H)，7.33(d，J＝2.0Hz，1H)，4.44(m，2H)，4.29(s，2H)，3.45(m，2H)，2.60(s，3H)，1.43(s，9H)

Second step

2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl] acetonitrile

2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl) acetonitrile 16a (9.38g, 34.4mmol) is dissolved in 80mL acetic acid, adds pyridinium tribromide salt (11g, 34.4mmol), stirring reaction 24 hours.In reaction solution, add 200mL water, by extracted with diethyl ether (100mL * 3), merge organic phase; with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product 2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl] acetonitrile 16b (3.0g; black solid), productive rate: 24.6%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.57(d，J＝2.0Hz，1H)，7.36(d，J＝2.0Hz，1H)，4.47(m，2H)，4.43(s，2H)，4.29(s，2H)，3.47(m，2H)，1.43(s，9H)

The 3rd step

By 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (257mg; 1.04mmol) be dissolved in 5mL tetrahydrofuran (THF), add 2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-1; 4-benzoxazine-4-yl] acetonitrile 16b (458mg; 1.30mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter; filter cake is used normal hexane (5mL * 2) and water washing (10mL * 2) successively; vacuum-drying; obtain the title product 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] acetonitrile hydrobromate 16 (317mg, yellow powder), productive rate: 50.8%.

MS?m/z(ESI)：517[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.67(br.s，1H)，9.17(br.s，1H)，7.89(s，1H)，7.48(s，1H)，7.45(s，1H)，7.07(s，1H)，5.19(s，2H)，4.72(s，2H)，4.42(m，2H)，4.18(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.40(m，2H)，1.75-1.62(m，4H)，1.38(m，15H)

Embodiment 17

1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-[3-(1-adamantyl)-4-hydroxy phenyl] ethyl ketone

1-(4-hydroxy phenyl) ethyl ketone 17a (408mg, 3mmol) and diamantane-1-alcohol 17b (456mg, 3mmol) are dissolved in 2mL methylene dichloride, add the vitriol oil (0.16mL, 3mmol), stirring at room 12 hours.Reaction solution is poured in 10mL water, add 10mL saturated sodium bicarbonate solution, with dichloromethane extraction (15mL * 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-[3-(1-adamantyl)-4-hydroxy phenyl] ethyl ketone 17c (560mg, white solid), productive rate: 69.1%

MS?m/z(ESI)：271[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.94(d，J＝2.0Hz，1H)，7.75(dd，J ₁＝8.4Hz，J ₂＝2.0Hz，1H)，6.76(d，J＝8.4Hz，1H)，6.00(s，1H)，2.60(s，3H)，2.24(s，9H)，1.83(s，6H)

Second step

1-[3-(1-adamantyl)-iodo-phenyl of 4-hydroxyl-5-] ethyl ketone

By 1-[3-(1-adamantyl)-4-hydroxy phenyl] ethyl ketone 17c (435mg, 1.61mmol) be dissolved in 11mL acetonitrile and N, dinethylformamide (V/V=9: 2) in mixed solvent, add N-N-iodosuccinimide (398.4mg, 1.77mmol), stirring reaction is 0.5 hour.Concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 1-[3-(1-adamantyl)-iodo-phenyl of 4-hydroxyl-5-] ethyl ketone 17d (300mg, white solid), productive rate: 47.0%.

MS?m/z(ESI)：395[M-1]

¹H?NMR(400MHz，CDC1 ₃，ppm)：δ8.20(d，J＝2.0Hz，1H)，7.89(d，J＝2.0Hz，1H)，6.02(s，1H)，2.58(s，3H)，2.15(s，9H)，1.82(s，6H)

The 3rd step

The iodo-4-p-methoxy-phenyl of 1-[3-(1-adamantyl)-5-] ethyl ketone

By 1-[3-(1-adamantyl)-iodo-phenyl of 4-hydroxyl-5-]-ethyl ketone 17d (303mg, 0.77mmol) be dissolved in 15mL acetone, add salt of wormwood (316.8mg, 2.3mmol) and methyl iodide (0.12mL, 1.91mmol), stirring reaction is 12 hours.Filter, ethyl acetate washing (10mL * 2) for filter cake, filtrate decompression is concentrated, add 20mL ethyl acetate, merge organic phase, successively water (20mL * 3) and saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains the iodo-4-p-methoxy-phenyl of title product 1-[3-(1-adamantyl)-5-] ethyl ketone 17e crude product directly casts single step reaction.

MS?m/z(ESI)：411[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.30(d，J＝2.4Hz，1H)，7.96(d，J＝2.4Hz，1H)，3.98(s，3H)，2.60(s，3H)，2.09(s，9H)，1.82(s，6H)

The 4th step

The iodo-2-p-methoxy-phenyl of 1-[5-(1,1-dimethoxy-ethyl)-3-] diamantane

By the iodo-4-p-methoxy-phenyl of 1-[3-(1-adamantyl)-5-] ethyl ketone 17e (123mg, 0.3mmol) be dissolved in 2mL methyl alcohol, add trimethyl orthoformate (95.5mg, 0.9mmol) and camphorsulfonic acid (3.48mg, 0.015mmol), stirring reaction 3 hours at 60 ℃.Add 200mg salt of wormwood and 20mL water, be extracted with ethyl acetate (10mL * 3), merge organic phase, use successively unsaturated carbonate potassium solution (10mL * 3) and saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying, filters, obtain title product 1-[5-(1,1-dimethoxy-ethyl) the iodo-2-p-methoxy-phenyl of-3-] diamantane 17f (135mg, yellow oil), productive rate: 98.7%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.85(d，J＝2.0Hz，1H)，7.41(d，J＝2.0Hz，1H)，3.93(s，3H)，3.21(s，6H)，2.11(s，9H)，1.81(s，6H)，1.54(s，3H)

The 5th step

1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] ethyl ketone

By 1-[5-(1,1-dimethoxy-ethyl) the iodo-2-p-methoxy-phenyl of-3-] diamantane 17f (123mg, 0.3mmol) is dissolved in 20mL toluene, adds successively morpholine (1.74g, 20mmol), 2-bis-hexamethylene phosphino-s-2 '-(N, N dimethylamine)-biphenyl (196.8mg, 0.5mmol), three (dibenzalacetone) two palladium (228.9mg, 0.25mmol) and sodium tert-butoxide (1.92g, 20mmol), stirring reaction 3 hours at 90 ℃.Filter, ethyl acetate washing (10mL * 3) for filter cake, filtrate decompression is concentrated, add 5mL acetic acid, stir concentrating under reduced pressure 1 hour, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] ethyl ketone 17g (560mg, yellow solid), productive rate: 60.5%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.61(d，J＝2.0Hz，1H)，7.49(d，J＝2.0Hz，1H)，3.99(s，3H)，3.89(m，4H)，3.08(m，4H)，2.57(s，3H)，2.09(s，9H)，1.79(s，6H)

The 6th step

1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] the bromo-ethyl ketone of-2-

By 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] ethyl ketone 17g (527mg, 1.42mmol) is dissolved in 8mL acetic acid, adds pyridinium tribromide salt (455mg, 1.42mmol), stirring reaction 3.5 hours.Concentrating under reduced pressure, add 10mL saturated sodium bicarbonate solution and 10mL water, be extracted with ethyl acetate (15mL * 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] the bromo-ethyl ketone 17h of-2-(230mg, yellow solid), productive rate: 36.0%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.65(d，J＝2.4Hz，1H)，7.53(d，J＝2.4Hz，1H)，4.42(s，2H)，4.01(s，3H)，3.90(m，4H)，3.09(m，4H)，2.09(s，9H)，1.79(s，6H)

The 7th step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (246mg, 1mmol) be dissolved in 6mL tetrahydrofuran (THF), add 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] the bromo-ethyl ketone 17h of-2-(516mg, 1.15mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, normal hexane for filter cake (5mL * 2) and water washing (10mL * 2), vacuum-drying, obtain title product 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone Hydrogen bromide 17 (317mg, white powder), productive rate: 22.9%.

MS?m/z(ESI)：614[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.64(br.s，1H)，9.08(br.s，1H)，7.87(s，1H)，7.59(d，J＝1.6Hz，1H)，7.52(d，J＝1.6Hz，1H)，7.05(s，1H)，5.20(s，2H)，4.17(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.96(s，3H)，3.82(m，4H)，3.01(m，4H)，2.07(m，9H)，1.76(m，6H)，1.75-1.60(m，4H)，1.40(m，6H)

Embodiment 18

The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-4-yl] ethyl acetate hydrobromate

The first step

The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindole]-2 '-yl) ethanoyl]-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-4-yl] ethyl acetate hydrobromate

By 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (252mg; 1.02mmol) be dissolved in 5mL tetrahydrofuran (THF), add 2-[6-(the bromo-ethanoyl of the 2-)-8-tertiary butyl-2,3-dihydro-1; 4-benzoxazine-4-yl]-ethyl acetate 5e (440mg; 1.10mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter; normal hexane for filter cake (10mL * 2) and water washing (10mL * 2); vacuum-drying; obtain the title product 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindole]-2 '-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate hydrobromate 22 (317mg, yellow powder), productive rate: 50.8%.

MS?m/z(ESI)：565[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.67(br.s，1H)，9.16(br.s，1H)，7.92(s，1H)，7.30(d，J＝1.2Hz，1H)，7.08(d，J＝1.2Hz，1H)，7.05(s，1H)，5.12(s，2H)，4.31(m，4H)，4.12(m，4H)，3.51(m，2H)，1.68-1.60(m，4H)，1.38(m，15H)，1.20(t，J＝7.2Hz，3H)

Embodiment 19

1-(8-tertiary butyl 4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone

By 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (1.5g, 6.4mmol) be dissolved in 20mL acetone, add salt of wormwood (1.78g, 12.8mmol) and methyl iodide (4.56g, 32.1mmol), stirring reaction is 40 hours.Concentrating under reduced pressure, adds 50mL water, is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtain title product 1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone 19a (375mg, brown oil), productive rate: 23.6%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.40(d，J＝2.0Hz，1H)，7.26(d，J＝2.0Hz，1H)，4.37-4.40(m，2H)，3.34-3.36(m，2H)，2.99(s，3H)，2.58(s，3H)，1.42(s，9H)

Second step

The bromo-1-of 2-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone

1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone 19a (511mg, 2.1mmol) is dissolved in 6mL acetic acid, adds pyridinium tribromide salt (800mg, 2.48mmol), stirring reaction 3 hours.Concentrating under reduced pressure, adds 50mL saturated sodium bicarbonate solution, is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 19b (200mg, yellow oil), productive rate: 29.6%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.42(d，J＝2.0Hz，1H)，7.27(d，J＝2.0Hz，1H)，4.45(s，2H)，4.39-4.42(m，2H)，3.35-3.38(m，2H)，2.99(s，3H)，1.44(s，9H)

The 3rd step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (249mg, 1.01mmol) with the bromo-1-of 2-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone 19b (390mg, 1.2mmol) be dissolved in 6mL tetrahydrofuran (THF), add triethylamine (0.15mL, 1.08mmol), stirring reaction 24 hours.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(8-tertiary butyl 4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 19 (316mg, buff powder), productive rate: 54.6%.

MS?m/z?(ESI)：492[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.69(br.s，1H)，9.14(br.s，1H)，7.94(s，1H)，7.30(d，J＝1.6Hz，1H)，7.22(d，J＝1.6Hz，1H)，7.05(s，1H)，5.18(s，2H)，4.35(m，2H)，4.13(m，4H)，3.07(m，2H)，2.94(s，3H)，1.70-1.60(m，4H)，1.38(m，15H)

Embodiment 20

1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

The 1-[4-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl] piperazine-1-yl] ethyl ketone

The 1-tertiary butyl-5-(1,1-dimethoxy-ethyl)-3-iodo-2-anisole 2f (11.5g, 30.42mmol) is dissolved in 60mL dioxane, add successively 1-piperazine-1-base-ethyl ketone (5.7g, 39.55mmol), three (dibenzalacetone) two palladiums (1.15g, 10%), 4, two (diphenylphosphine)-9 of 5-, 9-dimethyl oxa-anthracene (880mg, 1.52mmol) and sodium tert-butoxide (5.85g, 60.84mmol), stirring reaction 7 hours at 60 ℃.Reaction solution is poured in 30mL frozen water and 150mL ethyl acetate, separatory, water is extracted with ethyl acetate (50mL * 2), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), concentrating under reduced pressure, obtains the title product 1-[4-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl] piperazine-1-yl] ethyl ketone 20a directly casts single step reaction.

Second step

1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl] ethyl ketone

By the 1-[4-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl] piperazine-1-yl] ethyl ketone 20a (6.7g, 17.7mmol) is dissolved in 50mL methylene dichloride, adds acetic acid (3.2g, 53mmol), stirring reaction 12 hours.Concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system E, obtains title product 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl] ethyl ketone 20b (2.0g, yellow solid), productive rate: 20.0%.

MS?m/z(ESI)：333[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.68(d，J＝2.0Hz，1H)，7.48(d，J＝2.0Hz，1H)，3.99(s，3H)，3.81(m，2H)，3.66(m，2H)，3.07(m，4H)，2.56(s，3H)，2.15(s，3H)，1.41(s，9H)

The 3rd step

1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2 bromo-ethyl ketones

By 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl] ethyl ketone 20b (1.8g; 5.1mmol) be dissolved in 15mL methylene dichloride, add acetic acid (1.2g, 20.4mmol) and pyridinium tribromide salt (2.1g; 5.36mmol), stirring reaction is 12 hours.Concentrating under reduced pressure; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2 bromo-ethyl ketone 20c (950mg, yellow solid), productive rate: 43.0%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.72(d，J＝2.0Hz，1H)，7.51(d，J＝2.0Hz，1H)，4.40(s，2H)，4.01(s，3H)，3.81(m，2H)，3.66(m，2H)，3.07(m，4H)，2.16(s，3H)，1.41(s，9H)

The 4th step

By 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (125mg; 0.5mmol) be dissolved in 3mL tetrahydrofuran (THF); add 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2 bromo-ethyl ketone 20c (206mg; 0.5mmol) and triethylamine (76mg, 0.75mmol), stirring reaction 48 hours.Filter; tetrahydrofuran (THF) for filter cake (1mL); water (20mL * 2) and normal hexane washing (10mL * 2); vacuum-drying; obtain title product 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 20 (62mg; white solid), productive rate: 21.5%.

MS?m/z(ESI)：577[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.64(br.s，1H)，9.08(br.s，1H)，7.86(s，1H)，7.65(d，J＝2.0Hz，1H)，7.55(d，J＝2.0Hz，1H)，7.05(s，1H)，5.18(s，2H)，4.41(m，4H)，3.98(s，3H)，3.67(m，4H)，3.02(m，2H)，2.96(m，2H)，2.06(s，3H)，1.73-1.60(m，4H)，1.42-1.36(m，15H)

Embodiment 21

1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone

Dry ice-propanone is dissolved in aluminum chloride (1.31g, 9.79mmol) in 20mL methylene dichloride under bathing, and adds 2,6-di-t-butyl-phenol 1d (2.0g, 9.63mmol), stirring reaction 1 hour, drip Acetyl Chloride 98Min. 1e (0.401mL, 9.79mmol), continue stirring reaction 4 hours.In reaction solution, add 20mL frozen water, with dichloromethane extraction (40mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains title product 1-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone 21a (1.98g, yellow solid), productive rate: 82.3%.

MS?m/z(ESI)：249[M+1]

Second step

1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone

1-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone 21a (1.29g, 5.2mmol) is dissolved in 50mL acetone, add salt of wormwood (1.43g, 10.34mmol) and toluene-4-sulfonic acid methyl esters (1.93g, 10.36mmol), stirring reaction 12 hours at 50 ℃.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21b (1.03g, reddish-brown oily matter), productive rate: 75.4%.

MS?m/z(ESI)：263[M+1]

The 3rd step

The bromo-1-of 2-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone

At 40 ℃, 1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21b (711mg, 2.71mmol) is dissolved in 20mL chloroform, adds cupric bromide (964mg, 5.42mmol), stirring reaction 12 hours.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21c (295mg, red-brown solid), productive rate: 31.9%.MS?m/z(ESI)：343[M+1]

The 4th step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (198mg, 0.8mmol) be dissolved in 3mL tetrahydrofuran (THF), add the bromo-1-of 2-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21c (303mg, 0.89mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction is 48 hours.Filter, tetrahydrofuran (THF) for filter cake (1mL), water (20mL * 2) and normal hexane washing (10mL * 2), vacuum-drying, obtain title product 1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 21 (128mg, white powder), productive rate: 27.1%.

MS?m/z(ESI)：507[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.70(br.s，1H)，9.15(br.s，1H)，7.93(s，1H)，7.91(s，2H)，7.06(s，1H)，5.23(s，2H)，4.18(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.71(s，3H)，1.76-1.60(m，2H)，1.45(s，18H)，1.39(m，6H)

Embodiment 22

1-(3,5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(3,5-di-t-butyl-phenyl) ethyl ketone

Under dry ice-propanone is bathed, by 1-bromo-3,5-di-t-butyl-benzene 22a (3.58g, 13.31mmol) is dissolved in 26mL tetrahydrofuran (THF), adds Tetramethyl Ethylene Diamine (2.2mL, 14.6mmol) and n-Butyl Lithium (5.85mL, 14.6mmol), stirring reaction 1 hour, adds N,N-DIMETHYLACETAMIDE (2.46mL, 26.6mmol), continue stirring reaction 2 hours.In reaction solution, add 20mL saturated ammonium chloride solution, be extracted with ethyl acetate (20mL * 3), merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtain title product 1-(3,5-di-t-butyl-phenyl) ethyl ketone 22b (3.85g, colorless oil), productive rate: 58.2%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.82(s，2H)，7.66(s，1H)，2.62(s，3H)，1.37(s，18H)

Second step

The bromo-1-of 2-(3,5-di-t-butyl-phenyl) ethyl ketone

1-(3,5-di-t-butyl-phenyl) ethyl ketone 22b (3.8g, 16.4mmol) is dissolved in 100mL chloroform, adds cupric bromide (7.32g, 32.7mmol), stirring reaction is 24 hours at 36 ℃.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(3,5-di-t-butyl-phenyl) ethyl ketone 22c (3.4g, light yellow solid), productive rate: 66.8%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.85(s，2H)，7.70(s，1H)，4.48(s，2H)，1.37(s，18H)

The 3rd step 1-(3,5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (131mg, 0.53mmol) be dissolved in 5mL tetrahydrofuran (THF), add the bromo-1-of 2-(3,5-di-t-butyl-phenyl)-ethyl ketone 22c (193mg, 0.62mmol) and triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours.Filter, tetrahydrofuran (THF) for filter cake (1mL * 2) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(3,5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 22 (67mg, white powder), productive rate: 27.1%.

MS?m/z(ESI)：477[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.66(br.s，1H)，9.16(br.s，1H)，7.89(s，1H)，7.84(s，2H)，7.78(s，1H)，7.06(s，1H)，5.24(s，2H)，4.18(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，1.76-1.61(m，4H)，1.40(m，6H)，1.36(s，18H)

Embodiment 23

1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-7 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

The bromo-2-fluorophenol of 4-

Under ice bath, 2-fluorophenol 23a (210g, 1.88mol) is dissolved in 500mL chloroform, drips bromine (94mL, 1.88mol), stirring at room reaction 2 hours.Add 100mL saturated sodium bisulfite solution, with dichloromethane extraction (100mL * 3), merge organic phase, with the washing of 10mL saturated nacl aqueous solution, anhydrous magnesium sulfate drying, filters, filtrate decompression is concentrated, obtain the bromo-2-fluorophenol of title product 4-23b (321g, faint yellow oily matter), productive rate: 90.2%.

MS?m/z(ESI)：191[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.21(d，J＝2.4Hz，1H)，7.71(m，1H)，6.98(m，1H)，6.19(br.s，1H)

Second step

The fluoro-2-hydroxyl-phenyl aldehyde of the bromo-3-of 5-

4-bromo-2-fluorophenol 23b (170g, 0.89mol) is dissolved in 600mL trifluoroacetic acid, adds urotropine (225g, 1.6mol), back flow reaction 5 hours.Be cooled to room temperature, reaction solution is poured in 1L water, add 300mL 50% sulphuric acid soln, filter, with 20mL washing with alcohol filter cake, vacuum-drying, obtains the fluoro-2-hydroxyl-phenyl aldehyde of the bromo-3-of title product 5-23c (90g, yellow solid), productive rate: 46.2%.

MS?m/z(ESI)：219[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ10.87(br.s，1H)，9.88(s，1H)，7.50(m，1H)，7.28(s，1H)

The 3rd step

The bromo-3-of 5-is fluoro-1,2-biphenol

The 5-fluoro-2-hydroxyl-phenyl aldehyde 23c of bromo-3-(80g, 0.37mol) is dissolved in 402mL 1M sodium hydroxide solution, adds 402mL hydrogen peroxide, stirring reaction 3 hours.In reaction solution, add 100mL saturated sodium bisulfite solution, be extracted with ethyl acetate (200mL * 4), merge organic phase, with 100mL 1M salt acid elution, anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains the bromo-3-of title product 5-fluoro-1,2-biphenol 23d (60g, colorless solid), productive rate: 79.4%.

MS?m/z(ESI)：205[M-1]

The 4th step

5-is bromo-1, the fluoro-benzene of 2-diethoxy-3-

The bromo-3-of 5-is fluoro-1, and 2-biphenol 23d (20.7g, 0.1mol) is dissolved in 150mL methyl-sulphoxide, adds iodoethane (24.2mL, 0.3mol) and salt of wormwood (34.5g, 0.25mol), and stirring reaction is 3.5 hours at 50 ℃.In reaction solution, add 600mL water, be extracted with ethyl acetate (150mL * 3), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 5-bromo-1, the fluoro-benzene 23e of 2-diethoxy-3-(15.38g, faint yellow oily matter), productive rate: 58.5%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.89(d，J＝2.0Hz，1H)，6.82(t，J＝2.0Hz，1H)，4.09(m，4H)，1.45(t，J＝7.2Hz，3H)，1.36(t，J＝7.2Hz，3H)

The 5th step

1,2-bis-is bromo-4, the fluoro-benzene of 5-diethoxy-3-

5-is bromo-1, and the fluoro-benzene 23e of 2-diethoxy-3-(15g, 0.057mol) is dissolved in 100mL acetic acid, adds sodium-acetate (6.22g, 0.076mol) and bromine (12.12g, 0.076mol), and stirring reaction is 5 hours at 50 ℃.Add 100mL water, with n-hexane extraction (100mL * 3), merge organic phase, saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains title product 1,2-bis-bromo-4, the fluoro-benzene 23f of 5-diethoxy-3-(11g, colorless oil), productive rate: 56.0%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.05(s，1H)，4.29(q，J＝6.4Hz，2H)，4.19(q，J＝8.0Hz，2H)，1.52(t，J＝6.4Hz，3H)，1.41(t，J＝8.0Hz，3H)

The 6th step

The fluoro-dintrile of 4,5-diethoxy-3-

1,2-bis-is bromo-4, the fluoro-benzene 23f of 5-diethoxy-3-(11.1g, 0.032mol) be dissolved in 60mL DMF, add successively cuprous cyanide (11.6g, 0.13mol) and cuprous iodide (6.17g, 0.032mol), return stirring reaction is 8 hours.Concentrating under reduced pressure, adds 50mL ammoniacal liquor and 50mL ethyl acetate, and water is extracted with ethyl acetate (50mL * 3), merge organic phase, saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filters, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 4, the fluoro-dintrile 23g of 5-diethoxy-3-(2.6g, white solid), productive rate: 34.7%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.83(s，1H)，4.55(m，2H)，4.13(m，2H)，1.48(t，J＝6.0Hz，3H)，1.39(t，J＝6.8Hz，3H)

The 7th step

5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines

5 ', 6 '-diethoxy-4 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines

Under ice bath, by the fluoro-dintrile 23g of 4,5-diethoxy-3-(2.26g, 9.66mmol) be dissolved in 100mL ether, add titanium isopropylate (3.18mL, 10.75mmol) and ethylmagnesium bromide (7.1mL, 21.3mmol), stirring reaction is 2 hours.In reaction solution, add 55mL methyl alcohol, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 23h and 5 ', 6 '-diethoxy-4 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 23i (955mg, scarlet powder), productive rate: 37.4%.

MS?m/z(ESI)：265[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.01(s，1H)，4.14(m，4H)，1.82(m，2H)，1.67(m，2H)，1.34(m，6H)

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.94(s，1H)，4.17(m，4H)，1.81(m，2H)，1.69(m，2H)，1.34(m，6H)

The 8th step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 23h and 5 ', 6 '-diethoxy-4 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 23i (277mg, 1.05mmol) be dissolved in 3mL tetrahydrofuran (THF), add the bromo-1-of 2-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (352mg, 1.08mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction is 12 hours.Filter, normal hexane for filter cake (10mL * 2) and water washing (10mL * 2), vacuum-drying, obtain title product 1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-7 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 23 (17mg, brown ceramic powder), productive rate: 2.7%.

MS?m/z(ESI)：511[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.95(s，1H)，7.79(s，2H)，5.19(s，2H)，4.22(q，J＝7.2Hz，4H)，1.78(m，4H)，1.46(s，18H)，1.31(t，J＝7.2Hz，6H)

Embodiment 24

1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

2-(the fluoro-phenyl of 3,4-diethoxy-5-) propan-2-ol

At-78 ℃, 5-is bromo-1, and the fluoro-benzene 23e of 2-diethoxy-3-(26.3g, 0.1mol) is dissolved in 100mL ether, add n-Butyl Lithium (44mL, 0.11mol), stirring reaction 30 minutes, add acetone (8.1mL, 0.11mol), continue reaction 2 hours.In reaction solution, add 200mL water, be extracted with ethyl acetate (200mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL), concentrating under reduced pressure, obtains title product 2-(the fluoro-phenyl of 3,4-diethoxy-5-) propan-2-ol 24a (23.7g, yellow oil), productive rate: 97.9%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.87(m，1H)，6.81(m，1H)，4.14(m，4H)，1.57(s，6H)，1.47(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)

Second step

5-(1-nitrine-1-methyl-ethyl)-1, the fluoro-benzene of 2-diethoxy-3-

Under ice bath, by 2-(the fluoro-phenyl of 3,4-diethoxy-5-) propan-2-ol 24a (21.97g, 0.091mol) be dissolved in 200mL chloroform, add sodiumazide (17.7g, 0.27mol) and trifluoroacetic acid (33.7mL, 0.46mol), stirring reaction is 12 hours.Concentrating under reduced pressure, with dichloromethane extraction (200mL * 2), merge organic phase, with saturated sodium bicarbonate solution washing (100mL * 2), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains title product 5-(1-nitrine-1-methyl-ethyl)-1, the fluoro-benzene 24b of 2-diethoxy-3-(24.1g, yellow oil), productive rate: 99.2%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.75(m，2H)，4.12(m，4H)，1.60(s，6H)，1.45(t，J＝7.2Hz，3H)，1.36(t，J＝7.2Hz，3H)

The 3rd step

1-(1-nitrine-1-methyl-ethyl)-2-is bromo-4, the fluoro-benzene of 5-diethoxy-3-

By 5-(1-nitrine-1-methyl-ethyl)-1, the fluoro-benzene 24b of 2-diethoxy-3-(21.4g, 0.08mol) is dissolved in 200mL acetic acid, add sodium-acetate (13.1g, 0.16mol) and bromine (8mL, 0.16mol), stirring reaction 48 hours.Add 30mL saturated sodium bisulfite solution, with n-hexane extraction (150mL * 3), merge organic phase, use successively saturated sodium bicarbonate solution (150mL * 2) and saturated nacl aqueous solution washing (150mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains title product 1-(1-nitrine-1-methyl-ethyl)-2-bromo-4, the fluoro-benzene 24c of 5-diethoxy-3-(20.4g, yellow oil), productive rate: 73.5%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.01(d，J＝2.0Hz，1H)，4.16(m，4H)，1.83(s，6H)，1.49(t，J＝7.2Hz，3H)，1.41(t，J＝7.2Hz，3H)

The 4th step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine

By 1-(1-nitrine-1-methyl-ethyl)-2-bromo-4, the fluoro-benzene 24c of 5-diethoxy-3-(10g, 28.8mmol) be dissolved in 100mL methyl-sulphoxide, add cuprous cyanide (5.16g, 57.6mmol) and cuprous iodide (10.9g, 57.6mmol), stirring reaction 1 hour at 150 ℃.Add 300mL water and 300mL ethyl acetate, 300mL salt acid elution for organic phase, merges water, with the sodium hydroxide solution adjusting pH of 300mL 1M, is 12～13.Water is extracted with ethyl acetate (150mL * 3), merge organic phase, with weak ammonia (200mL) and saturated nacl aqueous solution washing (200mL), anhydrous magnesium sulfate drying, filters, filtrate decompression is concentrated, obtain title product 5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (0.9g, gray solid), productive rate: 11.5%.

