CN102471264A - 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof - Google Patents
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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
Disubstituted -2- imino groups the pyrroles of 5,5- burns analog derivative, its preparation method and its in applied technical field pharmaceutically
The present invention relates to a kind of new disubstituted -2- lminopyrrolidines analog derivatives of 5,5-, its preparation method and contain the derivative pharmaceutical composition and its as purposes of the therapeutic agent especially as thrombin receptor antagonist.Background technology
At present worldwide, thrombotic diseases are the main causes for causing angiocardiopathy high incidence and high mortality.Arterial thrombus can cause to include acute coronary syndrome, the various acute symptom such as ishemic stroke/TIA and peripheral arterial disease.These symptoms are due to that atherosclerotic plaque is damaged or vascular endothelial cell damage causes injury of blood vessel, and then induction forms arterial thrombus occlusion, blood supply insufficiency caused by entering and caused.Blood platelet 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 can cause injury of blood vessel, in a variety of platelet activating factors such as fibrin ferment, thromboxane A2And in the presence of ADP, cause platelet activation mechanism out of control and then cause a large amount of platelet activations and assemble, form thrombus, final blocking blood flow under the mediation of platelet glycoprotein (GP) lib I Ilia acceptors thereafter.In the exciting factor of these blood platelets, fibrin ferment (thrombin) is used as most potent platelet activating agent, blood platelet is activated by the interaction with the PAR family members in g protein coupled receptor family and induces it to assemble, and then realizes the biological actions such as blood coagulation.
Proteinase activated receptors family (；Proteinase-activated receptors, PARs) it is under the jurisdiction of g protein coupled receptor family, the family member has extensive expression, such as blood platelet, vascular endothelial cell and vascular smooth muscle cells in the various kinds of cell in cardiovascular system.PARs families take part in the blood coagulation under normal physiological conditions, maintain the inflammatory reaction under vascular homeostasis, and pathological conditions, the various physiological processes such as thrombus and atherogenesis, and play key effect wherein.The family receptors realize activation process with distinctive mechanism：The fibrin ferment (thrombin) combined with PARs is by proteolysis, original N-terminal in the function of extracellular area of PARs acceptors is hydrolyzed and a new N-terminal is formed, the N-terminal newly formed can be activated after being combined in the way of " being tethered at part " with PARs with inducing receptor, and then realize signal transduction process.
Have been acknowledged that PARs families include four kinds of receptor subtypes, including PARI, PAR2, PAR3 and PAR4 at present.PAR2 is removed as the sunset of trypsase (trypsin) and the acceptor of trypsinlike enzyme (tryptase) to foretell, remaining 3 hypotype is activated after can all being combined with fibrin ferment, thus is considered as main thrombin receptor (thrombin reCept0rS).Wherein PARI is the thrombin receptor of high-affinity, and it can be activated under the conditions of the fibrin ferment of low concentration (being less than nanomolar concentration).Relatively, PAR4 is the thrombin receptor of low-affinity, and activation and the transmittance process of thrombin signal are only participated under the conditions of the fibrin ferment of higher concentration.It is similar with PARI, although PAR3 is also high-affinity receptor, but generally individually signal is not transmitted in activation for it, but acts synergistically to improve PAR4 activity as accessory receptor and PAR4, realizes corresponding biological function (referring to Ho-Sam et al; Current Pharmaceutical Design, 2003, 9, 2349-2365).
It is used as topmost thrombin receptor, PARI is widely expressed in various kinds of cell and tissue in human body, including blood platelet, endothelial cell, blood vessel or tracheal smooth muscle, inflammatory cell (macrophage, lymphocyte), fibroblast, nerve cell, cardiovascular and Skeletal Muscle Cell.In addition to related to angiocardiopathy, in wound, the rise of PARI expressions can be observed under a variety of pathological states such as inflammatory conditions, and kinds of tumor cells.In addition, PARI by G-protein interconnection of signals activated receptor tyrosine kinase activity and can also influence corresponding signal cascade, so as to realize the regulation of cell proliferation and transfer process (referring to Derian CK, et al; Expert Opin. Investig Drugs, 2003, 12: 209-21).These all further predictive of PARI can as a variety of disease treatment target spots potential.
At present, the substantial amounts of non-peptides PARI inhibitor for being used to treat arterial thrombus class disease is in preclinical or clinical test.In early stage development, the main thromboxane A to adjust blood platelet building-up process of oral antiplatelet drug2(such as aspirin aspirin) or P2Y12Adp receptor mediation platelet activation process (；Such as ticlopidine ticlopidines) it is action target spot.However, both do not have direct inhibitory action CDavi G, et al for the fibrin ferment-platelet activation approach realized via PARI acceptors; N Engl J Med., 2007, 357: 2482-2494).Simultaneously as both can weaken or disturb the platelet aggregation that collagen is induced, so as to produce influence to normal hemostasis so that the probability rise of bleeding occurs in therapeutic process.By contrast, the antagonist developed using PARI as target spot is directly against this process of fibrin ferment-platelet activation, can play more fully with direct platelet activation inhibitory action, and then directly reduce the risk that thrombosis and acute ischemia symptom occur.Further, since PARI is non-essential in normal coagulation-hemostatic mechanism, thus suppression PARI can reduce the danger of generation bleeding in treatment (referring to Coughlin SR.; J Thromb Haemost., 2005, 3 : 1800-1814).What is more important, antagonist using PARI as target spot does not influence the normal coagulation activity of fibrin ferment (Thrombin) itself, under special emergency, fibrin ferment still by PAR4 signal inductions platelet activation and can be assembled, the coagulation function brought into normal play.Therefore, be the antiplatelet drug that target spot is developed compared with conventional medicament to suppress PARI, not only increase the effect and specificity for the treatment of, at the same also reduce may generation side effect so that the ideal medicament as treatment arterial thrombus class disease.
A series of patent application of thrombin receptor antagonists has been disclosed at present, including
The PCT Patent Applications such as WO2002085855, WO2005084679, WO2004078721 and WO2006051623, disclose a series of 2- lminopyrrolidines analog derivatives.
Present invention design has formula（I the compound shown in), and find that the compound with this class formation shows the activity that excellent thrombin receptor suppresses.The content of the invention
In order to overcome the deficiencies in the prior art part, it is an object of the invention to provide a kind of formula（I the new phthalazines ketones derivant shown in), and their dynamic isomer, enantiomer, diastereomer, raceme and pharmaceutically useful salt, and metabolite and metabolic precursor thereof or prodrug,
( I )
Its towel：
Ar is selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further by one or more RaSubstituent replaced；
Y is selected from-CR12- or N atoms；
L is selected from-CR13R14- or-(CH2) m -;
I 1、 R2And R3It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17Or-C (0) NR16R17Substituent replaced；
R1And R2Or R2And R3Aryl is formed together with the carbon atom being connected, wherein described aryl is optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
R4And R5Cyano group, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
Or, R4And R5Cycloalkyl is formed together with the carbon atom being connected, wherein described cycloalkyl is optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical or-NR by one or more16R17Substituent replaced；
R6Selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl ,-C (0) OR15、 -C(0)R15Or-C (0) NR16R17, wherein described alkyl, alkoxy, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl or heterocyclic radical；
RaHydrogen atom, hydroxyl, halogen, cyano group, nitro, silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR can be each independently selected from identical or different15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR by one or more15、 -OC(0)R15 -0(CH2)nC(0)OR15 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
R12Selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
R13And R14Alkyl or halogen are each independently selected from, wherein described alkyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group or nitro；
R15Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group, nitro, alkoxy or alkyl；
R16And R17Hydrogen atom, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；
Or, R16And R17Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalpHetero atom, and the heterocyclic radical is optionally further by one or more halogens, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；
R18And R19It is each independently selected from 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.The preferred scheme of the present invention, a kind of compound described in logical formula (I) or its pharmaceutically pharmaceutically useful salt, including the compound described in a kind of formula (Π)
( II )
Its towel：
Y is selected from-CR12- or N atoms；
L is selected from-CR13R14- or-(CH2) m -;
R R2And R3It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17Or-C (0) NR16R17Substituent replaced；
R1And R2Or R2And R3Aryl is formed together with the carbon being connected, wherein described aryl is optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
R4And R5Cyano group, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
Or, R4And R5Cycloalkyl is formed together with the carbon atom being connected, wherein described cycloalkyl is optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical or-NR by one or more16R17Substituent replaced；
R6Selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl ,-C (0) OR15、 -C(0)R15Or-C (0) NR16R17, wherein described alkyl, alkoxy, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl or heterocyclic radical；
R R8、 R9、 R1QAnd R11It is each independently selected from hydrogen atom, hydroxyl, halogen, cyano group, nitro, silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR by one or more15、 -OC(0)R15 -0(CH2)nC(0)OR15 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
Or, R9And R1QHeterocyclic radical, aryl or heteroaryl are formed together with the carbon atom being connected, wherein described heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15, -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
R12Selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
R13And R14Alkyl or halogen are each independently selected from, wherein described alkyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group or nitro；
R15Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group, nitro, alkoxy or alkyl；
R16And R17Hydrogen atom, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、
-C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；
Or, R16And R17Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalpHetero atom, and the heterocyclic radical is optionally further by one or more halogens, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；
R18And R19It is each independently selected from 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.The preferred scheme of the present invention, a kind of compound described in logical formula (I) or its pharmaceutically pharmaceutically useful salt, wherein
Ar is selected from 5 yuan or 6 unit's heteroaryls, preferably pyrrole radicals or pyridine radicals.
Preferred scheme-kind of formula of the present invention（I compound or its pharmaceutically useful salt, wherein R shown in)4And R5Selected from alkyl or aryl.
Preferred scheme-kind of formula of the present invention（I compound or its pharmaceutically useful salt, wherein R shown in)4And R5Cyclopropyl is formed together with the carbon atom being connected.
Preferred scheme-kind of formula of the present invention（I compound or its pharmaceutically useful salt, wherein R shown in)6Selected from hydrogen atom.
Preferred scheme-kind of formula of the present invention（I compound or its pharmaceutically useful salt, wherein R shown in)12Selected from hydrogen atom or halogen.
Preferred scheme-kind of formula of the present invention（I compound or its pharmaceutically useful salt shown in), wherein L are selected from-(CH2) m-, m is 1.The typical compound of the present invention includes, but are not limited to:
Salt π τ τ
1-(- 1-yl of 3- tert-butyl group pyrroles)-2- (5', the fluoro- 3'- imido grpups-spiral shell [cyclopropane-1 of 6'- diethoxies-4'-, 1'- isoindolines]-2'- bases) ethanone hydrobromide the present invention typical compound also include, but are not limited to:
The 3- tert-butyl groups -5- [2- (5,6- diethoxy -4- fluorine
73'-3- imino groups -1,1- dimethyl-isoindoline -2- bases) acetyl group] benzoic acid
1- [the 3- tert-butyl groups -5- (morpholine -4- carbonyls) benzene
74' yls] -2- (the fluoro- 3- imino groups of 5,6- diethoxy -4-
- 1,1- dimethyl-isoindoline -2- bases) ethyl ketone
v 、 (.
( 〇〇 〇 v
3- tert-butyl-N-cyclopropyls -5- [2- (5,6- diethyls
Fluoro- 3- imino groups -1, the 1- dimethyl of 75' epoxides -4--isoindoline -2- bases) acetyl group] the 1 o 3- tert-butyl groups -5- [2- (5', 6'- diethoxy -4'- fluorine of benzamide ^ people
76'-3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) acetyl group] benzoic acid
2- [[the 3- tert-butyl groups -5- [2- (5,6- diethoxy -4-
The fluoro- 3- imino groups -1,1- dimethyl-isoindolines of 77'
- 2- bases) acetyl group] phenyl] amino] acetonitrile
N- [the 3- tert-butyl groups -5- [2- (5', 6'- diethoxy -4'-
Fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 78') acetyl group] phenyl] acetamide
N- [the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl-isoindolines of 5,6- diethoxy -4-
79'
- 2- bases) acetyl group] phenyl] acetamide
3- tert-butyl-N-cyclopropyls -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxies -4--different
80'
Indoline -2- bases) acetyl group] -2- methoxy-b enzamides
3- tert-butyl-N-cyclopropyls -5- [2- (the fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
81 '
- 1,1'- isoindoline] -2'- bases) acetyl group] -2- methoxy-b enzamides
The 3- tert-butyl groups -5- [2- (5,6- diethoxy -4- fluorine
- 3- imino groups -1,1- dimethyl-isoindoline -2-
82'
Base) acetyl group]-N- (2,3- dihydroxypropyl) benzamide
3- tert-butyl-N-cyclopropyls -5- [2- (the fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
83'
- 1,1'- isoindoline] -2'- bases) acetyl group] benzamide
1- [the 3- tert-butyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (fluoro- 3'- imido of 5', 6'- diethoxy -4'-
84'
Base-spiral shell [cyclopropane -1,1'- isoindoline] -2'- base Ao ethyl ketones
.Work
The 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl-isoindoline -2- of 5,6- diethoxy -4-
85'
Base) acetyl group]-N- (2- hydroxyethyls) benzamide
2- [[the 3- tert-butyl groups -5- [2- (5', 6'- diethoxy -4'-
Fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 86') acetyl group] phenyl] amino] acetonitrile
The 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl-isoindoline -2- of 5,6- diethoxy -4-
87'
Base) acetyl group]-N, double (2- hydroxyethyls) benzene of N-." formamide
The 3- tert-butyl groups -5- [2- (the fluoro- 3'- imino groups of 5', 6'- diethoxy -4'--spiral shell [cyclopropane -1,1'- iso-indoles
88'
Quinoline] -2'- bases) acetyl group]-N- (2,3- dihydroxypropyl) benzamide
The 3- tert-butyl groups -5- [2- (the fluoro- 3'- imino groups of 5', 6'- diethoxy -4'--spiral shell [cyclopropane -1,1'- iso-indoles
89'
Quinoline] -2'- bases) acetyl group]-N- (2- hydroxypropyls) benzamide
1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (fluoro- 3'- imido of 5', 6'- diethoxy -4'-
90'
Base-spiral shell [cyclopropane -1,1'- isoindoline] -2'-base）Ethyl ketone
L- [the 3- tert-butyl group -5-0 methyl-pyrazol-4-yls) phenyl] -2- (the fluoro- 3'- imido of 5', 6'- diethoxy -4'-
100'
Base-spiral shell [cyclopropane -1,1'- isoindoline] -2'-base）Ethyl ketone
The 1- 3- tert-butyl group -5- isopropyl-phenyls) -2- (5,6-
The fluoro- 3- imino groups -1,1- dimethyl of 101 ' diethoxy -4-
- isoindoline -2- bases) ethyl ketone
【1- (the 3- tert-butyl group -5- isopropyl-phenyls) -2- (5', 6'-
Fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 102' diethoxies -4'-) ethyl ketone
1- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] -2- (5', 6'- diethoxy -4'- fluorine
103'o -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) ethyl ketone
The 1- 3- tert-butyl groups -5- cyclopropyl-phenyl) -2- (5', 6'-
The fluoro- 3'- imino groups of 104' diethoxies -4'--spiral shell [ring third
Alkane -1,1'- isoindoline] -2'- bases) ethyl ketone
The 1- 3- tert-butyl groups -5- cyclopropyl-phenyl) -2- (5,6-
The fluoro- 3- imino groups -1,1- dimethyl of 105' diethoxies -4-
- isoindoline -2- bases) ethyl ketone
1- [the 3- tert-butyl groups -5- (trifluoromethyl)-benzene
106' yls] -2- (the fluoro- 3- imino groups of 5,6- diethoxy -4-
- 1,1- dimethyl-isoindoline -2- bases) ethyl ketone
1- [the 3- tert-butyl groups -5- (the trifluoromethyl)-bases of benzene f NH 0] -2- (fluoro- 3'- imido of 5', 6'- diethoxy -4'-
107'
Base-spiral shell [cyclopropane -1,1'- isoindoline] -2'-base）Ethyl ketone
2- [the 3- tert-butyl groups -5- [2- (5', 6'- diethoxy -4'-
Fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 108') acetyl group] phenyl] -2- methyl-propanenitriles
2- [the 3- tert-butyl groups -5- [2- (5,6- diethoxy -4-
The fluoro- 3- imino groups -1,1- dimethyl-isoindolines of 109'
- 2- bases) acetyl group] phenyl] -2- methyl-propanenitriles
L- (3- tert-butyl group pyrroles -1- bases) -2- (5,6- diethyls
Fluoro- 3- imino groups -1, the 1- dimethyl of 119' epoxides -4--isoindoline -2- bases) ethyl ketone
1-(- 1-yl of 3- tert-butyl group pyrroles)-2- (5', 6'- diethyls
The fluoro- 3'- imido grpups-spiral shell [cyclopropane of 120' epoxides -4'-
- 1,1'- isoindoline] -2'- bases) ethyl ketone or its pharmaceutically useful salt.The present invention relates to a kind of formula（I compound or its pharmaceutically useful salt described in), its formula of（I) compound exists in the form of free state or pharmaceutically useful acid-addition salts, described pharmaceutically useful acid-addition salts include hydrochloride, hydrobromate, mesylate, sulfate, phosphate, maleate, malate, citrate, acetate or trifluoroacetate, preferably hydrobromate and hydrochloride.The present invention relates to a kind of formula（I the synthetic method of compound shown in), this method includes：
By formula（IA) compound or（IB) compound
(IA) or
Reacted with formula (IC) compound, obtain formula（I) compound;
Its towel：
X is selected from halogen, preferably chlorine atom or bromine atoms；
Wherein：L, Y, R^ R11Definition as described in general formula compound.The present invention relates to the compound shown in formula (IA) or (IB), it is as preparing formula（I) the centre of compound
(IA) (IB)
Its towel：
Y is selected from-CR12- or N atoms；
R R2And R3It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17Or-C (0) NR16R17Substituent replaced；
R1And R2Or R2And R3Aryl is formed together with the carbon atom being connected, wherein described aryl is optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
R4And R5Cyano group, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
Or, R4And R5Cycloalkyl is formed together with the carbon atom being connected, wherein described cycloalkyl is optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical or-NR by one or more16R17Substituent replaced；
R6Selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl ,-C (0) OR15、
-C(0)R15Or-C (0) NR16R17, wherein described alkyl, alkoxy, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl or heterocyclic radical；
R12Selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15 -0(CH2)nC(0)OR15 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、
-C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；
R15Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group, nitro, alkoxy or alkyl；
R16And R17Hydrogen atom, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；
Or, R16And R17Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalpHetero atom, and the heterocyclic radical is optionally further by one or more halogens, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；
R18And R19It is each independently selected from hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；
N is selected from 1,2 or 3;And
P is selected from 0,1 or 2.The preferred scheme of the present invention, a kind of formula (IA) or compound or its pharmaceutically useful salt, wherein R shown in (IB)4And R5Selected from alkyl or aryl.