MS?m/z(ESI)：267[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.01(s，1H)，4.18(m，2H)，4.10(m，2H)，1.48(t，J＝7.2Hz，3H)，1.44(s，6H)，1.37(t，J＝7.2Hz，3H)

The 5th step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1mmol) be dissolved in 7mL DMF, add the bromo-1-(3 of 2-, 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (360mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 70mL water, be extracted with ethyl acetate (25mL * 3), water (50mL) and saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 24 (110mg, yellow solid), productive rate: 21.6%.

MS?m/z(ESI)：513[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.37(br.s，1H)，8.98(br.s，1H)，8.05(br.s，1H)，7.83(s，2H)，7.48(s，1H)，5.47(s，2H)，4.26(m，2H)，4.11(m，2H)，1.51(s，6H)，1.44(s，18H)，1.41(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)

Embodiment 25

1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate

The first step

By 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (237mg, 1mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8d (424.8mg, 1.2mmol) be dissolved in 3mLN, in dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, be extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 25 (130mg, yellow solid), productive rate: 22.0%.

MS?m/z(ESI)：512[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.93(d，J＝7.6Hz，1H)，7.65(d，J＝7.6Hz，1H)，7.37(m，7H)，5.04(d，J＝16.8Hz，1H)，3.82(s，3H)，3.14(m，4H)，2.74(s，3H)，1.99(s，3H)，1.90(m，4H)，1.36(s，9H)

Embodiment 26

1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1mmol) be dissolved in 7mL N, in dinethylformamide, add the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8d (390mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 50mL water, be extracted with ethyl acetate (25mL * 4), merge organic phase, water (50mL) and saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 26 (61mg, yellow solid), productive rate: 11.3%.

MS?m/z(ESI)：540[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.50(d，J＝2.0Hz，1H)，7.45(s，2H)，5.41(s，2H)，4.27(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.67(s，3H)，3.19(m，4H)，1.94(m，4H)，1.51(s，6H)，1.41(m，12H)，1.32(t，J＝7.2Hz，3H)

Embodiment 27

1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (400mg, 1.5mmol) be dissolved in 10mLN, in dinethylformamide, add the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (610mg, 1.65mmol), stirring reaction 12 hours.In reaction solution, add 100mL water, be extracted with ethyl acetate (50mL * 5), merge organic phase, water (50 * 3mL) and saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 27 (84mg, yellow solid), productive rate: 8.4%.

MS?m/z(ESI)：556[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.35(br.s，1H)，8.99(br.s，1H)，7.67(d，J＝2.0Hz，1H)，7.59(d，J＝2.0Hz，1H)，7.46(s，1H)，5.47(s，2H)，4.27(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，4.01(s，3H)，3.84(m，4H)，3.04(m，4H)，1.58(s，6H)，1.41(m，12H)，1.32(t，J＝7.2Hz，3H)

Embodiment 28

The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1.0mmol) be dissolved in 7mL N, in dinethylformamide, add the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (400mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 70mL water, be extracted with ethyl acetate (40mL * 2), merge organic phase, water (50mL) and saturated nacl aqueous solution washing (50mL), concentrating under reduced pressure, add 100mL normal hexane, be evaporated to 15mL, filter, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 28 (116mg, white solid), productive rate: 20.9%.

MS?m/z(ESI)：554[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.27(br.s，1H)，8.95(br.s，1H)，7.64(d，J＝2.0Hz，1H)，7.59(d，J＝2.0Hz，1H)，7.45(s，1H)，5.41(s，2H)，4.27(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.98(s，3H)，2.99(m，4H)，1.73(m，4H)，1.57(m，2H)，1.51(s，6H)，1.39(m，12H)，1.34(t，J＝7.2Hz，3H)

Embodiment 29

The N-[3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-2-p-methoxy-phenyl] ethanamide hydrobromate

The first step

By 5; 6-diethoxy-7-fluoro-3; 3-dimethyl-isoindole-1-amine 24d (266mg; 1.0mmol) be dissolved in 6mLN; in dinethylformamide; add N-[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide 13b (380mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 100mL water; be extracted with ethyl acetate (50mL * 3); merge organic phase; water (50 * 2mL) and saturated nacl aqueous solution washing (50mL); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; obtain the title product N-[3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl]-2-p-methoxy-phenyl] ethanamide hydrobromate 29 (90mg, faint yellow solid), productive rate: 17.0%.

MS?m/z(ESI)：528[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.82(s，1H)，9.44(br.s，1H)，9.01(br.s，1H)，8.21(s，1H)，7.76(s，1H)，7.47(s，1H)，5.44(s，2H)，4.27(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.80(s，3H)，2.14(s，3H)，1.50(s，6H)，1.41(s，9H)，1.33(m，6H)

Embodiment 30

1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (300mg, 1.1mmol) be dissolved in 7mLN, in dinethylformamide, add the bromo-1-of 2-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 19b (440mg, 1.35mmol), stirring reaction 12 hours.In reaction solution, add 75mL water, be extracted with ethyl acetate (50mL * 2), merge organic phase, with saturated nacl aqueous solution (50mL), wash, anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtain title product 1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 30 (80mg, faint yellow solid), productive rate: 10.8%.

MS?m/z(ESI)：513[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.40(s，1H)，7.34(s，1H)，7.26(s，1H)，5.28(s，2H)，4.36(m，2H)，4.26(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.33(m，2H)，2.95(s，3H)，1.48(s，6H)，1.37(m，12H)，1.31(t，J＝7.2Hz，3H)

Embodiment 31

The 2-[8-tertiary butyl-6-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl] ethyl acetate hydrobromate

The first step

By 5; 6-diethoxy-7-fluoro-3; 3-dimethyl-isoindole-1-amine 24d (200mg; 0.75mmol) be dissolved in 5mLN, in dinethylformamide, add 2-[6-(2-the acetyl bromide)-8-tertiary butyl-2; 3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate 5e (330mg, 0.83mmol), stirring reaction 12 hours.In reaction solution, add 20mL water; be extracted with ethyl acetate (50mL * 2); merge organic phase; water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; obtain the title product 2-[8-tertiary butyl-6-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate hydrobromate 31 (88mg, faint yellow solid), productive rate: 17.7%.

MS?m/z(ESI)：584[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.44(br.s，1H)，8.96(br.s，1H)，7.48(s，1H)，7.32(s，1H)，7.14(s，1H)，5.38(s，2H)，4.31(m，4H)，4.25(m，2H)，4.11(m，4H)，3.50(m，2H)，1.48(s，6H)，1.40(t，J＝7.2Hz，3H)，1.37(s，9H)，1.30(t，J＝7.2Hz，3H)，1.19(t，J＝7.2Hz，3H)

Embodiment 32

1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1 '-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1mmol) be dissolved in 5mL N, in dinethylformamide, add 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] the bromo-ethyl ketone 17h of-2-(493mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 20mL water and 15mL ethyl acetate, water is extracted with ethyl acetate (5mL * 3), merge organic phase, water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtain title product 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1 '-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 32 (40mg, faint yellow solid), productive rate: 5.6%.

MS?m/z(ESI)：634[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.35(br.s，1H)，8.99(br.s，1H)，7.61(m，1H)，7.56(m，1H)，7.46(s，1H)，5.46(s，2H)，4.26(m，2H)，4.11(m，2H)，3.96(s，3H)，3.82(m，4H)，3.02(m，4H)，2.07(s，9H)，1.75(s，6H)，1.50(s，6H)，1.41(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)

Embodiment 33

1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (200mg, 0.75mmol) be dissolved in 4mL DMF, add the bromo-1-of 2-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6b (282mg, 0.83mmol), stirring reaction 12 hours.In reaction solution, add 5mL water and 5mL ethyl acetate, water is extracted with ethyl acetate (5mL * 3), merge organic phase, water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, add 2mL ethyl acetate, filter, filter cake vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-ethyl-2, 3-dihydro-1, 4-benzoxazine-6-yl)-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1, 1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 33 (55mg, faint yellow solid), productive rate: 12.1%.

MS?m/z(ESI)：526[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.23(br.s，1H)，8.92(br.s，1H)，7.45(s，1H)，7.56(m，1H)，7.27(m，1H)，5.35(s，2H)，4.27(m，4H)，4.12(m，2H)，3.43(m，2H)，3.37(t，J＝4.0Hz，2H)，1.50(s，6H)，1.42(t，J＝7.2Hz，3H)，1.37(s，9H)，1.31(t，J＝7.2Hz，3H)，1.12(t，J＝6.0Hz，3H)

Embodiment 34

1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (200mg, 0.75mmol) be dissolved in 4mL N, in dinethylformamide, add the bromo-1-of 2-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21c (0.28g, 0.83mmol), stirring reaction is 12 hours.In reaction solution, add 5mL water and 5mL ethyl acetate, water is extracted with ethyl acetate (5mL * 3), merge organic phase, water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, adds 2mL ethyl acetate, filter, vacuum-drying, obtains title product 1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 34 (60mg, faint yellow solid), productive rate: 13.2%.

MS?m/z(ESI)：527[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.31(br.s，1H)，8.96(br.s，1H)，7.93(s，2H)，7.45(s，1H)，5.43(s，2H)，4.27(m，2H)，4.12(m，2H)，3.71(s，3H)，1.51(s，6H)，1.45(s，18H)，1.41(m，3H)，1.31(t，J＝7.2Hz，3H)

Embodiment 35

1-(3,5-di-tert-butyl-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindole-2-yl)-ethyl ketone hydrobromate

The first step

1-(3,5-di-tert-butyl-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1mmol) be dissolved in 4mL DMF, add the bromo-1-(3 of 2-, 5-di-t-butyl-phenyl) ethyl ketone 22c (0.34g, 1.1mmol), stirring reaction 12 hours.Add 5mL water and 5mL ethyl acetate, water is extracted with ethyl acetate (5mL * 3), merge organic phase, water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, adds 2mL ethyl acetate, filter, filter cake vacuum-drying, obtains title product 1-(3,5-di-tert-butyl-phenyl)-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 35 (70mg, white solid), productive rate: 12.1%.

MS?m/z(ESI)：497[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.37(br.s，1H)，8.98(br.s，1H)，7.87(m，2H)，7.78(m，1H)，7.47(s，1H)，5.48(s，2H)，4.26(m，2H)，4.12(m，2H)，1.52(s，6H)，1.42(t，J＝7.2Hz，3H)，1.36(s，18H)，1.31(t，J＝7.2Hz，3H)

Embodiment 36

The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5,6-diethoxy-1, the fluoro-3-imino--isoindoline-2-of 1-diethyl-4-yl) ethyl ketone hydrobromate

The first step

3-(the fluoro-phenyl of 3,4-diethoxy-5-) penta-3-alcohol

At-78 ℃, 5-is bromo-1, and the fluoro-benzene 23e of 2-diethoxy-3-(26.3g, 0.1mol) is dissolved in 100mL ether, add n-Butyl Lithium (44mL, 0.11mol), stirring reaction 30 minutes, add propione (11.6mL, 0.11mol), continue reaction 2 hours.To reaction solution, add 200mL water, be extracted with ethyl acetate (100mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtain title product 3-(3, the fluoro-phenyl of 4-diethoxy-5-) penta-3-alcohol 36a (20.1g, faint yellow oily matter), productive rate: 74.7%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.77(d，J＝2.0Hz，1H)，6.72(dd，J ₁＝12.0Hz，J ₂＝2.0Hz，1H)，4.14(m，4H)，1.85(m，4H)，1.47(t，J＝7.2Hz，3H)，1.40(t，J＝7.2Hz，3H)，0.80(t，J＝7.6Hz，6H)

Second step

5-(1-nitrine-1-ethyl-propyl group)-1, the fluoro-benzene of 2-diethoxy-3-

Under ice bath, by 3-(the fluoro-phenyl of 3,4-diethoxy-5-) penta-3-alcohol 36a (20g, 0.074mol) be dissolved in 250mL chloroform, add sodiumazide (14.4g, 0.22mol) and trifluoracetic acid (27.4mL, 0.37mol), stirring reaction is 12 hours.In reaction solution, add 200mL water, with dichloromethane extraction (150mL * 2), merge organic phase, with saturated sodium bicarbonate solution washing (200mL * 5), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains title product 5-(1-nitrine-1-ethyl-propyl group)-1, the fluoro-benzene 36b of 2-diethoxy-3-(21.2g, faint yellow oily matter), productive rate: 97.2%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.72(d，J＝2.4Hz，1H)，6.69(dd，J ₁＝11.6Hz，J ₂＝2.4Hz，1H)，4.17(m，4H)，1.96(m，4H)，1.48(t，J＝7.2Hz，3H)，1.40(t，J＝7.2Hz，3H)，0.82(t，J＝7.6Hz，6H)

The 3rd step

1-(1-nitrine-1-ethyl-propyl group)-2-is bromo-4, the fluoro-benzene of 5-diethoxy-3-

By 5-(1-nitrine-1-ethyl-propyl group)-1, the fluoro-benzene 36b of 2-diethoxy-3-(21g, 71.2mmol) is dissolved in 250mL acetic acid, add bromine (7.1mL, 142.3mmol) and sodium-acetate (11.67g, 142.3mmol), stirring reaction 144 hours.In reaction solution, add 250mL saturated sodium bisulfite solution, with normal hexane and ethyl acetate (V/V=5: 1) mixed extractant solvent (100mL * 3), merge organic phase, with saturated sodium bicarbonate solution (100mL * 5) and saturated nacl aqueous solution washing (100mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtain title product 1-(1-nitrine-1-ethyl-propyl group)-2-bromo-4, the fluoro-benzene 36c of 5-diethoxy-3-(24.1g, yellow oil), productive rate: 90.2%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.12(d，J＝2.0Hz，1H)，4.16(m，4H)，2.69(m，2H)，1.97(m，2H)，1.48(t，J＝7.2Hz，3H)，1.41(t，J＝7.2Hz，3H)，0.79(t，J＝7.6Hz，6H)

The 4th step

5,6-diethoxy-3, the fluoro-isoindole-1-of 3-diethyl-7-amine

By 1-(1-nitrine-1-ethyl-propyl group)-2-bromo-4, the fluoro-benzene 36c of 5-diethoxy-3-(11g, 29.3mmol) be dissolved in 100mL methyl-sulphoxide, add cuprous cyanide (5.25g, 58.7mmol) and cuprous iodide (5.57g, 29.3mmol), stirring reaction 2 hours at 150 ℃.To reaction solution, add 300mL water, water is extracted with ethyl acetate (400mL), merge organic phase, with ammonia scrubbing (100mL), be washed with water to blueness, dilute hydrochloric acid extraction (100mL * 5), water regulates pH to 14, be extracted with ethyl acetate again (100mL * 3), merge organic phase, anhydrous sodium sulfate drying, filters, filtrate decompression is concentrated, obtain title product 5,6-diethoxy-3, the fluoro-isoindole-1-of 3-diethyl-7-amine 36d (2.24g, gray solid), productive rate: 26.0%.

MS?m/z(ESI)：295[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.93(s，1H)，6.37(br.s，2H)，4.12(d，J＝6.8Hz，2H)，4.02(d，J＝6.8Hz，2H)，1.74(m，4H)，1.36(t，J＝6.8Hz，3H)，1.26(t，J＝6.8Hz，3H)，0.46(br.s，6H)

The 5th step

By 5,6-diethoxy-3, fluoro-isoindole-the 1-of 3-diethyl-7-amine 36d (0.3g, 1mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(1-piperidines) phenyl]-ethyl ketone 12b (0.4g, 1.1mmol) be dissolved in 6mLN, in dinethylformamide, microwave reaction is 60 minutes at 60 ℃.In reaction solution, add 50mL water and 2mL saturated nacl aqueous solution, filter, filter cake water (100mL) and normal hexane and ethyl acetate (V/V=5: mixed solvent washing (100mL) 1), with silica gel column chromatography, with eluent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5,6-diethoxy-1, the fluoro-3-imino--isoindoline-2-of 1-diethyl-4-yl) ethyl ketone hydrobromate 36 (0.02g, yellow solid), productive rate: 3.0%.

MS?m/z(ESI)：582[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.63(s，1H)，7.60(s，1H)，7.29(s，1H)，5.28(s，2H)，4.25(m，2H)，4.15(m，2H)，3.97(s，3H)，2.99(m，4H)，2.02(m，4H)，1.57(m，4H)，1.43(m，2H)，1.34(m，15H)，0.45(t，J＝7.2Hz，6H)

Embodiment 37

1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-1, the fluoro-3-imino--isoindoline-2-of 1-diethyl-4-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-3, fluoro-isoindole-the 1-of 3-diethyl-7-amine 36d (0.3g, 1mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8d (0.39g, 1.1mmol) be dissolved in 6mL N, in dinethylformamide, microwave reaction is 60 minutes at 60 ℃.In reaction solution, add 100mL water, with normal hexane and ethyl acetate (V/V=5: mixed extractant solvent 1) (100mL), concentrating under reduced pressure, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-1, the fluoro-3-imino--isoindoline-2-of 1-diethyl-4-yl) ethyl ketone hydrobromate 37 (0.05g, yellow solid), productive rate: 8.8%.

MS?m/z(ESI)：568[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.43(br.s，1H)，9.06(br.s，1H)，7.49(s，1H)，7.46(s，1H)，7.30(s，1H)，5.30(s，2H)，4.27(q，J＝7.2Hz，2H)，4.15(q，J＝7.2Hz，2H)，3.67(s，3H)，3.20(m，4H)，2.05(m，4H)，1.94(m，4H)，1.40(s，9H)，1.33(m，6H)，0.45(t，J＝7.2Hz，6H)

Embodiment 38

1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5,6-diethoxy-1, the fluoro-3-imino--isoindoline-2-of 1-diethyl-4-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-3, fluoro-isoindole-the 1-of 3-diethyl-7-amine 36d (0.3g, 1mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (0.41g, 1.1mmol) be dissolved in 6mL N, in dinethylformamide, microwave reaction is 60 minutes at 60 ℃.In reaction solution, add 100mL water, with normal hexane and ethyl acetate (V/V=5: mixed extractant solvent 1) (100mL), concentrating under reduced pressure, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5,6-diethoxy-1, the fluoro-3-imino--isoindoline-2-of 1-diethyl-4-yl) ethyl ketone hydrobromate 38 (0.02g, yellow solid), productive rate: 2%.

MS?m/z(ESI)：568[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.48(br.s，1H)，9.10(br.s，1H)，7.66(s，1H)，7.61(s，1H)，7.32(s，1H)，5.35(s，2H)，4.27(q，J＝7.2Hz，2H)，4.14(q，J＝7.2Hz，2H)，3.97(s，3H)，3.84(m，4H)，3.05(m，4H)，2.00(m，4H)，1.39(s，9H)，1.33(m，6H)，0.52(t，J＝7.2Hz，6H)

Embodiment 39

The 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

[(2R, 5S)-5-(methylol) tetrahydrofuran (THF)-2 base] methyl alcohol

By 1,5-hexadiene 39a (4.6g, 56mmol) be dissolved in 620mL tetrahydrofuran (THF) and methylene dichloride (V/V=9: in mixed solvent 1), add sodium periodate (26.2g, 123mmol), ruthenium trichloride (23mg, 0.11mmol), 80g silica gel and 40mL water, stirring reaction 8 hours.Reaction solution concentrating under reduced pressure, add 100mL Virahol, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product [(2R, 5S)-5-(methylol) tetrahydrofuran (THF)-2 base] methyl alcohol 39b (4.34g, colourless liquid), productive rate: 58.6%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ4.08(m，2H)，3.76(m，2H)，3.73(m，4H)，1.92(m，2H)，1.79(m，2H)

Second step

[(2R, 5S)-5-(tolysulfonyl oxygen methyl)-tetrahydrofuran (THF)-2-yl]-methyl-4-toluene sulfonic acide ester

[(2R, 5S)-5-(methylol) tetrahydrofuran (THF)-2 base] methyl alcohol 39b (3.0g, 22.7mmol) is dissolved in 20mL methylene dichloride, add 4-toluene sulfonyl chloride (8.6g, 45.4mmol) and pyridine (4.4mL, 54.5mmol), stirring reaction 12 hours.In reaction solution, add 30mL water, dichloromethane extraction for water (20mL * 3), merge organic phase, use respectively saturated sodium carbonate solution (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, gained resistates ethyl alcohol recrystallization, obtain title product [(2R, 5S)-5-(tolysulfonyl oxygen methyl)-tetrahydrofuran (THF)-2-yl]-methyl-4-toluene sulfonic acide ester 39c (6.0g, white solid), productive rate: 60.0%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.79(d，J＝8.0Hz，4H)，7.36(d，J＝8.0Hz，4H)，4.11(m，2H)，3.94(m，4H)，2.46(s，6H)，1.95(m，2H)，1.72(m，2H)

The 3rd step

(1R, 5S)-3-benzyl-8-oxa--3-azabicyclo [3.2.1] octane

By [(2R, 5S)-5-(tolysulfonyl oxygen methyl)-tetrahydrofuran (THF)-2-yl]-methyl-4-toluene sulfonic acide ester 39c (4.1g, 9.32mmol) and benzylamine (3.56mL, 32.6mmol) be dissolved in 40mL toluene, stirring reaction is 12 hours at 120 ℃.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product (1R, 5S)-3-benzyl-8-oxa--3-azabicyclo [3.2.1] octane 39d (1.58g, colourless liquid), productive rate: 83.6%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.32(m，5H)，4.28(m，2H)，3.47(s，2H)，2.56(d，J＝12.0Hz，2H)，2.36(d，J＝12.0Hz，2H)，2.01(m，2H)，1.99(m，2H)

The 4th step

(1S, 5R)-8-oxa--3-azabicyclo [3.2.1] octane

(1R, 5S)-3-benzyl-8-oxa--3-azabicyclo [3.2.1] octane 39d (1.5g, 7.39mmol) is dissolved in 200mL ethyl acetate, adds palladium/carbon (75mg, 5%), hydrogen exchange three times, stirring reaction is 2 hours at 80 ℃.Reaction solution concentrating under reduced pressure, filters, and filtrate decompression is concentrated, obtains title product (1S, 5R)-8-oxa--3-azabicyclo [3.2.1] octane 39e (347mg, colourless liquid), productive rate: 83.3%.

MS?m/z?(ESI)：114[M+1]

The 5th step

The 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl] ethyl ketone

By the 1-tertiary butyl-5-(1,1-dimethoxy-ethyl) the iodo-2-anisole of-3-2f (76l mg, 2.01mmol) and 2-bis-hexamethylene phosphino--2 '-(N, N dimethylamine)-biphenyl (79mg, 0.20mmol) be dissolved in 10mL toluene, add palladium/carbon (76mg, 10%), potassium tert.-butoxide (786mg, 7.00mmol) with (1S, 5R)-8-oxa--3-azabicyclo [3.2.1] octane 39e (228mg, 2.01mmol), stirring reaction is 5 hours at 80 ℃.In reaction solution, add 20mL water, water is extracted with ethyl acetate (5mL * 3), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, adds 5mL acetic acid and 1mL water, stirring reaction 1 hour.Add 20mL water, water is extracted with ethyl acetate (5mL * 3), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl] ethyl ketone 39f (286mg, yellow solid), productive rate: 45.0%.

MS?m/z(ESI)：318[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.67(d，J＝2.0Hz，1H)，7.52(d，J＝2.0Hz，1H)，4.44(m，2H)，3.94(s，3H)，3.17(d，J＝12.0Hz，2H)，3.01(d，J＝12.0Hz，2H)，2.57(s，3H)，2.12(m，2H)，2.05(m，2H)，1.41(s，9H)

The 6th step

The bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl] ethyl ketone

At 40 ℃, by the 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl]-phenyl]-ethyl ketone 39f (258mg, 0.81mmol) be dissolved in 8mL chloroform, add cupric bromide (363.6g, 1.63mmol), stirring reaction 12 hours.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the bromo-1-[3-tertiary butyl-4-of title product 2-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl] ethyl ketone 39g (220mg, yellow solid), productive rate: 68.3%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.70(d，J＝2.4Hz，1H)，7.55(d，J＝2.4Hz，1H)，4.45(m，2H)，4.40(s，2H)，3.96(s，3H)，3.17(d，J＝12.0Hz，2H)，2.99(d，J＝12.0Hz，2H)，2.12(m，2H)，2.05(m，2H)，1.41(s，9H)

The 7th step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (189mg, 0.71mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl]-phenyl] ethyl ketone 39g (310mg, 0.78mmol) be dissolved in 5mLN, in dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, be extracted with ethyl acetate (5mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, by tlc, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 39 (72mg, yellow powder), productive rate: 15.3%.

MS?m/z(ESI)：582[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.35(br.s，1H)，8.97(br.s，1H)，7.62(m，2H)，7.46(s，1H)，5.45(s，2H)，4.41(m，2H)，4.24(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.92(s，3H)，3.12(m，2H)，2.89(m，2H)，2.07(m，2H)，1.92(m，2H)，1.50(s，6H)，1.41(t，J＝7.2Hz，3H)，1.39(s，9H)，1.31(t，J＝7.2Hz，3H)

Embodiment 40

The 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

2-(p-toluenesulfonyl)-6-oxa--2-azepine spiroheptane

3-is bromo-2,2-bis-(brooethyl) propane-1-alcohol 40a (65.0g, 0.20mol) and 4-methyl benzenesulfonamide 40b (41.0g, 0.24mol) be dissolved in 600mL ethanol, add potassium hydroxide (35.84g, 0.64mol), stirring reaction is 12 hours at 80 ℃.Filter, washing with alcohol for filter cake (10mL * 3), vacuum-drying, obtains title product 2-(p-toluenesulfonyl)-6-oxa--2-azepine spiroheptane 40c (30.0g, white solid), productive rate: 59.2%.

MS?m/z(ESI)：254[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.71(d，J＝8.0Hz，2H)，7.14(d，J＝8.0Hz，2H)，4.59(s，4H)，3.91(s，4H)，2.44(s，3H)

Second step

6-oxa--2-azaspiro [3.3] heptane oxalate

2-(p-toluenesulfonyl)-6-oxa--2-azaspiro [3,3] heptane 40c (5.5g, 22.0mmol) are dissolved in 120mL methyl alcohol, add magnesium powder (4.2g, 174mmol), ultrasonic response 1 hour.Concentrating under reduced pressure, add 180mL ether and 30g Disodium sulfate decahydrate, stir 1 hour, filter, the ethanolic soln that adds the oxalic acid of 5mL 1M in filtrate, stir 0.5 hour, filter washing with alcohol for filter cake (10mL * 3), vacuum-drying, obtain title product 6-oxa--2-azaspiro [3.3] heptane oxalate 40d (2.6g, white solid), productive rate: 74.2%.MS?m/z(ESI)：100[M+1]

The 3rd step

1-[3-tertiary butyl l-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone

By the 1-tertiary butyl-5-(1,1-dimethoxy-ethyl) the iodo-2-anisole of-3-2f (8.5g, 23mmol) be dissolved in 120mL toluene with 2-bis-hexamethylene phosphino--2 '-(N, N dimethylamine)-biphenyl (443mg, 1.13mmol), add palladium/carbon (850mg, 10%), potassium tert.-butoxide (7.6g, 68mmol) and 6-oxa--2-azaspiro [3.3] heptane oxalate 40d (9.0g, 25mmol), stirring reaction 1 hour at 60 ℃.In reaction solution, add 200mL water, water is extracted with ethyl acetate (50mL * 3), merges organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, adds 100mL acetic acid and 2mL water, stirring reaction 1 hour.Add 200mL water, water is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-[3-tertiary butyl l-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone 40e (6.0g, gray solid), productive rate: 88.2%.

MS?m/z(ESI)：304[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.46(d，J＝2.0Hz，1H)，7.05(d，J＝2.0Hz，1H)，4.85(s，4H)，4.02(s，4H)，3.70(s，3H)，2.56(s，3H)，1.41(s，9H)

The 4th step

The bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone

At-78 ℃, by two (trimethyl silicane) amido lithium (12.7mL, 12.7mmol) with 1-[3-tertiary butyl 1-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone 40e (3.5g, 11.6mmol) be dissolved in 50mL tetrahydrofuran (THF), stirring reaction 1 hour, add bromine (1.85g, 11.6mmol), stirring reaction 2 hours.In reaction solution, add 30mL water, water is extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-[3-tertiary butyl-4-of title product 2-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone 40f (820mg, yellow solid), productive rate: 18.6%.