The preferred scheme of the present invention, a kind of formula (IA) or compound or its pharmaceutically useful salt, wherein R shown in (IB)4And R5Cyclopropyl is formed together with the carbon atom being connected.
The preferred scheme of the present invention, a kind of formula (IA) or compound or its pharmaceutically useful salt shown in (IB), wherein
R6Selected from hydrogen atom.
The preferred scheme of the present invention, a kind of formula (IA) or compound or its pharmaceutically useful salt, wherein R shown in (IB)12Selected from hydrogen atom or halogen.
The equivalent one considered is those skilled in the art will appreciate that be, the form of dynamic isomer also may be present in compound (IA).Compound（I A) tautomeric form may include but be not limited to by following formula (IB) represent structure：
(IA) (IB)
All these tautomeric forms are included in the scope of the present invention and are inherently included in compound（I A) definition in.Formula (IA) or the typical compound of (IB) compound include, but are not limited to:
Or its pharmaceutically useful salt.The present invention relates to a kind of formula (1) or（The preparation method of IB compounds, this method includes:
By formula（III) dimethyl sulfoxide solution of compound is in the presence of cuprous cyanide and cuprous iodide, heating response, obtains formula (IA) or (IB) compound；
(IV)
Or, under ice bath, by formula（IV) compound is mixed with grignard reagent and titanate esters, at room temperature stirring reaction, obtains formula (IA) or (IB) compound；
(V)
Or, by formula（V) compound and concentrated ammonia liquor and tert-butoxy hydroperoxidation, obtain formula (IA) or (IB) compound；
(VI)
Or, by the tetrahydrofuran solution of logical formula (VI) compound in the presence of water and triphenylphosphine, stirring reaction, obtains formula (IA) or (IB) compound at room temperature.Another aspect of the present invention is related to a kind of pharmaceutical composition, and its present invention for containing treatment effective dose leads to formula (I) compound or its pharmaceutically useful salt and pharmaceutically useful carrier.
Another aspect of the present invention is related to formula of the present invention（I) compound or its pharmaceutically useful salt, or containing them
Pharmaceutical composition purposes in calcium ion transport inhibitor is prepared.
Another aspect of the present invention is related to formula of the present invention（I) compound or its pharmaceutically useful salt, or the purposes in thrombin receptor antagonist is prepared of the pharmaceutical composition containing them, wherein described thrombin receptor antagonist is
PARI receptor antagonists.
The present invention relates to formula of the present invention（I) compound or its pharmaceutically useful salt, or purposes of the pharmaceutical composition containing them in platelet aggregation inhibitor is prepared.
The present invention relates to formula of the present invention（I) compound or its pharmaceutically useful salt, or purposes of the pharmaceutical composition containing them in inhibitors of smooth muscle cell proliferation.
The present invention relates to formula of the present invention（I) compound or its pharmaceutically useful salt, or purposes of the pharmaceutical composition containing them in the medicine for preparing the treatment disease relevant with thrombin receptor, wherein the disease relevant with thrombin receptor is selected from DVT, reangiostenosis, deep vein thrombosis, pulmonary embolism disease, cerebral infarction, heart disease, sowing property vessel inner blood solidification syndrome, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.
The present invention relates to a kind of method for suppressing calcium ion transport, this method includes giving the formula for the effective therapeutic dose of patient for needing to treat（I) compound or its pharmaceutically useful salt, or the pharmaceutical composition containing them.
The present invention relates to a kind of method for suppressing thrombin receptor, this method includes giving the formula for the effective therapeutic dose of patient for needing to treat（I) compound or its pharmaceutically useful salt, or the pharmaceutical composition containing them, wherein described thrombin receptor is PARI acceptors.
The present invention relates to a kind of method for suppressing platelet aggregation, this method includes giving the formula for the effective therapeutic dose of patient for needing to treat（I) compound or its pharmaceutically useful salt, or the pharmaceutical composition containing them.
The present invention relates to a kind of method for suppressing smooth muscle cell proliferation, this method includes giving the formula for the effective therapeutic dose of patient for needing to treat（I) compound or its pharmaceutically useful salt, or the pharmaceutical composition containing them.
The present invention relates to a kind of method for treating the disease relevant with thrombin receptor, this method includes giving the formula for the effective therapeutic dose of patient for needing to treat（I) compound or its pharmaceutically useful salt, or the pharmaceutical composition containing them, wherein the disease relevant with thrombin receptor is selected from DVT, reangiostenosis, deep vein thrombosis, pulmonary embolism disease, cerebral infarction, heart disease, sowing property vessel inner blood solidification syndrome, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.
The present invention relates to formula（I) compound or its pharmaceutically useful salt, or contain their pharmaceutical composition as the medicine for suppressing calcium ion transport.
The present invention relates to formula（I) compound or its pharmaceutically useful salt, or contain their pharmaceutical composition as the medicine for suppressing thrombin receptor, wherein described thrombin receptor is PARI acceptors.
The present invention relates to formula（I) compound or its pharmaceutically useful salt, or contain their pharmaceutical composition as the medicine for suppressing platelet aggregation.
The present invention relates to formula（I) compound or its pharmaceutically useful salt, or contain their pharmaceutical composition as the medicine for suppressing smooth muscle cell proliferation.
The present invention relates to formula（I) compound or its pharmaceutically useful salt, or the pharmaceutical composition for containing them is as controlling
The medicine of the disease relevant with thrombin receptor is treated, wherein the disease relevant with thrombin receptor is selected from DVT, reangiostenosis, deep vein thrombosis, pulmonary embolism disease, cerebral infarction, heart disease, sowing property vessel inner blood solidification syndrome, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.The detailed description of invention
Unless stated to the contrary, the term used in the specification and in the claims has following implications.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.Preferably comprise the alkyl of 1 to 12 carbon atom,Non-limiting example includes methyl,Ethyl,N-propyl,Isopropyl,Normal-butyl,Isobutyl group,The tert-butyl group,Sec-butyl,N-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls,1- ethyl propyls,2- methyl butyls,3- methyl butyls,N-hexyl,1- Ethyl-2-Methyl propyl group, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1 ,3- dimethylbutyls,2- ethyl-butyls,2- methyl amyls,3- methyl amyls,4- methyl amyls, 2,3- dimethylbutyls,N-heptyl,2- methylhexyls,3- methylhexyls,4- methylhexyls,5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl amyl groups, 3,3- dimethyl amyl groups,2- ethyl pentyl groups,3- ethyl pentyl groups,N-octyl, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls,2- ethylhexyls,3- ethylhexyls,4- ethylhexyls,2- methyl -2- ethyl pentyl groups,2- methyl -3- ethyl pentyl groups,N-nonyl,2- methyl -2- ethylhexyls,2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups,Positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls,And its various branched chain isomers etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1- dimethyl propyls, 1, 2- dimethyl propyls, 2, 2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1, 1, 2- thmethylpropyls, 1, 1- dimethylbutyls, 1, 2- dimethylbutyls, 2, 2- dimethylbutyls, 1, 3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2, 3- dimethylbutyls etc..Alkyl can be substituted or unsubstituted, when substituted, substituent can be substituted on any workable tie point, preferably one or more following groups, independently selected from alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carbonyl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17。
" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring includes 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring.
" spiro cycloalkyl group " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic moiety of a carbon atom (title spiro-atom), these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into by single spiro cycloalkyl group, double spiro cycloalkyl group bases or many spiro cycloalkyl groups according to the number of shared spiro-atom between ring and ring, is preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.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 groups.The non-limiting reality of spiro cycloalkyl group
" cycloalkyl " refers to 5 to 20 yuan, the full carbon polycyclic moiety of each ring and shared a pair of the carbon atoms adjoined of other rings in system in system, wherein one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl can be divided into according to the number of composition ring.The non-limiting example of cycloalkyl is included
" bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, and these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, preferably bicyclic, three rings or Fourth Ring can be divided into according to the number of composition ring, bicyclic or three rings are more elected as.Bridge ring alkyl it is non-limiting
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being cycloalkyl with the ring that precursor structure links together, non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carbonyl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、
-C(0)NR16R17Or-S (0) ONR16R17。
" alkenyl " refers to the alkyl as defined above being made up of at least two carbon atoms and at least one carbon-to-carbon double bond.Such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyls etc..Alkenyl can be substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15 、 -S(0)pR15 、 -NR16R17 、 -OC(0)NR16R17 、 -C(0)NR16R17Or-S (0) ONR16R17。
" block base " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond are constituted.Such as second block base, third piece of base of 1-, 2- third piece of base, 1-, 2- or 3- fourth block bases etc..Block base can be substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15 、 -S(0)pR15 、 -NR16R17 、 -OC(0)NR16R17 、 -C(0)NR16R17Or-S (0) ONR16R17。
" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 annular atoms, and wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)nThe hetero atom of (wherein n is integer 0 to 2), but do not include -0-0-, -0-S- or-S-S- loop section, remaining annular atom is carbon.3 to 12 annular atoms are preferably included, wherein 14 are hetero atoms, more preferably cycloalkyl ring includes 3 to 10 annular atoms.The non-limiting example of monocyclic cycloalkyl includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc..Polycyclic naphthene base includes the heterocyclic radical of loop coil, condensed ring and bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic heterocyclic group of an atom (title spiro-atom), wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)pThe hetero atom of (wherein p is integer 0 to 2), remaining annular atom is carbon.These can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into by single spiro heterocyclic radical, double spiro heterocyclic radicals or many spiro heterocyclic radicals according to the number of shared spiro-atom between ring and ring, is preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.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 groups.The non-limiting example of spiro cycloalkyl group is included
" condensed hetero ring base " refers to each ring in 5 to 20 yuan, system and shared a pair of the atoms adjoined of other rings in system
Polycyclic heterocyclic group, one or more rings can contain one or more double bonds, but neither one ring has a pi-electron system of total conjugated, and wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)pThe hetero atom of (wherein p is integer 0 to 2), remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic fused heterocycloalkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases can be divided into according to the number of composition ring.The non-limiting example of condensed hetero ring base is included
" bridge heterocyclic radical " refers to 5 to 14 yuan, any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)pThe hetero atom of (wherein ρ is integer 0 to 2), remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, preferably bicyclic, three rings or Fourth Ring, more three rings can be divided into according to the number of composition ring.The non-limiting example of bridge ring alkyl is included：
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring being connected to precursor structure is heterocyclic radical, is applied example and included：
Deng.Heterocyclic radical can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, is washed epoxide, cycloalkylthio, heterocycle alkylthio group, carbonyl ,-C (0) OR independently selected from alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle15、 -OC(0)R15、 -0(CH2)nC(0)OR15 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17。
" aryl " refers to that 6 to 14 yuan of full carbon are monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group,
Polycyclic (i.e. its ring for carrying phase adjacency pair carbon atom) group, preferably 6 to 10 yuan, such as phenyl and naphthyl of pi-electron system with conjugation.The aryl rings can be condensed on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is aryl rings, non-limiting example is included：
Aryl can be substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, is washed sulfenyl, heterocycle alkylthio group ,-C (0) OR independently selected from alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, ^ elements, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, ring15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17。
" heteroaryl " refers to comprising 1 to 4 hetero atom, and the heteroaromatic system of 5 to 14 annular atoms, wherein hetero atom include oxygen, sulphur and nitrogen.Preferably 6 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl, which is preferably, such as furyl, thienyl, pyridine radicals, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical.The heteroaryl ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, wherein linked together with precursor structure：
Heteroaryl can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, is washed epoxide, cycloalkylthio, heterocycle alkylthio group ,-C (0) OR independently selected from alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle15、 -OC(0)R15、 -0(CH2)nC(0)OR15 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17。
" alkoxy " refers to-O- (base of washing) and-O- (unsubstituted cycloalkyl), and wherein alkyl is as defined above.Non-limiting example includes methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..Alkoxy can be optionally substituted or unsubstituted, when substituted, replace
Base is preferably one or more following groups, independently selected from for alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (0) OR15、 -OC(0)R15 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17。
" silylation " refers to silane (SiH4) in the organosilan group that is replaced by one or more alkyl, alkenyl, block base, aryl, heteroaryl, alkoxy, cycloalkyl, heterocyclic radical of hydrogen, wherein alkyl, alkenyl, block base, aryl, heteroaryl, alkoxy, cycloalkyl, heterocyclic radical can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkoxy, halogen, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carbonyl ,-C (0) OR15、 -OC(0)R15、
-0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17.Non-limiting example includes trimethyl silicon substrate, dimethyl ethyl silicon substrate, tri-tert silicon substrate, methyl diethoxy silicon substrate, trimethoxy silicon substrate, phenyl silicon substrate etc.
" hydroxyl " refers to-OH groups.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH2。
" cyano group " refers to-CN.
" nitro " refers to-N02。
" methenamine " refers to hexa.
" hydroxyalkyl " refers to alkyl and is optionally substituted by a hydroxyl group.
。
" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes the event or environment occurs or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " mean alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" pharmaceutical composition " is represented containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.The purpose of pharmaceutical composition is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.
M, n, p and R15〜R17Definition such as formula（I) described in compound.
The synthetic method of the compounds of this invention is in order to complete the purpose of the present invention, and the present invention is adopted the following technical scheme that：
Formula of the present invention（I) compound or the preparation method of its pharmaceutically useful salt, comprise the following steps:
(IA) (IB) (IC)
At room temperature, by formula（IA) compound or（IB) tetrahydrofuran solution of compound reacts with formula (IC) compound, under the conditions of triethylamine, obtains formula（I) compound；
Formula of the present invention（IA) or (IB) compound or:
(II) (IA) (IB) is by formula（π) dimethyl sulfoxide solution of compound is in the presence of cuprous cyanide and cuprous iodide, heating response, obtains formula (Ι Α) or (IB) compound；
(m) (IA) (IB) or, under ice bath, by formula（Π Ι) compound mixes with grignard reagent and titanate esters, and stirring reaction, obtains formula (IA) or (IB) compound at room temperature；
Or, by formula（IV) compound and concentrated ammonia liquor and tert-butoxy hydroperoxidation, obtain formula (IA) or (IB) chemical combination
(V) (IA) (IB)
Or, by the tetrahydrofuran solution of logical formula (V) compound in the presence of water and triphenylphosphine, stirring reaction, obtains formula (IA) or (IB) compound at room temperature.
Wherein X is selected from halogen, preferably chlorine atom or bromine atoms；L, Y and！^〜^1Definition such as formula（I described in).Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments not limit the scope of the present invention.
Embodiment
The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).NMR displacements (δ) with hundred a ten thousandths (；Ppm unit) is provided.NMR measure is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl sulfoxide (DMSO-), deuterochloroform (CDC13), deuterated methanol (CH3OD), be inside designated as tetramethylsilane (TMS), chemical shift be with 10-6(ppmM first provides for unit.
MS measure is with FINMGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model： Finnigan LCQ advantage MAX).
HPLC measure uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire C18 150x4.6mm chromatographic columns) and Waters 2695-2996 high pressure liquid chromatographs (Gimini C18 150x4.6mm chromatographic columns）.
IC50The measure of value with NovoStar ELIASAs (；German BMG companies）.
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used is the mm of 0.15 mm 0.2, and the specification that thin-layer chromatography isolates and purifies product use is the mm of 0.4 mm 0.5.
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200 300.
The known initiation material of the present invention can be used or synthesized according to methods known in the art, or it is commercially available from ABCR GmbH ＆ Co. KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry scientific and technological (Accela ChemBio Inc), up to companies such as auspicious chemicals.
Carried out in embodiment without specified otherwise under blanket of nitrogen or argon atmospher.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction using Parr 3916EKX types hydrogenation instrument and clear indigo plant QL-500 types hydrogen generator or
HC2-SS types hydrogenate instrument.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Microwave reaction uses the type microwave reactors of CEM Discover-S 908860.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 20 °C 30 °C.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), there is the system of solvent used in reaction：Dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, acetone, the volume ratio of solvent are adjusted according to the polarity difference of compound.
The system of the eluant, eluent for the column chromatography that purifying compound is used and the system of the solvent of thin-layered chromatography include： A:Dichloromethane and methanol system, B:N-hexane and ethyl acetate system, C:Ethyl acetate and methanol system, D:Just oneself washes, E:Ethyl acetate, the volume ratio of solvent is adjusted according to the polarity difference of compound, can also add the acid reagents such as the alkalescence such as a small amount of triethylamine or acetic acid and be adjusted.Embodiment 1
1- 3,5- di-tert-butyl-hydroxy phenyl) -2- 3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1,1'- isoindoline] -2'- base ethanone hydrobromides
4,5- dimethoxy phthalic nitriles
By 1,2- bis- bromo- 4,5- dimethoxy benzenes la (20.01 g, 68 mmol) it is dissolved in 100 mL N, in dinethylformamide, cuprous cyanide (24.00 g, 272 mmol) is added, 150 °C of lower stirring reactions continue stirring reaction 5 hours under 1 hour, 170 °C.Reaction solution is poured into 100 mL ammoniacal liquor, 400 mL ethyl acetate are added, filtering, filter cake is washed (100 mLx6) with ethyl acetate.Filtrate is extracted with ethyl acetate (200 mLx2), merges organic phase, anhydrous sodium sulfate drying, filtering, the dense Shrink of filtrate decompression, crude product recrystallization (methanol：The mL of ethyl acetate=10:20 mL) purifying, obtain title product 4,5- dimethoxy phthalic nitriles lb (4.50 g, white solid), yield： 35.0%.
Ή NMR (400 MHz, CDC13, ppm): δ 7.20 (s, 2H), 4.01 (s, 6H)
Second step
5', 6'- dimethoxy spiral shell [cyclopropane -1,3'- isoindolines] under-Γ-imines hydrobromate ice bath, 4,5- dimethoxy phthalic nitriles lb (0.94 g, 5 mmol) is dissolved in 50 mL ether, add tetraisopropyl titanate (1.65 mL, 5.58 mmol) and ethylmagnesium bromide (3.70 mL, 11.10 mmol), stirring reaction 2.5 hours.55 mL methanol are added into reaction solution, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 5', 6'- dimethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate lc (407 mg, brown solid), yield： 37.3%.
MS m/z (ESI): 219 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 10.37 (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- l- of 2- (3,5- di-tert-butyl-hydroxy phenyl) ethyl ketone
Under dry ice-propanone bath, by aluminium chloride (16.00 g, 0.12 mol) it is dissolved in 150 mL dichloromethane, sequentially add bromoacetyl chloride le (10 mL, 0.12 mol) and 70 mL 2,6- Di-tert-butyl-phenols Id (24.50 g, 0.12 mol) dichloromethane solution, stirring reaction 1 hour.300 mL frozen water are added into reaction solution, filtering, aqueous phase is washed (200 mLx3) with dichloromethane, merge organic phase, washed (200 mLx3) with saturated sodium bicarbonate solution (200 mLx3) and saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (3,5- di-tert-butyl-hydroxy phenyl) ethyl ketone If (28 g, yellow solid), yield： 72.0%.
MS m/z (ESI): 326 [M-l]
1H NMR (400 MHz, CDC13, ppm):δ 7.89 (s, 2H), 5.84 (br. s, 1H), 4.40 (s, 2H), 1.48 (s, 18H)
4th step
L- (3,5- di-tert-butyl-hydroxy phenyl) -2- 3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- dimethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate lc (223 mg, 1.02 mmol) it is dissolved in 3 mL tetrahydrofurans, add 2- bromo- 1- (3,5- di-tert-butyl-hydroxy phenyl) ethyl ketone If (398 mg, 1.22 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (5 mLx2) successively, water (3 mLx2) and ethyl acetate washing (0.5 mLx2), vacuum drying, obtains title product 1-C3,5- di-tert-butyl-hydroxy phenyl) -2-C3'- imino groups -5', 6'- dimethoxys-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethanone hydrobromide l (138 mg, yellow solid), 29.1%.
MS m/z (ESI): 465 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.64 (br. s, 1H), 9.08 (br. s, 1H), 7.86 (br. s, lH), 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
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1, Γ-different
- 2'- bases) ethanone hydrobromide
The first step
1- (3- tert-butyl-hydroxy phenyls) ethyl ketone
Under dry ice-propanone bath, by aluminium chloride C71.0 g, 0.53 mol) it is dissolved in 250 mL dichloromethane, add
Chloroacetic chloride 2b (37.9 mL, 0.53 mol) is added dropwise in 2- t-butyl-phenols 2a (81.6 mL, 0.53 mol), stirring reaction 2 hours, continues stirring reaction 1 hour.300 mL frozen water are added into reaction solution, are filtered, solid vacuum drying obtains title product 1- (3- tert-butyl-hydroxy phenyls) ethyl ketone 2c (32 g, white solid), yield： 31.3%.
MS m/z (ESI): 191 [M-l]
Second step
The iodo- phenyl of 1- 3- tertiary butyl-4-hydroxies -5-) ethyl ketone
1- (3- tert-butyl-hydroxy phenyls) ethyl ketone 2c (16.2 g, 84.3 mmol) is dissolved in 200 mL acetonitriles, N- N-iodosuccinimide C20.9 g, 92.8 mmol is added), stirring reaction 4 hours.Jian Ya Nong Shrink, add 50 mL water and 50 mL ethyl acetate, divide liquid, aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the iodo- phenyl of 3- tertiary butyl-4-hydroxies -5-) ethyl ketone 2d (16.1 g, yellow solid), yield： 60.0%
MS m/z (ESI): 317 [M-l]
1H NMR (400 MHz, CDC13, ppm):δ 8.17 (s, 1H), 7.90 (d, /=1.6 Hz, 1H), 5.98 (br. s,
1H), 2.55 (s, 3H), 1.48 (s, 9H)
3rd step
The iodo- 4- methoxyphenyls of the 1- 3- tert-butyl groups -5-) ethyl ketone
Under 25 °C, by 1- (the iodo- phenyl of 3- tertiary butyl-4-hydroxies -5-) ethyl ketone 2d (16.1 g, 51 mmol) it is dissolved in 200 mL acetone, add potassium carbonate (21.14 g, 153 mmol) and iodomethane (18 g, 127 mmol), stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the iodo- 4- methoxyphenyls of the 3- tert-butyl groups -5-) ethyl ketone 2e (14.2 g, pale yellow oil), yield： 84.5%.
1H NMR (400 MHz, CDC13, ppm):5 8.25 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 3.93 (s, 3H), 2.54 (s, 3H), 1.39 (s, 9H)
4th step
1-tert-butyl group-5- (l, l-dimethoxy-ethyl) the iodo- 2- methoxybenzenes of-3- are by 1- (the iodo- 4- methoxyphenyls of the 3- tert-butyl groups-5-) ethyl ketone 2e (2.6 g, 7.83 mmol) and trimethyl orthoformate (2.49 g, 23.5 mol) it is dissolved in 2.6 mL methanol, add D (+)-10- camphorsulfonic acids (91 mg, 0.39 mmol), stirring reaction 12 hours.217 mg potassium carbonate are added into reaction solution, stirring 0.5 hour, add 10 mL water and 10 mL n-hexanes, aqueous phase is with n-hexane extraction (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product the 1- tert-butyl groups -5-G, l- dimethoxy-ethyl) iodo- 2- methoxybenzenes 2f (2.3 g of -3-, pale yellow oil), yield： 79.3%.
1H NMR (400 MHz, CDC13, ppm):5 7.82 (d, J=2.0 Hz, 1H), the 7.41 (Hz of d, J=2.0,1H), 3.89 (s, 3H), 3.18 (s, 6H), 1.51 (s, 3H), 1.40 (s, 9H)
5th step
4- [the 3- tert-butyl group -5- (l, l- dimethoxy-ethyls) -2- methoxyphenyls]-morpholine is by the 1- tert-butyl groups -5- (1,1- dimethoxy-ethyls) iodo- 2- methoxybenzenes 2f (3.3 g of -3-, 8.73 mmol) and 2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl (172 mg, 0.44 mmol) it is dissolved in 33 mL toluene, add palladium/carbon (330 mg, 10%), sodium tert-butoxide（1.68 g, 17.46 mmol) and morpholine (1.52 g, 17.46 mmol), 60 °C of lower stirring reactions 3 hours.100 mL water are added into reaction solution, aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4- [the 3- tert-butyl groups -5- (1,1- dimethoxy-ethyls) -2- methoxyphenyls]-morpholine 2g (1.5 g, brown oil), yield： 51.0%.
MS m/z (ESI): 338 [M+l]
6th step
The bromo- l- of 2- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketones are by 4- [the 3- tert-butyl groups -5- (1,1- dimethoxy-ethyls) -2- methoxyphenyls]-morpholine 2g (1.5 g, 4.45 mmol) it is dissolved in 18 mL acetic acid, add pyridinium tribromide Key salt (1.57 g, 4.90 mmol), stirring reaction 2 hours.30 mL water are added into reaction solution, aqueous phase is extracted with ethyl acetate (20 mLx3), merge organic phase, with full
(10 mLx3) is washed with sodium chloride solution, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (the 3- tert-butyl groups -4- methoxyl groups -5- morpholinyl phenyls) ethyl ketone 2h (930 mg, faint yellow solid), yield： 56.4%.
MS m/z (ESI): 370 [M+l]
1H NMR (400 MHz, CDC13, ppm):5 7.70 (d, J=2.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 4.41 (s, 2H), 4.0 l (s, 3H), 3.90 (m, 4H), 3.09 (m, 4H), 1.40 (s, 9H)
7th step
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- dimethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate lc (229 mg, 1.05 mmol) it is dissolved in 4 mL tetrahydrofurans, add 2- bromo- 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketone 2h (440 mg, 1.19 mmol) and triethylamine (0.2 mL, 1.44 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (5 mLx2) successively, water (3 mLx2) and ethyl acetate washing (0.5 mLx2), vacuum drying, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) (168 mg of ethanone hydrobromide 2, buff powder), yield： 31.5% MS m/z (ESI): 508 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.71 (br. s, 1H), 9.13 (br. s, 1H), 7.91 (s, 1H), 7.62 (d, /=1.6 Hz, 1H), 7.55 (d, /=1.6 Hz, 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
L- (the 3- tert-butyl group -4- methoxyphenyls) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1, Γ-iso-indoles
'-yl) ethanone hydrobromide
2c 3a 3b 3 HBr
The first step
L- (the 3- tert-butyl group -4- methoxyphenyls) ethyl ketone
By l-O tert-butyl-hydroxy phenyls) ethyl ketone 2c (6.3 g, 32.8 mmol) it is dissolved in 50 mL acetone, add potassium carbonate (13.6 g, 98.4 mmol) and iodomethane (11.65 g, 82 mmol), 50 °C of lower stirring reactions 2 hours.Filtering, filtrate decompression Nong Shrink add 50 mL water and 50 mL dichloromethane, and point liquid, organic phase is washed (20 mLx3) with saturated nacl aqueous solution, anhydrous sodium sulfate drying, and filtering, filtrate decompression Nong Shrink obtain title
The product 1- 3- tert-butyl group -4- methoxyphenyls) ethyl ketone 3a (6.0 g, white solid), yield： 88.6%.
1H NMR (400 MHz, CDC13, ppm):δ 7.99 (d, J=2.0 Hz, 1H), 7.87 (dd ,=8.4 Hz, J2
=2.0 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.97 (s, 3H), 2.60 (s, 3H), 1.46 (s, 9H)
Second step
The bromo- l- of 2- (the 3- tert-butyl group -4- methoxyphenyls) ethyl ketone
1- (the 3- tert-butyl group -4- methoxyphenyls) ethyl ketone 3a (1.0 g, 4.8 mmol) are dissolved in 8 mL acetic acid, pyridinium tribromide Key salt (1.6 g, 5.04 mmol), stirring reaction 3.5 hours is added.Jian Ya Nong Shrink, add 20 mL water and 20 mL ethyl acetate, divide liquid, aqueous phase is extracted with ethyl acetate (50 mIX3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (the 3- tert-butyl group -4- methoxyphenyls) ethyl ketone 3b (900 mg, pale yellow oil), yield： 66.2%.
1H NMR (400 MHz, CDC13, ppm):δ 8.02 (d, J=2.0 Hz, 1H), 7.91 (dd ,/；= 8.8 Hz, J2=2.0 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 4.44 (s, 2H), 3.97 (s, 3H), 1.44 (s, 9H)
3rd step
L- (the 3- tert-butyl group -4- methoxyphenyls) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- dimethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate lc (240 mg, 1.1 mmol) it is dissolved in 3 mL tetrahydrofurans, add 2- bromo- 1- (the 3- tert-butyl group -4- methoxyphenyls) ethyl ketone 3b (360 mg, 1.26 mmol) and triethylamine (0.3 mL, 2.16 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (5 mLx2) successively, water (3 mLx2) and ethyl acetate washing (0.5 mLx2), vacuum drying, obtain title product 1- (the 3- tert-butyl group -4- methoxyphenyls) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) (287 mg of ethanone hydrobromide 3, buff powder), yield： 61.7%
MS m/z (ESI): 423 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.68 (br. s, 1H), 9.14 (br. s, 1H), 8.00 (dd ,/；= 8.8 Hz, /2=1.6 Hz, 1H), 7.88 (s, lH), 7.86 (d, /=1.6 Hz, 1H), 7.21 (d, /=8.8 Hz, 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
L- (the bromo- 5- tert-butyl-hydroxy phenyls of 3-) -2- (3'- imino groups -5', 6'- dimethoxy spiral shell [cyclopropane -1, Γ-isoindoline -2'- bases) ethanone hydrobromide
The first step
L- (the bromo- 5- tert-butyl groups of 3--4- hydroxy phenyl)-ethyl ketone
1- (3- tert-butyl-hydroxy phenyls) ethyl ketone 2c (6.3 g, 32.8 mmol) is dissolved in 50 mL acetonitriles and DMF (V/V=10:L) in the mixed solvent, adds N- bromo-succinimides (10.2 g, 57 mmol), stirring reaction 0.5 hour.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the bromo- 5- tert-butyl-hydroxy phenyls of 3-) ethyl ketone 4a (12.1 g, white solid), yield： 85.8%.
MS m/z (ESI): 269 [M-l]
1H NMR (400 MHz, CDC13, ppm):δ 8.03 (d, J=2.0 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 6.33 (br. s, 1H), 2.58 (s, 3H), 1.46 (s, 9H)
Second step
2-bromo- l- (the bromo- 5- tert-butyl-hydroxy phenyls of 3-) ethyl ketone
1- (the bromo- 5- tert-butyl-hydroxy phenyls of 3-) ethyl ketone 4a (5.0 g, 18.4 mmol) are dissolved in 50 mL acetic acid, pyridinium tribromide Key salt (6.2 g, 19.4 mmol), stirring reaction 12 hours is added.Jian Ya Nong Shrink, add 100 mL water and 100 mL ethyl acetate, divide liquid, aqueous phase is extracted with ethyl acetate (100 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (the bromo- 5- tert-butyl groups -4- hydroxy phenyls of 3-) ethyl ketone 4b (6.4 g, grey grease), yield： 99.2%.
MS m/z (ESI): 349 [M-l]
1H NMR (400 MHz, CDC13, ppm):δ 8.07 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 6.41 (br. s, 1H), 4.40 (s, 2H), 1.48 (s, 9H)
3rd step
L- (the bromo- 5- tert-butyl-hydroxy phenyls of 3-) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- dimethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate lc (228 mg, 1.05 mmol) it is dissolved in 4 mL tetrahydrofurans, add 2- bromo- 1- (the bromo- 5- tert-butyl-hydroxy phenyls of 3-) ethyl ketone 4b (540 mg, 1.54 mmol) and triethylamine (0.3 mL, 2.16 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (10 mLx2) successively, water (5 mLx4) and ethyl acetate washing (2 mLx2), vacuum drying, obtain title product 1- (the bromo- 5- tert-butyl-hydroxy phenyls of 3-) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) (166 mg of ethanone hydrobromide 4, buff powder), yield： 32.6% MS m/z (ESI): 487 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.63 (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
2- [the 8- tert-butyl groups -6- [2-C3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) acetyl
The first step
1- (3- tertiary butyl-4-hydroxy -5- nitro-phenyls)-ethyl ketone
Under 10 °C, 68% concentrated nitric acid (105 mL, 1.6 mol) is dissolved in 60 mL dichloromethane and water (V/V=2:1) in the mixed solvent, add 1- (3- tert-butyl-hydroxy phenyls) ethyl ketone 2c (12.87 g, 66.9 mmol), stirring reaction 0.5 hour, 60 mL ether, 0.6 mL acetic anhydrides and 105 mL concentrated hydrochloric acids are added, continue stirring reaction 1.5 hours.200 mL frozen water are added into reaction solution, it is extracted with ethyl acetate (150 mIX3), merge organic phase, it is 56 with saturated sodium bicarbonate regulation pH, washed with saturated nacl aqueous solution (50 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (3- tertiary butyl-4-hydroxy -5- nitro-phenyls) ethyl ketone 5a (6.27 g, yellow solid), yield： 39.6%.
MS m/z (ESI): 236 [M-l]
1H NMR (400 MHz, DMSO- , ppm):δ 11.40 (br. s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 2.59 (s, 3H), 1.42 (s, 9H)
Second step
L- [4- (2- the bromine oxethyls) -3- tert-butyl group -5- nitro-phenyls] ethyl ketones are by 1- (3- tertiary butyl-4-hydroxy -5- nitro-phenyls) ethyl ketone 5a (6.26 g, 26.4 mmol) it is dissolved in 80 mL N, in dinethylformamide, add potassium carbonate (18.25 g, 132 mmol) and 1,2- Bromofumes (24.8 g, 132
), mmol 100 °C of lower stirring reactions 10 hours.Jian Ya Nong Shrink, add 200 mL water, it is extracted with ethyl acetate (200 mLx3), merge organic phase, washed with saturated nacl aqueous solution (100 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [4- (2- the bromine oxethyls) -3- tert-butyl group -5- nitro-phenyls] ethyl ketone 5b (5.74 g, yellow oil), yield： 48.6%.
1H NMR (400 MHz, DMS0- , ppm):δ 8.32 (d, J=2.0 Hz, 1H), 8.11 (d, /=2.0 Hz, 1H), 4.25 (m, 2H), 3.82 (m, 2H), 2.62 (s, 3H), 1.44 (s, 9H)
3rd step
L- (the 8- tert-butyl groups -3,4- dihydros -2H-1,4- benzoxazine -6- bases) ethyl ketone is by 1- [4- (2- the bromine oxethyls) -3- tert-butyl group -5- nitro-phenyls] ethyl ketone 5b (3.65 g, 10.6 mmol) it is dissolved in 35 mL toluene, add palladium/carbon (0.5 g, 10%), hydrogen is replaced three times, stirring reaction 40 hours.30 mL ethyl acetate are added into reaction solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- (8- tert-butyl group -3,4- dihydro -2H-1,4- benzoxazine -6- bases) ethyl ketone 5c (400 mg, yellow solid), yield： 14.8% o
MS m/z (ESI): 234 [M+l]
4th step
2- (6- acetyl group -8- the tert-butyl groups -2; 3- dihydros -1; 4- benzoxazine -4- bases) ethyl acetate is by 1- (8- tert-butyl group -3,4- dihydro -2H-1,4- benzoxazine -6- bases) ethyl ketone 5c (4.8 g; 20.5 mmol) it is dissolved in 80 mL N; in dinethylformamide, potassium carbonate (8.5 g, 61.7 mmol) and bromoacetate (11.5 mL are added; 102 mmol), 100 °C of lower stirring reactions 3 hours.Jian Ya Nong Shrink; add 200 mL water; it is extracted with ethyl acetate (100 mLx3); merge organic phase; washed with saturated nacl aqueous solution (50 mLx3); anhydrous sodium sulfate drying; filtering; filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the title product 2- (6- acetyl group -8- tert-butyl groups -2; 3- dihydros -1; 4- benzoxazine -4- bases) ethyl acetate 5d (4.7 g, yellow solid), yield： 71.5%.