MS?m/z(ESI)：383[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.49(d，J＝2.4Hz，1H)，7.07(d，J＝2.4Hz，1H)，4.85(s，4H)，4.41(s，2H)，4.02(s，4H)，3.71(s，3H)，1.40(s，9H)

The 5th step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (132mg, 0.50mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone 40f (190mg, 0.50mmol) be dissolved in 2mL tetrahydrofuran (THF), add triethylamine (1mL, 0.72mmol), stirring reaction 12 hours.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 40 (15mg, yellow solid), productive rate: 4.6%.

MS?m/z(ESI)：567[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ8.99(br.s，1H)，7.45(s，2H)，7.13(s，1H)，5.42(s，2H)，4.71(m，4H)，4.25(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，4.09(m，4H)，3.67(s，3H)，1.50(s，6H)，1.41(t，J＝7.2Hz，3H)，1.38(s，9H)，1.31(t，J＝7.2Hz，3H)

Embodiment 41

1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

6-is bromo-3, the fluoro-phenyl aldehyde of 4-diethoxy-2-

5-is bromo-1, and the fluoro-benzene 23e of 2-diethoxy-3-(15.38g, 58.5mmol) is dissolved in 250mL trifluoroacetic acid, adds vulkacit H (16.4g, 117mmol), and stirring reaction 30 minutes continues reaction 5 hours at 90 ℃.In reaction solution, add 500mL water, be extracted with ethyl acetate (250mL * 2), merge organic phase, use successively saturated sodium bicarbonate solution (250mL * 5), water (200mL) and saturated nacl aqueous solution washing (200mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 6-bromo-3, the fluoro-phenyl aldehyde 41a of 4-diethoxy-2-(7.87g, yellow solid), productive rate: 46.3%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ10.25(s，1H)，7.00(d，J＝1.6Hz，1H)，4.20(m，4H)，1.54(t，J＝7.2Hz，3H)，1.43(t，J＝7.2Hz，3H)

Second step

6-is bromo-3, the fluoro-phenylformic acid of 4-diethoxy-2-

Under ice bath, 6-is bromo-3, the fluoro-phenyl aldehyde 41a of 4-diethoxy-2-(5.5g, 18.8mmol) be dissolved in 50mL tetrahydrofuran (THF), add 50mL water, sodium hydroxide (1.2g, 30.1mmol) and potassium permanganate (3.28g, 20.7mmol), room temperature reaction 12 hours.Filter, filtrate decompression is concentrated, is extracted with ethyl acetate (150mL * 3), merges organic phase, with saturated nacl aqueous solution washing (100mL), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, obtain title product 6-bromo-3, the fluoro-phenylformic acid 41b of 4-diethoxy-2-(3.8g, yellow solid), productive rate: 65.8%.

MS?m/z(ESI)：307[M-1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ13.74(br.s，1H)，7.18(s，1H)，4.13(q，J＝7.2Hz，2H)，4.05(q，J＝7.2Hz，2H)，1.34(t，J＝7.2Hz，3H)，1.25(t，J＝7.2Hz，3H)

The 3rd step

6-is bromo-3, the fluoro-methyl benzoate of 4-diethoxy-2-

6-is bromo-3, and the fluoro-phenylformic acid 41b of 4-diethoxy-2-(3.8g, 12.4mmol) is dissolved in 30mL thionyl chloride, refluxes 5 hours.Concentrating under reduced pressure, adds 45mL methyl alcohol and methylene dichloride (V/V=2: mixing solutions 1), stirring at room 12 hours under ice bath.It is bromo-3 that concentrating under reduced pressure obtains title product 6-, the fluoro-methyl benzoate 41c of 4-diethoxy-2-(3.46g, yellow oil), productive rate: 86.9%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.90(d，J＝2.0Hz，1H)，4.10(m，4H)，3.94(s，3H)，1.46(t，J＝7.2Hz，3H)，1.36(t，J＝7.2Hz，3H)

The 4th step

6-cyano group-3, the fluoro-methyl benzoate of 4-diethoxy-2-

6-is bromo-3, and the fluoro-methyl benzoate 41c of 4-diethoxy-2-(3.46g, 10.8mmol) is dissolved in 50mLN, in dinethylformamide, adds successively cuprous cyanide (2.9g, 32.3mmol) and 1mL pyridine, and stirring reaction is 3 hours at 150 ℃.In reaction solution, add 300mL water, filter, be extracted with ethyl acetate (100mL * 3), merge organic phase, water (200mL) and saturated nacl aqueous solution washing (200mL) successively, anhydrous sodium sulfate drying, filters, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 6-cyano group-3, the fluoro-methyl benzoate 41d of 4-diethoxy-2-(1.5g, white solid), productive rate: 52.1%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.08(d，J＝1.2Hz，1H)，4.27(q，J＝7.2Hz，2H)，4.19(q，J＝7.2Hz，2H)，4.03(s，3H)，1.54(t，J＝7.2Hz，3H)，1.43(t，J＝7.2Hz，3H)

The 5th step

5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-one

Under ice bath, by 6-cyano group-3, the fluoro-methyl benzoate 41d of 4-diethoxy-2-(2.66g, 9.96mmol) be dissolved in 30mL ether, add titanium isopropylate (3.3mL, 11.1mmol) and ethylmagnesium bromide (7.3mL, 21.9mmol), stirring reaction is 2.5 hours.In reaction solution, add 65mL methyl alcohol, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-one 41e (1.48g, yellow solid), productive rate: 56.0%.

MS?m/z(ESI)：266[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.02(s，1H)，6.25(s，1H)，4.12(m，4H)，1.63(m，，2H)，1.48(t，J＝7.2Hz，3H)，1.38(t，J＝7.2Hz，3H)，1.35(m，2H)

The 6th step

5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-thioketones

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-one 41e (906mg, 3.42mmol) is dissolved in 40mL tetrahydrofuran (THF), adds lawesson reagent (734mg, 1.81mmol), and stirring reaction is 12 hours at 50 ℃.In reaction solution, add 50mL unsaturated carbonate potassium solution and 40mL ethyl acetate, water is extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-thioketones 41f (338mg, grey powder), productive rate: 22.8%.

MS?m/z(ESI)：282[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ9.68(s，1H)，6.24(s，1H)，4.14(m，4H)，1.89(m，2H)，1.52(m，2H)，1.49(t，J＝7.2Hz，3H)，1.39(t，J＝7.2Hz，3H)

The 7th step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-thioketones 41f (300mg, 1.07mmol) be dissolved in 30mL methyl alcohol, the strong aqua and the tertbutyl peroxide (0.6mL, 6mmol) that add 12mL 28%, stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, the hydrochloric acid and the 80mL water that add 10mL 2M, with ethyl acetate washing (30mL * 3), water regulates pH > 7 with 5mL 5M sodium hydroxide solution, be extracted with ethyl acetate (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtain title product 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (147mg, gray solid), productive rate: 52.1%.

MS?m/z?(ESI)：265[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ6.71(s，1H)，6.10(br.s，2H)，4.09(q，J＝7.2Hz，2H)，4.01(q，J＝7.2Hz，2H)，1.49(m，2H)，1.42(m，2H)，1.35(t，J＝7.2Hz，3H)，1.26(t，J＝7.2Hz，3H)

The 8th step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (184mg, 0.7mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (370mg, 0.7mmol) be dissolved in 6mL tetrahydrofuran (THF), add triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 41 (52mg, white powder), productive rate: 11.8%.

MS?m/z(ESI)：554[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.35(br.s，1H)，9.06(br.s，1H)，7.62(d，J＝2.0Hz，1H)，7.53(d，J＝2.0Hz，1H)，7.03(s，1H)，5.22(s，2H)，4.24(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.96(s，3H)，3.82(m，4H)，3.02(m，4H)，1.80(m，2H)，1.66(m，2H)，1.40(t，J＝7.2Hz，3H)，1.38(s，9H)，1.31(t，J＝7.2Hz，3H)

Embodiment 42

1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (201mg, 0.76mmol) be dissolved in 6mL tetrahydrofuran (THF) with the bromo-1-of 2-(3,5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (327mg, 0.87mmol), add triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours, continues reaction 48 hours at 30 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 42 (66mg, white powder), productive rate: 14.7%.

MS?m/z(ESI)：511[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.06(br.s，2H)，7.77(s，2H)，7.03(s，1H)，5.27(s，2H)，4.23(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，1.78(m，2H)，1.64(m，2H)，1.43(s，18H)，1.40(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)

Embodiment 43

The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-4-yl] ethyl acetate hydrobromate

The first step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (121mg; 0.46mmol) and 2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl] ethyl acetate 5e (201mg; 0.50mmol) be dissolved in 4mL tetrahydrofuran (THF); add triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours at 25 ℃.Filter; normal hexane for filter cake (10mL) and water washing (10mL * 3); vacuum-drying; obtain the title product 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate hydrobromate 43 (147mg, yellow powder), productive rate: 48.4%.

MS?m/z(ESI)：583[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.72(br.s，1H)，9.18(br.s，1H)，7.30(s，1H)，7.13(s，1H)，7.06(s，1H)，5.33(s，2H)，4.31(s，2H)，4.29(m，2H)，4.23(q，J＝7.2Hz，2H)，4.11(m，4H)，3.49(m，2H)，1.74(m，2H)，1.65(m，2H)，1.39(t，J＝7.2Hz，3H)，1.36(s，9H)，1.30(t，J＝7.2Hz，3H)，1.19(t，J＝7.2Hz，3H)

Embodiment 44

1-(3,5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (132mg, 0.5mmol) with the bromo-1-(3 of 2-, 5-di-t-butyl-phenyl) ethyl ketone 22c (178mg, 0.57mmol) is dissolved in 4mL tetrahydrofuran (THF), adds triethylamine (0.1mL, 0.72mmol), stirring reaction 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(3,5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 44 (54mg, white powder), productive rate: 18.8%.

MS?m/z(ESI)：495[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.38(br.s，1H)，9.05(br.s，1H)，7.82(d，J＝1.6Hz，2H)，7.78(d，J＝1.6Hz，1H)，7.03(s，1H)，5.25(s，2H)，4.24(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，1.83(m，2H)，1.67(m，2H)，1.41(t，J＝7.2Hz，3H)，1.36(s，18H)，1.31(t，J＝7.2Hz，3H)

Embodiment 45

1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (147mg, 0.56mmol) with the bromo-1-(3 of 2-, 5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21c (198mg, 0.58mmol) is dissolved in 4mL tetrahydrofuran (THF), adds triethylamine (0.1mL, 0.72mmol), stirring reaction 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 45 (47mg, white powder), productive rate: 13.9%.

MS?m/z(ESI)：525[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.67(br.s，1H)，9.12(br.s，1H)，7.90(s，2H)，7.04(s，1H)，5.38(s，2H)，4.23(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.70(s，3H)，1.79(m，2H)，1.64(m，2H)，1.43(s，18H)，1.40(m，6H)

Embodiment 46

1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (160mg, 0.56mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8d (301mg, 0.58mmol) be dissolved in 4mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 46 (118mg, white powder), productive rate: 31.5%.

MS?m/z(ESI)：538[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.36(br.s，1H)，9.06(br.s，1H)，7.46(s，1H)，7.41(s，1H)，7.05(s，1H)，5.24(s，2H)，4.24(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.18(m，4H)，1.93(m，4H)，1.80(m，2H)，1.66(m，2H)，1.40(t，J＝7.2Hz，3H)，1.36(s，9H)，1.31(t，J＝7.2Hz，3H)

Embodiment 47

1-[3-(1-diamantane)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (156mg, 0.59mmol) and 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] the bromo-ethyl ketone 17h of-2-(298mg, 0.67mmol) be dissolved in 5mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-[3-(1-diamantane)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 47 (126mg, white powder), productive rate: 29.9%.

MS?m/z(ESI)：632[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.74(br.s，1H)，9.16(br.s，1H)，7.57(m，2H)，7.07(s，1H)，5.44(s，2H)，4.25(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.96(s，3H)，3.81(m，4H)，3.02(m，4H)，2.06(m，9H)，1.76(m，6H)，1.72(m，2H)，1.66(m，2H)，1.40(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)

Embodiment 48

1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

Cyclopropane-1,2-diethyl dicarboxylate

Under ice bath, 60% sodium hydride (22.0g, 0.51mol) is dissolved in 150mL toluene, drip 2-ethyl propenoate 48a (50.0g, 0.5mol) and the mixing solutions of 2-ethyl chloroacetate 48b (61.3g, 0.5mol), stirring reaction 12 hours.In ice bath downhill reaction liquid, add a small amount of shrend reaction of going out, water is extracted with ethyl acetate (50mL * 3), merges organic phase, successively water (50mL) and saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and the cut of 65-92 ℃ is collected in oil bath underpressure distillation, obtain title product cyclopropane-1,2-diethyl dicarboxylate 48c (39.78g, colourless liquid), productive rate: 42.8%.

MS?m/z(ESI)：187[M+1]

Second step

[(1S, 2R)-2-(hydroxymethyl) cyclopropyl] methyl alcohol

Under ice bath, by lithium aluminum hydride (8.98g, 0.24mol) be dissolved in 180mL tetrahydrofuran (THF), hydrogen exchange three times, drip 20mL cyclopropane-1, the tetrahydrofuran solution of 2-diethyl dicarboxylate 48c (22.0g, 0.12mol), at 70 ℃, stirring reaction is 3 hours, and room temperature continues stirring reaction 12 hours.In ice bath downhill reaction liquid, drip 22mL saturated ammonium chloride solution, concentrating under reduced pressure, adds 200mL ethyl acetate, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product [(1S, 2S)-2-(hydroxymethyl) cyclopropyl] methyl alcohol 48d (1.14g, yellow liquid), productive rate: 9.4% and [(1S, 2R)-2-(hydroxymethyl) cyclopropyl] methyl alcohol 48e (5.3g, yellow liquid), productive rate: 43.9%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ3.81(m，2H)，3.53(br.s，2H)，3.10(m，2H)，1.03(m，2H)，0.45(m，2H)

¹H?NMR(400MHz，CDCl ₃，ppm)：δ4.11(m，2H)，3.24(m，4H)，1.32(m，2H)，0.81(m，1H)，0.22(m，1H)

The 3rd step

(1R, 2S)-1,2-bis-(brooethyl) cyclopropane

Under ice bath, by triphenylphosphine (28.19g, 0.107mol) be dissolved in 130mL acetonitrile, drip bromine (5.4mL, 0.107mol), under room temperature, drip 30mL[(1S, 2R)-2-(hydroxymethyl) cyclopropyl] methyl alcohol 48e (5.22g, acetonitrile solution 0.051mol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, add 100mL ethyl acetate, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product (1R, 2S)-1,2-bis-(brooethyl) cyclopropane 48f (9.68g, yellow liquid), productive rate: 83.9%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ3.50(m，4H)，1.66(m，2H)，1.18(m，1H)，0.43(m，1H)

The 4th step

1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl] ethyl ketone

By 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl)-ethyl ketone 8b (1.0g, 4.5mmol) with (1R, 2S)-1,2-bis-(brooethyl) cyclopropane 48f (2.06g, 9.0mmol) be dissolved in 20mL water, add salt of wormwood (680mg, 4.95mmol), microwave stirring reaction is 20 minutes at 120 ℃.Add 20mL ethyl acetate, water is extracted with ethyl acetate (30mL * 3), merge organic phase, water (50mL) and saturated nacl aqueous solution washing (50mL) successively, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl] ethyl ketone 48g (596mg, yellow liquid), productive rate: 45.9%.

MS?m/z(ESI)：288[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.52(d，J＝2.0Hz，1H)，7.37(d，J＝2.0Hz，1H)，3.64(s，3H)，3.6l(m，2H)，3.00(m，2H)，2.56(s，3H)，1.56(m，2H)，1.42(s，9H)，0.6(m，2H)

The 5th step

1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl] the bromo-ethyl ketone of-2-

At 40 ℃, by 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl] ethyl ketone 48g (2.0g, 6.97mmol) be dissolved in 20mL chloroform, add cupric bromide (3.11g, 13.94mmol), stirring reaction 12 hours.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl] the bromo-ethyl ketone 48h of-2-(558mg, yellow solid), productive rate: 21.9%.

MS?m/z(ESI)：368[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.55(d，J＝2.0Hz，1H)，7.43(d，J＝2.0Hz，1H)，4.42(s，2H)，3.64(s，3H)，3.60(m，2H)，3.01(m，2H)，1.56(m，2H)，1.41(s，9H)，0.6(m，2H)

The 6th step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (161mg, 0.61mmol) and 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl] the bromo-ethyl ketone 48h of-2-(246mg, 0.67mmol) is dissolved in 5mL tetrahydrofuran (THF), adds triethylamine (0.1mL, 0.72mmol), stirring reaction 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 48 (118mg, white powder), productive rate: 30.7%.

MS?m/z(ESI)：550[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.34(br.s，1H)，9.05(br.s，1H)，7.49(d，J＝1.6Hz，1H)，7.39(d，J＝1.6Hz，1H)，7.04(s，1H)，5.22(s，2H)，4.24(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.61(s，3H)，3.54(d，J＝8.8Hz，2H)，2.99(d，J＝8.8Hz，2H)，1.80(br.s，2H)，1.66(m，4H)，1.40(t，J＝7.2Hz，3H)，1.38(s，9H)，1.31(t，J＝7.2Hz，3H)，0.61(m，1H)，0.55(m，1H)

Embodiment 49

The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-4-yl] acetonitrile hydrobromate

The first step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (160mg; 0.61mmol) and 2-[6-(the bromo-ethanoyl of the 2-)-8-tertiary butyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-4-yl] acetonitrile 16b (320mg; 0.91mmol) be dissolved in 5mL tetrahydrofuran (THF); add triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours at 25 ℃.Filter; normal hexane for filter cake (10mL) and water washing (10mL * 3); vacuum-drying; obtain the title product 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] acetonitrile hydrobromate 49 (150mg, yellow powder), productive rate: 40.2%.

MS?m/z?(ESI)：535[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.40(br.s，2H)，7.67(s，1H)，7.41(s，1H)，7.05(s，1H)，5.41(s，2H)，4.85(s，2H)，4.39(m，2H)，4.24(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.36(m，2H)，1.85(m，2H)，1.65(m，2H)，1.39(t，J＝7.2Hz，3H)，1.35(s，9H)，1.30(t，J＝7.2Hz，3H)

Embodiment 50

1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (157mg, 0.59mmol) with the bromo-1-of 2-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl) ethyl ketone 19b (230mg, 0.71mmol) be dissolved in 5mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 50 (164mg, buff powder), productive rate: 46.7%.

MS?m/z(ESI)：510[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.34(br.s，1H)，9.07(br.s，1H)，7.30(s，1H)，7.22(s，1H)，7.04(s，1H)，5.21(s，2H)，4.35(m，2H)，4.24(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.34(m，2H)，2.94(s，3H)，1.78(m，2H)，1.67(m，2H)，1.41(t，J＝7.2Hz，3H)，1.36(s，9H)，1.31(t，J＝7.2Hz，3H)

Embodiment 51

1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (165mg, 0.62mmol) with the bromo-1-of 2-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-ethyl ketone 6b (255mg, 0.75mmol) be dissolved in 4mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-Isosorbide-5-Nitrae-benzoxazines-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 51 (133mg, white powder), productive rate: 35.2%.

MS?m/z(ESI)：524[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.35(br.s，1H)，9.04(br.s，1H)，7.24(s，1H)，7.22(s，1H)，7.04(s，1H)，5.19(s，2H)，4.29(t，J＝4.4Hz，2H)，4.24(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.43(q，J＝7.2Hz，2H)，3.37(t，J＝4.4Hz，2H)，1.78(m，2H)，1.66(m，2H)，1.40(t，J＝7.2Hz，3H)，1.36(s，9H)，1.31(t，J＝7.2Hz，3H)，1.12(t，J＝7.2Hz，3H)

Embodiment 52

The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate

The first step

By 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (237mg, 1mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(1-piperidines) phenyl]-ethyl ketone 12b (441.6mg, 1.2mmol) be dissolved in 3mLN, in dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, be extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 52 (150mg, light yellow solid), productive rate: 24.8%.

MS?m/z(ESI)：525[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.92(d，J＝7.6Hz，1H)，7.63(d，J＝7.6Hz，1H)，7.46(m，7H)，5.43(d，J＝18.8Hz，1H)，5.03(d，J＝18.8Hz，1H)，3.94(s，3H)，2.92(m，4H)，2.67(s，3H)，1.99(s，3H)，1.71(m，4H)，1.54(m，2H)，1.33(s，9H)

Embodiment 53

2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl)-1-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone hydrobromate

The first step

1-(the iodo-phenyl of 4-hydroxyl-3-) ethyl ketone

By 1-(4-hydroxy phenyl) ethyl ketone 53a (4.0g, 29.38mmol) be dissolved in 250mL strong aqua, add 300mL iodine (7.46g, 29.38mmol) and potassiumiodide (23.75g, aqueous solution 143.08mmol), stirring reaction is 48 hours at 50 ℃.Filter, filtrate regulates pH=1 with concentrated hydrochloric acid 100mL, filters, and filter cake washes (100mL * 3) with water, and vacuum-drying obtains title product 1-(the iodo-phenyl of 4-hydroxyl-3-) ethyl ketone 53b (3.75g, yellow solid), productive rate: 48.8%.

MS?m/z(ESI)：261[M-1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ11.13(s，1H)，8.10(d，J＝2.0Hz，1H)，7.70(dd，J ₁＝8.4Hz，J ₂＝2.0Hz，1H)，6.81(d，J＝8.4Hz，2H)，2.34(s，3H)

Second step

1-(the iodo-4-p-methoxy-phenyl of 3-) ethyl ketone

1-(the iodo-phenyl of 4-hydroxyl-3-) ethyl ketone 53b (3.52g, 13mmol) is dissolved in 50mL acetone, adds toluene-4-sulfonic acid methyl esters (2mL, 14mmol) and salt of wormwood (2.78g, 20mmol), stirring reaction is 6 hours at 50 ℃.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the iodo-4-p-methoxy-phenyl of 3-) ethyl ketone 53c (3.03g, Off-white solid), productive rate: 81.6%.

MS?m/z(ESI)：277[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.39(d，J＝2.4Hz，1H)，7.95(dd，J ₁＝8.4Hz，J ₂＝2.4Hz，1H)，6.85(d，J＝8.4Hz，1H)，3.96(s，3H)，2.55(s，3H)

The 3rd step

1-(4-methoxyl group-3-morpholinyl phenyl) ethyl ketone

By 1-(the iodo-4-p-methoxy-phenyl of 3-) ethyl ketone 53c (3.03g, 10.96mmol) with 2-bis-hexamethylene phosphino--2 '-(N, N dimethylamine)-biphenyl (216mg, 0.55mmol) be dissolved in 120mL toluene, add palladium/carbon (302mg, 10%), sodium tert-butoxide (2.10g, 21.91mmol) and morpholine (1.9mL, 21.91mmol), stirring reaction 3 hours at 80 ℃.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system A, obtains title product 1-(4-methoxyl group-3-morpholinyl phenyl) ethyl ketone 53d (1.77g, brown color oily matter), productive rate: 68.8%.

MS?m/z(ESI)：236[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.66(dd，J ₁＝8.4Hz，J ₂＝2.4Hz，1H)，7.58(d，J＝2.4Hz，1H)，6.89(d，J＝8.4Hz，1H)，3.94(s，3H)，3.90(m，4H)，3.10(m，4H)，2.56(s，3H)

The 4th step

4-[5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl] morpholine

By 1-(4-methoxyl group-3-morpholinyl phenyl) ethyl ketone 53d (971mg, 4.13mmol) and trimethyl orthoformate (1.4mL, 12.38mol) be dissolved in 40mL methyl alcohol, add D (+)-10-camphorsulfonic acid (1.054g, 4.54mmol), stirring reaction is 12 hours.In reaction solution, add 626mg salt of wormwood, stir 0.5 hour, add 50mL water, be extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains title product 4-[5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl] morpholine 53e (1.09g, brownish black oily matter), productive rate: 94.0%.

MS?m/z(ESI)：282[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.13(dd，J ₁＝8.8Hz，J ₂＝2.0Hz，1H)，7.06(d，J＝2.0Hz，1H)，6.84(d，J＝8.8Hz，1H)，3.90(m，4H)，3.87(s，3H)，3.18(s，6H)，3.09(m，4H)，1.53(s，3H)

The 5th step

[5-(1,1-dimethoxy-ethyl)-2-methoxyl group-3-morpholinyl phenyl]-trimethyl silane

Under dry ice-propanone is bathed, by 4-[5-(1,1-dimethoxy-ethyl)-2-p-methoxy-phenyl] morpholine 53e (1.09g, 3.88mmol) is dissolved in 40mL normal hexane, adds Tetramethyl Ethylene Diamine (116 μ L, 0.78mmol) and n-Butyl Lithium (3.1mL, 7.76mmol), stirring at room reaction 4 hours, adds trimethylchlorosilane (975 μ L under ice bath, 7.76mmol), room temperature continues stirring reaction 12 hours.In reaction solution, add 50mL saturated ammonium chloride solution, be extracted with ethyl acetate (30mL * 3), merge organic phase, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains title product [5-(1,1-dimethoxy-ethyl)-2-methoxyl group-3-morpholinyl phenyl]-trimethyl silane 53f (1.31g, brown color oily matter), productive rate: 95.7%.

MS?m/z(ESI)：354[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.14(d，J＝2.0Hz，1H)，7.09(d，J＝2.0Hz，1H)，3.90(s，3H)，3.87(m，4H)，3.19(s，6H)，3.10(m，4H)，1.53(s，3H)，0.28(s，9H)

The 6th step

The bromo-1-of 2-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone

[5-(1,1-dimethoxy-ethyl)-2-methoxyl group-3-morpholinyl phenyl]-trimethyl silane 53f (1.31g, 3.71mmol) is dissolved in 20mL acetic acid, adds pyridinium tribromide salt (1.19g, 3.71mmol), stirring reaction 2 hours.In reaction solution, add 30mL saturated nacl aqueous solution, be extracted with ethyl acetate (30mL * 3), merge organic phase, with saturated sodium bicarbonate solution (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the bromo-1-of title product 2-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone 53g (560mg, yellow solid), productive rate: 39.0%.

MS?m/z(ESI)：386[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ7.70(d，J＝2.4Hz，1H)，7.63(d，J＝2.4Hz，1H)，4.42(s，2H)，3.97(s，3H)，3.90(m，4H)，3.11(m，4H)，0.32(s，9H)

The 7th step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (156mg, 0.59mmol) and the bromo-1-of 2-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone 53g (298mg, 0.67mmol) be dissolved in 5mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl)-1-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone hydrobromate 53 (126mg, yellow powder), productive rate: 29.9%.

MS?m/z(ESI)：632[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.46(br.s，2H)，7.67(d，J＝2.4Hz，2H)，7.07(s，1H)，5.49(s，2H)，4.24(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.91(s，3H)，3.79(m，4H)，3.05(m，4H)，1.79(m，2H)，1.66(m，2H)，1.39(t，J＝7.2Hz，3H)，1.30(t，J＝7.2Hz，3H)，0.29(s，9H)

Embodiment 54

The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (198mg, 0.75mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (324mg, 0.88mmol) be dissolved in 5mL tetrahydrofuran (THF), add triethylamine (0.15mL, 1.08mmol), stirring reaction is 12 hours at 25 ℃.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 54 (257mg, white powder), productive rate: 54.2%.

MS?m/z(ESI)：552[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.36(br.s，1H)，9.08(br.s，1H)，7.59(s，1H)，7.54(s，1H)，7.05(s，1H)，5.24(s，2H)，4.24(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.96(s，3H)，2.97(m，4H)，1.82(m，2H)，1.73(m，4H)，1.66(m，2H)，1.55(m，2H)，1.40(t，J＝7.2Hz，3H)，1.38(s，9H)，1.31(t，J＝7.2Hz，3H)

Embodiment 55

1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (258mg, 0.97mmol) be dissolved in 4mLN, in dinethylformamide, add 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl] the bromo-ethyl ketone 48h of-2-(558mg, 1.07mmol), stirring reaction is 12 hours.In reaction solution, add 10mL water and 10mL ethyl acetate, merge organic phase, water (5mL * 3) and saturated nacl aqueous solution washing (5mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 55 (36mg, yellow solid), productive rate: 5.9%.