MS m/z (ESI): 320 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 7.11 (d, /=2.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.94 (br. s, 1H), 4.19 (m, 2H), 3.32 (m, 2H), 2.44 (s, 3H), 1.33 (s, 9H)
5th step
2- [6- (2- acetyl bromides) -8- tert-butyl groups -2; benzoxazine -4- the bases of 3- dihydros-Isosorbide-5-Nitrae -] ethyl acetate is by 2- (6- acetyl group -8- tert-butyl groups -2,3- dihydros -1; 4- benzoxazine -4- bases) ethyl acetate 5d (6.68 g
20.9 mmol) it is dissolved in 80 mL acetic acid, add pyridinium tribromide Key salt (8.18 g, 25.6 mmol), stirring reaction 5 hours.Jian Ya Nong Shrink; add 100 mL saturated sodium bicarbonate solutions; divide liquid; aqueous phase is extracted with ethyl acetate (100 mLx3); merge organic phase; washed with saturated nacl aqueous solution (50 mLx3); anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 2- [6- (2- acetyl bromides) -8- tert-butyl groups -2, the 3- dihydro-benzoxazine -4- bases of Isosorbide-5-Nitrae -] ethyl acetate 5e (3.3 g; brownish black solid), yield： 39.0%.
MS m/z (ESI): 400 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.42 (d, /=2.0 Hz, 1H), 7.13 (d, /=2.0 Hz, 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)
6th step
2- [the 8- tert-butyl groups -6- [2-C3'- imino groups -5', 6'- dimethoxys-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) acetyl group] -2, 3- dihydros -1, 4- benzoxazine -4- bases] ethyl acetate hydrobromate is by 5', 6'- dimethoxy spiral shell [cyclopropane -1, 3'- isoindolines]-Γ-imines hydrobromate lc (241 mg, 1.11 mmol) it is dissolved in 4 mL tetrahydrofurans, add 2- [6- (2- acetyl bromides) -8- tert-butyl groups -2, 3- dihydros -1, 4- benzoxazine -4- bases] ethyl acetate 5e (708 mg, 1.77 mmol) and triethylamine (0.4 mL, 2.88 mmol), stirring reaction 12 hours.Filtering; filter cake uses n-hexane (10 mLx2) successively; water (5 mIX3) and ethyl acetate washing (1 mLx2); vacuum drying; obtain title product 2- [the 8- tert-butyl groups -6- [2- (3'- imino groups -5'; 6'- dimethoxys-spiral shell [cyclopropane -1; 1'- isoindolines] -2'- bases) acetyl group] -2; 3- dihydros -1; 4- benzoxazine -4- bases] (142 mg of ethyl acetate hydrobromate 5; white powder), yield： 23.9%.
MS m/z (ESI): 536 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the br. s of δ 9.70, 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, the Hz of /=4.4, 2H), 4.00 (s, 2H), 4.14 (q, the Hz of /=7.2, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.51 (t, the Hz of /=4.4, 2H), 1.63 (m, 4H), 1.39 (s, 9H), 1.22 (t, the Hz of /=7.2, 3H) embodiment 6
L- (the 8- tert-butyl group -4- ethyls -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [rings
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
5c 6a 6b 6
The first step
1-(the 8- tert-butyl group-4- ethyls-2,3- dihydros-1,4- benzoxazine-6- bases) ethyl ketone is by 1- (8- tert-butyl group-3,4- dihydro-2H-1,4- benzoxazine-6- bases) ethyl ketone 5c (1.5 g, 6.4 mmol) it is dissolved in 20 mL N, in dinethylformamide, potassium carbonate (2.66 g, 19.3 mmol) and iodoethane (2.6 mL are added, 32.1 mmol), 80 °C of lower stirring reactions 12 hours.Jian Ya Nong Shrink, add lOO mL water, use ethyl acetate
Extract (100 mLx3), merge organic phase, (50 mLx3), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the 8- tert-butyl group -4- ethyls -2,3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone 6a (1.0 g, yellow solid), yield： 59.5%.
MS m/z (ESI): 262 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.35 (d, J=2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), the 4.33 (Hz of t, J=4.4,2H), 3.45 (q, J=6.6 Hz, 2H), 3.40 (t, J=4.4 Hz, 2H), 2.58 (s, 3H), 1.42 (s, 9H), 1.22 (t, J=6.6 Hz, 3H)
Second step
The bromo- l- of 2- (the 8- tert-butyl group -4- ethyls -2,3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone is by 1- (the 8- tert-butyl group -4- ethyls -2,3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone 6a (1.0 g, 3.8 mmol) is dissolved in 18 mL acetic acid, adds pyridinium tribromide Key salt (1.28 g, 4.0 mmol), 100 °C of lower stirring reactions 10 hours.Jian Ya Nong Shrink, add 100 mL saturated sodium bicarbonate solutions, it is extracted with ethyl acetate (100 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (the 8- tert-butyl group -4- ethyls -2,3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone 6b (194 mg, yellow solid), yield： 29.2%.
MS m/z (ESI): 340 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.38 (d, J=2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 4.45 (s, 2H), 4.35 (t, /=4.4 Hz, 2H), 3.45 (m, 2H), 3.41 (t, /=4.4 Hz, 2H), 1.42 (s, 9H), 1.22 (m, 3H)
3rd step
L- (the 8- tert-butyl group -4- ethyls -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (3'- imino groups -5', 6'- dimethoxy-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- dimethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate lc (151 mg, 0.69 mmol) it is dissolved in 3 mL tetrahydrofurans, add small (the 8- tert-butyl group -4- ethyls -2, the 3- dihydro -1 of 2- bromines, 4- benzoxazine -6- bases) ethyl ketone 6b (253 mg, 0.74 mmol) and triethylamine (0.2 mL, 1.44 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (10 mLx2) and water washing (10 mLx3) successively, vacuum drying, obtain title product 1- (the 8- tert-butyl group -4- ethyl -2,3- dihydro -1,4- benzoxazine -6- bases) -2- (3'- imino groups -5', 6'- dimethoxys-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethanone hydrobromide 6 (139 mg, white powder), yield： 35.9%
MS m/z (ESI): 478 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.68 (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, /=4.4 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.44 (q, /=7.2 Hz, 2H), 3.38 (t, /=4.4 Hz, 2H), 1.68 (m, 4H), 1.37 (s, 9H), 1.23 (t, /=7.2 Hz, 3H)
Embodiment 7
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-different Yin -2'- bases) ethanone hydrobromide
The first step
1,2- bis- bromo- 4,5- diethoxybenzenes
Under ice bath, 1,2- diethoxybenzenes 7a (16.6 g, 100 mmol) is dissolved in 200 mL dichloromethane, bromine (10 mL, 200 mmol) is added dropwise, reaction 4 hours is stirred at room temperature.100 mL water and 1 g sodium sulfites are added into reaction solution, divide liquid, organic phase is washed (150 mL) with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product 1, bromo- 4,5- diethoxybenzenes 7b (29.8 g of 2- bis-, white solid), yield： 92.0%.
1H NMR (400 MHz, CDC13, ppm):δ 7.10 (s, 2H), 4.07 (q, /=7.2 Hz, 4H), 1.47 (t, /=7.2 Hz, 6H)
Second step
4,5- diethoxy phthalic nitriles
By 1,2- bis- bromo- 4,5- diethoxybenzenes 7b (13.62 g, 42 mmol) it is dissolved in 150 mL dimethyl sulfoxides, add cuprous cyanide (14.97 g, 167.2 mmol) and cuprous iodide (7.18 g, 37.7 mmol), 160 °C of lower stirring reactions 4 hours.Reaction solution is poured into 250 mL concentrated ammonia liquors and ethyl acetate (V/V=1:1.5) in the mixed solvent, filtering, filter cake is washed (100 mLx2) with water (100 mL) and ethyl acetate, aqueous phase is extracted with ethyl acetate (100 mL), merge organic phase, concentrated ammonia liquor (50 mL) is used successively, water (250 mL) and saturated nacl aqueous solution washing (200 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4, 5- diethoxy phthalic nitrile 7c (5.42 g, pale solid), yield： 59.7%.
1H NMR (400 MHz, CDC13, ppm):δ 7.16 (s, 2H), 4.20 (q, /=4.1 Hz, 4H), 1.54 (t, /=4.1 Hz, 6H)
3rd step
5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindoline] -1'- imines hydrobromates
Under ice bath, by 4,5- diethoxy phthalic nitrile 7c (2.16 g, 10 mmol) it is dissolved in 100 mL ether, add tetraisopropyl titanate (3.3 mL, 11.2 mmol) and ethylmagnesium bromide (7.3 mL, 21.9 mmol), reaction 2 hours is stirred at room temperature.Add 55 mL methanol, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (1.26 g, orange powder), yield： 51.2%.
MS m/z (ESI): 247 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 10.35 (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
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (195 mg, 0.79 mmol) it is dissolved in 3 mL tetrahydrofurans, add 2- bromo- 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketone 2h (310 mg, 0.84 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (10 mLx2) and water washing (10 mLx3) successively, vacuum drying, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethanone hydrobromide 7 (180 mg, white powder), yield： 36.9%
MS m/z (ESI): 536 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.69 (br. s, 1H), 9.13 (br. s, 1H), 7.91 (s, 1H), 7.65 (d, /=2.0 Hz, 1H), 7.56 (d, /=2.0 Hz, 1H), 7.06 (s, 1H), 5.23 (s, 2H), 4.18 (q, /=7.2 Hz, 2H), 4.12 (q, /=7.2 Hz, 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
L- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane
- 1,1'- -2'- bases) ethanone hydrobromide
The first step
L- (the 3- tert-butyl group -4- methoxyl group -5- nitro-phenyls) ethyl ketones are by 1- (3- tertiary butyl-4-hydroxy -5- nitro-phenyls) ethyl ketone 5a (11.6 g, 48.9 mmol) it is dissolved in 150 mL acetone, add potassium carbonate (16.9 g, 122 mmol) and iodomethane (23.2 mL, 372 mmol), 80 °C of lower stirring reactions 12 hours.Jian Ya Nong Shrink, 200 mL water are added, are extracted with ethyl acetate (200 mIX3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- nitro-phenyls) ethyl ketone 8a (8.94 g, yellow oil), yield： 72.8%.
MS m/z (ESI): 252 [M+l]
Second step
The 1- 3- amino -5- tert-butyl group -4- methoxyphenyls) ethyl ketone
1-(the 3- tert-butyl group-4- methoxyl group-5- nitro-phenyls) ethyl ketone 8a (4.8 g, 19 mmol) is dissolved in 50 mL second alcohol and waters (V/V=4:1) in the mixed solvent, adds ammonium chloride (4.1 g, 75 mmol) and iron powder (2.1 g, 38 mmol), 80 °C of lower stirring reactions 1 hour.Filtering, filtrate decompression Nong Shrink, add lOO mL water and 100 mL ethyl acetate, aqueous phase is extracted with ethyl acetate (100 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system D purify gained residue, obtain title product 1- (the 3- amino -5- tert-butyl group -4- methoxyphenyls) ethyl ketone 8b (3.6 g, gray solid), yield： 81.0%.
MS m/z (ESI): 222 [M+l]
3rd step
1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketones are by 1- (the 3- amino -5- tert-butyl group -4- methoxyphenyls) ethyl ketone 8b (2.0 g, 9.05 mmol) and 1,4- dibromobutanes (2.54 g, 11.77 mmol) it is dissolved in 20 mL N, in dinethylformamide, add potassium carbonate (3.1 g, 22.63 mmol) and KI (0.15 g, 0.91 mmol), 80 °C of lower stirring reactions 48 hours.Filtering, filtrate decompression Nong Shrink, add 50 mL water, extracted with ether (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, purify gained residue with eluant, eluent system B with silica gel column chromatography, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- pyrroles wash -1- bases-phenyl) ethyl ketone 8c (1.1 g, white solid), yield： 44.2%.
MS m/z (ESI): 276 [M+l]
4th step
The bromo- l- of 2- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketones are by 1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketone 8c (900 mg, 3.27 mmol) it is dissolved in 10 mL acetic acid, add pyridinium tribromide Key salt (1.1 g, 3.43 mmol), stirring reaction 12 hours.Jian Ya Nong Shrink, add 30 mL water and 30 mL ethyl acetate, aqueous phase is extracted with ethyl acetate (50 mIX3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketone 8d (560 mg, yellow solid), yield： 48.3%. MS m/z (ESI): 356 [M+l]
5th step
L- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (250 mg, 1.02 mmol) it is dissolved in 4 mL tetrahydrofurans, add 2- bromo- 1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketone 8d (360 mg, 1.02 mmol) and triethylamine (0.2 mL, 1.44 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (10 mLx2) and water washing (10 mLx3) successively, vacuum drying, obtain title product 1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethanone hydrobromide 8 (232 mg, white powder), yield： 38.0%.
MS m/z (ESI): 520 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.65 (br. s, 1H), 9.08 (br. s, 1H), 7.88 (s, 1H), 7.77 (b, /=2.0 Hz, 1H), 7.41 (b, /=2.0 Hz, 1H), 7.05 (s, 1H), 5.19 (s, 2H), 4.17 (the Hz of q, J=7.2,2H), 4.11 (q, /=7.2 Hz, 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
(7- imino group -2,5- dimethyl -5- phenyl-pyrrols are simultaneously [3,4-b] by l- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2-
The first step
l-(6- methyl -3- pyridines)-I-phenyl-ethanol
Under dry ice-propanone bath, by the bromo- 2- methyl-B of 5- than pyridine 9a (1.72 g, lO mmol) it is dissolved in 10 mL ether, 2.5 M n-BuLis (4.4 mL are added dropwise, 11 mmol) hexane solution, stirring reaction 1 hour adds acetophenone (1.29 mL, 11 mmol), continue stirring reaction 1 hour.10 mL saturated ammonium chloride solutions are added into reaction solution, aqueous phase is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (6- methyl -3- pyridines) -1- phenyl-ethanols 9b (1.8 g, yellow solid), yield： 84.5%.
MS m/z (ESI): 214 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.55 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.35 (m, 5H), 7.11 (d, /=8.4 Hz, 1H), 2.56 (s, 3H), 1.98 (s, 3H)
Second step
5- (l- nitrine -1- phenyl-ethyl groups) -2- methvl-pyridiniums
Under ice bath, 1- (6- methyl -3- pyridines) -1- phenyl-ethanols 9b (1.75 g, 8.2 mmol) and sodium azide (1.6 g, 24.6 mmol) are dissolved in 10 mL water, 9 mL concentrated hydrochloric acids, stirring reaction 12 hours are added dropwise.It is 78 that 200 mL saturated sodium bicarbonate solutions regulation pH is added into reaction solution, it is extracted with ethyl acetate (50 mLx3), merge organic phase, washed (20 mLx3), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression Nong Shrink, title product 5- (1- nitrine -1- phenyl-ethyl groups) -2- methyl-B are obtained than pyridine 9c (1.8 g, light yellow oil), yield： 92.3%.
MS m/z (ESI): 239 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.53 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.37 (m, 5H), 7.16 (d, J=8.0 Hz, 1H), 2.62 (s, 3H), 2.07 (s, 3H)
3rd step
5- (l- nitrine -1- phenyl-ethyl groups) -2- methvl-pyridinium 1- oxides are by 5- (1- nitrine -1- phenyl-ethyl groups) -2- methyl-B than pyridine 9c (1.8 g, 7.6 mmol) it is dissolved in 30 mL dichloromethane, add metachloroperbenzoic acid (2.6 g, 15.1 mmol), stirring reaction 12 hours.20 mL dichloromethane are added into reaction solution, washed with saturated sodium bicarbonate solution (30 mLx3), aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying
Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 5- (1- nitrine -1- phenyl-ethyl groups) -2- methvl-pyridinium 1- oxides 9d (1.42 g, light yellow oil), yield： 74.0%
1H NMR (400 MHz, CDC13, ppm):δ 8.31 (s, 1H), 7.36 (m, 7H), 2.58 (s, 3H), 2.04 (s, 3H)
4th step
(l- nitrine -1- phenyl-ethyl group 6- methvl-pyridinium -2- nitriles are by 5- (1- nitrine -1- phenyl-ethyl groups) -2- methyl-B than pyridine 1- oxides 9d (1.3 g by 3-, 5.1 mmol) it is dissolved in 15 mL acetonitriles, add cyano group trimethyl silane (1.16 mL, 8.7 mmol) and dimethylaminoethyl chloride (0.70 mL, 7.7 mmol), 80 °C of lower stirring reactions 2 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 3- (1- nitrine -1- phenyl-ethyl groups) -6- methvl-pyridinium -2- nitriles 9e (1.6 g, light yellow oil) crude product.
MS m/z (ESI):264 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.04 (d, J=8.4 Hz, 1H), 7.47 (m, 6H), 2.63 (s, 3H), 2.28 (s, 3H)
5th step
2,5- dimethyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines is by 3- (1- nitrine -1- phenyl-ethyl groups) -6- methvl-pyridinium -2- nitriles 9e (1.68 g, 6.39 mmol) it is dissolved in 35 mL tetrahydrofurans, add 1 mL water and triphenylphosphine (3.35g, 12.8 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 2,5- dimethyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 9f (0.44 g, light yellow solid), yield： 29.1%.
MS m/z (ESI): 238 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.91 (d, J=7.6 Hz, 1H), the 7.50 (Hz of d, J=7.6,1H), 7.17 (m, 5H), 6.61 (s, 2H), 2.55 (s, 3H), 1.69 (s, 3H)
6th step
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (7- imino group -2,5- dimethyl -5- phenyl-pyrrols simultaneously [3,4-b] pyridine -6- bases) ethanone hydrobromide
By 2,5- dimethyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 9f (237 mg, 1 mmol) and the bromo- 1- of 2- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketone 2h (444 mg, 1.2 mmol) it is dissolved in 3 mL N, in N- dimethylformamides, stirring reaction 12 hours.5 mL water are added into reaction solution, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain the title product 1- 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (7- imino groups -2, 5- dimethyl -5- phenyl-pyrrols simultaneously [3, 4-b] pyridine -6- bases) (120 mg of ethanone hydrobromide 9, light yellow solid), yield： 19.8%.
MS m/z (ESI): 527 [M+l]
Ή NMR (400 MHz, DMSO-J6, ppm):δ 7.97 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.38 (m, 5H), 5.50 (d, /=18.8 Hz, 1H), 5.16 (d, /=18.8 Hz, 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 groups-spiral shell [cyclopropane -1, Γ-iso-indoles
- 2'- bases) ethanone hydrobromide
The first step
1- 3,5- di-tert-butyl-hydroxy phenyl) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (247 mg, 1 mmol) it is dissolved in 4 mL tetrahydrofurans, add 2- bromo- 1- (3,5- di-tert-butyl-hydroxy phenyl) ethyl ketone If (393 mg, 1.27 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (10 mLx2) and water washing (10 mLx3) successively, vacuum drying, obtain title product 1- (3,5- di-tert-butyl-hydroxy phenyls) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) (233 mg of ethanone hydrobromide 10, white powder), yield： 41.8%.
MS m/z (ESI): 493 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.65 (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, /=7.2 Hz, 2H), 4.11 (q, /=7.2 Hz, 2H), 1.76-1.66 (m, 2H), 1.35 (m, 24H) embodiment 11
L- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
The first step
1- (the 3- amino -5- tert-butyl group -4- methoxyphenyls) ethyl ketone 8b (9.8 g, 44 mmol) is dissolved in 50 mL by l- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) ethyl ketones
In DMF, potassium carbonate (18.35 g, 133 mmol) and iodoethane (20.7 g, 133 mmol), stirring reaction 12 hours are added.100 mL water are added into reaction solution, extracted with ether (50 mLx3), merge organic phase, (20 mLx3), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) ethyl ketone 11a (2.4 g, yellow oil), yield： 19.5%. MS m/z (ESI): 278 [M+l]
Second step
The bromo- l- of 2- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) ethyl ketones are by 1- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) ethyl ketone 11a (2.4 g, 8.66 mmol) it is dissolved in 10 mL acetic acid, add pyridinium tribromide Key salt (3.6 g, 11.25 mmol), stirring reaction 12 hours.Jian Ya Nong Shrink, add 20 mL water, it is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) ethyl ketone lib (850 mg, yellow solid), yield： 27.5%
MS m/z (ESI): 358 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.67 (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)
3rd step
L- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (246 mg, 1 mmol) it is dissolved in 5 mL tetrahydrofurans, add 2- bromo- 1- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) ethyl ketone lib (368 mg, 1.03 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering, filter cake uses tetrahydrofuran (1 mL) successively, n-hexane (10 mLx2) and water washing (10 mLx3), vacuum drying, obtain title product 1- (the 3- tert-butyl group -5- diethylin -4- methoxyphenyls) -2- (5', 6'- diethoxy -3'-
Imino group-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide 11 (314 mg, white powder), yield： 52.2%.
MS m/z (ESI): 523 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the br. s of δ 9.69, 1H), 9.15 (br. s, 1H), 7.93 (s, 1H), 7.59 (d, the Hz of /=1.6, 1H), 7.54 (d, the Hz of /=1.6, 1H), 7.06 (s, 1H), 5.20 (s, 2H), 4.18 (q, the Hz of J=7.2, 2H), 4.12 (q, the Hz of J=7.2, 2H), 3.88 (s, 3H), 3.17 (q, the Hz of J=7.2, 4H), 1.76-1.61 (m, 4H), 1.40 (m, 15H), 1.20 (t, the Hz of /=7.2, 6H) embodiment 12
L- [the 3- tert-butyl group -4- methoxyl groups -5- (l- piperidines) phenyl] -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) ethanone hydrobromide
The first step
The tert-butyl group-4- methoxyl groups-5- (1-piperidines) phenyl] ethyl ketone
By 1- (the 3- amino -5- tert-butyl group -4- methoxyphenyls) ethyl ketone 8b (2.21 g, lO mmol) and 1,5- dibromos penta are washed (4.6 g, 20 1^^1) it is dissolved in 20 1111^, in dimethylformamide, add potassium carbonate (4.14 g, 30 mmol) and KI (；0.17 g, l .O mmol), 50 °C of lower stirring reactions 12 hours.20 mL water are added into reaction solution, are extracted with ether (50 mLx3), merges organic phase, (20 mL is washed with saturated nacl aqueous solution><3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] ethyl ketone 12a (1.8 g, gray solid), yield： 62.3%.
MS m/z (ESI): 290 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.66 (d, J=2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 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
Small [the 3- tert-butyl group -4- methoxyl groups -5- (l- piperidines) phenyl] ethyl ketone of 2- bromines is by 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] ethyl ketone 12a (1.8 g, 6.2 mmol) it is dissolved in 20 mL acetic acid, add pyridinium tribromide Key salt (2.29 g, 7.15 mmol), stirring reaction 12 hours.Jian Ya Nong Shrink,
Add 20 mL water, it is extracted with ethyl acetate (50 mLx3), merge organic phase, (20 mLx3), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] ethyl ketone 12b (850 mg, yellow solid), yield： 37.3%.
MS m/z (ESI): 370 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.68 (d, J=2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 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)
3rd step
L- [the 3- tert-butyl group -4- methoxyl groups -5- (l- piperidines) phenyl] -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (247 mg, 1 mmol) it is dissolved in 5 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] ethyl ketone 12b (424 mg, 1.15 mmol) and triethylamine (0.2 mL, 1.44 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (5 mLx2) and water washing (5 mLx2) successively, vacuum drying, obtain title product 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] -2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethanone hydrobromide 12 (246 mg, white powder), yield： 39.9%.
MS m/z (ESI): 523 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.70 (br. s, 1H), 9.13 (br. s, 1H), 7.93 (s, 1H), 7.62 (d, /=1.8 Hz, 1H), 7.56 (d, /=1.8 Hz, 1H), 7.06 (s, 1H), 5.22 (s, 2H), 4.18 (q, J=7.2 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.97 (s, 3H), 2.98 (m, 4H), 1.74 (m, 6H), 1.57 (m, 4H), 1.39 (m, 15H) embodiment 13
N- [the 3- tert-butyl groups -5- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) acetyl
- 2- methoxyphenyls] acetamide hydrobromate
The first step
Under Ν-(the 5- acetyl group -3- tert-butyl group -2- methoxyphenyls) acetamide ice bath, by the 1-0 amino -5- tert-butyl group -4- methoxyphenyls) ethyl ketone 8b (12.0 g, 54 mmol) dissolvings
In 100 mL tetrahydrofurans, triethylamine (15 mL, 109 mmol) is added, stirring reaction 0.5 hour is added dropwise chloroacetic chloride 2b (6.14 mL, 81 mmol), continues stirring reaction 2 hours.Jian Ya Nong Shrink; 200 mL frozen water are added, are extracted with ethyl acetate (100 mLx3), merge organic phase; washed with saturated nacl aqueous solution (50 mLx3); anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product N- (the 5- acetyl group -3- tert-butyl group -2- methoxyphenyls) acetamide 13a (13.4 g, white solid), yield： 94.4%.
MS m/z (ESI): 264 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.54 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 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 bromides) -3- tert-butyl group -2- methoxyphenyls] acetamides are by N- (the 5- acetyl group -3- tert-butyl group -2- methoxyphenyls) acetamide 13a (3.7 g; 14.1 mmol) it is dissolved in 20 mL acetic acid; add pyridinium tribromide Key salt (4.5 g; 14.1 mmol), stirring reaction 12 hours.Jian Ya Nong Shrink; add lOO mL water; it is extracted with ethyl acetate (100 mIX3); merge organic phase; washed with saturated nacl aqueous solution (50 mLx3); anhydrous sodium sulfate drying; filtering; filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product N- [5- (2- the acetyl bromides) -3- tert-butyl group -2- methoxyphenyls] acetamide 13b (3.2 g, white solid), yield： 66.0%.
1H NMR (400 MHz, CDC13, ppm):δ 8.68 (d, J=2.0 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.30 (br. s, 1H), 4.48 (s, 2H), 3.86 (s, 3H), 2.31 (s, 3H), 1.43 (s, 9H)
3rd step
N- [the 3- tert-butyl groups -5- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) acetyl group] -2- methoxyphenyls] acetamide hydrobromate
By 5'; 6'- diethoxy spiral shell [cyclopropane -1; 3'- isoindolines]-Γ-imines hydrobromate 7d (243 mg; 0.99 mmol) it is dissolved in 5 mL tetrahydrofurans; add N- [5- (2- the acetyl bromides) -3- tert-butyl group -2- methoxyphenyls] acetamide 13b (395 mg; 1.15 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (5 mLx2) and water washing (10 mLx3) successively, vacuum drying, obtain title product N- [the 3- tert-butyl groups -5- [2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) acetyl group] -2- methoxyphenyls] acetamide hydrobromate 13 (193 mg, white powder), yield： 33.2%.
MS m/z (ESI): 508 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.76 (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 (the Hz of q, J=7.2,2H), 4.16 (q, /=7.2 Hz, 2H), 3.80 (s, 3H), 2.15 (s, 3H), 1.74-1.60 (m, 4H), 1.39 (m, 15H) embodiment 14
2- [[the 3- tert-butyl groups -5- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) acetyl
The first step
2- [(the 5- acetyl group -3- tert-butyl group -2- methoxyphenyls) amino] acetonitriles are by 1- (the 3- amino -5- tert-butyl group -4- methoxyphenyls) ethyl ketone 8b (14.4 g; 65.2 mmol) it is dissolved in 100 mL N; in dinethylformamide; add potassium carbonate (9.9 g; 72 mmol) and bromoacetonitrile (26.4 g; 220 mmol), 70 °C of lower stirring reactions 12 hours.Filtering; filtrate decompression Nong Shrink; add 300 mL water; extracted with ether (200 mLx3); merge organic phase; washed with saturated nacl aqueous solution (50 mLx3); anhydrous sodium sulfate drying; filtering; filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- [(the 5- acetyl group -3- tert-butyl group -2- methoxyphenyls) amino] acetonitrile 14a (15.3 g; yellow solid), yield： 88.0%.
MS m/z (ESI): 261 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.56 (d, J=2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 4.49 (br. s, 1H), 4.24 (d, /=6.8 Hz, 2H), 3.82 (s, 3H), 2.62 (s, 3H), 1.45 (s, 9H)
Second step
2- [[5- (2- the acetyl bromides) -3- tert-butyl group -2- methoxyphenyls] amino] acetonitriles are by 2- [(the 5- acetyl group -3- tert-butyl group -2- methoxyphenyls) amino] acetonitrile 14a (14.24 g; 54.7 mmol) it is dissolved in 80 mL acetic acid; add pyridinium tribromide Key salt (18.37 g; 57.4 mmol), stirring reaction 24 hours.300 mL water are added into reaction solution; aqueous phase is extracted with ethyl acetate (200 mLx3); merge organic phase; washed with saturated nacl aqueous solution (50 mLx3); anhydrous sodium sulfate drying; filtering; filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 2- [[5- (2- the acetyl bromides) -3- tert-butyl group -2- methoxyphenyls] amino] acetonitrile 14b (1.26 g; yellow oil), yield： 7.0%.
MS m/z (ESI): 339 [M+l]
3rd step
2- [[the 3- tert-butyl groups -5- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) acetyl group] -2- methoxyphenyls] amino] acetonitrile hydrobromate
By 5'; 6'- diethoxy spiral shell [cyclopropane -1; 3'- isoindolines]-Γ-imines hydrobromate 7d (249 mg; 1.03 mmol) it is dissolved in 5 mL tetrahydrofurans; add 2- [[5- (2- the acetyl bromides) -3- tert-butyl group -2- methoxyphenyls] amino] acetonitrile 14b (408 mg; 1.19 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 is small
When.Filtering; filter cake uses n-hexane (5 mLx2) and water washing (10 mLx3) successively; vacuum drying; obtain title product 2- [[the 3- tert-butyl groups -5- [2- (5'; 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1; 1'- isoindolines] -2'- bases) acetyl group] -2- methoxyphenyls] amino] acetonitrile hydrobromate 14 (262 mg, white powder), yield： 43.6%. MS m/z (ESI): 504 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.66 (br. s, 1H), 9.17 (br. s, 1H), 7.87 (s, 1H), 7.43 (d, /=1.6 Hz, 1H), 7.36 (d, /=1.6 Hz, 1H), 7.07 (s, 1H), 6.16 (t, /=6.8 Hz, 1H), 5.20 (s, 2H), 4.40 (d, /=6.8 Hz, 2H), 4.18 (q, /=7.2 Hz, 2H), 4.11 (q, /=7.2 Hz, 2H):(m, the 15H) embodiment 15 of 3.74 (s, 3H), 1.73-1.62 (m, 4H), 1.40
L- (the 8- tert-butyl group -4- ethyls -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- -2'- bases) ethanone hydrobromide
The first step
1- (the 8- tert-butyl group -4- ethyl -2,3- dihydro -1,4- benzoxazine -6- bases) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (250 mg, 1.02 mmol) it is dissolved in 5 mL tetrahydrofurans, add small (the 8- tert-butyl group -4- ethyls -2, the 3- dihydro -1 of 2- bromines, 4- benzoxazine -6- bases)-ethyl ketone 6b (408 mg, 1.19 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (5 mLx2) and water washing (10 mLx2) successively, vacuum drying, obtain title product 1- (the 8- tert-butyl group -4- ethyl -2,3- dihydro -1,4- benzoxazine -6- bases) -2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethanone hydrobromide 15 (224 mg, white powder), yield： 37.6%.
MS m/z (ESI): 506 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.70 (br. s, 1H), 9.14 (br. s, 1H), 7.89 (s, 1H), 7.27 (m, 2H), 7.04 (s, 1H), 5.16 (s, 2H), 4.29 (t, /=4.4 Hz, 2H), 4.17 (q, /=7.2 Hz, 2H), 4.11 (q, /=7.2 Hz, 2H), 3.10 (m, 4H), 1.75 (m, 4H), 1.36 (m, 15H), 1.19 (t, /=7.2 Hz, 3H)
Embodiment 16
2- [the 8- tert-butyl groups -6- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) acetyl
Benzoxazine -4- the bases of -2,3- dihydro-Isosorbide-5-Nitrae -] acetonitrile hydrobromate
The first step
2- (6- acetyl group -8- the tert-butyl groups -2; 3- dihydros -1; 4- benzoxazine -4- bases)-acetonitrile is by 1- (8- tert-butyl group -3,4- dihydro -2H-1,4- benzoxazine -6- bases) ethyl ketone 5c (12 g; 51.4 mmol) it is dissolved in 60 mL N; in dinethylformamide, potassium carbonate (7.82 g, 56.6 mmol) and bromoacetonitrile (12.33 g are added; 103 mmol), 70 °C of lower stirring reactions 4 hours.200 mL water are added into reaction solution; extracted with ether (200 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx3); anhydrous sodium sulfate drying; filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify obtained by residue; obtain the title product 2- (6- acetyl group -8- tert-butyl groups -2; benzoxazine -4- the bases of 3- dihydros-Isosorbide-5-Nitrae -) acetonitrile 16a (9.4 g, white solid yield： 67.3%.
MS m/z (ESI): 273 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.52 (d, J=2.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 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- acetyl bromides) -8- tert-butyl groups -2; 3- dihydros -1; 4- benzoxazine -4- bases] acetonitrile is by the 2- (6- acetyl group -8- tert-butyl groups -2; 3- dihydros -1; 4- benzoxazine -4- bases) acetonitrile 16a (9.38 g, 34.4 mmol) is dissolved in 80 mL acetic acid, adds pyridinium tribromide Key salt (11 g; 34.4 mmol), stirring reaction 24 hours.200 mL water are added into reaction solution; extracted with ether (100 mIX3); merge organic phase; washed with saturated nacl aqueous solution (50 mLx3); anhydrous sodium sulfate drying; filtering; filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 2- [6- (2- acetyl bromides) -8- tert-butyl groups -2, the 3- dihydro-benzoxazine -4- bases of Isosorbide-5-Nitrae -] acetonitrile 16b (3.0 g; black solid), yield： 24.6%.
1H NMR (400 MHz, CDC13, ppm):δ 7.57 (d, J=2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 4.47 (m, 2H), 4.43 (s, 2H), 4.29 (s, 2H), 3.47 (m, 2H), 1.43 (s, 9H)
3rd step
2- [benzoxazine -4- bases of the 8- tert-butyl groups -6- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) acetyl group] -2,3- dihydros-Isosorbide-5-Nitrae -] acetonitrile hydrobromate
By 5'; 6'- diethoxy spiral shell [cyclopropane -1; 3'- isoindolines]-Γ-imines hydrobromate 7d (257 mg; 1.04 mmol) it is dissolved in 5 mL tetrahydrofurans, add 2- [6- (2- acetyl bromides) -8- tert-butyl groups -2,3- dihydros -1; 4- benzoxazines -4- yls] acetonitrile 16b (458 mg; 1.30 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering; filter cake uses n-hexane (5 mLx2) and water washing (10 mLx2) successively; vacuum drying; obtain title product 2- [the 8- tert-butyl groups -6- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) acetyl group] -2; 3- dihydros -1; 4- benzoxazine -4- bases] acetonitrile hydrobromate 16 (317 mg, yellow powder), yield： 50.8%.