MS?m/z(ESI)：552[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.34(br.s，1H)，8.97(br.s，1H)，7.53(s，1H)，7.48(s，1H)，7.44(s，1H)，5.44(s，2H)，4.26(m，2H)，4.11(m，2H)，3.61(s，3H)，3.55(m，2H)，2.99(m，2H)，1.63(m，2H)，1.50(s，6H)，1.41(t，J＝7.2Hz，3H)，1.39(s，9H)，1.31(t，J＝7.2Hz，3H)，0.60(m，2H)

Embodiment 56

1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (172mg, 0.70mmol) be dissolved in 4mL tetrahydrofuran (THF), add 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl] the bromo-ethyl ketone 48h of-2-(360mg, 0.98mmol) and triethylamine (0.1mL, 0.72mmol), stirring reaction is 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-3-yl]-5-the tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 56 (27mg, white powder), productive rate: 6.3%

MS?m/z(ESI)：532[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.64(br.s，1H)，9.08(br.s，1H)，7.87(s，1H)，7.50(s，1H)，7.40(s，1H)，7.05(s，1H)，5.18(s，2H)，4.17(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.61(s，3H)，3.55(d，J＝8.8Hz，2H)，2.99(d，J＝8.8Hz，2H)，1.72(m，2H)，1.63(m，4H)，1.38(m，15H)，0.62(d，J＝4.4Hz，1H)，0.55(d，J＝4.4Hz，1H)

Embodiment 57

2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl)-1-(4-methoxyl group-3-morpholine-5-trimethyl silicane-phenyl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1.0mmol) and the bromo-1-of 2-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone 53g (425mg, 1.1mmol) be dissolved in 5mLN, in dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, water is extracted with ethyl acetate (5mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, filters normal hexane for filter cake (10mL) and water washing (10mL), vacuum-drying, obtain title product 2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl)-1-(4-methoxyl group-3-morpholine-5-trimethyl silicane-phenyl) ethyl ketone hydrobromate 57 (84mg, yellow powder), productive rate: 12.0%.

MS?m/z(ESI)：572[M+1]

1H?NMR(400MHz，DMSO-d6，ppm)：δ9.35(br.s，1H)，8.99(br.s，1H)，7.67(m，2H)，7.46(s，1H)，5.47(s，2H)，4.26(q，J＝7.2Hz，2H)，4.10(q，J＝7.2Hz，2H)，3.93(s，3H)，3.89(m，4H)，3.05(m，4H)，1.51(s，6H)，1.41(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)，0.31(s，9H)

Embodiment 58

1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate

The first step

1-(6-methoxyl group-3-pyridine)-1-phenylethyl alcohol

Under dry ice-propanone is bathed, by the bromo-2-methoxyl group-pyridine of 5-58a (21.0g, 111mmol) be dissolved in 120mL ether, drip 2.5M n-Butyl Lithium (49.1mL, hexane solution 123mmol), stirring reaction 1 hour, adds methyl phenyl ketone (14.4mL, 123mmol), continue stirring reaction 1 hour.In reaction solution, add 50mL saturated ammonium chloride solution, water is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(6-methoxyl group-3-pyridine)-1-phenylethyl alcohol 58b (19.3g, white solid), productive rate: 75.4%.

MS?m/z(ESI)：230[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.26(s，1H)，7.63(m，6H)，6.72(m，1H)，3.96(s，3H)，1.99(s，3H)

Second step

5-(1-nitrine-1-phenyl-ethyl)-2-methoxypyridine

Under ice bath, 1-(6-methoxyl group-3-pyridine)-1-phenyl-ethanol 58b (14.4g, 63mmol) and sodiumazide (12.3g, 189mmol) are dissolved in 72mL water, drip 56mL concentrated hydrochloric acid, stirring reaction 12 hours.To adding in reaction solution 800mL saturated sodium bicarbonate solution to regulate pH, be 7～8, be extracted with ethyl acetate (200mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, obtain title product 5-(1-nitrine-1-phenyl-ethyl)-2-methoxypyridine 58c (16.0g, yellow oil) crude product.

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ8.23(s，1H)，7.51(d，J＝9.2Hz，1H)，7.38(m，5H)，6.73(d，J＝9.2Hz，1H)，3.98(s，3H)，2.05(s，3H)

The 3rd step

5-(1-nitrine-1-phenyl-ethyl)-2-methoxyl group-pyridine 1-oxide compound

5-(1-nitrine-1-phenyl-ethyl)-2-methoxyl group-pyridine 58c (16.0g, 63mmol) is dissolved in 200mL methylene dichloride, adds metachloroperbenzoic acid (21.7g, 126mmol), stirring reaction 13 hours.Reaction solution concentrating under reduced pressure, add 300mL ethyl acetate, with saturated sodium bicarbonate solution washing (100mL * 3), water is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purifies gained resistates, obtains title product 5-(1-nitrine-1-phenyl-ethyl)-2-methoxyl group-pyridine 1-oxide compound 58d (12.0g, light yellow oil), productive rate: 70.6%.

MS?m/z(ESI)：271[M+1]

The 4th step

3-(1-nitrine-1-phenyl-ethyl)-6-methoxyl group-pyridine-2-nitrile

By 5-(1-nitrine-1-phenyl-ethyl)-2-methoxyl group-pyridine 1-oxide compound 58d (8.9g, 33mmol) be dissolved in 120mL acetonitrile, add cyano group trimethyl silane (17.6mL, 132mmol) and dimethylaminoethyl chloride (3.63mL, 39.5mmol), stirring reaction is 24 hours.In reaction solution, add 100mL methylene dichloride, merge organic phase, use successively saturated sodium bicarbonate solution (20mL * 3) and wash (20mL * 3) with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 3-(1-nitrine-1-phenyl-ethyl)-6-methoxyl group-pyridine-2-nitrile 58e (4.5g, light yellow oil), productive rate: 48.9%.

MS?m/z(ESI)：280[M+1]

The 5th step

2-methoxyl group-5-methyl-5-phenyl-6H-pyrroles [3,4-b] pyridine-7-imines

3-(1-nitrine-1-phenyl-ethyl)-6-methoxyl group-pyridine-2-nitrile 58e (4.4g, 15.7mmol) is dissolved in 120mL tetrahydrofuran (THF), adds 6mL water and triphenylphosphine (8.26mg, 31.5mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system A, obtains title product 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (3.0g, white solid), productive rate: 75.2%.

MS?m/z(ESI)：254[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.95(d，J＝8.4Hz，1H)，7.48(m，2H)，7.28(m，2H)，7.20(m，1H)，6.84(d，J＝8.4Hz，1H)，3.95(s，3H)，1.71(s，3H)

The 6th step

By 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (253mg, 1mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl) ethyl ketone 8d (424.8mg, 1.2mmol) be dissolved in 5mL methyl alcohol, add triethylamine (0.l66mL, 1.2mmol), stirring reaction is 12 hours.Reaction solution concentrating under reduced pressure, with silica gel column chromatography, with eluent system C, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-pyrrolidin-1-yl-phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 58 (65mg, light yellow solid), productive rate: 10.7%.

MS?m/z(ESI)：527[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.92(d，J＝8.8Hz，1H)，7.36(m，7H)，7.22(d，J＝8.4Hz，1H)，5.46(d，J＝18.4Hz，1H)，5.04(d，J＝18.4Hz，1H)，4.03(s，3H)，3.82(s，3H)，3.14(m，4H)，1.98(s，3H)，1.91(m，4H)，1.36(s，9H)

Embodiment 59

1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate

The first step

By 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (253mg, 1mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (444mg, 1.2mmol) be dissolved in 4mL tetrahydrofuran (THF), add triethylamine (0.166mL, 1.2mmol), stirring reaction is 12 hours.Reacting liquid filtering, filtrate decompression is concentrated, by tlc, with developping agent system A, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 59 (120mg, light yellow solid), productive rate: 19.3%.

MS?m/z(ESI)：543[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.96(d，J＝8.8Hz，1H)，7.38(m，7H)，7.25(d，J＝8.4Hz，1H)，5.53(d，J＝18.8Hz，1H)，5.10(d，J＝18.8Hz，1H)，4.06(s，3H)，3.88(s，3H)，3.80(m，4H)，3.03(m，4H)，2.13(s，3H)，1.36(s，9H)

Embodiment 60

1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate

The first step

1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrroles [3,4-b] pyridine-6-yl) ethyl ketone hydrobromate

By 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (64mg, 0.25mmol) with the bromo-1-(3 of 2-, 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (248mg, 0.76mmol) be dissolved in 2mL methyl alcohol, add triethylamine (0.105mL, 0.76mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, by tlc, with developping agent system C, purify gained resistates, obtain title product 1-(3,5-di-tert-butyl-hydroxy phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 60 (30mg, yellow solid), productive rate: 23.8%.

MS?m/z(ESI)：500[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.95(d，J＝8.4Hz，1H)，7.69(s，2H)，7.39(m，5H)，7.25(d，J＝8.8Hz，1H)，5.43(d，J＝18.4Hz，1H)，5.06(d，J＝18.4Hz，1H)，4.04(s，3H)，1.98(s，3H)，1.40(s，18H)

Embodiment 61

The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate

The first step

By 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (253mg, 1mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (441.6mg, 1.2mmol) be dissolved in 3mLN, in dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, be extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 61 (180mg, light yellow solid), productive rate: 30.0%.

MS?m/z(ESI)：541[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.96(s，2H)，7.94(d，J＝8.8Hz，1H)，7.49(s，1H)，7.45(s，1H)，7.37(m，5H)，7.22(d，J＝8.4Hz，1H)，5.45(d，J＝18.4Hz，1H)，5.07(d，J＝18.4Hz，1H)，4.04(s，3H)，3.94(s，3H)，2.90(m，4H)，1.91(s，3H)，1.70(m，4H)，1.54(m，2H)，1.34(s，9H)

Embodiment 62

The 2-[[3-tertiary butyl-5-[2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethanoyl]-2-p-methoxy-phenyl] amino] acetonitrile hydrobromate

The first step

By 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3; 4-b] pyridine-7-imines 58f (253mg; 1mmol) and 2-[[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] amino] acetonitrile 14b (406.8mg; 1.2mmol) be dissolved in 3mLN; in dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water; be extracted with ethyl acetate (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 3); anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated; with silica gel column chromatography, with eluent system A, purify gained resistates; obtain the title product 2-[[3-tertiary butyl-5-[2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3; 4-b] pyridine-6-yl) ethanoyl]-2-p-methoxy-phenyl] amino] acetonitrile hydrobromate 62 (150mg, light yellow solid), productive rate: 25.3%.

MS?m/z(ESI)：512[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.90(s，2H)，8.05(d，J＝8.4Hz，1H)，7.37(m，7H)，7.10(d，J＝6.8Hz，1H)，6.09(t，J＝6.8Hz，1H)，5.50(d，J＝18.8Hz，1H)，5.05(d，J＝18.8Hz，1H)，4.38(d，J＝7.2Hz，2H)，4.03(s，3H)，3.72(s，3H)，1.99(s，3H)，1.36(s，9H)

Embodiment 63

1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline-2-yl) ethyl ketone hydrobromate

The first step

1-phenyl-1-(3-quinoline) ethanol

Under dry ice-propanone is bathed, by the bromo-quinoline 63a of 3-(20.0g, 96.6mmol) be dissolved in 120mL ether, drip 2.5M n-Butyl Lithium (42.5mL, hexane solution 106mmol), stirring reaction 1 hour, adds methyl phenyl ketone (12.4mL, 106mmol), continue stirring reaction 12 hours.In reaction solution, add 50mL saturated ammonium chloride solution, water is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-phenyl-1-(3-quinoline) ethanol 63b (9.3g, light yellow oil), productive rate: 38.8%.

MS?m/z(ESI)：250[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.90(s，1H)，8.24(s，1H)，8.11(m，1H)，7.73(m，1H)，7.60(m，1H)，7.57(m，1H)，7.50(m，2H)，7.40(m，2H)，7.37(m，1H)，2.12(s，3H)

Second step

3-(1-nitrine-1-phenyl-ethyl) quinoline

Under ice bath, 1-phenyl-1-(3-quinoline) ethanol 63b (7.0g, 28mmol) and sodiumazide (5.5g, 84mmol) are dissolved in 35mL water, drip 35mL concentrated hydrochloric acid, stirring reaction 12 hours.To adding in reaction solution 450mL saturated sodium bicarbonate solution to regulate pH, be 7～8, water is extracted with ethyl acetate (150mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 3-(1-nitrine-1-phenyl-ethyl) quinoline 63c (6.8g, light yellow oil), productive rate: 88.3%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.82(s，1H)，8.24(s，1H)，8.13(d，J＝8.8Hz，1H)，7.88(d，J＝8.0Hz，1H)，7.77(t，J＝8.8Hz，1H)，7.63(t，J＝8.0Hz，1H)，7.43(m，5H)，2.19(s，3H)

The 3rd step

3-(1-nitrine-1-phenyl-ethyl) quinoline 1-oxide compound

3-(1-nitrine-1-phenyl-ethyl) quinoline 63c (6.2g, 22.6mmol) is dissolved in 60mL methylene dichloride, adds metachloroperbenzoic acid (4.8g, 27mmol), stirring reaction 3 hours.In reaction solution, add 50mL saturated sodium bicarbonate solution, dichloromethane extraction for water (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 3-(1-nitrine-1-phenyl-ethyl) quinoline 1-oxide compound 63d (6.0g, yellow oil), productive rate: 91.0%.

MS?m/z(ESI)：291[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.70(d，J＝8.0Hz，1H)，8.49(s，1H)，7.91(d，J＝8.0Hz，1H)，7.85(s，1H)，7.78(t，J＝8.0Hz，1H)，7.69(t，J＝8.0Hz，1H)，7.45(m，5H)，2.15(s，3H)

The 4th step

3-(1-nitrine-1-phenyl-ethyl)-quinoline-2-nitrile

By 3-(1-nitrine-1-phenyl-ethyl) quinoline 1-oxide compound 63d (5.95g, 20mmol) be dissolved in 120mL acetonitrile, add cyano group trimethyl silane (4.65mL, 35mmol) and dimethylaminoethyl chloride (2.82mL, 30mmol), stirring reaction 4 hours at 80 ℃.Reaction solution concentrating under reduced pressure, add 100mL ethyl acetate and 50mL saturated sodium bicarbonate solution, water is extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 3-(1-nitrine-1-phenyl-ethyl)-quinoline-2-nitrile 63e (3.3g, light yellow oil), productive rate: 54.1%.

MS?m/z(ESI)：300[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.65(s，1H)，7.87(m，4H)，7.45(m，5H)，2.34(s，3H)

The 5th step

1-methyl isophthalic acid-phenyl-2H-pyrrolo-[3,4-b] quinoline-3-imines

3-(1-nitrine-1-phenyl-ethyl)-quinoline-2-nitrile 63e (2.1g, 7mmol) is dissolved in 100mL tetrahydrofuran (THF), adds 0.5mL water and triphenylphosphine (3.68mL, 14mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system A, obtains title product 1-methyl isophthalic acid-phenyl-2H-pyrrolo-[3,4-b] quinoline-3-imines 63f (1.6g, light yellow solid), productive rate: 83.5%.

¹H?NMR(400MHz，CDCl ₃，ppm)：δ8.53(s，1H)，8.13(m，1H)，8.07(m，1H)，7.69(m，1H)，7.60(m，1H)，7.59(m，2H)，7.30(m，2H)，7.19(m，1H)，6.82(s，2H)，1.82(s，3H)

The 6th step

By 1-methyl isophthalic acid-phenyl-2H-pyrrolo-[3,4-b] quinoline-3-imines 63f (273mg, 1mmol) with the bromo-1-of 2-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (444mg, 1.2mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=3: 2) in mixed solvent, add triethylamine (0.166mL, 1.2mmol), stirring reaction is 24 hours.Reaction solution concentrating under reduced pressure, with silica gel column chromatography, with eluent system C, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline-2-yl) ethyl ketone hydrobromate 63 (120mg, light yellow solid), productive rate: 18.7%.

MS?m/z(ESI)：563[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ8.29(m，12H)，5.60(d，J＝18.0Hz，1H)，5.19(d，J＝18.0Hz，1H)，3.95(s，3H)，3.80(m，4H)，2.99(m，4H)，2.12(s，3H)，1.36(s，9H)

Embodiment 64

The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline-2-yl) ethyl ketone hydrobromate

The first step

By 1-methyl isophthalic acid-phenyl-2H-pyrrolo-[3,4-b] quinoline-3-imines 63f (273mg, 1mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(1-piperidines) phenyl]-ethyl ketone 12b (441.6mg, 1.2mmol) be dissolved in 3mLN, in N dimethyl formamide, stirring reaction 12 hours.In reaction solution, add 5mL water, be extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline-2-yl) ethyl ketone hydrobromate 64 (160mg, light yellow solid), productive rate: 25.0%.

MS?m/z(ESI)：561[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ8.64(s，1H)，8.28(m，1H)，8.15(m，1H)，7.97(m，1H)，7.80(m，1H)，7.39(m，7H)，5.56(d，J＝18.4Hz，1H)，5.06(d，J＝18.4Hz，1H)，3.94(s，3H)，2.93(m，4H)，2.11(s，3H)，1.70(m，4H)，1.53(m，2H)，1.34(s，9H)

Embodiment 65

The N-[3-tertiary butyl-5-[2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethanoyl]-2-p-methoxy-phenyl] ethanamide hydrobromate

The first step

By 2; 5-dimethyl-5-phenyl-6H-pyrrolo-[3; 4-b] pyridine-7-imines 9f (237mg; 1mmol) and N-[5-(the bromo-ethanoyl of the 2-)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide 13b (410.4mg; 1.2mmol) be dissolved in 3mLN; in dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water; be extracted with ethyl acetate (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 3); anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated; with silica gel column chromatography, with eluent system A, purify gained resistates; obtain the title product N-[3-tertiary butyl-5-[2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethanoyl]-2-p-methoxy-phenyl] ethanamide hydrobromate 65 (120mg; light yellow solid), productive rate: 20.7%.

MS?m/z(ESI)：499[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ10.20(br.s，1H)，9.74(br.s，1H)，8.09(d，J＝1.6Hz，1H)，7.96(d，J＝8.4Hz，1H)，7.69(d，J＝8.0Hz，1H)，7.62(d，J＝2.0Hz，1H)，7.37(m，5H)，5.45(d，J＝18.8Hz，1H)，5.08(d，J＝18.8Hz，1H)，4.12(s，3H)，2.64(s，3H)，2.11(s，3H)，2.00(s，3H)，1.37(s，9H)

Embodiment 66

The 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (134mg, 0.51mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone 40f (202mg, 0.53mmol) be dissolved in 2mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), stirring reaction 12 hours.Filter, normal hexane for filter cake (10mL) and water washing (10mL * 3), vacuum-drying, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 66 (108mg, yellow solid), productive rate: 32.9%.

MS?m/z(ESI)：566[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.31(br.s，1H)，9.03(br.s，1H)，7.41(d，J＝2.0Hz，1H)，7.07(d，J＝2.0Hz，1H)，7.02(s，1H)，5.17(s，2H)，4.74(m，4H)，4.23(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.99(m，4H)，3.67(s，3H)，1.77(m，2H)，1.65(m，2H)，1.40(t，J＝7.2Hz，3H)，1.37(s，9H)，1.31(t，J＝7.2Hz，3H)

Embodiment 67

The 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (156mg, 0.56mmol) with the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl]-phenyl] ethyl ketone 39g (250mg, 0.63mmol) is dissolved in 5mL tetrahydrofuran (THF), adds triethylamine (0.10mL, 0.72mmol), stirring reaction is 12 hours.Concentrating under reduced pressure, by tlc, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone Hydrogen bromide 67 (102mg, light yellow solid), productive rate: 26.1%.

MS?m/z(ESI)：580[M+1]

¹HNMR(400MHz，DMSO-d ₆，ppm)：7.63(d，J＝1.6Hz，1H)，7.57(d，J＝1.6Hz，1H)，6.98(s，1H)，5.22(s，2H)，4.41(m，2H)，4.22(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.91(s，3H)，3.12(d，J＝10.5Hz，2H)，2.88(d，J＝10.5Hz，2H)，2.07(m，2H)，1.92(m，2H)，1.73(m，2H)，1.58(m，2H)，1.40(t，J＝7.2Hz，3H)，1.38(s，9H)，1.30(t，J＝7.2Hz，3H)

Embodiment 68

The 1-[3-tertiary butyl-4-methoxyl group-5-(morpholine-4-carbonyl) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

The 1-tertiary butyl-2-methoxyl group-benzene

The 2-tertiary butyl-phenol 2a (15g, 100mmol) is dissolved in 200mL acetone, adds salt of wormwood (20.70g, 150mmol) and methyl iodide (21g, 150mmol), stirring reaction 12 hours.Filter, filtrate decompression is concentrated, adds 100mL water, be extracted with ethyl acetate (100mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 1-tertiary butyl-2-methoxyl group-benzene 68a (14.20g, colorless oil), productive rate: 86.6%.

Second step

The 3-tertiary butyl-2-methoxyl group-phenyl aldehyde

Under ice bath, by the 1-tertiary butyl-2-methoxyl group-benzene 68a (12.50g, 76mmol) and N, N, N ', N '-Tetramethyl Ethylene Diamine (12.40g, 107mmol) be dissolved in 200mL methyl tertiary butyl ether, drip 2.5M n-Butyl Lithium (33.40mL, 84mmol), under room temperature, stirring reaction is 2 hours, at 0 ℃, drip N, dinethylformamide (16.60g, 228mmol), stirring reaction 2 hours.100mL frozen water will be poured in reaction solution, be extracted with ethyl acetate (100mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 3-tertiary butyl-2-methoxyl group-phenyl aldehyde 68b (12.10g, colorless oil), productive rate: 83.0%.

MS?m/z(ESI)：193.1[M+1]

The 3rd step

The 3-tertiary butyl-2-methoxyl group-phenylformic acid

Under ice bath, by the 3-tertiary butyl-2-methoxyl group-phenyl aldehyde 68b (8.30g, 43.20mmol) be dissolved in 100mL acetonitrile, add 50mL sodium hydroxide (3.80g, 95mmol) aqueous solution and Tetrabutyl amonium bromide (695mg, 2.20mmol) add potassium permanganate (8.90g in batches, 56.20mmol), stirring reaction 2 hours under room temperature.Under ice bath, in reaction solution, add 5% hypo solution to reaction solution scarlet to take off, add 200mL 1M hydrochloric acid, be extracted with ethyl acetate (250mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 3-tertiary butyl-2-methoxyl group-phenylformic acid 68c (5.85g, white solid), productive rate: 65.0%.

The 4th step

(the 3-tertiary butyl-2-methoxyl group-phenyl)-morpholinyl-benzophenone

By the 3-tertiary butyl-2-methoxyl group-phenylformic acid 68c (632mg, 3.04mmol) be dissolved in 10mL methylene dichloride, add I-hydroxybenzotriazole (432mg, 3.20mmol) with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (613mg, 3.20mmol), stir 10 minutes, add morpholine (265mg, 3.04mmol), stirring reaction is 12 hours.In reaction solution, add 5mL water, with dichloromethane extraction (5mL * 2), merge organic phase, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product (the 3-tertiary butyl-2-methoxyl group-phenyl)-morpholinyl-benzophenone 68d (650mg, colorless oil), productive rate: 77.0%.

The 5th step

The bromo-1-[3-tertiary butyl-4-hydroxy-5-of 2-(morpholinyl-4-carbonyl) phenyl] ethyl ketone

By aluminum chloride (133mg, 1mmol) be dissolved in 2mL methylene dichloride, add 2-bromoacetyl bromide (110mg, 0.55mmol), add again 2mL (the 3-tertiary butyl-2-methoxyl group-phenyl)-morpholinyl-benzophenone 68d (139mg, dichloromethane solution 0.50mmol), stirring reaction 12 hours.In reaction solution, add 5mL frozen water, be extracted with ethyl acetate (5mL * 2), merge organic phase, with saturated nacl aqueous solution washing (2mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system B, purifies gained resistates, obtains the bromo-1-[3-tertiary butyl-4-hydroxy-5-of title product 2-(morpholinyl-4-carbonyl) phenyl] ethyl ketone 68e (71mg, red oily), productive rate: 39.0%.

MS?m/z(ESI)：384.1[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)：δ11.57(s，1H)，8.06(d，J＝2.0Hz，1H)，7，87(d，J＝2.0Hz，1H)，4.37(s，2H)，3.82(m，8H)，1.48(s，9H)

The 6th step

The bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(morpholinyl-4-carbonyl) phenyl] ethyl ketone

By the bromo-1-[3-tertiary butyl-4-hydroxy-5-of 2-(morpholinyl-4-carbonyl) phenyl] ethyl ketone 68e (30mg, 0.08mmol) is dissolved in 2mL tetrahydrofuran (THF), drips the diethyl ether solution of 0.5mL1M formaldehyde, stirring reaction 2 hours.In reaction solution, add 2mL frozen water, extraction separatory, saturated nacl aqueous solution washing (2mL * 2) for organic phase, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system B, purify gained resistates, obtain the bromo-1-[3-tertiary butyl-4-of title product 2-methoxyl group-5-(morpholinyl-4-carbonyl) phenyl] ethyl ketone 68f (32mg, colourless thickness), productive rate: 99.9%.

The 7th step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (19.70mg, 0.08mmol) be dissolved in 0.5mL N, in dinethylformamide, add the bromo-1-[3-tertiary butyl-4-of 2-methoxyl group-5-(morpholinyl-4-carbonyl) phenyl] ethyl ketone 68f (30mg, 0.08mmol), stirring reaction 12 hours.In reaction solution, add 2mL water, be extracted with ethyl acetate (5mL * 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(morpholine-4-carbonyl) phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 68 (13mg, white solid), productive rate: 26.0%.

MS?m/z(ESI)：584.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.35(br，1H)，8.99(br，1H)，7.93(d，J＝2.2Hz，1H)，7.90(d，J＝2.0Hz，1H)，7.44(s，1H)，5.44(s，2H)，4.25(m，2H)，4.11(m，2H)，3.85(s，3H)，3.70(m，4H)，3.58(m，2H)，3.20(m，2H)，1.51(s，6H)，1.42(m，3H)，1.38(s，9H)，1.29(m，3H)

Embodiment 69

The 1-[bis-3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

The 3-tertiary butyl-5-methoxycarbonyl-phenylformic acid

By 5-tert.-butylbenzene-1,3-dibenzoic acid 69a (12g, 54mmol) and the vitriol oil (2mL, cat.) are dissolved in 360mL tetrahydrofuran (THF) and methyl alcohol (V/V=10: 1) in mixed solvent, stirring reaction is 4 hours at 80 ℃.Reaction solution concentrating under reduced pressure, filtered through silica gel, purifies gained resistates with silica gel column chromatography with eluent system A, obtains the title product 3-tertiary butyl-5-methoxycarbonyl-phenylformic acid 69b (3.08g, white solid), productive rate: 24.3%.MS?m/z(ESI)：237.2[M+1]

Second step

The 3-tertiary butyl-5-(methoxyl group (methyl) formamyl) methyl benzoate

The 3-tertiary butyl-5-methoxycarbonyl-phenylformic acid 69b (2.85g, 12mmol) is dissolved in 16.4mL sulfur oxychloride, and stirring reaction is 2 hours at 85 ℃.Reaction solution concentrating under reduced pressure, adds 30mL methylene dichloride, adds successively N-methyl methylamine (1.87g, 19.20mmol) and DIPEA (6.30mL, 36mmol), stirring at room reaction 0.5 hour.Reaction solution concentrating under reduced pressure; add ethyl acetate 50mL; wash (50mL * 2) with water; anhydrous sodium sulfate drying; filter, filtrate decompression is concentrated, obtains the crude product title product 3-tertiary butyl-5-(methoxyl group (methyl) formamyl) methyl benzoate 69c (3.27g; yellow thick liquid), productive rate: 97.6%.

MS?m/z(ESI)：280.1[M+1]

The 3rd step

The 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl] ethyl ketone

Under ice bath; by the crude product 3-tertiary butyl-5-(methoxyl group (methyl) formamyl) methyl benzoate 69c (2.86g; 10.25mmol) be dissolved in 42mL tetrahydrofuran (THF); drip the diethyl ether solution of 5.20mL 3M methyl-magnesium-bromide; stir 10 minutes, under room temperature, stirring reaction is 3.5 hours.Under ice bath, in reaction solution, adding 1M salt acid for adjusting pH is 3-5, be extracted with ethyl acetate (100mL * 2), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl] ethyl ketone 69d (0.38g, orange liquid), productive rate: 15.8%.