MS m/z (ESI): 517 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.67 (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:/=7.2 Hz, 2H), 4.11 (q, /=7.2 Hz, 2H), 3.40 (m, 2H), 1.75-1.62 (m, 4H), 1.38 (m, 15H) embodiments 17
L- [3- (l- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
1- [3- (1- adamantyls) -4- hydroxy phenyls] ethyl ketone
By 1- (4- hydroxy phenyls) ethyl ketone 17a (408 mg, 3 mmol) and adamantane -1- alcohol 17b (456 mg, 3 mmol) be dissolved in 2 mL dichloromethane, add the concentrated sulfuric acid (0.16 mL, 3 mmol), it is stirred at room temperature 12 hours.Reaction solution is poured into 10 mL water, 10 mL saturated sodium bicarbonate solutions is added, is extracted with dichloromethane (15 mLx3), merges organic phase, anhydrous sodium sulfate drying, filtering, the dense Shrink of filtrate decompression uses silica gel column chromatography
Gained residue is purified with eluant, eluent system B, title product 1- [3- (1- adamantyls) -4- hydroxy phenyls] ethyl ketone 17c (560 mg, white solid), yield is obtained： 69.1%
MS m/z (ESI): 271 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.94 (d, J=2.0 Hz, 1H), 7.75 (dd ,/； = 8.4 Hz, J2=2.0 Hz, 1H), 6.76 (d, /=8.4 Hz, 1H), 6.00 (s, 1H), 2.60 (s, 3H), 2.24 (s, 9H), 1.83 (s, 6H)
Second step
L- [the iodo- phenyl of 3- (l- adamantyls) -4- hydroxyls -5-] ethyl ketones are by 1- [3- (1- adamantyls) -4- hydroxy phenyls] ethyl ketone 17c (435 mg, 1.61 mmol) it is dissolved in 11 mL acetonitriles and DMF (V/V=9:2) in the mixed solvent, adds N- N-iodosuccinimides (398.4 mg, 1.77 mmol), stirring reaction 0.5 hour.Jian Ya Nong Shrink, purify gained residue with eluant, eluent system B with silica gel column chromatography, obtain title product l- [3-G- adamantyls) the iodo- phenyl of -4- hydroxyls -5-] ethyl ketone 17d (300 mg, white solid), yield： 47.0%
MS m/z (ESI): 395 [M-l]
1H NMR (400 MHz, CDC13, ppm):δ 8.20 (d, J=2.0 Hz, 1H), the 7.89 (Hz of d, J=2.0,1H), 6.02 (s, 1H), 2.58 (s, 3H), 2.15 (s, 9H), 1.82 (s, 6H)
3rd step
L- [the iodo- 4- methoxyphenyls of 3- (l- adamantyls) -5-] ethyl ketones are by 1- [the iodo- phenyl of 3- (1- adamantyls) -4- hydroxyls -5-]-ethyl ketone 17d (303 mg, 0.77 mmol) it is dissolved in 15 mL acetone, add potassium carbonate (316.8 mg, 2.3 mmol) and iodomethane (0.12 mL, 1.91 mmol), stirring reaction 12 hours.Filtering, filter cake is washed (10 mLx2) with ethyl acetate, filtrate decompression Nong Shrink, 20 mL ethyl acetate are added, merges organic phase, is washed (20 mL) with water (20 mLx3) and saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink obtain title product 1- [the iodo- 4- methoxyphenyls of 3- (1- adamantyls) -5-] ethyl ketone 17e crude products and directly cast single step reaction.
MS m/z (ESI): 411 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.30 (d, J=2.4 Hz, 1H), the 7.96 (Hz of d, J=2.4,1H), 3.98 (s, 3H), 2.60 (s, 3H), 2.09 (s, 9H), 1.82 (s, 6H)
4th step
L- [5- (l, l- dimethoxy-ethyls) the iodo- 2- methoxyphenyls of -3-] adamantane is by 1- [the iodo- 4- methoxyphenyls of 3- (1- adamantyls) -5-] ethyl ketone 17e (123 mg, 0.3 mmol) it is dissolved in 2 mL methanol, add trimethyl orthoformate (95.5 mg, 0.9 mmol) and camphorsulfonic acid (3.48 mg, 0.015 mmol), 60 °C of lower stirring reactions 3 hours.Add 200 mg potassium carbonate and 20 mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed (10 mLx2), anhydrous sodium sulfate drying, filtered with unsaturated carbonate potassium solution (10 mLx3) and saturated nacl aqueous solution successively, obtain title product 1- [5- (1,1- dimethoxy-ethyls) the iodo- 2- methoxyphenyls of -3-] adamantane 17f (135 mg, yellow oil), yield： 98.7%.
1H NMR (400 MHz, CDC13, ppm):δ 7.85 (d, J=2.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H),
3.93 (s, 3H), 3.21 (s, 6H), 2.11 (s, 9H), 1.81 (s, 6H), 1.54 (s, 3H)
5th step
L- [3- (l- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] ethyl ketones are by 1- [5- (1, 1- dimethoxy-ethyls) the iodo- 2- methoxyphenyls of -3-] adamantane 17f (123 mg, 0.3 mmol) it is dissolved in 20 mL toluene, sequentially add morpholine (1.74 g, 20 mmol), 2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl (196.8 mg, 0.5 mmol), three (dibenzalacetone) two palladium (228.9 mg, 0.25 mmol) and sodium tert-butoxide (1.92 g, 20 mmol), 90 °C of lower stirring reactions 3 hours.Filtering, filter cake is washed (10 mLx3) with ethyl acetate, filtrate decompression Nong Shrink, 5 mL acetic acid are added, are stirred 1 hour, Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] ethyl ketone 17g (560 mg, yellow solid), yield： 60.5%.
1H NMR (400 MHz, CDC13, ppm):δ 7.61 (d, J=2.0 Hz, 1H), 7.49 (d, J=2.0 Hz, 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)
6th step
L- [3- (l- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] the bromo- ethyl ketones of -2- are by 1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] ethyl ketone 17g (527 mg, 1.42 mmol) it is dissolved in 8 mL acetic acid, add pyridinium tribromide Bell salt (455 mg, 1.42 mmol), stirring reaction 3.5 hours.Jian Ya Nong Shrink, add 10 mL saturated sodium bicarbonate solutions and 10 mL water, it is extracted with ethyl acetate (15 mLx3), merges organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] bromo- ethyl ketone 17h (230 mg of -2-, yellow solid), yield： 36.0%.
1H NMR (400 MHz, CDC13, ppm):δ 7.65 (d, /=2.4 Hz, 1H), 7.53 (d, /=2.4 Hz, 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)
7th step
L- [3- (l- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (246 mg, 1 mmol) it is dissolved in 6 mL tetrahydrofurans, add 1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] bromo- ethyl ketone 17h (516 mg of -2-, 1.15 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering, filter cake n-hexane (5 mLx2) and water washing (10 mLx2), vacuum drying, obtain title product 1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] -2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethyl ketone hydrobromic acid 17 (317 mg, white powder), yield： 22.9%.
MS m/z (ESI): 614 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the br. s of δ 9.64, 1H), 9.08 (br. s, 1H), 7.87 (s, 1H), 7.59 (d, the Hz of /=1.6, 1H), 7.52 (d, the Hz of /=1.6, 1H), 7.05 (s, 1H), 5.20 (s, 2H), 4.17 (q, the Hz of J=7.2, 2H), 4.11 (q, the Hz of /=7.2, 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
2- [the 8- tert-butyl groups -6- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [protective embankment -1, Γ of ring third-isoindoline] -2'- bases) acetyl group -2,3- dihydro -1,4- benzoxazine -4- bases] ethyl acetate hydrobromates
The first step
2- [the 8- tert-butyl groups -6- [2- (5', 6'- diethoxies -3'- imino groups-spiral shell [the third protective embankment of ring-Ι, Γ-iso-indoles] -2'- bases) acetyl group] -2, 3- dihydros -1, 4- benzoxazine -4- bases] ethyl acetate hydrobromate is by 5', 6'- diethoxy spiral shell [cyclopropane -1, 3'- isoindolines]-Γ-imines hydrobromate 7d (252 mg, 1.02 mmol) it is dissolved in 5 mL tetrahydrofurans, add 2- [6- (the bromo- acetyl group of 2-) -8- tert-butyl groups -2, 3- dihydros -1, 4- benzoxazine -4- bases]-ethyl acetate 5e (440 mg, 1.10 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering; filter cake n-hexane (10 mLx2) and water washing (10 mLx2); vacuum drying; obtain title product 2- [the 8- tert-butyl groups -6- [2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-iso-indoles] -2'- bases) acetyl group] -2; 3- dihydros -1; 4- benzoxazine -4- bases] ethyl acetate hydrobromate 22 (317 mg, yellow powder), yield： 50.8%.
MS m/z (ESI): 565 [M+l ]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.67 (br. s, 1H), 9.16 (br. s, 1H), 7.92 (s, 1H), 7.30 (d, /=1.2 Hz, 1H), 7.08 (d, /=1.2 Hz, 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, /=7.2 Hz;3H) embodiment 19
L-(8- tert-butyl group 4- methyl -2,3- dihydro -1,4- benzoxazine -6- bases) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline -2'- bases) ethanone hydrobromide
The first step
L- (the 8- tert-butyl group -4- methyl -2,3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone is by 1- (the 8- tert-butyl groups -3,4- dihydros -2H-1,4- benzoxazine -6- bases) ethyl ketone 5c (1.5 g, 6.4 mmol) is dissolved in 20 mL acetone, add potassium carbonate (1.78 g, 12.8 mmol) and iodomethane (4.56 g, 32.1 mmol), stirring reaction 40 hours.Jian Ya Nong Shrink, add 50 mL water, are extracted with ethyl acetate (50 mLx3), merge organic phase, washed (20 mLx3), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression Nong Shrink, obtain the title product 1-C8- tert-butyl group -4- methyl -2,3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) ethyl ketone 19a (375 mg, brown oil), yield： 23.6%.
1H NMR (400 MHz, CDC13, ppm):δ 7.40 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 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- l- of 2- (the 8- tert-butyl group -4- methyl -2,3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone is by 1- (the 8- tert-butyl group -4- methyl -2,3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone 19a (511 mg, 2.1 mmol) is dissolved in 6 mL acetic acid, adds pyridinium tribromide Key salt (800 mg, 2.48 mmol), stirring reaction 3 hours.Jian Ya Nong Shrink, add 50 mL saturated sodium bicarbonate solutions, it is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (the 8- tert-butyl group -4- methyl -2,3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone 19b (200 mg, yellow oil), yield： 29.6%.
1H NMR (400 MHz, CDC13, ppm):δ 7.42 (d, J=2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 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)
3rd step
L- (8- tert-butyl group 4- methyl -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (249 mg, 1.01 mmol) the bromo- 1- of standing grain B 2- (the 8- tert-butyl group -4- methyl -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) ethyl ketone 19b (390 mg, 1.2 mmol) it is dissolved in 6 mL tetrahydrofurans, add triethylamine (0.15 mL, 1.08 mmol), stirring reaction 24 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mIX3), vacuum drying, obtain title product 1- (8- tert-butyl group 4- methyl -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethanone hydrobromide 19 (316 mg, buff powder), yield： 54.6%.
MS m/z (ESI):492 [M+l]
Ή NMR (400 MHz, DMSO-J6, ppm):δ 9.69 (br. s, 1H), 9.14 (br. s, 1H), 7.94 (s, 1H):7.30 (d, /=1.6 Hz, 1H), 7.22 (d, /=1.6 Hz, 1H), 7.05 (s, 1H), 5.18 (s, 2H), 4.35 (m:2H), (m, the 15H) embodiment 20 of 4.13 (m, 4H), 3.07 (m, 2H), 2.94 (s, 3H), 1.70-1.60 (m, 4H), 1.38
L- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls] -2- (5', 6'- diethoxy -3'- imino groups-spiral shell
'-isoindoline] -2'- bases) ethanone hydrobromide
The first step
1- [4- [the 3- tert-butyl groups -5- (1, 1- dimethoxy-ethyls) -2- methoxyphenyls] the small base of piperazine] ethyl ketone is by the 1- tert-butyl groups -5- (1, 1- dimethoxy-ethyls) iodo- 2- methoxybenzenes 2f (11.5 g of -3-, 30.42 mmol) it is dissolved in 60 mL dioxane, sequentially add 1- piperazines -1- bases-ethyl ketone (5.7 g, 39.55 mmol), three (dibenzalacetone) two palladium (1.15 g, 10%), 4, double (diphenylphosphines) -9 of 5-, 9- dimethyl xanthene (880 mg, 1.52 mmol) and sodium tert-butoxide C5.85 g, 60.84 mmol), 60 °C of lower stirring reactions 7 hours.Reaction solution is poured into 30 mL frozen water and 150 mL ethyl acetate, divide liquid, aqueous phase is extracted with ethyl acetate (50 mLx2), merge organic phase, washed with saturated nacl aqueous solution (50 mLx2), Jian Ya Nong Shrink, obtain title product 1- [4- [the 3- tert-butyl groups-5-(U- dimethoxy-ethyl)-2-methoxyphenyl] the small base of piperazine] ethyl ketone20aDirectly cast single step reaction.
Second step
I-p-Acetylpiperazine -1- bases) -5- the tert-butyl group -4- methoxyphenyls] ethyl ketone is by 1- [4- [the 3- tert-butyl groups -5- (1; 1- dimethoxy-ethyls) -2- methoxyphenyls] piperazine -1- bases] ethyl ketone 20a (6.7 g; 17.7 mmol) it is dissolved in 50 mL dichloromethane; add acetic acid (3.2 g; 53 mmol), stirring reaction 12 hours.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtaining title product 1- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls], (2.0 g, yellow is solid by ethyl ketone 20b
Body), yield： 20.0%.
MS m/z (ESI): 333 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.68 (d, J=2.0 Hz, 1H), 7.48 (d, J=2.0 Hz, 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)
3rd step
L- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls] -2 bromo- ethyl ketones are by 1- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls] ethyl ketone 20b (1.8 g; 5.1 mmol) it is dissolved in 15 mL dichloromethane; add acetic acid (1.2 g, 20.4 mmol) and pyridinium tribromide Key salt (2.1 g:5.36 mmol), stirring reaction 12 hours.Jian Ya Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 1- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls] -2 bromo- ethyl ketone 20c (950 mg; yellow solid), yield： 43.0%.
1H NMR (400 MHz, CDC13, ppm):δ 7.72 (d, J=2.0 Hz, 1H), 7.51 (d, /=2.0 Hz, 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)
4th step
L- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls] -2- (5', 6'- diethoxy -3'- imino groups-spiral shell
[cyclopropane -1; 1'- isoindolines] -2'- bases) ethanone hydrobromide is by 5'; 6'- diethoxy spiral shell [cyclopropane -1; 3'- isoindolines]-Γ-imines hydrobromate 7d (125 mg; 0.5 mmol) it is dissolved in 3 mL tetrahydrofurans; add 1- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls] -2 bromo- ethyl ketone 20c (206 mg; 0.5 mmol) and triethylamine (76 mg; 0.75 mmol), stirring reaction 48 hours.Filtering; filter cake is with tetrahydrofuran (1 mL); water (20 mLx2) and n-hexane washing (10 mLx2); vacuum drying; obtain title product 1- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls] -2- (5'; 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1; 1'- isoindolines] -2'- bases) (62 mg of ethanone hydrobromide 20; white solid), yield： 21.5%.
MS m/z (ESI): 577 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.64 (br. s, 1H), 9.08 (br. s, 1H), 7.86 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 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- methoxyphenyls) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide
The first step
1- 3,5- di-tert-butyl-hydroxy phenyl) ethyl ketone
Under dry ice-propanone bath, by aluminium chloride (1.31 g, 9.79 mmol) it is dissolved in 20 mL dichloromethane, add 2,6- Di-tert-butyl-phenols Id (2.0 g, 9.63 mmol), stirring reaction 1 hour, chloroacetic chloride le (0.401 mL, 9.79 mmol) is added dropwise, continues stirring reaction 4 hours.20 mL frozen water are added into reaction solution, extracted with dichloromethane (40mLx3), merge organic phase, (10 mLx3), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, obtain title product 1- 3,5- di-tert-butyl-hydroxy phenyls) ethyl ketone 21a (1.98 g, yellow solid), yield： 82.3%.
MS m/z (ESI): 249 [M+l]
Second step
1- 3,5- di-t-butyl -4- methoxyphenyls) ethyl ketone
1- (3,5- di-tert-butyl-hydroxy phenyl) ethyl ketone 21a (1.29 g, 5.2 mmol) is dissolved in 50 mL acetone, potassium carbonate is added（1.43 g, 10.34 mmol) and toluene-4-sulfonic acid methyl esters (1.93 g, 10.36 mmol), 50 °C of lower stirring reactions 12 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 1- (3,5- di-t-butyl -4- methoxyphenyls) ethyl ketone 21b (1.03 g, rufous grease), yield： 75.4%.
MS m/z (ESI): 263 [M+l]
3rd step
The bromo- l- of 2- (3,5- di-t-butyl -4- methoxyphenyls) ethyl ketone
Under 40 °C, by 1- (3,5- di-t-butyl -4- methoxyphenyls) ethyl ketone 21b (711 mg, 2.71 mmol) it is dissolved in 20 mL chloroforms, add copper bromide (964 mg, 5.42 mmol), stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain the bromo- 1- (3 of title product 2-, 5- di-t-butyl -4- methoxyphenyls) ethyl ketone 21c (295 mg, brown-red solid), yield： 31.9%. MS m/z (ESI): 343 [M+l]
4th step
1- 3,5- di-t-butyl -4- methoxyphenyls) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide
By 5', 6'- diethoxies spiral shell [cyclopropane -1,3'- isoindoline]-Γ-imines hydrobromate 7d (198 mg, 0.8
Mmol) it is dissolved in 3 mL tetrahydrofurans, add 2- bromo- l- (3,5- di-t-butyl -4- methoxyphenyls) ethyl ketone 21c (303 mg, 0.89 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring reaction 48 hours.Filtering, filter cake is with tetrahydrofuran (1 mL), water (20 mLx2) and n-hexane washing (10 mLx2), vacuum drying, obtains title product 1- 3,5- di-t-butyl -4- methoxyphenyls) -2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindolines] -2'- bases) ethanone hydrobromide 21 (128 mg, white powder), yield： 27.1%.