MS?m/z(ESI)：235.2[M+1]

The 4th step

The bromo-1-[3-tertiary butyl-5-of 2-(1-hydroxyl-1-methyl-ethyl) phenyl] ethyl ketone

By the 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl] ethyl ketone 69d (420mg, 1.79mmol) and phenyltrimethyl-ammonium tribromide (672mg, 1.79mmol) be dissolved in 42mL tetrahydrofuran (THF) stirring reaction 3 hours, standing 12 hours.In reaction solution, add 50mL water, be extracted with ethyl acetate (50mL * 2), merge organic phase, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the bromo-1-[3-tertiary butyl-5-of title product 2-(1-hydroxyl-1-methyl-ethyl) phenyl] ethyl ketone 69e (287mg, yellow oily), productive rate: 51.3%.

MS?m/z(ESI)：315.0[M+1]

The 5th step

The 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (85mg, 0.32mmol) be dissolved in 3mL N, in dinethylformamide, add the bromo-1-[3-tertiary butyl-5-of 2-(1-hydroxyl-1-methyl-ethyl) phenyl] ethyl ketone 69e (100mg, 0.32mmol), stirring reaction 2 hours.In reaction solution, add 10mL water, be extracted with ethyl acetate (10mL * 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 69 (61mg, yellow solid), productive rate: 38.4%.

MS?m/z(ESI)499.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.37(br，1H)，8.98(br，1H)，7.97(s，1H)，7.89(d，J＝1.5Hz，2H)，7.47(s，1H)，5.47(s，2H)，5.25(s，1H)，4.30-4.24(m，2H)，4.16-4.11(m，2H)，1.50(s，9H)，1.45-1.41(m，3H)，1.31(s，6H)，1.34-1.30(m，3H)

Embodiment 70

The 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (91mg, 0.35mmol) with the bromo-1-[3-tertiary butyl-5-of 2-(1-hydroxyl-1-methyl-ethyl) phenyl] ethyl ketone 69e (108mg, 0.35mmol) be dissolved in 2mL tetrahydrofuran (THF), add triethylamine (51mg, 0.52mmol), stirring reaction 12 hours.Filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 70 (22mg, yellow solid), productive rate: 11.0%.

MS?m/z(ESI)：497.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.43(br，1H)，9.06(br，1H)，7.90(s，1H)，7.88(s，1H)，7.83(s，1H)，7.03(s，1H)，5.23(s，2H)，4.26-4.21(m，2H)，4.15-4.10(m，2H)，2.03-2.00(m，2H)，1.66-1.48(m，2H)，1.42(s，6H)，1.41-1.39(m，3H)，1.35(s，9H)

Embodiment 71

1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-methoxyl group-phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (112mg; 0.27mmol) be dissolved in 1mLN; in dinethylformamide; add 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2 bromo-ethyl ketone 20c (60mg, 0.23mmol), stirring reaction 12 hours.In reaction solution, add 4mL saturated nacl aqueous solution and 4mL ethyl acetate, extraction separatory, water is extracted with ethyl acetate (2mL * 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain title product 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-methoxyl group-phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1, 1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 71 (14.50mg, white solid), productive rate: 7.9%.

MS?m/z(ESI)：595.4[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.64(s，1H)，7.54(s，1H)，7.00(s，1H)，5.19(s，2H)，4.23(m，2H)，4.12(m，2H)，3.98(s，3H)，3.67(m，4H)，3.02(m，2H)，2.96(m，2H)，2.06(s，3H)，1.76(m，2H)，1.63(m，2H)，1.41(m，3H)，1.39(s，9H)，1.31(m，3H)

Embodiment 72

1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-methoxyl group-phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5; 6-diethoxy-7-fluoro-3; 3-dimethyl-isoindole-1-amine 24d (100mg; 0.24mmol) be dissolved in 1mL tetrahydrofuran (THF); add 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2 bromo-ethyl ketone 20c (61mg; 0.24mmol), stirring reaction is 12 hours.Reaction solution concentrating under reduced pressure; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates; obtain title product 1-[3-(4-ethanoyl piperazine-1-yl)-5-tertiary butyl-4-methoxyl group-phenyl]-2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 72 (80mg; light yellow solid), productive rate: 48.5%.

MS?m/z(ESI)：597.4[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.27(s，1H)，8.96(s，1H)，7.68(s，1H)，7.60(s，1H)，7.45(s，1H)，5.41(s，2H)，4.27(m，2H)，4.13(m，2H)，3.99(s，3H)，3.68(m，4H)，3.04(m，2H)，2.98(m，2H)，2.06(s，3H)，1.51(s，6H)，1.42(m，3H)，1.40(s，9H)，1.32(m，3H)

Embodiment 73

The 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] benzoate hydrochlorate

The first step

3-ethanoyl-5-the tertiary butyl-methyl benzoate

Under ice bath; by the crude product 3-tertiary butyl-5-(methoxyl group (methyl) formamyl) methyl benzoate 69c (2.86g; 10.25mmol) be dissolved in 42mL tetrahydrofuran (THF); drip the diethyl ether solution of 5.20mL 3M methyl-magnesium-bromide; stir 10 minutes, under room temperature, stirring reaction is 3.5 hours.Under ice bath; in reaction solution, adding 1M salt acid for adjusting pH is 3-5; be extracted with ethyl acetate (100mL * 2), merge organic phase, anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl] the ethyl ketone 3-ethanoyl-5-tertiary butyl-methyl benzoate 73a (1.37g; white solid), productive rate: 57.1%.

MS?m/z(ESI)：235.2[M+1]

Second step

3-(2-the acetyl bromide)-5-tertiary butyl-methyl benzoate

By the 1-[3-tertiary butyl-5-(1-hydroxyl-1-methyl-ethyl) phenyl] the ethyl ketone 3-ethanoyl-5-tertiary butyl-methyl benzoate 73a (598mg; 2.60mmol) and phenyltrimethyl-ammonium tribromide (978mg; 2.60mmol) be dissolved in 60mL tetrahydrofuran (THF) stirring reaction 12 hours.In reaction solution, add 50mL water; be extracted with ethyl acetate (50mL * 2); merge organic phase; anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product 3-(2-the acetyl bromide)-5-tertiary butyl-methyl benzoate 73b (693mg, yellow liquid), productive rate: 85.1%.

MS?m/z(ESI)：313.0[M+1]

The 3rd step

The 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] methyl benzoate hydrobromate

By 5; 6-diethoxy-7-fluoro-3; 3-dimethyl-isoindole-1-amine 24d (380mg; 1.44mmol) be dissolved in 12mL N; in dinethylformamide; add 3-(2-the acetyl bromide)-5-tertiary butyl-methyl benzoate 73b (450mg, 1.44mmol), stirring reaction 4 hours.In reaction solution, add 30mL water; be extracted with ethyl acetate (40mL * 2); merge organic phase; water washing (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; separate out white solid, water washing (10mL * 2), obtains the crude product title product 3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl] methyl benzoate hydrobromate 73c (229mg, white solid), productive rate: 27.5%.

The 4th step

By the crude product 3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl] methyl benzoate hydrobromate 73c (193mg; 0.33mmol) be dissolved in 8mL methyl alcohol; drip 4mL lithium hydroxide (70mg; aqueous solution 1.67mmol), stirring reaction 4 hours.Reaction solution concentrating under reduced pressure; add water 4mL; adding 3M salt acid for adjusting pH is 1-2, filters, and gained resistates washes (10mL * 2) with water; vacuum-drying; obtain the title product 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] phenylformic acid hydrobromate 73 (148mg; yellow solid), productive rate: 85.5%.

MS?m/z(ESI)：483.2[M-1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ13.37(s，1H)，9.43(s，1H)，9.02(s，1H)，8.43(s，1H)，8.27(s，1H)，8.25(s，1H)，7.46(s，1H)，5.56(s，2H)，4.26(m，2H)，4.12(m，2H)，1.52(s，6H)，1.44(m，3H)，1.39(s，9H)，1.33(m，3H)

Embodiment 74

The 1-[3-tertiary butyl-5-(morpholine-4-carbonyl) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) acetophenone hydrochloride

The first step

By the 3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl] phenylformic acid hydrobromate 73 (52mg; 0.10mmol) be dissolved in 2mL methylene dichloride; add I-hydroxybenzotriazole (14mg; 0.10mmol) with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (38mg; 0.20mmol); stirring reaction 45 minutes; add again morpholine (18mg; 0.20mmol), stirring reaction is 3.5 hours.Reaction solution concentrating under reduced pressure, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(morpholine-4-carbonyl) phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) acetophenone hydrochloride 74 (19mg, white solid), productive rate: 32.2%.

MS?m/z(ESI)：554.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.42(s，1H)，9.02(s，1H)，8.06(s，1H)，7.94(s，1H)，7.77(s，1H)，7.46(s，1H)，5.50(s，2H)，4.26(m，2H)，4.12(m，2H)，3.64(m，6H)，3.40(m，2H)，1.51(s，6H)，1.42(m，3H)，1.38(s，9H)，1.32(m，3H)

Embodiment 75

The 3-tertiary butyl-N-cyclopropyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] benzamide hydrochloride salt

The first step

By the 3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl] phenylformic acid hydrobromate 73 (52mg; 0.10mmol) be dissolved in 2mL N; in dinethylformamide; add cyclopropylamine (11mg; 0.20mmol) and 2-(7-azo benzotriazole)-N, N, N '; N '-tetramethyl-urea phosphofluoric acid ester (46mg; 0.12mmol), stirring reaction 2 hours, then add N-isobutyl-propyl group-2-amine (24mg; 0.24mmol), stirring reaction is 4 hours.In reaction solution, add 10mL saturated nacl aqueous solution; be extracted with ethyl acetate (10mL * 3); merge organic phase; saturated nacl aqueous solution washing (10mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates; obtain the title product 3-tertiary butyl-N-cyclopropyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] benzamide hydrochloride salt 75 (13mg; white solid), productive rate: 23.2%.

MS?m/z(ESI)：524.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.34(br，1H)，8.98(br，1H)，8.78(br，1H)，8.40(s，1H)，8.19(s，1H)，8.11(s，1H)，7.45(s，1H)，5.51(s，2H)，4.26(m，2H)，4.12(m，2H)，2.89(m，1H)，1.52(s，6H)，1.38(m，12H)，1.31(m，3H)，0.74(m，2H)，0.64(m，2H)

Embodiment 76

The 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] benzoate hydrochlorate

The first step

The 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] methyl benzoate hydrobromate

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (395mg; 1.50mmol) be dissolved in 12mL N; in dinethylformamide; add 3-(2-the acetyl bromide)-5-tertiary butyl-methyl benzoate 73b (540mg, 1.50mmol), stirring reaction is 1.5 hours at 30 ℃.In reaction solution, add 100mL saturated nacl aqueous solution; ethyl acetate extraction (100mL * 3); merge organic phase; with saturated nacl aqueous solution washing (100mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; ethyl acetate washing (5mL * 3) gained resistates, vacuum-drying, obtain the title product 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] methyl benzoate hydrobromate 76a (231mg, white solid), productive rate: 26.7%.

MS?m/z(ESI)：497.3[M+1]

Second step

By the 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] methyl benzoate hydrobromate 76a (226mg; 0.39mmol) be dissolved in 20mL methyl alcohol; drip 4mL lithium hydroxide (164mg; aqueous solution 3.92mmol), stirring reaction 6 hours.Reaction solution concentrating under reduced pressure; add water 50mL; adding 3M salt acid for adjusting pH is 1-2, filters, and gained resistates washes (10mL * 3) with water; vacuum-drying; obtain the title product 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] benzoate hydrochlorate 76 (136mg; white solid), productive rate: 67.0%.

MS?m/z(ESI)：483.2[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.09(br，1H)，8.39(s，1H)，8.23(s，1H)，8.14(s，1H)，7.03(s，1H)，5.38(s，2H)，4.23(m，2H)，4.12(m，2H)，1.85(m，2H)，1.64(m，2H)，1.41(m，3H)，1.34(m，12H)

Embodiment 77

The 2-[[3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] phenyl] amino] acetonitrile hydrobromate

The first step

The bromo-4-tertiary butyl-aniline of 2,6-bis-

Under ice bath, 4-tertiary butyl aniline 77a (50g, 335.60mmol) is dissolved in 300mL methylene dichloride, is added dropwise to bromine (118g, 738.30mmol), under room temperature, stirring reaction is 1.5 hours.Under ice bath, in reaction solution, add 1M sodium hydroxide solution to regulate pH value for 9-10, extraction separatory, dichloromethane extraction for water (30mL * 3), merge organic phase, use successively 1M sodium hydroxide solution (30mL * 3), water (30mL * 3) and saturated nacl aqueous solution washing (30mL * 3), anhydrous magnesium sulfate drying, filters, and filtrate decompression is concentrated, obtain crude product title product 2, the bromo-4-tertiary butyl-aniline of 6-bis-77b (107g, sorrel liquid), product is not purified directly carries out next step reaction.

MS?m/z(ESI)：307.9[M+1]

Second step

The bromo-5-tertiary butyl-benzene of 1,3-bis-

2-methyl-2-nitro-propane (53.90g, 522.80mmol) is dissolved in 200mL DMF, drips the bromo-4-tertiary butyl-aniline 77b of 2,6-bis-(107g, 348.50mmol), stirring reaction is 12 hours at 65 ℃.In reaction solution, add 400mL water, ethyl acetate extraction (300mL * 4), merges organic phase, successively water (100mL * 3) and saturated nacl aqueous solution washing (100mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtain title product 1, the bromo-5-tertiary butyl-benzene of 3-bis-77c (80.60g, colourless liquid), productive rate: 79.2%.

The 3rd step

1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone

Under the dry ice bath, the bromo-5-tertiary butyl-benzene 77c of 1,3-bis-(10g, 34.25mmol) is dissolved in 80mL tetrahydrofuran (THF), drips 13.40mL2.5M n-butyllithium solution, stirring reaction 0.5 hour.Add again N,N-dimethylacetamide (4.47g, 51.37mmol), stirring reaction 0.5 hour.In reaction solution, add 30mL water and 30mL saturated ammonium chloride solution, ethyl acetate extraction (30mL * 5), merge organic phase, water (30mL * 3) and saturated nacl aqueous solution washing (30mL * 3) successively, anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (3.60g, yellow liquid), productive rate: 41.2%.

MS?m/z(ESI)：255.0[M+1]

The 4th step

1-(the 3-amino-5-tertiary butyl-phenyl) ethyl ketone

By 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (1.02g, 4mmol), Red copper oxide (60mg, 0.40mmol) and cuprous iodide (76mg, 0.40mmol) be dissolved in N-Methyl pyrrolidone 2.60mL, add ammoniacal liquor 2.60mL, microwave stirring reaction is 2 hours at 110 ℃ again.In reaction solution, add 20mL water, ethyl acetate extraction (20mL * 3), merge organic phase, water (20mL * 3) and saturated nacl aqueous solution washing (20mL * 3) successively, anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the 3-amino-5-tertiary butyl-phenyl) ethyl ketone 77e (1.38g, yellow liquid), productive rate: 90.3%.

MS?m/z(ESI)：192.1[M+1]

The 5th step

2-[(3-ethanoyl-5-the tertiary butyl-phenyl) amino] acetonitrile

1-(the 3-amino-5-tertiary butyl-phenyl) ethyl ketone 77e (760mg, 3.98mmol) is dissolved in to 10mLN, in dinethylformamide, add salt of wormwood (825mg, 5.97mmol) and 2-bromoacetonitrile (955mg, 7.96mmol), stirring reaction 3 hours at 70 ℃.In reaction solution, add 30mL water; ethyl acetate extraction (30mL * 3); merge organic phase, successively water (15mL * 3) and wash saturated nacl aqueous solution (15mL * 3), anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 2-[(3-ethanoyl-5-tertiary butyl-phenyl) amino] acetonitrile 77f (950mg; yellow liquid), productive rate: 99.9%.

MS?m/z(ESI)：248.2[M+18]

The 6th step

2-[[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl] amino] acetonitrile

By the 2-[(3-ethanoyl-5-tertiary butyl-phenyl) amino] acetonitrile 77f (200mg, 0.87mmol) is dissolved in 25mL tetrahydrofuran (THF), adds phenyltrimethyl-ammonium tribromide (327mg, 0.87mmol), stirring reaction 20 hours in batches.Filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system B, purifies gained resistates, obtains title product 2-[[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl] amino] acetonitrile 77g (95mg, red liquid), productive rate: 35.3%.

MS?m/z(ESI)：310.1[M+1]

The 7th step

By 5; 6-diethoxy-7-fluoro-3; 3-dimethyl-isoindole-1-amine 24d (77mg; 0.29mmol) be dissolved in 3mL N; in dinethylformamide; add 2-[[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl] amino] acetonitrile 77g (90mg, 0.29mmol), stirring reaction 1 hour.In reaction solution, add 10mL water; ethyl acetate extraction (10mL * 3); merge organic phase; water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3) successively; anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates; obtain the title product 2-[[3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] phenyl] amino] acetonitrile hydrobromate 77 (35mg; yellow solid), productive rate: 21.1%.

MS?m/z(ESI)：495.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.38(br，1H)，8.96(br，1H)，7.45(s，2H)，7.21(s，1H)，7.12(s，1H)，6.52(t，J＝6.8Hz，1H)，5.39(s，2H)，4.40(d，J＝6.8Hz，2H)，4.25(m，2H)，4.12(m，2H)，1.51(s，6H)，1.42(m，3H)，1.40(m，12H)

Embodiment 78

The N-[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] phenyl] ethanamide hydrobromate

The first step

N-(the 3-ethanoyl-5-tertiary butyl-phenyl) ethanamide

1-(the 3-amino-5-tertiary butyl-phenyl) ethyl ketone 77e (600mg, 3.14mmol) is dissolved in 15mL methylene dichloride, adds triethylamine (635mg, 6.28mmol), drip Acetyl Chloride 98Min. (495mg, 6.28mmol), stirring reaction 0.5 hour.In reaction solution, add 30mL water; dichloromethane extraction (20mL * 3); merge organic phase, water (15mL * 3) and saturated nacl aqueous solution washing (15mL * 3) successively, anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product N-(the 3-ethanoyl-5-tertiary butyl-phenyl) ethanamide 78a (700mg; yellow liquid), productive rate: 95.6%.

MS?m/z(ESI)：234.2[M+1]

Second step

N-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl] ethanamide

N-(the 3-ethanoyl-5-tertiary butyl-phenyl) ethanamide 78a (200mg, 0.86mmol) is dissolved in 25mL tetrahydrofuran (THF), adds phenyltrimethyl-ammonium tribromide (323mg, 0.86mmol), stirring reaction 1 hour in batches.Filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system B, purifies gained resistates, obtains title product N-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl] ethanamide 78b (110mg, yellow liquid), productive rate: 41.0%.

MS?m/z(ESI)：311.1[M-1]

The 3rd step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (50mg; 0.19mmol) be dissolved in 1.50mL tetrahydrofuran (THF); add N-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl] ethanamide 78b (60mg; 0.19mmol), stirring reaction is 3 hours.Filter; obtain white solid; with tetrahydrofuran (THF) washing (0.3mL * 3); obtain the title product N-[3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] phenyl] ethanamide hydrobromate 78 (50mg, white solid), productive rate: 45.9%.

MS?m/z(ESI)：496.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ10.16(s，1H)，9.44(br，1H)，9.06(br，1H)，8.15(s，1H)，7.88(s，1H)，7.71(s，1H)，7.03(s，1H)，5.20(s，2H)，4.23(m，2H)，4.12(m，2H)，2.07(s，3H)，1.79(m，2H)，1.66(m，2H)，1.41(m，3H)，1.34(m，12H)

Embodiment 79

The N-[3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] phenyl] ethanamide hydrobromate

The first step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (47mg; 0.18mmol) be dissolved in 1mL tetrahydrofuran (THF); add N-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl] ethanamide 78b (55mg, 0.18mmol), stirring reaction 2 hours.Filter; obtain white solid; with tetrahydrofuran (THF) washing (0.2mL * 3); vacuum-drying; obtain the title product N-[3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] phenyl] ethanamide hydrobromate 79 (55mg; white solid), productive rate: 53.9%.

MS?m/z(ESI)：498.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ10.16(s，1H)，9.33(br，1H)，8.94(br，1H)，8.19(s，1H)，7.88(s，1H)，7.75(s，1H)，7.44(s，1H)，5.39(s，2H)，4.24(m，2H)，4.12(m，2H)，2.08(s，3H)，1.51(s，6H)，1.41(m，3H)，1.35(m，12H)

Embodiment 80

The 3-tertiary butyl-N-cyclopropyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-2-methoxyl group-benzamide hydrobromate

The first step

5-ethanoyl-3-the tertiary butyl-2-hydroxy-benzoic acid

The 3-tertiary butyl-2-methoxyl group-phenylformic acid 68c (1.60g, 7.70mmol) is dissolved in 20mL methylene dichloride, drips Acetyl Chloride 98Min. (0.72g, 9.23mmol) and aluminum chloride (2.55g, 19.25mmol), stirring reaction is 6 hours at 40 ℃.In reaction solution, add 20mL frozen water, add 100mL ethyl acetate, extraction separatory; water is extracted with ethyl acetate (20mL * 2), merges organic phase, with saturated nacl aqueous solution washing (20mL * 3); anhydrous magnesium sulfate drying; filter, filtrate decompression is concentrated, separates out solid; with system B recrystallization purifying gained resistates; obtain the title product 5-ethanoyl-3-tertiary butyl-2-hydroxy-benzoic acid 80a (1.21g, gray solid), productive rate: 62.7%.

Second step

5-ethanoyl-3-the tertiary butyl-N-cyclopropyl-2-hydroxyl-benzamide

By the 5-ethanoyl-3-tertiary butyl-2-hydroxy-benzoic acid 80a (1.20g; 5.08mmol) be dissolved in 15mL methylene dichloride; add I-hydroxybenzotriazole (720mg; 5.33mmol) with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.02g; 5.33mmol), stirring and dissolving, then add cyclopropylamine (290mg; 5.08mmol), stirring reaction is 12 hours.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the title product 5-ethanoyl-3-tertiary butyl-N-cyclopropyl-2-hydroxyl-benzamide 80b (600mg, colourless sticky solid), productive rate: 42.8%.

The 3rd step

5-ethanoyl-3-the tertiary butyl-N-cyclopropyl-2-methoxyl group-benzamide

By the 5-ethanoyl-3-tertiary butyl-N-cyclopropyl-2-hydroxyl-benzamide 80b (275mg; 1mmol) be dissolved in 3mL acetone, add salt of wormwood (207mg, 1.50mmol) and methyl iodide (0.3mL; 6mmol), stirring reaction 12 hours at 40 ℃.Filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system B, purifies gained resistates, obtains the title product 5-ethanoyl-3-tertiary butyl-N-cyclopropyl-2-methoxyl group-benzamide 80c (230mg, colorless oil), productive rate: 79.0%.

MS?m/z(ESI)：290.2[M+1]

The 4th step

5-(2-the acetyl bromide)-3-tertiary butyl-N-cyclopropyl-2-methoxyl group-benzamide

5-ethanoyl-3-the tertiary butyl-N-cyclopropyl-2-methoxyl group-benzamide 80c (230mg, 0.79mmol) is dissolved in 3mL trichloromethane, adds cupric bromide (355mg, 1.59mmol), stirring reaction is 12 hours at 40 ℃.Filter; filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system B, purifies gained resistates, obtains title product 5-(2-the acetyl bromide)-3-tertiary butyl-N-cyclopropyl-2-methoxyl group-benzamide 80d (190mg; white sticky solid), productive rate: 65.0%.

MS?m/z(ESI)：369.1[M+1]

The 5th step

By 5; 6-diethoxy-7-fluoro-3; 3-dimethyl-isoindole-1-amine 24d (31.80mg; 0.12mmol) be dissolved in 1mL tetrahydrofuran (THF); add 5-(2-the acetyl bromide)-3-tertiary butyl-N-cyclopropyl-2-methoxyl group-benzamide 80d (44mg; 0.12mmol), stirring reaction is 12 hours.Filter; obtain white solid; with tetrahydrofuran (THF) washing (0.2mL * 3); vacuum-drying; obtain the title product 3-tertiary butyl-N-cyclopropyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-2-methoxyl group-benzamide hydrobromate 80 (38mg; white solid), productive rate: 50.0%.

MS?m/z(ESI)：554.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.26(s，1H)，8.96(s，1H)，8.51(d，J＝4.2Hz，1H)，7.96(d，J＝2.0Hz，1H)，7.93(d，J＝2.0Hz，1H)，7.45(s，1H)，5.41(s，2H)，4.26(m，2H)，4.13(m，2H)，3.83(s，3H)，2.89(m，1H)，1.49(s，6H)，1.42(m，3H)，1.40(s，9H)，1.31(m，3H)，0.73(m，2H)，0.60(m，2H)

Embodiment 81

The 3-tertiary butyl-N-cyclopropyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2-methoxyl group-benzamide hydrobromate

The first step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (44.50mg; 0.17mmol) be dissolved in 1mL tetrahydrofuran (THF); add 5-(2-the acetyl bromide)-3-tertiary butyl-N-cyclopropyl-2-methoxyl group-benzamide 80d (62mg; 0.17mmol), stirring reaction is 12 hours.Filter; obtain white solid; with tetrahydrofuran (THF) washing (0.2mL * 3); vacuum-drying; obtain the title product 3-tertiary butyl-N-cyclopropyl-5-[2-(5 ', 6 (diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2-methoxyl group-benzamide hydrobromate 81 (55mg; white solid), productive rate: 51.6%.

MS?m/z(ESI)：552.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.36(s，1H)，9.06(s，1H)，8.51(d，J＝4.3Hz，1H)，7.88(s，2H)，7.02(s，1H)，5.21(s，2H)，4.23(m，2H)，4.12(m，2H)，3.81(s，3H)，2.86(m，1H)，1.75(m，2H)，1.65(m，2H)，1.40(m，3H)，1.38(s，9H)，1.30(m，3H)，0.72(m，2H)，0.60(m，2H)

Embodiment 82

The 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-N-(2,3-dihydroxypropyl) benzamide hydrochloride salt

The first step

By the 3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl] phenylformic acid hydrobromate 73 (104mg; 0.20mmol) be dissolved in 4mL N; in dinethylformamide; add 3-aminopropane-1; 2-glycol (36mg, 0.40mmol), 2-(7-azo benzotriazole)-N; N; N ', N '-tetramethyl-urea phosphofluoric acid ester (93mg, 0.24mmol) and N-sec.-propyl propane-2-amine (49mg; 0.48mmol), stirring reaction is 5 hours.In reaction solution, add 10mL saturated nacl aqueous solution; ethyl acetate extraction (15mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl]-N-(2; 3-dihydroxypropyl) benzamide hydrochloride salt 82 (31mg, white solid), productive rate: 26.1%.

MS?m/z(ESI)：558.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.36(br，1H)，8.99(br，1H)，8.86(br，1H)，8.48(s，1H)，8.27(s，1H)，8.12(s，1H)，7.45(s，1H)，5.54(s，2H)，4.93(s，1H)，4.64(s，1H)，4.29-4.26(m，2H)，4.16-4.10(m，2H)，3.69(s，1H)，3.48-3.25(m，4H)，1.53(s，6H)，1.44-1.23(m，15H)

Embodiment 83

The 3-tertiary butyl-N-cyclopropyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] benzamide hydrochloride salt

The first step

By the 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] benzoate hydrochlorate 76 (51mg; 0.10mmol) be dissolved in 2mL N; in dinethylformamide; add cyclopropylamine (11mg; 0.20mmol); 2-(7-azo benzotriazole)-N, N, N '; N '-tetramethyl-urea phosphofluoric acid ester (46mg; 0.12mmol) with N-sec.-propyl propane-2-amine (24mg, 0.24mmol), stirring reaction 3 hours.In reaction solution, add 10mL saturated nacl aqueous solution; ethyl acetate extraction (10mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates; obtain the title product 3-tertiary butyl-N-cyclopropyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] benzamide hydrochloride salt 83 (48mg; white solid), productive rate: 87.3%.

MS?m/z?(ESI)：522.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.51(br，1H)，9.12(br，1H)，8.87(br，1H)，8.42(s，1H)，8.20(s，1H)，8.07(s，1H)，7.03(s，1H)，5.38(s，2H)，4.26-4.21(m，2H)，4.15-4.10(m，2H)，2.92-2.86(m，1H)，1.92-1.82(m，2H)，1.69-1.65(m，2H)，1.42-1.38(m，3H)，1.37(s，9H)，1.33-1.31(m，3H)，0.76-0.64(m，4H)

Embodiment 84

The 1-[3-tertiary butyl-5-(morpholine-4-carbonyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-Ji acetophenone hydrochloride

The first step

By the 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] benzoate hydrochlorate 76 (48mg; 0.09mmol) be dissolved in 2mL N; in dinethylformamide; add morpholine (l6mg; 0.19mmol); 2-(7-azo benzotriazole)-N, N, N '; N '-tetramethyl-urea phosphofluoric acid ester (43mg; 0.11mmol) with N-sec.-propyl propane-2-amine (22mg, 0.22mmol), stirring reaction 3 hours.In reaction solution, add 10mL saturated nacl aqueous solution, ethyl acetate extraction (10mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(morpholine-4-carbonyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-Ji acetophenone hydrochloride 84 (52mg, white solid), productive rate: 96.3%.

MS?m/z(ESI)：552.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.70(br，1H)，9.16(br，1H)，8.04(s，1H)，7.88(s，1H)，7.77(s，1H)，7.04(s，1H)，5.40(s，2H)，4.24(m，2H)，4.12(m，2H)，3.67-3.38(m，8H)，1.98-1.65(m，4H)，1.40(m，3H)，1.36(s，9H)，1.31(m，3H)

Embodiment 85

The 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-N-(2-hydroxyethyl) benzamide hydrochloride salt

The first step

By 2-monoethanolamine (13mg; 0.20mmol) be dissolved in 2mL methylene dichloride; add DMAP (37mg; 0.30mmol), the 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl] phenylformic acid hydrobromate 73 (52mg; 0.10mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (51mg, 0.20mmol), stirring reaction 3 hours.Reaction solution concentrating under reduced pressure; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates; obtain the title product 3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl]-N-(2-hydroxyethyl) benzamide hydrochloride salt 85 (32mg; white solid), productive rate: 57.1%.

MS?m/z(ESI)：528.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.40(br，1H)，8.98(br，2H)，8.54(s，1H)，8.27(s，1H)，8.11(s，1H)，7.46(s，1H)，5.58(s，2H)，4.91(br，1H)，4.27(m，2H)，4.14(m，2H)，3.58-3.38(m，4H)，1.54(s，6H)，1.43-1.31(m，15H)

Embodiment 86

The 2-[[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] phenyl] amino] acetonitrile hydrobromate

The first step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (38mg; 0.15mmol) be dissolved in 1mL tetrahydrofuran (THF); add 2-[[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl] amino] acetonitrile 77g (45mg; 0.15mmol), stirring reaction is 2 hours.By thin-layer chromatography chromatography, with developping agent system A, purify gained resistates; obtain yellow solid; add 1mL tetrahydrofuran (THF) to stir 10 minutes; filter, vacuum-drying, obtain the title product 2-[[3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] phenyl] amino] acetonitrile hydrobromate 86 (12mg, white solid), productive rate: 14.6%.

MS?m/z(ESI)：512.6[M+23]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.48(br，1H)，9.07(br，1H)，7.41(s，1H)，7.13(m，2H)，7.03(s，1H)，6.97(s，1H)，6.52(t，J＝7.2Hz，1H)，5.21(s，2H)，4.38(d，J＝7.2Hz，2H)，4.23(m，2H)，4.12(m，2H)，1.79(m，2H)，1.66(m，2H)，1.40(m，3H)，1.33(m，12H)

Embodiment 87

The 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-N, two (2-hydroxyethyl) benzamide hydrochloride salts of N-

The first step

By the 3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl] phenylformic acid hydrobromate 73 (104mg; 0.20mmol) be dissolved in 4mL N; in dinethylformamide; add 2-(2-hydroxyethyl amine) ethanol (42mg; 0.40mmol) and 2-(7-azo benzotriazole)-N; N, N ', N '-tetramethyl-urea phosphofluoric acid ester (93mg; 0.24mmol); add again N-sec.-propyl propane-2-amine (48mg, 0.48mmol), stirring reaction 1 hour.In reaction solution, add 20mL saturated nacl aqueous solution; ethyl acetate extraction (10mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl]-N; two (2-hydroxyethyl) benzamide hydrochloride salts 87 (35mg, white solid) of N-, productive rate: 28.7%.

MS?m/z(ESI)：572.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.42(br，1H)，9.02(br，1H)，8.02(s，1H)，7.96(s，1H)，7.82(s，1H)，7.46(s，1H)，5.49(s，2H)，4.94(s，2H)，4.27(m，2H)，4.13(m，2H)，3.66-3.51(m，8H)，1.51(s，6H)，1.41-1.23(m，15H)

Embodiment 88

The 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-N-(2,3-dihydroxypropyl) benzamide hydrochloride salt

The first step

By the 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] benzoate hydrochlorate 76 (70mg; 0.14mmol) be dissolved in 3mL N; in dinethylformamide; add 3-aminopropane-1; 2-glycol (25mg, 0.27mmol), 2-(7-azo benzotriazole)-N; N; N ', N '-tetramethyl-urea phosphofluoric acid ester (63mg, 0.16mmol) and N-sec.-propyl propane-2-amine (33mg; 0.32mmol), stirring reaction is 4 hours.In reaction solution, add 10mL saturated nacl aqueous solution, ethyl acetate extraction (15mL * 3), merge organic phase, with saturated nacl aqueous solution washing (15mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1, 1 '-isoindoline]-2 '-yl) ethanoyl]-N-(2, 3-dihydroxypropyl) benzamide hydrochloride salt 88 (45mg, white solid), productive rate: 56.3%.

MS?m/z(ESI)：556.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.45(br，1H)，9.10(br，1H)，8.79(br，1H)，8.38(s，1H)，8.25(s，1H)，8.08(s，1H)，7.03(s，1H)，5.30(s，2H)，4.90(s，1H)，4.64(s，1H)，4.24(m，2H)，4.13(m，2H)，3.67-3.25(m，5H)，1.90(m，2H)，1.65(m，2H)，1.38(s，9H)，1.31(m，3H)，1.23(m，3H)

Embodiment 89

The 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-N-(2-hydroxypropyl) benzamide hydrochloride salt

The first step

By the 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] benzoate hydrochlorate 76 (70mg; 0.14mmol) be dissolved in 3mL methylene dichloride, add DMAP (50mg, 0.40mmol) and 2-monoethanolamine (16mg; 0.27mmol); add again two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (69mg, 0.27mmol), stirring reaction 4 hours.Reaction solution concentrating under reduced pressure; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates; obtain the title product 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl]-N-(2-hydroxypropyl) benzamide hydrochloride salt 89 (20mg; white solid), productive rate: 26.3%.

MS?m/z(ESI)：526.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.61(s，1H)，9.19(s，1H)，9.03(s，1H)，8.58(s，1H)，8.33(s，1H)，8.15(s，1H)，7.11(s，1H)，5.49(s，2H)，4.97(s，1H)，4.31(m，2H)，4.20(m，2H)，3.63(m，2H)，3.40(m，2H)，1.93(s，2H)，1.73(s，2H)，1.44(m，15H)

Embodiment 90

The 1-[3-tertiary butyl-5-(2-hydroxyl-oxethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

The 1-[3-tertiary butyl-5-(2-hydroxyl-oxethyl) phenyl] ethyl ketone

By cuprous iodide (573mg, 3mmol), L-PROLINE (690mg, 6mmol) and cesium carbonate (19.56g, 60mmol) join in reaction flask, by 5mL 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (2.55g, dimethyl sulfoxide (DMSO) 10mmol) adds reaction system, add again ethylene glycol (15mL, 305mmol), stirring reaction 12 hours.5mL saturated ammonium chloride solution will be poured in reaction solution, add 20mL ethyl acetate and 20mL water, extraction separatory, water is extracted with ethyl acetate (20mL), merge organic phase, water (20mL * 2) and saturated nacl aqueous solution washing (30mL * 2), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 1-[3-tertiary butyl-5-(2-hydroxyl-oxethyl) phenyl] ethyl ketone 90a (198mg, brown oil), productive rate: 8.4%.

Second step

The bromo-1-[3-tertiary butyl-5-of 2-(2-hydroxyl-oxethyl) phenyl] ethyl ketone

By the 1-[3-tertiary butyl-5-(2-hydroxyl-oxethyl) phenyl] ethyl ketone 90a (198mg, 0.84mmol) be dissolved in 7mL tetrahydrofuran (THF) and methyl alcohol (V/V=6: 1) in mixed solvent, add trimethylphenyl tribromide ammonium (404mg, 0.84mmol), stirring reaction 3 hours.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the bromo-1-[3-tertiary butyl-5-of title product 2-(2-hydroxyl-oxethyl) phenyl] ethyl ketone 90b (190mg, yellow oily), productive rate: 71.9%.

The 3rd step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (85mg, 0.32mmol) be dissolved in 2mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(2-hydroxyl-oxethyl) phenyl] ethyl ketone 90b (100mg, 0.32mmol), stirring reaction is 12 hours.Filter, obtain white solid, with tetrahydrofuran (THF) washing (0.3mL * 3), vacuum-drying, obtain the title product 1-[3-tertiary butyl-5-(2-hydroxyl-oxethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 90 (42mg, white solid), productive rate: 22.9%.

MS?m/z(ESI)：499.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.42(s，1H)，9.09(s，1H)，7.59(s，1H)，7.40(s，1H)，7.30(s，1H)，7.04(s，1H)，5.23(s，2H)，4.93(t，J＝5.2Hz，1H)，4.25(m，2H)，4.12(m，2H)，3.77(m，2H)，3.40(m，2H)，1.80(m，2H)，1.67(m，2H)，1.41(m，3H)，1.33(s，9H)，1.31(m，3H)

Embodiment 91

1-(the 3-tertiary butyl-5-methylsulfonyl-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

1-(the 3-tertiary butyl-5-methylsulfonyl-phenyl) ethyl ketone

By 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (1.53g; 6mmol); methylsulfonyl sodium (2.45g; 24mmol) and copper triflate (I) close benzene (300mg; 0.40mmol) be dissolved in 40mL dimethyl sulfoxide (DMSO), drip N, N '-dimethyl-ethylenediamine (108mg; 0.80mmol), stirring reaction 2.5 hours at 150 ℃.In reaction solution, pour 50mL water and 50mL ethyl acetate into; extraction separatory; water is extracted with ethyl acetate (30mL * 2); merge organic phase; water (30mL * 3) and saturated nacl aqueous solution washing (30mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product 1-(the 3-tertiary butyl-5-methylsulfonyl-phenyl) ethyl ketone 91a (1.16g, yellow liquid), productive rate: 76.1%.

Second step

The bromo-1-of 2-(the 3-tertiary butyl-5-methylsulfonyl-phenyl) ethyl ketone

1-(the 3-tertiary butyl-5-methylsulfonyl-phenyl) ethyl ketone 91a (200mg, 0.79mmol) is dissolved in 20mL tetrahydrofuran (THF), adds trimethylphenyl tribromide ammonium (296mg, 0.79mmol), stirring reaction 30 minutes.Reaction solution concentrating under reduced pressure, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains the bromo-1-of title product 2-(the 3-tertiary butyl-5-methylsulfonyl-phenyl) ethyl ketone 91b (210mg, weak yellow liquid), productive rate: 80.2%.

MS?m/z(ESI)：350.0[M+18]

The 3rd step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (79mg; 0.30mmol) be dissolved in 1.50mL tetrahydrofuran (THF); add the bromo-1-of 2-(the 3-tertiary butyl-5-methylsulfonyl-phenyl) ethyl ketone 91b (100mg, 0.30mmol), stirring reaction 14 hours.Reaction solution concentrating under reduced pressure; by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates and obtain yellow solid; add 2mL tetrahydrofuran (THF) to stir 5 minutes, filter, with tetrahydrofuran (THF) (0.5mL * 3) washing; vacuum-drying; obtain title product 1-(the 3-tertiary butyl-5-methylsulfonyl-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 91 (30mg; white solid), productive rate: 16.8%.

MS?m/z(ESI)：519.2[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.42(br，1H)，9.02(br，1H)，8.39(s，1H)，8.32(s，1H)，8.23(s，1H)，7.46(s，1H)，5.58(s，2H)，4.26(m，2H)，4.12(m，2H)，3.36(s，3H)，1.53(s，6H)，1.41(m，12H)，1.30(m，3H)

Embodiment 92

1-(the 3-tertiary butyl-5-methylsulfonyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (79mg; 0.30mmol) be dissolved in 2mL tetrahydrofuran (THF); add the bromo-1-of 2-(the 3-tertiary butyl-5-methylsulfonyl-phenyl) ethyl ketone 91b (100mg; 0.30mmol), stirring reaction 2 hours, adularescent solid is separated out.Filter; with tetrahydrofuran (THF) washing (0.5mL * 2); vacuum-drying; obtain title product 1-(the 3-tertiary butyl-5-methylsulfonyl-phenyl)-2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 92 (85mg, white solid), productive rate: 47.5%.

MS?m/z(ESI)：517.2[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.42(br，1H)，9.12(br，1H)，8.33(s，1H)，8.24(m，2H)，7.04(s，1H)，5.34(s，2H)，4.23(m，2H)，4.12(m，2H)，3.34(s，3H)，1.88(m，2H)，1.67(m，2H)，1.40(m，12H)，1.29(m，3H)

Embodiment 93

The 1-[3-tertiary butyl-5-(2,3-dihydroxyl propoxy-) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

The 1-[3-tertiary butyl-5-(2,3-dihydroxyl propoxy-) phenyl] ethyl ketone

By cuprous iodide (153mg, 0.80mmol), L-PROLINE (184mg, 1.60mmol) and cesium carbonate (5.20g, l6mmol) add in reaction flask, add 3mL to contain 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (1.02g, DMF solution 4mmol) and the N of 27mL glycerol (11g, 0.12mol), dinethylformamide solution, stirring reaction is 48 hours at 90 ℃.Be cooled to room temperature, in reaction solution, add 10mL saturated ammonium chloride solution cancellation reaction, add 20mL ethyl acetate and 20mL water, extraction separates organic phase, water is extracted with ethyl acetate (20mL), merge organic phase, water (30mL) and saturated nacl aqueous solution washing (30mL * 2) successively, anhydrous magnesium sulfate drying, filters, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(2,3-dihydroxyl propoxy-) phenyl] ethyl ketone 93a (289mg, brown liquid), productive rate: 27.2%.

Second step

The bromo-1-[3-tertiary butyl-5-of 2-(2,3-dihydroxyl propoxy-) phenyl] ethyl ketone

Cupric bromide (103mg, 0.46mmol) is suspended in 1.50mL ethyl acetate, is heated to reflux, add the 2.50mL 1-[3-tertiary butyl-5-(2,3-dihydroxyl propoxy-) phenyl] chloroform soln of ethyl ketone 93a (61mg, 0.23mmol), back flow reaction 3 hours.Be cooled to room temperature, filter, concentrating under reduced pressure filtrate, obtains the bromo-1-[3-tertiary butyl-5-of crude product title product 2-(2,3-dihydroxyl propoxy-) phenyl] ethyl ketone 93b (105mg, chocolate oily matter), product is not purified directly carries out next step reaction.

The 3rd step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (84mg, 0.30mmol) with the bromo-1-[3-tertiary butyl-5-(2 of crude product 2-, 3-dihydroxyl propoxy-) phenyl] ethyl ketone 93b (105mg, 0.30mmol) be dissolved in 1.50mL tetrahydrofuran (THF), stirring reaction 4 hours, separates out a large amount of solids.Suction filtration, tetrahydrofuran (THF) washing (2mL * 3) for filter cake, vacuum-drying, preparation, obtains the title product 1-[3-tertiary butyl-5-(2,3-dihydroxyl propoxy-) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 93 (38mg, white solid), productive rate: 23.7%.

MS?m/z(ESI)：529.7[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.40(br，1H)，9.06(br，1H)，7.58(s，1H)，7.39(s，1H)，7.30(s，1H)，7.03(s，1H)，5.21(s，2H)，4.98(m，1H)，4.71(m，1H)，4.23(m，2H)，4.11(m，3H)，3.97(m，1H)，3.82(m，1H)，3.60(m，1H)，1.80(m，2H)，1.66(m，2H)，1.40(m，3H)，1.33(m，12H)

Embodiment 94

The 3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] cyanobenzene hydrobromate

The first step

3-ethanoyl-5-the tertiary butyl-cyanobenzene

1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (1g, 3.92mmol) and cupric cyanide (386mg, 4.31mmol) are dissolved in 15mLN-N-methyl-2-2-pyrrolidone N-, and stirring reaction is 2 hours at 170 ℃.In reaction solution, add 20mL ethyl acetate and 20mL water; add again 10mL ammoniacal liquor; stir 30 minutes; extraction separates organic phase; water is extracted with ethyl acetate (10mL * 3); merge organic phase; water (15mL * 3) and saturated nacl aqueous solution washing (15mL * 3) successively; anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain the title product 3-ethanoyl-5-tertiary butyl-cyanobenzene 94a (480mg, yellow solid), productive rate: 60.9%.

MS?m/z(ESI)：219.1[M+18]

Second step

3-(2-the acetyl bromide)-5-tertiary butyl-cyanobenzene

3-ethanoyl-5-the tertiary butyl-cyanobenzene 94a (300mg, 1.49mmol) is dissolved in 15mL tetrahydrofuran (THF), adds trimethylphenyl tribromide ammonium (561mg, 1.49mmol), stirring reaction 30 minutes.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with developping agent system B, purifies gained resistates, obtains title product 3-(2-the acetyl bromide)-5-tertiary butyl-cyanobenzene 94b (345mg, yellow liquid), productive rate: 82.5%.

MS?m/z(ESI)：299.0[M+18]

The 3rd step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (95mg; 0.36mmol) be dissolved in 1.5mL tetrahydrofuran (THF); add 3-(2-the acetyl bromide)-5-tertiary butyl-cyanobenzene 94b (100mg, 0.36mmol), stirring reaction 12 hours.Directly preparation; obtain yellow solid, add 1.5mL tetrahydrofuran (THF), stir 10 minutes; filter to obtain solid; with tetrahydrofuran (THF) washing (0.5mL * 3), vacuum-drying, obtains the title product 3-tertiary butyl-5-[2-(5; the fluoro-3-of 6-diethoxy-4-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl] cyanobenzene hydrobromate 94 (35mg, white solid), productive rate: 17.9%.

MS?m/z(ESI)：466.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.44(br，1H)，9.05(br，1H)，8.45(s，1H)，8.25(m，2H)，7.46(s，1H)，5.52(s，2H)，4.26(m，2H)，4.11(m，2H)，1.51(s，6H)，1.43(m，3H)，1.37(s，9H)，1.31(m，3H)

Embodiment 95

The 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] cyanobenzene hydrobromate

The first step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (94mg; 0.36mmol) be dissolved in 1.5mL tetrahydrofuran (THF); add 3-(2-the acetyl bromide)-5-tertiary butyl-cyanobenzene 94b (100mg; 0.36mmol), stirring reaction is 12 hours.Filter to obtain solid; with tetrahydrofuran (THF) washing (0.5mL * 2); vacuum-drying; obtain the title product 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] cyanobenzene hydrobromate 95 (100mg, white solid), productive rate: 51.5%.

MS?m/z(ESI)：464.2[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.40(br，1H)，9.11(br，1H)，8.35(s，1H)，8.26(s，1H)，8.20(s，1H)，7.04(s，1H)，5.27(s，2H)，4.23(m，2H)，4.10(m，2H)，1.77(m，2H)，1.66(m，2H)，1.41(m，3H)，1.36(s，9H)，1.31(m，3H)

Embodiment 96

The 1-[3-tertiary butyl-5-(hydroxymethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the bromo-5-tertiary butyl-phenyl of 3-) formaldehyde

The bromo-5-tertiary butyl-benzene 77c of 1,3-bis-(17g, 58.40mmol) is dissolved in 120mL tetrahydrofuran (THF), drips n-Butyl Lithium (23.4mL, 58.40mmol), stirring reaction 0.5 hour at-78 ℃.Add again DMF (6.40g, 87.70mmol), stirring reaction 0.5 hour.In reaction solution, add 120mL saturated ammonium chloride solution, ethyl acetate extraction (50mL * 2), merge organic phase, with saturated nacl aqueous solution washing (30mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the bromo-5-tertiary butyl-phenyl of 3-) formaldehyde 96a (11.26g, yellow solid), productive rate: 80.0%.

Second step

(the bromo-5-tertiary butyl-phenyl of 3-) methyl alcohol

1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 96a (1.20g, 4.98mmol) is dissolved in 16mL dehydrated alcohol, adds sodium borohydride (57mg, 1.49mmol), stirring reaction 45 minutes in batches.To adding the 20mL shrend reaction of going out in reaction solution, reaction solution concentrating under reduced pressure, water is extracted with ethyl acetate (20mL * 2), merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains title product (the bromo-5-tertiary butyl-phenyl of 3-) methyl alcohol 96b (1g, white solid), productive rate: 82.0%.

The 3rd step

The 1-[3-tertiary butyl-5-(hydroxymethyl) phenyl] ethyl ketone

By (the bromo-5-tertiary butyl-phenyl of 3-) methyl alcohol 96b (790mg, 3.25mmol) be dissolved in 15mL tetrahydrofuran (THF), at-78 ℃, drip n-Butyl Lithium (5.20mL, 13mmol), stirring reaction 30 minutes, then drip N,N-dimethylacetamide (850mg, 9.75mmol), drip complete stirring reaction 30 minutes.In reaction solution, add 60mL saturated ammonium chloride solution, extraction separates organic phase, and water is extracted with ethyl acetate (30mL * 2), merges organic phase, with saturated nacl aqueous solution washing (60mL), anhydrous magnesium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(hydroxymethyl) phenyl] ethyl ketone 96c (114mg, colourless liquid), productive rate: 17.0%.

MS?m/z(ESI)：207.1[M+1]

The 4th step

The bromo-1-[3-tertiary butyl-5-of 2-(hydroxymethyl) phenyl] ethyl ketone

By the 1-[3-tertiary butyl-5-(hydroxymethyl) phenyl] ethyl ketone 96c (107mg, 0.52mmol) is dissolved in 3mL tetrahydrofuran (THF), adds trimethylphenyl tribromide ammonium (195mg, 0.52mmol), stirring reaction 1 hour.Filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system B, purifies gained resistates, obtains the bromo-1-[3-tertiary butyl-5-of title product 2-(hydroxymethyl) phenyl] ethyl ketone 96d (90mg, colourless liquid), productive rate: 60.8%.

MS?m/z(ESI)：287.0[M+1]

The 5th step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (73mg, 0.28mmol) be dissolved in 2mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(hydroxymethyl) phenyl] ethyl ketone 96d (87mg, 0.30mmol), stirring reaction is 2.5 hours.Filter to obtain solid, with tetrahydrofuran (THF) washing (0.5mL * 2), vacuum-drying, obtain the title product 1-[3-tertiary butyl-5-(hydroxymethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 96 (55mg, white solid), productive rate: 34.3%.

MS?m/z(ESI)：469.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.42(br，1H)，9.16(br，1H)，7.85(s，1H)，7.81(s，1H)，7.72(s，1H)，7.03(s，1H)，5.24(s，2H)，4.60(s，2H)，4.26-4.21(m，2H)，4.15-4.10(m，2H)，1.86-1.78(m，2H)，1.69-1.63(m，2H)，1.42-1.38(m，3H)，1.34(s，9H)，1.32-1.29(m，3H)

Embodiment 97

The 1-[3-tertiary butyl-5-(2-hydroxyl-oxethyl) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (76mg, 0.29mmol) be dissolved in 2mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(2-hydroxyl-oxethyl) phenyl] ethyl ketone 90b (90mg, 0.29mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(2-hydroxyl-oxethyl) phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 97 (33mg, light yellow solid), productive rate: 23.1%.

MS?m/z(ESI)：501.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.32(br，1H)，8.96(br，1H)，7.63(s，1H)，7.44(s，2H)，7.30(s，1H)，5.41(s，2H)，4.60(s，2H)，4.26(m，2H)，4.12(m，4H)，3.76(m，2H)，1.51(s，6H)，1.42(m，3H)，1.34(m，12H)

Embodiment 98

The 1-[3-tertiary butyl-5-(hydroxymethyl) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (90mg, 0.34mmol) be dissolved in 3mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(hydroxymethyl) phenyl] ethyl ketone 96d (116mg, 0.41mmol), stirring reaction 16 hours.Filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(hydroxymethyl) phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 98 (30mg, white solid), productive rate: 16.1%.

MS?m/z(ESI)：471.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.42(br，1H)，9.00(br，1H)，7.90-7.88(m，2H)，7.72(s，1H)，7.46(s，1H)，5.47-5.44(m，2H)，4.61-4.60(m，2H)，4.29-4.24(m，2H)，4.15-4.10(m，2H)，1.53(s，3H)，1.51(s，3H)，1.43-1.39(m，3H)，1.35(s，9H)，1.32-1.30(m，3H)

Embodiment 99

The 1-[3-tertiary butyl-5-(1-methyl-pyrazol-4-yl) phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

The 1-[3-tertiary butyl-5-(1-methyl-pyrazol-4-yl) phenyl] ethyl ketone

By 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (720mg, 2.83mmol) and tetrakis triphenylphosphine palladium (327mg, 0.28mmol) be dissolved in 50mL dme, stirring reaction 10 minutes, add again 7mL1-methyl-pyrazol-4-yl boric acid (533mg, 4.23mmol) and the aqueous solution of salt of wormwood (1.95g, 14.10mmol), be warming up to return stirring reaction 4 hours.Filter, in filtrate, add 20mL ethyl acetate, extraction, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(1-methyl-pyrazol-4-yl) phenyl] ethyl ketone 99a (318mg, light yellow oil), productive rate: 44.0%.

MS?m/z(ESI)：257.1[M+1]

Second step

The bromo-1-[3-tertiary butyl-5-of 2-(1-methyl-pyrazol-4-yl) phenyl] ethyl ketone

By the 1-[3-tertiary butyl-5-(1-methyl-pyrazol-4-yl) phenyl] ethyl ketone 99a (300mg, 1.17mmol) is dissolved in 5mL trichloromethane, adds cupric bromide (522mg, 2.34mmol), is warming up to 40 ℃ of stirring reactions 12 hours.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the bromo-1-[3-tertiary butyl-5-of title product 2-(1-methyl-pyrazol-4-yl) phenyl] ethyl ketone 99b (216mg, light yellow oil), productive rate: 55.0%.

The 3rd step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (40mg, 0.15mmol) be dissolved in 1mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(1-methyl-pyrazol-4-yl) phenyl] ethyl ketone 99b (51mg, 0.15mmol), stirring reaction 12 hours.Filter to obtain solid, with tetrahydrofuran (THF) washing (0.5mL * 2), vacuum-drying, obtain the title product 1-[3-tertiary butyl-5-(1-methyl-pyrazol-4-yl) phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 99 (40mg, white solid), productive rate: 44.0%.

MS?m/z(ESI)：521.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.33(br，1H)，8.95(br，1H)，8.36(s，1H)，8.09(s，1H)，8.06(s，1H)，7.95(s，1H)，7.83(s，1H)，7.46(s，1H)，5.46(s，2H)，4.30-4.25(m，2H)，4.17-4.11(m，2H)，3.91(s，3H)，1.53(s，6H)，1.43(m，3H)，1.39(s，9H)，1.32(m，3H)

Embodiment 100

The 1-[3-tertiary butyl-5-(1-methyl-pyrazol-4-yl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (51mg, 0.19mmol) be dissolved in 0.5mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(1-methyl-pyrazol-4-yl) phenyl] ethyl ketone 99b (65mg, 0.19mmol), stirring reaction is 12 hours.Reaction solution is concentrated, preparation, obtain yellow solid, use tetrahydrofuran (THF) recrystallization, vacuum-drying, obtains the title product 1-[3-tertiary butyl-5-(1-methyl-pyrazol-4-yl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 100 (11mg, white solid), productive rate: 10.0%.

MS?m/z(ESI)：519.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.59(br，1H)，9.13(br，1H)，8.37(s，1H)，8.07(s，1H)，8.05(s，1H)，7.94(s，1H)，7.79(s，1H)，7.05(s，1H)，5.37(s，2H)，4.27-4.22(m，2H)，4.16-4.11(m，2H)，3.90(s，3H)，1.78(m，2H)，1.68(m，2H)，1.41(m，3H)，1.38(s，9H)，1.32(m，3H)

Embodiment 101

1-(the 3-tertiary butyl-5-sec.-propyl-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

The bromo-3-tertiary butyl-5-of 1-sec.-propyl-benzene

Zinc chloride (3.64g, 26.70mmol) is dissolved in 20mL tetrahydrofuran (THF), adds 2M isopropylmagnesium chloride 13.3mL, 50 ℃ of stirring reactions 3 hours.By 1, the bromo-5-tertiary butyl-benzene of 3-bis-77c (5.20g, 17.80mmol) add in another reaction flask, add cuprous iodide (203mg, 1.07mmol), 1,1 '-bis-(dibenzyl phosphorus) dichloro diamyl iron palladium (651mg, 0.89mmol), with 20mL tetrahydrofuran (THF), splash into above-mentioned cooling reaction solution, lucifuge stirring reaction 36 hours.Filter, ethyl acetate washing (20mL * 3) for filter cake, merge organic phase, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the bromo-3-tertiary butyl-5-of title product 1-sec.-propyl-benzene 101a (433mg, yellow oil), productive rate: 95.0%.