MS m/z (ESI): 507 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.70 (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=7.2 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.71 (s, 3H), 1.76- 1.60 (m, 2H), 1.45 (s, 18H), 1.39 (m, 6H) embodiment 22
L- (3,5- di-tert-butyl-phenyl) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases)
The first step
1- (3,5- di-t-butyls-phenyl) ethyl ketone
Under dry ice-propanone bath, by 1- bromo- 3,5- di-t-butyls-benzene 22a (3.58 g, 13.31 mmol) are dissolved in 26 mL tetrahydrofurans, add tetramethylethylenediamine (2.2 mL, 14.6 mmol) and n-BuLi (5.85 mL, 14.6 mmol), stirring reaction 1 hour adds dimethyl acetamide (2.46 mL, 26.6 mmol), continue stirring reaction 2 hours.20 mL saturated ammonium chloride solutions are added into reaction solution, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed (10 mLx2) with water (10 mLx2) and saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (3,5- di-t-butyls-phenyl) ethyl ketone 22b (3.85g, colorless oil), yield： 58.2%.
1H NMR (400 MHz, CDC13, ppm):δ 7.82 (s, 2H), 7.66 (s, 1H), 2.62 (s, 3H), 1.37 (s, 18H)
Second step
The bromo- l- of 2- (3,5- di-t-butyls-phenyl) ethyl ketone
1- (3,5- di-t-butyls-phenyl) ethyl ketone 22b (3.8 g, 16.4 mmol) is dissolved in 100 mL chloroforms, copper bromide (7.32 g, 32.7 mmol), 36 °C of lower stirring reactions 24 hours is added.Filtering, filtrate decompression Nong Shrink,
With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (3,5- di-t-butyls-phenyl) ethyl ketone 22c C3.4g, light yellow solid), yield： 66.8%.
1H NMR (400 MHz, CDC13, ppm): δ 7.85 (s, 2H), 7.70 (s, 1H), 4.48 (s, 2H), 1.37 (s, 18H)
3rd step
L- (3,5- di-tert-butyl-phenyl) -2- (5', 6'- diethoxy -3'- imino groups-spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases）Ethanone hydrobromide
By 5', 6'- diethoxy spiral shell [cyclopropane -1,3'- isoindolines]-Γ-imines hydrobromate 7d (131 mg, 0.53 mmol) it is dissolved in 5 mL tetrahydrofurans, add the bromo- 1- of 2- (3,5- di-t-butyls-phenyl)-ethyl ketone 22c (193 mg, 0.62 mmol) and triethylamine (0.1 mL, 0.72 mmol), stirring reaction 12 hours.Filtering, filter cake tetrahydrofuran (l mLx2) and water washing (10 mLx3), vacuum drying, obtain title product 13,5- di-tert-butyl-phenyls) -2- (5', 6'- diethoxies -3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases) ethanone hydrobromide 22
(67 mg, white powder), yield： 27.1%.
MS m/z (ESI): 477 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.66 (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, /=7.2 Hz, 2H), 4.11 (q, J
=7.2 Hz, 2H), 1.76-1.61 (m, 4H), 1.40 (m, 6H), 1.36 (s, 18H) embodiments 23
L- (3,5- di-tert-butyl-hydroxy phenyl) -2- (the fluoro- 3'- imino groups-spiral shells of 5', 6'- diethoxy -7'- [cyclopropane -1, Γ-isoindoline -2'- bases) ethanone hydrobromide
The bromo- 2- fluorophenols of 4-
Under ice bath, 2- fluorophenols 23a (210 g, 1.8 8 mol) is dissolved in 500 mL chloroforms, bromine (94 mL, 1.88 mol) is added dropwise, reaction 2 hours is stirred at room temperature.100 mL saturated sodium bisulfite solutions are added, with two
Chloromethanes extracts (100 mLx3), merges organic phase, is washed with 10 mL saturated nacl aqueous solutions, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain the bromo- 2- fluorophenols 23b of title product 4- (321 g, pale yellow oil), yield： 90.2%.
MS m/z (ESI): 191 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.21 (d, J=2.4 Hz, 1H), 7.71 (m, 1H), 6.98 (m, m), 6A9 (br. s, 1H)
Second step
The fluoro- 2- hydroxy-benzaldehydes of the bromo- 3- of 5-
The bromo- 2- fluorophenols 23b of 4- (170 g, 0.89 mol) are dissolved in 600 mL trifluoroacetic acids, methenamine (225 g, 1.6 mol), back flow reaction 5 hours is added.Room temperature is cooled to, reaction solution is poured into 1 L water, the sulfuric acid solutions of 300 mL 50% are added, filtering, filter cake is washed with 20 mL ethanol, is dried in vacuo, obtain the fluoro- 2- hydroxy-benzaldehydes 23c of the bromo- 3- of title product 5- (90 g, yellow solid), yield： 46.2%.
MS m/z (ESI): 219 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 10.87 (br. s, 1H), 9.88 (s, 1H), 7.50 (m, 1H), 7.28 (s, 1H)
3rd step
Fluoro- 1, the 2- biphenols of the bromo- 3- of 5-
The fluoro- 2- hydroxy-benzaldehydes 23c of the bromo- 3- of 5- (80 g, 0.37 mol) are dissolved in 402 mL 1M sodium hydroxide solutions, 402 mL hydrogen peroxide, stirring reaction 3 hours are added.100 mL saturated sodium bisulfite solutions are added into reaction solution, it is extracted with ethyl acetate (200 mLx4), merge organic phase, with lOO mL 1M salt acid elutions, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain fluoro- 1,2- biphenols 23d (60 g of the bromo- 3- of title product 5-, colorless solid), yield： 79.4%.
MS m/z (ESI): 205 [M-l]
4th step
The bromo- fluoro- benzene of 1,2- diethoxies -3- of 5-
By the bromo- 3- of 5- fluoro- 1,2- biphenols 23d (20.7 g, 0.1 mol) it is dissolved in 150 mL dimethyl sulfoxides, add iodoethane (24.2 mL, 0.3 mol) and potassium carbonate (34.5 g, 0.25 mol), 50 °C of lower stirring reactions 3.5 hours.600 mL water are added into reaction solution, it is extracted with ethyl acetate (150 mIX3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain fluoro- benzene 23e (15.38 g of bromo- 1, the 2- diethoxies -3- of title product 5-, pale yellow oil), yield： 58.5%.
1H NMR (400 MHz, CDC13, ppm):δ 6.89 (d, J=2.0 Hz, 1H), the 6.82 (Hz of t, J=2.0,1H), 4.09 (m, 4H), 1.45 (t, /=7.2 Hz, 3H), 1.36 (t, /=7.2 Hz, 3H)
5th step
1, the 2- bis- fluoro- benzene of bromo- 4,5- diethoxies -3-
The fluoro- benzene 23e of bromo- 1, the 2- diethoxies -3- of 5- (15 g, 0.057 mol) are dissolved in 100 mL acetic acid, plus
Enter sodium acetate (6.22g, 0.076 mol) and bromine (12.12 g, 0.076 mol), 50 °C of lower stirring reactions 5 hours.Add 100 mL water, with n-hexane extraction (100 mLx3), merge organic phase, saturated nacl aqueous solution washing (50 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink obtain title product 1,2- bis- bromo- 4, the fluoro- benzene 23f of 5- diethoxies -3- (l l g, colorless oil), yield： 56.0%.
1H NMR (400 MHz, CDC13, ppm):δ 7.05 (s, 1H), 4.29 (q, /=6.4 Hz, 2H), 4.19 (q, /=8.0 Hz, 2H), 1.52 (t, /=6.4 Hz, 3H), 1.41 (t, /=8.0 Hz, 3H)
6th step
The fluoro- dintrile of 4,5- diethoxies -3-
By 1,2- bis- bromo- 4, fluoro- benzene 23f (11.1 g of 5- diethoxies -3-, 0.032 mol) it is dissolved in 60 mL N, in dinethylformamide, cuprous cyanide (11.6 g, 0.13 mol) and cuprous iodide (6.17 g are sequentially added, 0.032 mol), return stirring reacts 8 hours.Jian Ya Nong Shrink, add 50 mL ammoniacal liquor and 50 mL ethyl acetate, and aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, saturated nacl aqueous solution washs (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4, fluoro- dintrile 23g (2.6 g of 5- diethoxies -3-, white solid), yield： 34.7%. 1H NMR (400 MHz, CDC13, ppm):δ 6.83 (s, 1H), 4.55 (m, 2H), 4.13 (m, 2H), 1.48 (t, /=6.0 Hz, 3H), 1.39 (t, /=6.8 Hz, 3H)
7th step
5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines] -1'- imines 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -4'-, 3'- isoindolines] under -1'- imines ice baths, by 4, fluoro- dintrile 23g (2.26 g of 5- diethoxies -3-, 9.66 mmol) it is dissolved in 100 mL ether, add tetraisopropyl titanate (3.18 mL, 10.75 mmol) and ethylmagnesium bromide (7.1 mL, 21.3 mmol), stirring reaction 2 hours.55 mL methanol are added into reaction solution, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 5', [ring third washes -1 to the fluoro- spiral shells of 6'- diethoxies -7'-, 3'- isoindolines] -1'- imines 23h and the fluoro- spiral shells of 5', 6'- diethoxy -4'- [cyclopropane -1,3'- isoindoline]-Γ-imines 23i (955 mg, dark red powder), yield： 37.4%.
MS m/z (ESI): 265 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.01 (s, 1H), 4.14 (m, 4H), 1.82 (m, 2H), 1.67 (m, 2H), 1.34 (m, 6H)
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.94 (s, 1H), 4.17 (m, 4H), 1.81 (m, 2H), 1.69 (m, 2H), 1.34 (m, 6H)
8th step
1- 3,5- di-tert-butyl-hydroxy phenyl) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -7'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 23h and 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -4'-, 3'- isoindolines]-Γ-imines 23i (277 mg, 1.05 mmol) is dissolved in 3 mL tetrahydrofurans, adds the bromo- 1- (3 of 2-, 5- di-tert-butyl-hydroxy phenyls) ethyl ketone If (352 mg, 1.08 mmol) and three
Ethamine (0.2 mL, 1.44 mmol), stirring reaction 12 hours.Filtering, filter cake n-hexane (10 mLx2) and water washing (10 mLx2), vacuum drying, obtain title product 1-C3,5- di-tert-butyl-hydroxy phenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -7-) (17 mg of ethanone hydrobromide 23, brown ceramic powder), yield： 2.7%.
MS m/z (ESI): 511 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 7.95 (s, 1H), 7.79 (s, 2H), 5.19 (s, 2H), 4.22 (q, /=7.2 Hz, 4H), 1.78 (m, 4H), 1.46 (s, 18H), 1.31 (t, /=7.2 Hz, 6H) embodiments 24
1- 3,5- di-tert-butyl-hydroxy phenyl) -2- (fluoro- 3- imino groups -1, the 1- dimethyl-isoindolines of 5,6- diethoxy -4-
- 2- bases) ethanone hydrobromide
The first step
2- (3,4- diethoxy -5- fluoro-phenyls) propan-2-ol
Under -78 °C, the fluoro- benzene 23e of bromo- 1, the 2- diethoxies -3- of 5- (26.3 g, 0.1 mol) are dissolved in 100 mL ether, addition n-BuLi (；44 mL, 0.11 mol), stirring reaction 30 minutes adds acetone (8.1 mL, 0.11 mol), continues to react 2 hours.200 mL water are added into reaction solution, it is extracted with ethyl acetate (200 mLx2), merge organic phase, washed with saturated nacl aqueous solution (100 mL), Jian Ya Nong Shrink, obtain title product 2- (3,4- diethoxy -5- fluoro-phenyls) propan-2-ol 24a (23.7 g, yellow oil yield： 97.9%.
1H NMR (400 MHz, CDC13, ppm):δ 6.87 (m, 1H), 6.81 (m, 1H), 4.14 (m, 4H), 1.57 (s, 6H), 1.47 (t, /=7.2 Hz, 3H), 1.31 (t, /=7.2 Hz, 3H)
Second step
Under 5- (l- nitrine -1- methyl-ethyls) fluoro- benzene ice baths of -1,2- diethoxies -3-, 2- (3,4- diethoxy -5- fluoro-phenyls) propan-2-ol 24a (21.97 g, 0.091 mol) are dissolved in
In 200 mL chloroforms, sodium azide is added（17.7 g, 0.27 mol) and trifluoroacetic acid (33.7 mL, 0.46 mol), stirring reaction 12 hours.Subtract the dense Shrink of pressure, extracted with dichloromethane (200 mLx2), merge organic phase, use saturation
Sodium bicarbonate solution washs (100 mLx2), and anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain title product 5- (1- nitrine -1- methyl-ethyls) the fluoro- benzene 24b of -1,2- diethoxies -3- (24.1 g, yellow oil yield： 99.2%.
1H NMR (400 MHz, CDC13, ppm):δ 6.75 (m, 2H), 4.12 (m, 4H), 1.60 (s, 6H), 1.45 (t, J=1.2 Hz, 3H), 1.36 (t, J=7.2 Hz, 3H)
3rd step
1- (1- nitrine -1- methyl-ethyls) -2- bromo- 4, the fluoro- benzene of 5- diethoxies -3- is by 5- (1- nitrine -1- methyl-ethyls) -1, fluoro- benzene 24b (21.4 g of 2- diethoxies -3-, 0.08 mol) it is dissolved in 200 mL acetic acid, add sodium acetate (13.1 g, 0.16 mol) and bromine (8 mL, 0.16 mol), stirring reaction 48 hours.Add 30 mL saturated sodium bisulfite solutions, with n-hexane extraction (150 mLx3), merge organic phase, washed (150 mL) with saturated sodium bicarbonate solution (150 mLx2) and saturated nacl aqueous solution successively, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain title product 1- (1- nitrine -1- methyl-ethyls) -2- bromo- 4, fluoro- benzene 24c (20.4 g of 5- diethoxies -3-, yellow oil), yield： 73.5%.
1H NMR (400 MHz, CDC13, ppm):δ 7.01 (d, J=2.0 Hz, 1H), 4.16 (m, 4H), 1.83 (s, 6H), 1.49 (t, /=7.2 Hz, 3H), 1.41 (t, /=7.2 Hz, 3H)
4th step
5,6- diethoxies -7- fluoro- 3,3- dimethyl-small amine of iso-indoles is by 1- (the small methyl-ethyl of 1- nitrine) -2- bromo- 4, fluoro- benzene 24c (10 g of 5- diethoxies -3-, 28.8 mmol) it is dissolved in 100 mL dimethyl sulfoxides, add cuprous cyanide (5.16 g, 57.6 mmol) and cuprous iodide (10.9 g, 57.6 mmol), 150 °C of lower stirring reactions 1 hour.300 mL water and 300 mL ethyl acetate are added, organic phase merges aqueous phase with 300 mL salt acid elutions, be 12 13 with the M of 300 mL 1 sodium hydroxide solution regulation pH.Aqueous phase is extracted with ethyl acetate (150 mLx3), merge organic phase, washed (200 mL) with weak aqua ammonia (200 mL) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain title product 5, fluoro- 3, the 3- dimethyl of 6- diethoxies -7--iso-indoles -1- amine 24d (0.9 g, gray solid), yield： 11.5%. MS m/z (ESI): 267 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.01 (s, 1H), 4.18 (m, 2H), 4.10 (m, 2H), 1.48 (t, J=1.2 Hz, 3H), 1.44 (s, 6H), 1.37 (t, /=7.2 Hz, 3H)
5th step
1- 3,5- di-tert-butyl-hydroxy phenyl) -2- (fluoro- 3- imino groups -1, the 1- dimethyl-isoindolines of 5,6- diethoxy -4-
- 2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (266 mg of 3- dimethyl-iso-indoles, 1 mmol) it is dissolved in 7 mL N, in dinethylformamide, 2- bromo- 1- (3,5- di-tert-butyl-hydroxy phenyl) ethyl ketone lf (360 mg are added, 1.1 mmol), stirring reaction 12 hours.70 mL water are added into reaction solution, it is extracted with ethyl acetate (25 mLx3), washed (50 mL) with water (50 mL) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- (3,5- di-tert-butyl-hydroxy phenyls) -2- (the fluoro- 3- imino groups-U- dimethyl-isoindolines of 5,6- diethoxy -4-
- 2- bases) ethanone hydrobromide 24 (110 mg, yellow solid), yield： 21.6%.
MS m/z (ESI): 513 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.37 (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, /=7.2 Hz, 3H), 1.31 (t, /=7.2 Hz, 3H) embodiments 25
The 1- 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) (7- imino group -2,5- dimethyl -5- phenyl-pyrrols are simultaneously by -2-
[3,4-b] pyridine -6- base ethanone hydrobromides
9f 25
The first step
The 1- 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) (7- imino group -2,5- dimethyl -5- phenyl-pyrrols are simultaneously by -2-
[3,4-b] pyridine -6- bases) ethanone hydrobromide
By 2,5- dimethyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 9f (237 mg, 1 mmol) and the bromo- 1- of 2- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketone 8d (424.8 mg, 1.2 mmol) it is dissolved in 3 mL N, in dinethylformamide, stirring reaction 12 hours.5 mL water are added into reaction solution, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain the title product 1- 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (7- imino groups -2, 5- dimethyl -5- phenyl-B ratios cough up simultaneously [3, 4-b] pyridine -6- bases) (130 mg of ethanone hydrobromide 25, yellow solid), yield： 22.0%.
MS m/z (ESI): 512 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 7.93 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.37 (m, 7H), 5.04 (d, /=16.8 Hz, 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
L- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (fluoro- 3- imino groups -1,1- dimethyl hydrochlorates of 5,6- diethoxy -4-
The first step
1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (266 mg of 3- dimethyl-iso-indoles, 1 mmol) it is dissolved in 7 mL N, in dinethylformamide, add 2- bromo- 1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketone 8d (390 mg, 1.1 mmol), stirring reaction 12 hours.50 mL water are added into reaction solution, it is extracted with ethyl acetate (25 mLx4), merge organic phase, washed (50 mL) with water (50 mL) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (61 mg of ethanone hydrobromide 26, yellow solid), yield： 11.3%.