Second step

1-(the 3-tertiary butyl-5-sec.-propyl-phenyl) ethyl ketone

By the bromo-3-tertiary butyl-5-of 1-sec.-propyl-benzene 101a (730mg, 2.86mmol) be dissolved in 5mL tetrahydrofuran (THF), at-78 ℃, drip 2.50M n-Butyl Lithium (1.37mL, 3.44mmol), stirring reaction 2 hours, then drip N,N-dimethylacetamide (0.37mL, 4.29mmol), drip complete stirring reaction 30 minutes.In reaction solution, add 20mL saturated ammonium chloride solution cancellation reaction, add again 5mL water and 20mL ethyl acetate, extraction separates organic phase, with saturated nacl aqueous solution washing (5mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 1-(the 3-tertiary butyl-5-sec.-propyl-phenyl) ethyl ketone 101b (379mg, colourless liquid), productive rate: 60.8%.

MS?m/z(ESI)：219.1[M+1]

The 3rd step

The bromo-1-of 2-(the 3-tertiary butyl-5-sec.-propyl-phenyl) ethyl ketone

1-(the 3-tertiary butyl-5-sec.-propyl-phenyl) ethyl ketone 101b (326mg, 1.50mmol) is dissolved in 3mL tetrahydrofuran (THF), adds trimethylphenyl tribromide ammonium (562mg, 1.50mmol), stirring reaction 1 hour.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with developping agent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(the 3-tertiary butyl-5-sec.-propyl-phenyl) ethyl ketone 101c (207mg, colourless liquid), productive rate: 46.0%.

MS?m/z(ESI)：299.9[M+1]

The 4th step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (49mg, 0.18mmol) be dissolved in 0.5mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 3-tertiary butyl-5-sec.-propyl-phenyl) ethyl ketone 101c (55mg, 0.18mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-5-sec.-propyl-phenyl)-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 101 (20mg, white solid), productive rate: 19.0%.

MS?m/z(ESI)：483.5[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.86(s，1H)，7.77(s，1H)，7.65(s，1H)，7.44(s，1H)，5.40(s，2H)，4.27-4.26(m，2H)，4.16-4.11(m，2H)，3.04(m，1H)，1.52(s，6H)，1.43(m，3H)，1.36(s，9H)，1.34-1.27(m，9H)

Embodiment 102

1-(the 3-tertiary butyl-5-sec.-propyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (50mg, 0.19mmol) be dissolved in 0.5mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 3-tertiary butyl-5-sec.-propyl-phenyl) ethyl ketone 101c (56mg, 0.19mmol), stirring reaction is 12 hours.Filter to obtain solid, with tetrahydrofuran (THF) washing (0.5mL * 2), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-5-sec.-propyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 102 (30mg, white solid), productive rate: 28.0%.

MS?m/z(ESI)：481.6[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.39(br，1H)，9.06(br，1H)，7.82(s，1H)，7.72(s，1H)，7.66(s，1H)，7.04(s，1H)，5.23(s，2H)，4.27-4.22(m，2H)，4.16-4.11(m，2H)，3.04-2.99(m，1H)，1.83(m，2H)，1.67(m，2H)，1.41(m，3H)，1.35(s，9H)，1.32(m，3H)，1.25(d，J＝9.3Hz，1H)

Embodiment 103

The 1-[3-tertiary butyl-5-[4-(2-hydroxyethyl) piperazine-1-yl] phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

The bromo-3-tertiary butyl-5-of 1-(1,1-dimethoxy-ethyl) benzene

1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (2.30g, 9mmol) is dissolved in 3mL methyl alcohol, then adds trimethoxy-methane (2.88g, 27mmol) and camphorsulfonic acid (105mg, 0.45mmol), stirring reaction 12 hours.In reaction solution, add 500mg salt of wormwood, stir 10 minutes, then add 10mL water and 10mL normal hexane, extraction separatory, n-hexane extraction for water (10mL * 2), merges organic phase, saturated nacl aqueous solution washing (10mL), anhydrous magnesium sulfate drying, filters, and filtrate decompression is concentrated, obtain the bromo-3-tertiary butyl-5-(1 of crude product title product 1-, 1-dimethoxy-ethyl) benzene 103a (2.70g, light yellow oil), product is not purified directly carries out next step reaction.

Second step

The 1-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl) phenyl] piperazine

The bromo-3-tertiary butyl-5-of crude product 1-(1,1-dimethoxy-ethyl) benzene 103a (2.70g, 9mmol) is placed in to reaction flask, add successively 2-dicyclohexyl phosphorus-2-(N, N-dimethylamino) biphenyl (177mg, 0.45mmol), three (dibenzalacetone) two palladium (270mg, 10%), sodium tert-butoxide (2.60g, 27mmol) and piperazine (1.50g, 18mmol), finally add 40mL dioxane, stirring reaction is 3 hours at 60 ℃.In reaction solution, add 50mL water and 20mL ethyl acetate, separatory, water is extracted with ethyl acetate (20mL * 4), merges organic phase, with saturated nacl aqueous solution washing (30mL * 1), anhydrous magnesium sulfate drying, filters, and filtrate decompression is concentrated, obtain the crude product title product 1-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl) phenyl] piperazine 103b (2g, brown oil), product is not purified directly carries out next step reaction.

The 3rd step

1-(the 3-tertiary butyl-5-piperazine-1-base-phenyl) ethyl ketone

By the crude product 1-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl) phenyl] piperazine 103b (2g, 6.50mmol) is dissolved in 30mL 2M hydrogenchloride dioxane solution, stirring reaction 1 hour.Reaction solution concentrating under reduced pressure, add 30mL water and 20mL ethyl acetate, extraction separatory, water is extracted with ethyl acetate (10mL * 2), merges organic phase, anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains crude product title product 1-(the 3-tertiary butyl-5-piperazine-1-base-phenyl) ethyl ketone 103c (1.45g, yellow oily), product is not purified directly carries out next step reaction.

MS?m/z(ESI)：261.1[M+1]

The 4th step

The 1-[3-tertiary butyl-5-[4-(2-hydroxyethyl) piperazine-1-yl] phenyl] ethyl ketone

By crude product 1-(the 3-tertiary butyl-5-piperazine-1-base-phenyl) ethyl ketone 103c (1.40g, 5.38mmol) be dissolved in 10mL N, in dinethylformamide, add again ethylene chlorhydrin (694mg, 8.60mmol) and salt of wormwood (1.48g, 10.76mmol), be warming up to 70 ℃ of stirring reactions 12 hours.In reaction solution, add 30mL water, be extracted with ethyl acetate (30mL * 4), merge organic phase, saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purifies gained resistates, obtains the title product 1-[3-tertiary butyl-5-[4-(2-hydroxyethyl) piperazine-1-yl] phenyl] ethyl ketone 103d (630mg, yellow oil), productive rate: 39.3%.

MS?m/z(ESI)：305.1[M+1]

The 5th step

The bromo-1-[3-tertiary butyl-5-[4-of 2-(2-hydroxyethyl) piperazine-1-yl] phenyl] ethyl ketone

By the 1-[3-tertiary butyl-5-[4-(2-hydroxyethyl) piperazine-1-yl] phenyl] ethyl ketone 103d (103mg, 0.34mmol) is dissolved in 2mL Glacial acetic acid, adds pyridinium tribromide salt (108mg, 0.34mmol), stirring reaction 5 hours.In reaction solution, add 5mL water, with sodium bicarbonate, regulate pH value to 7-8, be extracted with ethyl acetate (10mL * 4), merge organic phase, saturated nacl aqueous solution washing (10mL), anhydrous magnesium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain the bromo-1-[3-tertiary butyl-5-[4-of title product 2-(2-hydroxyethyl) piperazine-1-yl] phenyl] ethyl ketone 103e (38mg, white solid), productive rate: 29.2%.

MS?m/z(ESI)：385.1[M+1]

The 6th step

The 1-[3-tertiary butyl-5-[4-(2-hydroxyethyl) piperazine-1-yl] phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--

Spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (26mg, 0.10mmol) be dissolved in 1mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-[4-of 2-(2-hydroxyethyl) piperazine-1-yl] phenyl] ethyl ketone 103e (38mg, 0.10mmol), stirring reaction is 4 hours.Reaction solution concentrating under reduced pressure, by thin-layer chromatography chromatography, with eluent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-[4-(2-hydroxyethyl) piperazine-1-yl] phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 103 (28mg, white solid), productive rate: 43.7%.

MS?m/z(ESI)：566.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ8.69(s，1H)，7.92(s，1H)，7.88(s，1H)，7.04(s，1H)，5.32(s，2H)，4.25(m，2H)，4.14(m，2H)，3.60(m，2H)，3.27(m，2H)，2.71(m，2H)，2.64(m，2H)，1.69(m，2H)，1.38(m，2H)，1.37(s，9H)，1.31(m，6H)

Embodiment 104

1-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-ethyl ketone

By 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (1g, 3.90mmol) and tetra-triphenylphosphine palladium (450mg, 0.39mmol) be dissolved in 60mL dioxane, stir 10 minutes, again 10mL is contained to cyclopropylboronic acid (500mg, 5.90mmol) and the aqueous solution of cesium carbonate (6.30g, 19.50mmol) add in reaction system, be warming up at 90 ℃ stirring reaction 5 hours.Be cooled to room temperature, filter, in filtrate, add 50mL ethyl acetate and 10mL water, extraction separates organic phase, with saturated nacl aqueous solution washing (30mL * 2), anhydrous magnesium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-ethyl ketone 104a (600mg, colourless liquid), productive rate: 71.2%.

MS?m/z(ESI)：217.1[M+1]

Second step

The bromo-1-of 2-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-ethyl ketone

1-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-ethyl ketone 104a (540mg, 2.50mmol) is dissolved in 7.5mL tetrahydrofuran (THF), adds trimethylphenyl tribromide ammonium (940mg, 2.50mmol), stirring reaction 2 hours.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with developping agent system B, purifies gained resistates, obtains the bromo-1-of title product 2-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-ethyl ketone 104b (510mg, colourless liquid), productive rate: 68.9%.

The 3rd step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (82mg, 0.31mmol) with the bromo-1-of 2-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-ethyl ketone 104b (92mg, 0.31mmol) be dissolved in 1mL tetrahydrofuran (THF), stirring reaction 12 hours, separates out a large amount of solids.Suction filtration, tetrahydrofuran (THF) washing (0.5mL * 3) for filter cake, vacuum-drying, obtain title product 1-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 104 (139mg, white solid), productive rate: 80.0%.

MS?m/z(ESI)：479.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.36(br，1H)，9.05(br，1H)，7.75(s，1H)，7.53(s，1H)，7.48(s，1H)，7.03(s，1H)，5.20(s，2H)，4.27-4.22(m，2H)，4.16-4.11(m，2H)，2.08-2.05(m，1H)，1.80(m，2H)，1.66(m，2H)，1.41(m，3H)，1.33(s，9H)，1.32(m，3H)，1.03(m，2H)，0.78(m，2H)

Embodiment 105

1-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (62mg, 0.21mmol) be dissolved in 1mL tetrahydrofuran (THF), add the bromo-1-of 2-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-ethyl ketone 104b (56mg, 0.21mmol), stirring reaction 12 hours.Filter, filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain title product 1-(the 3-tertiary butyl-5-cyclopropyl-phenyl)-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 105 (72mg, white solid), productive rate: 61.0%.

MS?m/z(ESI)：481.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.78(s，1H)，7.55(s，1H)，7.51(s，1H)，7.44(s，1H)，5.39(s，2H)，4.29-4.23(m，2H)，4.15-4.10(m，2H)，2.07(m，1H)，1.50(s，6H)，1.42(m，3H)，1.34(s，9H)，1.30(m，3H)，1.02(m，2H)，0.80(m，2H)

Embodiment 106

The 1-[3-tertiary butyl-5-(trifluoromethyl)-phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

The 3-tertiary butyl-5-(trifluoromethyl) phenylformic acid

At-78 ℃, by 3-bromo-5-(trifluoromethyl) phenylformic acid 106a (5g, 18.60mmol) and cuprous iodide (178mg, 0.93mmol) be dissolved in 50mL tetrahydrofuran (THF), add again tertiary butyl chlorination magnesium (27.30mL, 46.50mmol), stirring reaction 1 hour.In reaction solution, add 20mL saturated ammonium chloride solution cancellation reaction, add again 20mL ethyl acetate and 20mL water, with 1M hydrogen chloride solution, regulate pH value to 2-3, extraction separatory, water is extracted with ethyl acetate (30mL * 3), merge organic phase, water (30mL * 3) and saturated nacl aqueous solution washing (30mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain the title product 3-tertiary butyl-5-(trifluoromethyl) phenylformic acid 106b (3.75g, yellow solid), productive rate: 82.0%.

MS?m/z(ESI)：245.0[M-1]

Second step

The 3-tertiary butyl-N-methoxyl group-5-(trifluoromethyl) benzamide

The 3-tertiary butyl-5-(trifluoromethyl) phenylformic acid 106b (3.71g, 15.08mmol) is dissolved in 25mL sulfur oxychloride, and stirring reaction is 2 hours at 85 ℃.Reaction solution is concentrated, at 0 ℃, adds 30mL methylene dichloride, then adds N-methoxymethyl amine (2.34g, 23.98mmol), drips DIPEA (5.84g, 45.24mmol), rises to stirring at room reaction 12 hours.In reaction solution, add 30mL water, extraction separatory, dichloromethane extraction for water (15mL * 3), merges organic phase, water (15mL * 3) and saturated nacl aqueous solution washing (15mL * 3), anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the title product 3-tertiary butyl-N-methoxyl group-5-(trifluoromethyl) benzamide 106c (985mg, yellow liquid), productive rate: 22.6%.

MS?m/z(ESI)：290.0[M+1]

The 3rd step

The 1-[3-tertiary butyl-5-(trifluoromethyl)-phenyl] ethyl ketone

At 0 ℃, the 3-tertiary butyl-N-methoxyl group-5-(trifluoromethyl) benzamide 106c (900mg, 3.10mmol) is dissolved in 15mL tetrahydrofuran (THF), then adds methylmagnesium-chloride (2.10mL, 6.23mmol), under room temperature, stirring reaction is 2 hours.In reaction solution, add 20mL saturated ammonium chloride solution cancellation reaction, add again 15mL ethyl acetate and 10mL water, extraction separatory, water is extracted with ethyl acetate (15mL * 3), merge organic phase, water (15mL * 3) and saturated nacl aqueous solution washing (15mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains the title product 1-[3-tertiary butyl-5-(trifluoromethyl)-phenyl] ethyl ketone 106d (720mg, yellow liquid), productive rate: 94.7%.

The 4th step

The bromo-1-[3-tertiary butyl-5-of 2-(trifluoromethyl)-phenyl] ethyl ketone

By the 1-[3-tertiary butyl-5-(trifluoromethyl)-phenyl] ethyl ketone 106d (300mg, 1.23mmol) is dissolved in 15mL tetrahydrofuran (THF), adds trimethylphenyl tribromide ammonium (462mg, 1.23mmol), stirring reaction 1 hour.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with developping agent system B, purifies gained resistates, obtains the bromo-1-[3-tertiary butyl-5-of title product 2-(trifluoromethyl)-phenyl] ethyl ketone 106e (290mg, yellow liquid), productive rate: 73.0%.

The 5th step

5,6-diethoxy-7-is fluoro-3,3-dimethyl-isoindole-1-amine 24d (115mg, 0.43mmol) be dissolved in 5mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(trifluoromethyl)-phenyl] ethyl ketone 106e (140mg, 0.43mmol), stirring reaction 1 hour.In reaction solution, add 5mL water and 5mL ethyl acetate, extraction separatory, water is extracted with ethyl acetate (5mL * 2), merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(trifluoromethyl)-phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1, 1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 106 (24mg, yellow solid), productive rate: 9.4%.

MS?m/z(ESI)：509.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.60(br，1H)，8.97(br，1H)，8.27(s，1H)，8.21(s，1H)，8.04(s，1H)，7.45(s，1H)，5.56(s，2H)，4.26(m，2H)，4.11(m，2H)，1.52(s，6H)，1.40(m，12H)，1.32(m，3H)

Embodiment 107

The 1-[3-tertiary butyl-5-(trifluoromethyl)-phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (57mg, 0.22mmol) be dissolved in 1mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(trifluoromethyl)-phenyl] ethyl ketone 106e (70mg, 0.22mmol), stirring reaction is 1 hour.Filter to obtain solid, with tetrahydrofuran (THF) washing (0.5mL * 3), vacuum-drying, obtain the title product 1-[3-tertiary butyl-5-(trifluoromethyl)-phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 107 (75mg, white solid), productive rate: 59.1%.

MS?m/z(ESI)：507.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.38(br，1H)，8.09(br，1H)，8.22(s，1H)，8.15(s，1H)，8.05(s，1H)，7.03(s，1H)，5.29(s，2H)，4.23(m，2H)，4.12(m，2H)，1.86(m，2H)，1.66(m，2H)，1.39(m，12H)，1.31(m，3H)

Embodiment 108

The 2-[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] phenyl]-2-methyl-propionitrile hydrobromate

The first step

1-(the bromotrifluoromethane)-3-tertiary butyl-5-methyl-benzene

By the 1-tertiary butyl-3,5-dimethyl-benzene 108a (5g, 30.81mmol), Diisopropyl azodicarboxylate (50mg, 0.30mmol) and N-bromosuccinimide (4.39g, 24.65mmol) be dissolved in 50mL tetracol phenixin, 80 ℃ of stirring reactions 2 hours.Reaction solution concentrating under reduced pressure, add 30mL water, be extracted with ethyl acetate (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains crude product title product 1-(the bromotrifluoromethane)-3-tertiary butyl-5-methyl-benzene 108b (6.10g, colorless oil), product is not purified directly carries out next step reaction.

Second step

2-(the 3-tertiary butyl-5-methyl-phenyl) acetonitrile

Crude product 1-(the bromotrifluoromethane)-3-tertiary butyl-5-methyl-benzene 108b (482mg, 2mmol) and cyaniding 4-butyl amine (805mg, 3mmol) are dissolved in 5mL DMF, and stirring reaction is 1.5 hours at 60 ℃.In reaction solution, add 10mL water, with extracted with diethyl ether (10mL * 2), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains title product 2-(the 3-tertiary butyl-5-methyl-phenyl) acetonitrile 108c (176mg, light yellow oily), productive rate: 47.0%.

The 3rd step

2-(the 3-tertiary butyl-5-methyl-phenyl)-2-methyl-propionitrile

At-78 ℃, by potassium tert.-butoxide (198mg, 1.76mmol) be dissolved in 5mL tetrahydrofuran (THF), drip 5mL containing 2-(the 3-tertiary butyl-5-methyl-phenyl) acetonitrile 108c (150mg, 0.80mmol) and methyl iodide (342mg, tetrahydrofuran solution 2.40mmol), stirring reaction 0.5 hour, room temperature reaction 3 hours.Add 5mL water, be extracted with ethyl acetate (5mL * 2), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtain crude product title product 2-(the 3-tertiary butyl-5-methyl-phenyl)-2-methyl-propionitrile 108d (151mg, yellow oily), product is not purified directly carries out next step reaction.

The 4th step

The 3-tertiary butyl-5-(1-cyano group-1-methyl-ethyl) phenylformic acid

Crude product 2-(the 3-tertiary butyl-5-methyl-phenyl)-2-methyl-propionitrile 108d (150mg, 0.69mmol) is dissolved in 1.3mL acetic acid, adds the 0.1mL vitriol oil and chromic oxide (206mg, 2.07mmol), stirring reaction 2 hours.In reaction solution, add 20mL water and 10mL ethyl acetate, extraction separatory, water is extracted with ethyl acetate (5mL * 3), merges organic phase, successively water (10mL * 2) and saturated nacl aqueous solution washing (10mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains the crude product title product 3-tertiary butyl-5-(1-cyano group-1-methyl-ethyl) phenylformic acid 108e (154mg, yellow oily), product is not purified directly carries out next step reaction.

The 5th step

The 3-tertiary butyl-5-(1-cyano group-1-methyl-ethyl)-N-methoxyl group-N-methyl-benzamide

The crude product 3-tertiary butyl-5-(1-cyano group-1-methyl-ethyl) phenylformic acid 108e (154mg, 0.62mmol) is dissolved in 2mL sulfur oxychloride, and stirring reaction is 2 hours at 80 ℃.Reaction solution concentrating under reduced pressure, adds 5mL methylene dichloride, under ice bath is cooling, adds N, O-dimethyl hydroxylamine hydrochloride (97mg, 0.99mmol), then drip DIPEA (240mg, 1.86mmol), stirring reaction 0.5 hour.In reaction solution, add 5mL water, be extracted with ethyl acetate (10mL * 2), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system A, purifies gained resistates, obtains the title product 3-tertiary butyl-5-(1-cyano group-1-methyl-ethyl)-N-methoxyl group-N-methyl-benzamide 108f (100mg, yellow oily), productive rate: 55.2%.

MS?m/z(ESI)：289.1[M+1]

The 6th step

2-(the 3-ethanoyl-5-tertiary butyl-phenyl)-2-methyl-propionitrile

Under ice bath, the 3-tertiary butyl-5-(1-cyano group-1-methyl-ethyl)-N-methoxyl group-N-methyl-benzamide 108f (100mg, 0.34mmol) is dissolved in 2mL tetrahydrofuran (THF), then adds 3M methylmagnesium-chloride (0.23mL, 0.68mmol), stirring reaction is 2 hours.In reaction solution, add 5mL water; with 2mL1M hydrogen chloride solution, regulate pH value; be extracted with ethyl acetate (5mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2); anhydrous magnesium sulfate drying; filter, filtrate decompression is concentrated, obtains crude product title product 2-(the 3-ethanoyl-5-tertiary butyl-phenyl)-2-methyl-propionitrile 108g (75mg; pale solid), product is not purified directly carries out next step reaction.

MS?m/z(ESI)：26l.2[M+18]

The 7th step

2-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl]-2-methyl-propionitrile

Crude product 2-(the 3-ethanoyl-5-tertiary butyl-phenyl)-2-methyl-propionitrile 108g (75mg, 0.30mmol) is dissolved in 10mL tetrahydrofuran (THF), adds trimethylphenyl tribromide ammonium (115mg, 0.30mmol), stirring reaction 1.5 hours.Filter; filtrate decompression is concentrated, by thin-layer chromatography chromatography, with developping agent system B, purifies gained resistates, obtains title product 2-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl]-2-methyl-propionitrile 108h (72mg; colourless liquid), productive rate: 74.2%.

MS?m/z(ESI)：341.1[M+18]

The 8th step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (40mg; 0.15mmol) be dissolved in 0.5mL tetrahydrofuran (THF); add 2-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl]-2-methyl-propionitrile 108h (49mg; 0.15mmol), stirring reaction is 3 hours.Filter to obtain solid; with tetrahydrofuran (THF) washing (0.2mL * 3); vacuum-drying; obtain the title product 2-[3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] phenyl]-2-methyl-propionitrile hydrobromate 108 (33mg, white solid), productive rate: 44.0%.

MS?m/z(ESI)：506.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.97(s，1H)，7.93(s，1H)，7.88(s，1H)，7.04(s，1H)，5.27(s，2H)，4.23(m，2H)，4.12(m，2H)，1.67(s，6H)，1.43(m，2H)，1.39(m，2H)，1.38(s，9H)，1.33(m，6H)

Embodiment 109

The 2-[3-tertiary butyl-5-[2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl] phenyl]-2-methyl-propionitrile hydrobromate

The first step

By 5; 6-diethoxy-7-fluoro-3; 3-dimethyl-isoindole-1-amine 24d (106mg; 0.40mmol) be dissolved in 5mL tetrahydrofuran (THF); add 2-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl]-2-methyl-propionitrile 108h (129mg; 0.40mmol), stirring reaction is 4 hours.Reaction solution concentrating under reduced pressure, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(2-hydroxyl-oxethyl) phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 109 (86mg, white solid), productive rate: 36.5%.

MS?m/z(ESI)：508.3[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ8.01(s，1H)，7.98(s，1H)，7.88(s，1H)，7.45(s，1H)，5.48(s，2H)，4.28(m，2H)，4.12(m，2H)，1.78(s，6H)，1.44(s，6H)，1.40(m，3H)，1.38(s，9H)，1.31(m，3H)

Embodiment 110

The 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-N, N-bis-(2-hydroxyethyl) benzamide hydrochloride salt

The first step

By the 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] benzoate hydrochlorate 76 (350mg; 0.68mmol) and 2-(2-hydroxyethylamino) ethanol (142mg; 1.35mmol) be dissolved in 3mLN; in dinethylformamide; add 2-(7-azo benzotriazole)-N; N; N '; N '-tetramethyl-urea phosphofluoric acid ester (308mg, 0.81mmol), stirring reaction 2 hours.Add 5mL saturated nacl aqueous solution; be extracted with ethyl acetate (20mL * 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; with silica gel column chromatography, with eluent system A, purify gained resistates; obtain the title product 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-N, N-bis-(2-hydroxyethyl) benzamide hydrochloride salt 110 (110mg; light yellow solid), productive rate: 22.3%.

MS?m/z(ESI)：570.1[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.99(s，1H)，7.96(s，1H)，7.88(s，1H)，7.82(s，1H)，6.97(s，1H)，5.16(s，2H)，4.87(m，2H)，4.23-4.15(m，2H)，4.13-4.09(m，2H)，3.66(m，2H)，3.56(m，2H)，3.51(m，2H)，3.32(m，2H)，1.76(m，2H)，1.58(m，2H)，1.40(m，3H)，1.36(s，9H)，1.29(m，3H)

Embodiment 111

The 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-N-[2-hydroxyl-1-(hydroxymethyl) ethyl] benzamide hydrochloride salt

The first step

By the 3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] benzoate hydrochlorate 76 (150mg; 0.29mmol) with 2-aminopropyl-1; 3-glycol (53mg, 0.58mmol) is dissolved in 1mLN, in dinethylformamide; add 2-(7-azo benzotriazole)-N; N, N ', N '-tetramethyl-urea phosphofluoric acid ester (132mg; 0.35mmol), stirring reaction is 2 hours.Add 5mL saturated nacl aqueous solution; be extracted with ethyl acetate (20mL * 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; with silica gel column chromatography, with eluent system A, purify gained resistates; obtain the title product 3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl]-N-[2-hydroxyl-1-(hydroxymethyl) ethyl] benzamide hydrochloride salt 111 (120mg, light yellow solid), productive rate: 70.0%.

MS?m/z(ESI)：556.2[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.47(br，1H)，9.03(br，1H)，8.45-8.42(m，2H)，8.25(s，1H)，8.08(s，1H)，7.02(s，1H)，5.36(s，2H)，4.77(m，2H)，4.25(m，2H)，4.13(m，2H)，3.59(m，4H)，1.84(m，2H)，1.65(m，2H)，1.41(m，3H)，1.39(s，1H)，1.32(m，3H)

Embodiment 112

The 1-[3-tertiary butyl-5-[4-(2-hydroxyethyl) piperazine-1-yl] phenyl]-2-(the fluoro-3-of 5,6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate

The first step

By 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (56mg, 0.20mmol) be dissolved in 5mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-[4-of 2-(2-hydroxyethyl) piperazine-1-yl] phenyl] ethyl ketone 103e (80mg, 0.20mmol) and triethylamine (80mg, 0.20mmol), stirring reaction 48 hours.Reaction solution concentrating under reduced pressure, by thin-layer chromatography chromatography, with developping agent system A, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-[4-(2-hydroxyethyl) piperazine-1-yl] phenyl]-2-(5, the fluoro-3-of 6-diethoxy-4-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 112 (21mg, yellow solid), productive rate: 16.2%.

MS?m/z(ESI)：569.7[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.22(s，1H)，6.93(s，1H)，6.74(s，1H)，5.48(s，2H)，4.27(m，2H)，4.12(m，2H)，3.62(m，2H)，3.44(m，4H)，3.22(m，4H)，2.53(m，2H)，1.32(m，6H)，1.35(s，9H)，1.27(s，6H)

Embodiment 113

The 1-[3-tertiary butyl-5-(1,2-dihydroxy ethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

1-(the 3-tertiary butyl-5-vinyl-phenyl) ethyl ketone

By 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (360mg, 1.41mmol) and tetrakis triphenylphosphine palladium (163mg, 0.14mmol) be dissolved in 4mL dioxane, stir 10 minutes, add again three normal-butyls (vinyl) tin (492mg, 1.55mmol) and cesium fluoride (428mg, 2.82mmol), stirring reaction 2 hours at 90 ℃.In reaction solution, add 5mL water and 10mL ethyl acetate, extraction separatory, organic phase anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purifies gained resistates, obtains crude product title product 1-(the 3-tertiary butyl-5-vinyl-phenyl) ethyl ketone 113a (407mg, colorless oil), product is not purified directly carries out next step reaction.

MS?m/z(ESI)：203.1[M+1]

Second step

The 1-[3-tertiary butyl-5-(1,2-dihydroxy ethyl) phenyl] ethyl ketone

By crude product 1-(the 3-tertiary butyl-5-vinyl-phenyl) ethyl ketone 113a (404mg, 2mmol) be dissolved in the 10mL trimethyl carbinol, add successively N-methyl-N-morpholine oxide (257mg, 2.20mmol) and perosmic anhydride (25mg, 0.10mmol), stirring reaction is 1 hour.In reaction solution, add 10mL 5% hypo solution and 20mL ethyl acetate, separatory, saturated nacl aqueous solution washing (5mL * 2) for organic phase, anhydrous magnesium sulfate drying, filters, filtrate decompression is concentrated, with silica gel column chromatography, with eluent system B, purify gained resistates, obtain the title product 1-[3-tertiary butyl-5-(1,2-dihydroxy ethyl) phenyl] ethyl ketone 113b (182mg, colorless oil), productive rate: 38.0%.

MS?m/z(ESI)：237.1[M+1]

The 3rd step

The bromo-1-[3-tertiary butyl-5-of 2-(1,2-dihydroxy ethyl) phenyl] ethyl ketone

By the 1-[3-tertiary butyl-5-(1,2-dihydroxy ethyl) phenyl] ethyl ketone 113b (180mg, 0.76mmol) is dissolved in 2mL tetrahydrofuran (THF), adds trimethylphenyl tribromide ammonium (287mg, 0.76mmol), stirring reaction 4 hours.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with developping agent system B, purifies gained resistates, obtain the bromo-1-[3-tertiary butyl-5-(1 of title product 2-, 2-dihydroxy ethyl) phenyl] ethyl ketone 113c (30mg, colourless liquid), productive rate: 12.5%.

The 4th step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (25mg, 0.10mmol) be dissolved in 0.5mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-(1 of 2-, 2-dihydroxy ethyl) phenyl] ethyl ketone 118c (30mg, 0.10mmol), stirring reaction 12 hours.Suction filtration, tetrahydrofuran (THF) washing (0.5mL * 3) for solid, solid vacuum-drying, collects mother liquor, with silica gel column chromatography, with eluent system A, purifies gained resistates, obtain the title product 1-[3-tertiary butyl-5-(1,2-dihydroxy ethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 113 (10mg, white solid), productive rate: 18.0%.

MS?m/z(ESI)：499.2[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ7.87(s，1H)，7.83(s，1H)，7.73(s，1H)，7.01(s，1H)，5.49(s，1H)，5.25(s，2H)，4.88(s，1H)，4.22(m，2H)，4.12(m，2H)，3.49(m，2H)，1.76(m，2H)，1.62(m，2H)，1.40(m，3H)，1.34(s，9H)，1.31(m，3H)

Embodiment 114

The 2-[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl] phenyl]-2-methyl-propionic acid hydrobromate

The first step

2-(the 3-ethanoyl-5-tertiary butyl-phenyl)-2-methyl-methyl propionate

By 1-(the bromo-5-tertiary butyl-phenyl of 3-) ethyl ketone 77d (4.27g, 17mmol), two (dibenzalacetone) palladium (96mg, 0.17mmol) and zinc fluoride (866mg, 8.37mmol) be dissolved in 40mLN, in dinethylformamide, add 1-methoxyl group-2-methyl isophthalic acid-(trimethylsiloxy group) propylene (4.35g, 25mmol) and tri-butyl phosphine (1.69g, 0.84mmol), stirring reaction 16 hours at 100 ℃.In reaction solution, add 50mL water; be extracted with ethyl acetate (50mL * 3); merge organic phase; anhydrous magnesium sulfate drying, filters, and filtrate decompression is concentrated; with silica gel column chromatography, with eluent system B, purify gained resistates; obtain title product 2-(the 3-ethanoyl-5-tertiary butyl-phenyl)-2-methyl-methyl propionate 114a (1.68g, brown color oily matter), productive rate: 36.2%.

Second step

2-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl]-2-methyl-methyl propionate

2-(the 3-ethanoyl-5-tertiary butyl-phenyl)-2-methyl-methyl propionate 114a (276mg, 1mmol) is dissolved in 5mL tetrahydrofuran (THF), adds phenyl trimethylammonium bromide (376mg, 1mmol), stirring reaction 1 hour.Filter; ethyl acetate washing (10mL) for filter cake; merge organic phase; concentrating under reduced pressure; by thin-layer chromatography chromatography, with developping agent system B, purify gained resistates; obtain title product 2-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl]-2-methyl-methyl propionate 114b (154mg, light yellow liquid), productive rate: 43.4%.

The 3rd step

By 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (92mg; 0.35mmol) be dissolved in 3mL tetrahydrofuran (THF); add 2-[3-(2-the acetyl bromide)-5-tertiary butyl-phenyl]-2-methyl-methyl propionate 114b (124mg; 0.35mmol) and triethylamine (0.5mL, 0.35mmol), stirring reaction 8 hours.Reaction solution concentrating under reduced pressure; with silica gel column chromatography, with eluent system A, purify; obtain the title product 2-[3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl] phenyl]-2-methyl-propionic acid hydrobromate 114 (13mg; yellow solid), productive rate: 6.2%.

MS?m/z(ESI)：525.2[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ10.98(br，1H)，8.19(br，1H)，8.02(br，1H)，7.48(m，2H)，7.30(s，1H)，6.88(m，1H)，5.24(s，2H)，4.16(m，2H)，4.02(m，2H)，1.90(m，2H)，1.55(m，2H)，1.53(s，6H)，1.40-1.23(m，15H)

Embodiment 115

The 1-[3-tertiary butyl-5-(2-hydroxyl-1,1-dimethyl-ethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate

The first step

The 2-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl) phenyl]-2-methyl-methyl propionate

By 2-(the 3-ethanoyl-5-tertiary butyl-phenyl)-2-methyl-methyl propionate 114a (600mg; 2.17mmol) be dissolved in 5mL methyl alcohol, add trimethoxy-methane (714uL, 6.51mmol) and camphorsulfonic acid (50mg; 0.22mmol), stirring reaction is 3 hours.In reaction solution, add 50mL water and 40mg salt of wormwood, be extracted with ethyl acetate (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains the crude product title product 2-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl) phenyl]-2-methyl-methyl propionate 115a (676mg, red-brown oily matter), product is not purified directly carries out next step reaction.

Second step

The 1-[3-tertiary butyl-5-(2-hydroxyl-1,1-dimethyl-ethyl) phenyl] ethyl ketone

By the crude product 2-[3-tertiary butyl-5-(1,1-dimethoxy-ethyl) phenyl]-2-methyl-methyl propionate 115a (670mg, 2.08mmol) is dissolved in 5mL tetrahydrofuran (THF), under ice bath, add Li-Al hydrogen (87mg, 2.29mmol), stirring reaction 10 minutes.In reaction solution, add 50mL water, be extracted with ethyl acetate (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, adds the dioxane solution of 4mL1.60M hydrogenchloride, stirring reaction 5 minutes.In reaction solution, add 50mL water, be extracted with ethyl acetate (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, obtains the crude product title product 1-[3-tertiary butyl-5-(2-hydroxyl-1,1-dimethyl-ethyl) phenyl] ethyl ketone 115b (471mg, red-brown oily matter), product is not purified directly carries out next step reaction.

The 3rd step

The bromo-1-[3-tertiary butyl-5-of 2-(2-hydroxyl-1,1-dimethyl-ethyl) phenyl] ethyl ketone

By the crude product 1-[3-tertiary butyl-5-(2-hydroxyl-1,1-dimethyl-ethyl) phenyl] ethyl ketone 115b (471mg, 1.90mmol) is dissolved in 10mL tetrahydrofuran (THF), adds phenyl trimethylammonium bromide (713mg, 1.90mmol), stirring reaction is 0.5 hour.Filter, filtrate decompression is concentrated, with silica gel column chromatography, with developping agent system B, purifies gained resistates, obtain the bromo-1-[3-tertiary butyl-5-of title product 2-(2-hydroxyl-1,1-dimethyl-ethyl) phenyl] ethyl ketone 115c (170mg, light yellow liquid), productive rate: 27.4%.

MS?m/z(ESI)：327.0[M+1]

The 4th step

By 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (120mg, 0.46mmol) be dissolved in 1mL tetrahydrofuran (THF), add the bromo-1-[3-tertiary butyl-5-of 2-(2-hydroxyl-1,1-dimethyl-ethyl) phenyl] ethyl ketone 115c (l64mg, 0.50mmol), stirring reaction 12 hours.Filter, tetrahydrofuran (THF) washing (1mL) for filter cake, vacuum-drying, obtain the title product 1-[3-tertiary butyl-5-(2-hydroxyl-1,1-dimethyl-ethyl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 115 (190mg, white solid), productive rate: 70.6%.

MS?m/z(ESI)：511.2[M+1]

¹H?NMR(400MHz，DMSO-d ₆，ppm)：δ9.41(br，1H)，9.10(br，1H)，7.82(s，1H)，7.80(s，1H)，7.76(s，1H)，7.04(s，1H)，5.25(s，2H)，4.23(m，2H)，4.12(m，2H)，3.49(m，2H)，1.76(m，2H)，1.66(m，2H)，1.40(m，3H)，1.35(s，9H)，1.31(m，3H)，1.28(m，6H)

Test case:

biological assessment

Example 1 calcium ion transport suppresses experiment

Following methods can be used to measure the restraining effect of the compounds of this invention to the calcium ion transport of PAR1 mediation.By using Chinese hamster ovary cell CHO-K1 (to be purchased from Shanghai Inst. of Life Science, CAS cell resource center, catalog number (Cat.No.) GNHa 7), the exciting polypeptide thrombin of Fluo-4NW calcium assay kit (invitrogen Cat.No F36206) and PAR1 receptor activator peptide 6 (Sigma, T1573-5MG) measure the impact of invention compound on the calcium ion transport of PAR1 mediation.

Probenecid storing solution (probenecid stock solution) and sample-loading buffer (loading buffer) required in experiment can be prepared according to Fluo-4NW calcium assay kit test kit specification sheets.

Experimental procedure:

DEME substratum (Gibco) for CHO-K1 cell is equipped with to 10% foetal calf serum as perfect medium, and is inoculated in 96 porocyte culture plates at 37 ℃ with the concentration of 25,000 cells/well, under 5% carbon dioxide conditions, cultivate until converge.Discard subsequently substratum, to the loading buffer that adds 100 μ L to configure in each hole of culture plate, at 37 ℃, under 5% carbon dioxide conditions, incubation is 45 minutes.First test compounds dissolves with methyl-sulphoxide, uses subsequently analysis buffer (assay buffer) (containing 1X HBSS, 20mM HEPES, 2.5mMprobenecid) to be diluted to experiment desired concn.With the test compounds sample adding in each hole of test group on backward 96 orifice plates after 100uL dilution, negative control group adds the assay buffer of equal volume.Culture plate is incubation 30 minutes at room temperature subsequently, with in backward each hole, add 25 μ for L buffer (1X HBSS, 20mM HEPES) be diluted to the exciting polypeptide 6 (thrombin receptor activator peptide 6) of thrombin receptor of 20 μ M.At excitation wavelength 485nm, under emission wavelength 525nm, measure the relative intensity of fluorescence in each hole, the inhibiting rate of computerized compound to the calcium ion transport of PAR1 mediation.

Test compounds is calculated as follows to the inhibiting rate of PAR1:

IR＝(F _NC-F _TC)/FNC％

F _nC: the fluorescence intensity in negative control group hole

F _tC: the fluorescence intensity in test compounds hole

The half-inhibition concentration IC of test compounds ₅₀can calculate by the inhibiting rate under different concns.

Conclusion: the numerical value of the calcium current inhibiting rate of test compounds of the present invention is 0.006～0.099 μ M, the compounds of this invention has obvious restraining effect to the calcium ion transport of PAR1 mediation.

The external platelet aggregation experiment of example 2

It is active to the inhibition of platelet aggregation that following methods can be used to measure the compounds of this invention.Experimental technique is summarized as follows:

With ACD, as antithrombotics, in venipuncture mode, from the male Chinese cavy (being purchased from Shanghai Sheng Wang laboratory animal plant) (body weight 450～600g) of health, obtain whole blood sample.At room temperature with 200 * g speed, within centrifugal 20 minutes, obtain and be rich in hematoblastic blood plasma subsequently.With 800 * g speed, blood plasma is obtained to thrombocyte precipitation for centrifugal 10 minutes subsequently.With tyrode's solution Tyrode`s buffer, (contain 140mM NaCl, 2.7mM KCl, 12mMNaHCO ₃, 0.76mM NaHPO4,5.5mM Glucose, 5mM HEPES, 2mg/mL bovine serum albumin, and pH 7.4,20 μ g/mL apyrase) and suspendible thrombocyte precipitates and calculates again after washed twice, is finally diluted to 2～3 * 10 ⁸individual/mL is standby.

Aggegation experiment is carried out at ambient temperature.First in each hole of 96 orifice plates, add 90 μ L thrombocyte suspensions.Test compounds is dissolved and is mixed with after experiment desired concn with methyl-sulphoxide, in each test group hole, adds 8 μ L compounds, and negative control group replaces with the DMSO of same volume.The preincubation 6 minutes at 37 ℃ of compound and thrombocyte, with adding 2 μ L in backward each hole, the exciting peptide T RAP of the zymoplasm of 20 μ M, starts aggegation process by 96 holes as for concuss on shaking table.Aggegation rate obtains by measure the transmittance counting in each hole under 405nm.

The agglutinate rate of blood platelet of test compounds calculates as follows:

AR＝(Tc-T0)/(T100-T0)％

Tc: the transmittance in test compounds hole

T0: the transmittance of negative control hole

T100: the transmittance of blank well

The thrombocyte of compound suppresses aggegation IC ₅₀value can calculate by the aggegation rate under different concns.

Conclusion: test compounds of the present invention has obvious restraining effect to guinea pig blood platelet aggregation.

pharmacokinetic Evaluation

The pharmacokinetics test of test case 1 the compounds of this invention

1, summary

The drug level in blood plasma in the same time not after the research embodiment of the present invention 24,35,40,44 and 108 compounds.The pharmacokinetics behavior of research the compounds of this invention in rat body, evaluates its characteristics of pharmacokinetics.

2, testing program

2.1 test drug

Embodiment 24,35,40,44 and 108 compounds

2.2 experimental animal

20 of healthy adult SD rats, male and female half and half, are divided into 5 groups, purchased from Shanghai western pul-Bi Kai laboratory animal company limited, animal production licence number: SCXK (Shanghai) 2008-0016.

2.3 medicine preparations

Take appropriate amount of drug, add 0.5% Xylo-Mucine to be ground to the even suspendible of sample, sample concentration is that used time preparation is faced in 2.0mg/mL reservation.

2.4 administration

Difference gastric infusion after SD rat overnight fasting, dosage is that 20.0mg/kg retains (in alkali original shape), administration volume 10mL/kg.

2.5 sample collecting

Each treated animal respectively at administration before and after administration 1.0,2.0,3.0,4.0,6.0,8.0,12.0,24.0,36.0,48.0 hours by eye socket blood sampling 0.1mL, is placed in heparinization test tube, 3500 leave 10 minutes separated plasmas of the heart, preserve at-20 ℃.Feed in 2 hours after administration.

3. operation

Draw each 20 μ L of each rat plasma constantly after medicine, add inner mark solution (100ng/mL, methyl alcohol preparation) 50 μ L, methyl alcohol 95 μ L, vortex mixed 3 minutes, centrifugal 10 minutes (13500 revs/min), get supernatant liquor 10 μ L and carry out LC-MS/MS analysis.Main pharmacokinetic parameter adopts DAS 2.0 computed in software.

4, pharmacokinetic parameter result

The pharmacokinetic parameter of the compounds of this invention is as following table:

Conclusion: the compound of the present invention test in rat body Plasma Concentration and exposure level all higher, there is obvious pharmacokinetics advantage.

efficacy testing

Experiment purpose:

Measure the effect of PAR-1 inhibitor embodiment 44 compounds to the cavy platelet aggregation rate of TARP induction.

Experimental drug:

Embodiment 44 compounds; Prostaglandin I ₂, TRAP provides by Sigma company.

Experimental technique:

Drug dose is 50mg/kg (2.5ml/kg), with 0.5% Xylo-Mucine, add 5% tween-80 and make suspension, get male guinea pig body weight 250g～350g, random packet, gastric infusion, put back to former cage after 2 hours, with 20% urethane anesthesia, cavy abdominal aortic blood adopts disposable plastic injector, includes 3.8% Sodium Citrate (1: 10 volume, a Citric Acid and nine parts of blood anticoagulants).

The preparation of platelet rich plasma: the aorta abdominalis blood of cavy after centrifugal 10 minutes (22 ℃), is taken out to the platelet rich plasma 1.5mL on upper strata with 200g rotating speed.Hematoblastic washing method: with Tyrode ' s buffer ' solution (NaCl 129mM, KCl 2.8mM, KH ₂pO ₄0.8mM, MgCl ₂0.8mM, NaHCO ₃8.9mM, HEPEs 10mM, glucose 5.5mM).Platelet aggregation test: measure with platelet aggregation instrument, thrombocyte damping fluid 291 μ L are added in transparent plastics cuvette, in cuvette, add 3 μ L damping fluids and 6 μ L calcium chloride (50 μ M), add magnetic stirring apparatus to incubate in advance in 37 ℃ and bathe 2 minutes, then add 40 μ M platelet aggregation TRAP, carry out the interior changes in aggregation rate of continuous detecting 5min (1 minute, 3 minutes, 5 minutes, MA), to evaluate medicine to anticoagulant effect.

Experimental result:

Embodiment 44 compounds have very strong restraining effect to platelet aggregation in the cavy of TRAP induction 5 minutes, with the comparison of blank group, the amplitude that embodiment 85 compounds (10mg/kg) were assembled percentage minimizing in the time of 3 minutes, 5 minutes is 47.47% and 45.21% (P < 0.05, P < 0.05); It is 57.63% and 48.57% (P < 0.05, P < 0.05) that SHR130362 (30mg/kg) assembles the amplitude that percentage reduces when 3 minutes and 5 minutes; It is 69.96%, 82.55% and 78.51% (P < 0.05 that SHR130362 (50mg/kg) assembles the amplitude that percentage reduces when 1 minute, 3 minutes and 5 minutes, P < 0.001, P < 0.001).Therefore, embodiment 44 compounds have preferably blood coagulation resisting function.

Claims

1. the compound shown in general formula (I) or its pharmaceutically useful salt,

Wherein:

Ar is selected from phenyl or pyrryl, and wherein said phenyl is optionally further by one or more R ^asubstituting group replace; Wherein said pyrryl is further by one or more C _1-6alkyl replaces;

Be selected from-CR of Y ¹²-or N atom;

Be selected from-(CH of L ₂) _m-;

R ¹, R ²and R ³independently be selected from separately hydrogen atom, halogen, C _1-6alkoxyl group or C _1-6alkyl;

R ⁴and R ⁵independently be selected from separately C _1-6alkyl, C _3-10cycloalkyl, phenyl;

Or, R ⁴and R ⁵form C together with the carbon atom being connected _3-10cycloalkyl;

R ⁶be selected from hydrogen atom;

R ^acan be identical or different, be independently selected from separately hydrogen atom, hydroxyl, halogen, cyano group, silylation, C _1-6alkoxyl group, C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical, heteroaryl ,-C (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷or-C (O) NR ¹⁶r ¹⁷, wherein said C _1-6alkoxyl group, C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, C of being selected from _1-6alkoxyl group, C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical, C _1-6hydroxyalkyl ,-C (O) OR ¹⁵,-C (O) R ¹⁵substituting group replace; Described silylation refers to SiH ₄in hydrogen by one or more C _1-6alkyl replaces;

R ¹²be selected from hydrogen atom or halogen;

R ¹⁵be selected from hydrogen atom, C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical, wherein said C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical are optionally further by one or more halogen, hydroxyl, cyano group, C of being selected from _1-6alkoxyl group or C _1-6the substituting group of alkyl replaces;

R ¹⁶and R ¹⁷independently be selected from separately hydrogen atom, halogen, C _1-6alkyl, C _1-6alkoxyl group or C _3-10cycloalkyl, wherein said C _1-6alkyl, C _1-6alkoxyl group or C _3-10cycloalkyl is optionally further by one or more halogen, hydroxyl, cyano group, C of being selected from _1-6alkoxyl group, C _1-6alkyl, C _3-10the substituting group of cycloalkyl replaces;

Or, R ¹⁶and R ¹⁷form heterocyclic radical with the nitrogen-atoms being connected, wherein said heterocyclic radical contains one or more N or O heteroatoms, and described heterocyclic radical is optionally further by one or more hydroxyls, C _1-6alkyl, C _1-6hydroxyalkyl ,-C (O) R ¹⁵substituting group replace;

M is selected from 1;

N is selected from 1,2 or 3; And

P is selected from 0,1 or 2;

Described heterocyclic radical is monocycle, comprises 3 to 10 annular atomses, and wherein 1～4 is the heteroatoms that is selected from N or O, and described heteroaryl is 5 yuan or 6 yuan of heteroaryls, wherein comprises 1 to 4 heteroatoms that is selected from oxygen, sulphur and nitrogen.

2. the compound shown in general formula (II) or its pharmaceutically useful salt,

Wherein:

R ⁷, R ⁸, R ⁹, R ¹⁰and R ¹¹independently be selected from separately hydrogen atom, hydroxyl, halogen, cyano group, silylation, C _1-6alkoxyl group, C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical, heteroaryl ,-C (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷or-C (O) NR ¹⁶r ¹⁷, wherein said C _1-6alkoxyl group, C _1-6alkyl, C _3-10cycloalkyl or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, C of being selected from _1-6alkyl, C _3-10the substituting group of cycloalkyl replaces; Described silylation refers to SiH ₄in hydrogen by one or more C _1-6alkyl replaces;

Or, R ⁹and R ¹⁰form morpholinyl together with the carbon atom being connected, wherein said morpholinyl is optionally further by one or more halogen, hydroxyl, cyano group ,-(CH of being selected from ₂) _nc (O) OR ¹⁵or-C (O) R ¹⁵substituting group replace;

R ¹⁵be selected from hydrogen atom, C _1-6alkyl or C _3-10cycloalkyl;

R ¹⁶and R ¹⁷independently be selected from separately hydrogen atom, halogen, C _1-6alkyl, C _3-10cycloalkyl, wherein said C _1-6alkyl, C _3-10cycloalkyl is optionally further replaced by one or more substituting groups that are selected from hydroxyl or cyano group;

N is selected from 1,2 or 3; And

P is selected from 0,1 or 2;

Y wherein, L, R ¹to R ⁶as defined in claim 1;

3. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein heterocyclic radical is selected from:

4. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein R ⁴and R ⁵be selected from C _1-6alkyl or phenyl.

5. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein R ⁴and R ⁵form cyclopropyl together with the carbon atom being connected.

6. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein this compound is selected from:

7. the compound with following structural formula:

8. according to the compound described in claim 1 or 7 or its pharmaceutically useful salt, wherein compound exists with the form of free state or pharmaceutically useful acid salt, and described acid salt comprises hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, maleate, malate, Citrate trianion, acetate or trifluoroacetate.

9. according to the compound described in claim 1 or 7 or its pharmaceutically useful salt, wherein compound exists with the form of free state or pharmaceutically useful acid salt, and described acid salt comprises hydrobromate and hydrochloride.

10. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein the salt of this compound is selected from:

11. compounds according to claim 7 or its pharmaceutically useful salt, wherein the salt of this compound is selected from:

12. 1 kinds of methods of preparing compound shown in general formula (I), the method comprises:

By general formula (IA) compound or (IB) compound react with general formula (IC) compound, obtain general formula (I) compound;

Wherein: X is halogen; L, Y, R ¹～R ¹¹definition described in claim 1～5.

13. general formula (IA) or (IB) methods of compound prepared as claimed in claim 12, wherein said halogen is chlorine atom or bromine atoms.

14. 1 kinds of general formulas (IA) or (IB) shown in compound or its pharmaceutically useful salt, it is as the intermediate of preparing general formula (I) compound,

Be selected from-CR of Y ¹²-or N atom;

R ¹, R ²and R ³independently be selected from separately hydrogen atom, halogen, C _1-6alkoxyl group, C _1-6alkyl;

R ⁶be selected from hydrogen atom;

R ^acan be identical or different, be independently selected from separately hydrogen atom, hydroxyl, halogen, cyano group, silylation, C _1-6alkoxyl group, C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical, heteroaryl ,-C (O) OR ¹⁵,-(CH ₂) _nc (O) OR ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-S (O) _pr ¹⁵,-NR ¹⁶r ¹⁷or-C (O) NR ¹⁶r ¹⁷, wherein said C _1-6alkoxyl group, C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical or heteroaryl are optionally further by one or more halogen, hydroxyl, cyano group, C of being selected from _1-6alkoxyl group, C _1-6alkyl, C _3-10cycloalkyl, heterocyclic radical, C _1-6the substituting group of hydroxyalkyl replaces; Described silylation refers to SiH ₄in hydrogen by one or more C _1-6alkyl replaces;

R ¹²be selected from hydrogen atom or halogen;

M is selected from 1;

N is selected from 1,2 or 3; And

P is selected from 0,1 or 2;

15. general formulas according to claim 14 (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R ⁴and R ⁵form cyclopropyl together with the carbon atom being connected.

16. general formulas according to claim 14 (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein this compound is selected from:

Prepare general formula (IA) or (IB) method of compound for 17. 1 kinds, the method comprises:

General formula (III) compound is reacted under the cuprous existence of catalyzer iodate with cuprous cyanide, obtain general formula (IA) or (IB) compound;

Or, by general formula (IV) compound Yu Geshi reagent react, obtain general formula (IA) or (IB) compound;

Or, will lead to formula V compound and react with strong aqua, obtain general formula (IA) or (IB) compound;

Or under water and triphenylphosphine exist, stirring reaction under room temperature, obtains general formula (IA) or (IB) compound by the tetrahydrofuran solution of general formula (VI) compound,

Wherein X is selected from halogen, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶define as claim 1 with Y.

18. 1 kinds of pharmaceutical compositions, described pharmaceutical composition contains the compound shown in the general formula according to claim 1 (I) for the treatment of effective dose or its pharmaceutically useful salt and pharmaceutically useful carrier.

19. 1 kinds of pharmaceutical compositions, described pharmaceutical composition contain treatment effective dose according to the compound shown in claim 7 or its pharmaceutically useful salt and pharmaceutically useful carrier.

Compound shown in 20. general formulas as claimed in claim 1 (I) or its pharmaceutically useful salt or pharmaceutical composition as claimed in claim 18 or pharmaceutical composition as claimed in claim 19 purposes in preparation calcium ion transport inhibitor.

21. compounds as claimed in claim 1 or its pharmaceutically useful salt or pharmaceutical composition as claimed in claim 18 or pharmaceutical composition as claimed in claim 19 purposes in preparing thrombin receptor antagonist.

22. purposes according to claim 21, wherein thrombin receptor antagonist is PAR1 receptor antagonist.

Compound shown in 23. general formulas as claimed in claim 1 (I) or its pharmaceutically useful salt or pharmaceutical composition as claimed in claim 18 or the purposes of pharmaceutical composition as claimed in claim 19 in preparing anticoagulant.

Compound shown in 24. general formulas as claimed in claim 1 (I) or its pharmaceutically useful salt or pharmaceutical composition as claimed in claim 18 or the purposes of pharmaceutical composition as claimed in claim 19 in preparing inhibitors of smooth muscle cell proliferation.

Compound shown in 25. general formulas as claimed in claim 1 (I) or its pharmaceutically useful salt or pharmaceutical composition as claimed in claim 18 or pharmaceutical composition as claimed in claim 19 purposes in the medicine of the preparation treatment disease relevant with thrombin receptor.

26. purposes according to claim 25, the wherein said disease relevant with thrombin receptor is selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary infarction disease, cerebral infarction, heart disease, sowing vessel inner blood and solidifies syndromes, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.