MS m/z (ESI): 540 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.50 (d, /=2.0 Hz, 1H), 7.45 (s, 2H), 5.41 (s, 2H), 4.27 (q, /=7.2 Hz, 2H), 4.13 (q, /=7.2 Hz, 2H), 3.67 (s, 3H), 3.19 (m, 4H), 1.94 (m, 4H), 1.51 (s, 6H), 1.41 (m, 12H), 1.32 (t, /=7.2 Hz, 3H) embodiments 27
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--different
The first step
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
The fluoro- small amine 24d of 3,3- dimethyl-iso-indoles (400 mg, 1.5 mmol) of 5,6- diethoxies -7- are dissolved in
In 10 mL DMFs, 2- bromo- 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketone 2h (610 mg, 1.65 mmol), stirring reaction 12 hours is added.100 mL water are added into reaction solution, it is extracted with ethyl acetate (50 mLx5), merge organic phase, washed (50 mL) with water (50x3 mL) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide 27 (84 mg, yellow solid), yield： 8.4%.
MS m/z (ESI): 556 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.35 (br. s, 1H), 8.99 (br. s, 1H), 7.67 (d, /=2.0 Hz, 1H), 7.59 (the Hz of d, J=2.0,1H), 7.46 (s, 1H), 5.47 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 4.13 (q, J=7.2 Hz, 2H), 4.01 (s, 3H), 3.84 (m, 4H), 3.04 (m, 4H), 1.58 (s, 6H), 1.41 (m, 12H), 1.32 (t, /=7.2 Hz, 3H) embodiment 28
L- [the 3- tert-butyl group -4- methoxyl groups -5- (l- piperidines) phenyl] -2- (fluoro- 3- imino groups -1,1- bis- of 5,6- diethoxy -4-
- 2- bases) ethanone hydrobromide
The first step
1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] -2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5, the fluoro- small amine 24d of 3,3- dimethyl-iso-indoles (266 mg, 1.0 mmol) of 6- diethoxies -7- are dissolved in 7 mL N, in dinethylformamide, 2- bromo- 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] ethyl ketone is added
12b (400 mg, 1.1 mmol), stirring reaction 12 hours.70 mL water are added into reaction solution, it is extracted with ethyl acetate (40 mLx2), merge organic phase, washed (50 mL) with water (50 mL) and saturated nacl aqueous solution, Jian Ya Nong Shrink, add 100 mL n-hexanes, Jian Ya Nong Shrink to 15 mL, filtering, obtain title product 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (116 mg of ethanone hydrobromide 28, white solid), yield： 20.9%.
MS m/z (ESI): 554 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the br. s of δ 9.27, 1H), 8.95 (br. s, 1H), 7.64 (d, the Hz of /=2.0, 1H), 7.59 (d, the Hz of J=2.0, 1H), 7.45 (s, 1H), 5.41 (s, 2H), 4.27 (q, the Hz of J=7.2, 2H), 4.13 (q, the Hz of /=7.2, 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, the Hz of /=7.2, 3H) embodiment 29
N- [the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group -2- methoxyphenyls] acetamide hydrobromates
The first step
N- [the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] -2- methoxyphenyls] acetamide hydrobromate
By 5; 6- diethoxies -7- fluoro- 3; small amine 24d (266 mg of 3- dimethyl-iso-indoles; 1.0 mmol) it is dissolved in 6 mL N; in dinethylformamide; add N- [5- (2- the acetyl bromides) -3- tert-butyl group -2- methoxyphenyls] acetamide 13b (380 mg, 1.1 mmol), stirring reaction 12 hours.100 mL water are added into reaction solution; it is extracted with ethyl acetate (50 mLx3); merge organic phase; washed (50 mL) with water (50x2 mL) and saturated nacl aqueous solution; anhydrous magnesium sulfate is dried; filtering; filtrate decompression Nong Shrink; obtain title product N- [the 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group] -2- methoxyphenyls] (90 mg of acetamide hydrobromate 29; faint yellow solid), yield： 17.0%.
MS m/z (ESI): 528 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.82 (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, 7=7.2 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 2.14 (s, 3H), 1.50 (s, 6H), 1.41 (s, 9H), 1.33 (m, 6H) embodiments 30
L- (the 8- tert-butyl group -4- methyl -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (fluoro- 3- imino groups of 5,6- diethoxy -4-
The first step
1- (the 8- tert-butyl group -4- methyl -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (fluoro- 3- imino groups of 5,6- diethoxy -4-
- U- dimethyl-isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (300 mg of 3- dimethyl-iso-indoles, 1.1 mmol) it is dissolved in 7 mL DMFs, add the small (the 8- tert-butyl group -4- methyl -2 of 2- bromines, 3- dihydros -1,4- benzoxazine -6- bases) ethyl ketone 19b (440 mg, 1.35 mmol), stirring reaction 12 hours.75 mL water are added into reaction solution, it is extracted with ethyl acetate (50 mLx2), merge organic phase, washed with saturated nacl aqueous solution (50 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression is concentrated, obtain title product 1- (the 8- tert-butyl group -4- methyl -2,3- dihydro-Isosorbide-5-Nitrae-benzoxazine -6- bases) -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) (80 mg of ethanone hydrobromide 30, faint yellow solid), yield： 10.8%.
MS m/z (ESI): 513 [M+l]
1H NMR (400 MHz, DMSO- , ppm): δ 7.40 (s, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 5.28 (s;2H), 4.36 (m, 2H), 4.26 (q, J=7.2 Hz, 2H), the 4.12 (Hz of q, J=7.2,2H), 3.33 (m, 2H), 2.95 (s, 3H), 1.48 (s, 6H), 1.37 (m, 12H), 1.31 (t, /=7.2 Hz, 3H) embodiments 31
2- [the 8- tert-butyl groups -6- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] -
2,3- dihydro -1,4 ester hydrobromates
The first step
2- [the 8- tert-butyl groups -6- [2- (5; the fluoro- 3- imino groups -1 of 6- diethoxies -4-; 1- dimethyl-isoindoline -2- bases) acetyl group] -2; 3- dihydros -1; 4- benzoxazine -4- bases] ethyl acetate hydrobromate is by 5; the fluoro- small amine 24d of 3,3- dimethyl-iso-indoles (200 mg, 0.75 mmol) of 6- diethoxies -7- are dissolved in
In 5 mL DMFs, 2- [6- (2- acetyl bromides) -8- tert-butyl groups -2 are added; 3- dihydros -1; 4- Ben Bing Evil piperazine -4- bases] ethyl acetate 5e (330 mg, 0.83 mmol), stirring reaction 12 hours.20 mL water are added into reaction solution, it is extracted with ethyl acetate (50 mLx2), merge organic phase, washed (10 mLx3) with water (10 mLx3) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain title product 2- [the 8- tert-butyl groups -6- [2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) acetyl group] -2, 3- dihydros -1, 4- benzoxazine -4- bases] (88 mg of ethyl acetate hydrobromate 31, faint yellow solid), yield： 17.7%. MS m/z (ESI): 584 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.44 (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, /=7.2 Hz, 3H), 1.37 (s, 9H), 1.30 (t, /=7.2 Hz, 3H), 1.19 (t, /=7.2 Hz, 3H) embodiment 32
L- [3- (l- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] -2- (fluoro- 3- imino groups -1, the Γ-dimethyl of 5,6- diethoxy -4---2- bases) ethanone hydrobromide
The first step
1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] -2- (fluoro- 3- imino groups -1, the 1'- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (266 mg of 3- dimethyl-iso-indoles, 1 mmol) it is dissolved in 5 mL N, in dinethylformamide, add 1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] bromo- ethyl ketone 17h of -2- (493 mg, 1.1 mmol), stirring reaction 12 hours.20 mL water and 15 mL ethyl acetate are added into reaction solution, aqueous phase is extracted with ethyl acetate (5 mLx3), merge organic phase, washed (10 mLx3) with water (10 mLx3) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain title product 1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1 '-dimethyl-isoindoline -2- bases) (40 mg of ethanone hydrobromide 32, faint yellow solid), yield： 5.6%.
MS m/z (ESI): 634 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.35 (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, /=7.2 Hz, 3H), 1.31 (t, /=7.2 Hz, 3H) embodiments 33
L- (the 8- tert-butyl group -4- ethyls -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (fluoro- 3- imino groups of 5,6- diethoxy -4-
- 1,1- diformazan hydrobromate
The first step
1- (the 8- tert-butyl group -4- ethyl -2,3- dihydro -1,4- benzoxazine -6- bases) -2- (fluoro- 3- imino groups of 5,6- diethoxy -4-
- 1,1- dimethyl-isoindoline -2- bases) ethanone hydrobromide is by 5, the fluoro- small amine 24d of 3,3- dimethyl-iso-indoles (200 mg, 0.75 mmol) of 6- diethoxies -7- are dissolved in 4 mL N, in dinethylformamide, add 2- bromo- 1- (the 8- tert-butyl group -4- ethyl -2,3- dihydro -1,4- benzoxazine -6- bases) ethyl ketone 6b (282 mg, 0.83 mmol), stirring reaction 12 hours.5 mL water and 5 mL ethyl acetate are added into reaction solution, aqueous phase is extracted with ethyl acetate (5 mIX3), merge organic phase, with water (10 mL><3) with saturated nacl aqueous solution washing (10 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, add 2 mL ethyl acetate, filtering, filter cake is dried in vacuo, obtain title product 1- (the 8- tert-butyl group -4- ethyl -2,3- dihydro -1,4- benzoxazine -6- bases) -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide 33 (55 mg, faint yellow solid), yield： 12.1%.
MS m/z (ESI): 526 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.23 (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, /=4.0 Hz, 2H), 1.50 (s, 6H), 1.42 (t, /=7.2 Hz, 3H), 1.37 (s, 9H), 1.31 (t, /=7.2 Hz, 3H), 1.12 (t, /=6.0 Hz, 3H) embodiments 34
L- (3,5- di-t-butyl -4- methoxyphenyls) -2- (fluoro- 3- imino groups-U- dimethyl-iso-indoles of 5,6- diethoxy -4-
- 2- bases) ethanone hydrobromide
The first step
1- (3,5- di-t-butyl -4- methoxyphenyls) -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (200 mg of 3- dimethyl-iso-indoles, 0.75 mmol) it is dissolved in 4 mL N, in dinethylformamide, 2- bromo- 1- (3,5- di-t-butyl -4- methoxyphenyls) ethyl ketone 21c (0.28 g are added, 0.83 mmol), stirring reaction 12 hours.5 mL water and 5 mL ethyl acetate are added into reaction solution, aqueous phase is extracted with ethyl acetate (5 mLx3), merge organic phase, washed (10 mLx3) with water (10 mLx3) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, add 2 mL ethyl acetate, filtering, vacuum drying, obtain title product 1- (3, 5- di-t-butyl -4- methoxyphenyls) -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (60 mg of ethanone hydrobromide 34, faint yellow solid), yield： 13.2%.
MS m/z (ESI): 527 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.31 (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, /=7.2 Hz, 3H) embodiment 35
L- (3,5- di-tert-butyl-phenyl) -2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--iso-indoles -2- bases)-ethanone hydrobromide
The first step
L- (3,5- di-tert-butyl-phenyl) -2- (fluoro- 3- imino groups -1,1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases）Ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (266 mg of 3- dimethyl-iso-indoles, 1 mmol) it is dissolved in 4 mL N, in dinethylformamide, 2- bromo- 1- (3,5- di-t-butyls-phenyl) ethyl ketone 22c (0.34 g are added, 1.1 mmol), stirring reaction 12 hours.Add 5 mL water and 5 mL ethyl acetate, aqueous phase is extracted with ethyl acetate (5 mLx3), merge organic phase, with water CIO mLx3) and saturated nacl aqueous solution wash (；10 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, add 2 mL ethyl acetate, filtering, filter cake vacuum drying, obtains title product 1-C3,5- di-tert-butyl-phenyls) -2- (5, the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) ethanone hydrobromide 35 (70 mg, white solid), yield： 12.1%.
MS m/z (ESI): 497 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.37 (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, /=7.2 Hz, 3H), 1.36 (s, 18H), 1.31 (t, /=7.2 Hz, 3H) embodiments 36
L- [the 3- tert-butyl group -4- methoxyl groups -5- (l- piperidines) phenyl] -2- (fluoro- 3- imino groups-salt of 5,6- diethoxy -1,1- diethyl -4-
The first step
3- (3,4- diethoxy -5- fluoro-phenyls) amyl- 3- alcohol
Under -78 °C, by 5- bromo- 1, fluoro- benzene 23e (26.3 g of 2- diethoxies -3-, 0.1 mol) it is dissolved in 100 mL ether, add n-BuLi (44 mL, 0.11 mol), stirring reaction 30 minutes, propione (11.6 mL, 0.11 mol) is added, continues to react 2 hours.200 mL water are added to reaction solution, it is extracted with ethyl acetate (100 mLx2), merge organic phase, (100 mL), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 3- (3,4- diethoxy -5- fluoro-phenyls) amyl- 3- alcohol 36a (20.1 g, pale yellow oil yield： 74.7%.
1H NMR (400 MHz, CDC13, ppm):δ 6.77 (d, J=2.0 Hz, 1H), 6.72 (dd ,/；=12.0 Hz, J 2=2.0 Hz, 1H), 4.14 (m, 4H), 1.85 (m, 4H), 1.47 (t, /=7.2 Hz, 3H), 1.40 (t, /=7.2 Hz, 3H), 0.80 (t, /=7.6 Hz, 6H)
Second step
5- (l- nitrine -1- Ethyl-propyls) -1, under the fluoro- benzene ice baths of 2- diethoxies -3-, by 3- (3,4- diethoxy -5- fluoro-phenyls) amyl- 3- alcohol 36a (20 g, 0.074 mol) it is dissolved in 250 mL chloroforms, add sodium azide (14.4 g, 0.22 mol) and trifluoracetic acid (27.4 mL, 0.37 mol), stirring reaction 12 hours.200 mL water are added into reaction solution, extracted with dichloromethane (150 mLx2), merge organic phase, washed (200 mLx5), anhydrous sodium sulfate drying, filtered with saturated sodium bicarbonate solution, filtrate decompression Nong Shrink, obtain title product 5- (1- nitrine -1- Ethyl-propyls) -1,2- diethoxies -3- fluoro- benzene 36b (21.2 g, pale yellow oil）, yield： 97.2%.
1H NMR (400 MHz, CDC13, ppm):δ 6.72 (d, J=2.4 Hz, 1H), 6.69 (dd ,/；=11.6 Hz, J 2=2.4 Hz, 1H), 4.17 (m, 4H), 1.96 (m, 4H), 1.48 (t, /=7.2 Hz, 3H), 1.40 (t, /=7.2 Hz, 3H), 0.82 (t, J=7.6 Hz, 6H)
3rd step
1- (1- nitrine -1- Ethyl-propyls) -2- bromo- 4, the fluoro- benzene of 5- diethoxies -3- is by 5- (1- nitrine -1- Ethyl-propyls) -1, fluoro- benzene 36b (21 g of 2- diethoxies -3-, 71.2 mmol) it is dissolved in 250 mL acetic acid, add bromine (7.1 mL, 142.3 mmol) and sodium acetate（11.67 g, 142.3 mmol), stirring reaction 144 hours.250 mL saturated sodium bisulfite solutions are added into reaction solution, with n-hexane and ethyl acetate (V/V = 5:L) mixed extractant solvent (100 mLx3), merges organic phase, is washed (lOO mL) with saturated sodium bicarbonate solution (100 mLx5) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink
Obtain title product 1- (1- nitrine -1- Ethyl-propyls) fluoro- benzene 36c of bromo- 4, the 5- diethoxies -3- of -2- (24.1 g, yellow oil), yield： 90.2%.
1H NMR (400 MHz, CDC13, ppm):δ 7.12 (d, J=2.0 Hz, 1H), 4.16 (m, 4H), 2.69 (m, 2H), 1.97 (m, 2H), 1.48 (t, /=7.2 Hz, 3H), 1.41 (t, /=7.2 Hz, 3H), 0.79 (t, /=7.6 Hz, 6H)
4th step
5,6- diethoxies -3, the small amine of the fluoro- iso-indoles of 3- diethyl -7- is by 1- (1- nitrine -1- Ethyl-propyls) -2- bromo- 4, fluoro- benzene 36c (11 g of 5- diethoxies -3-, 29.3 mmol) it is dissolved in 100 mL dimethyl sulfoxides, add cuprous cyanide (5.25 g, 58.7 mmol) and cuprous iodide (5.57 g, 29.3 mmol), 150 °C of lower stirring reactions 2 hours.300 mL water are added to reaction solution, aqueous phase is extracted with ethyl acetate (400 mL), merge organic phase, with ammonia scrubbing (lOO mL), it is washed with water to blueness, watery hydrochloric acid extracts (100 mLx5), and aqueous phase adjusts pH to 14, then (100 mIX3) is extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product 5, the fluoro- iso-indoles of 6- diethoxy -3,3- diethyl -7- small amine 36d (2.24 g, gray solid）, yield： 26.0% o
MS m/z (ESI): 295 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 6.93 (s, 1H), 6.37 (br. s, 2H), 4.12 (d, /=6.8 Hz, 2H), 4.02 (d, /=6.8 Hz, 2H), 1.74 (m, 4H), 1.36 (t, /=6.8 Hz, 3H), 1.26 (t, /=6.8 Hz, 3H), 0.46 (br. s, 6H)
5th step
L- [the 3- tert-butyl group -4- methoxyl groups -5- (l- piperidines) phenyl] -2- (the fluoro- 3- imino groups of 5,6- diethoxy -1,1- diethyl -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -3, small amine 36d (0.3 g of the fluoro- iso-indoles of 3- diethyl -7-, 1 mmol) and small [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl]-ethyl ketone 12b (0.4 g of 2- bromines, 1.1 mmol) it is dissolved in 6 mL N, in dinethylformamide, 60 °C of lower microwave reactions 60 minutes.50 mL water and 2 mL saturated nacl aqueous solutions are added into reaction solution, are filtered, filter cake water (100 mL) and n-hexane and ethyl acetate (V/V=5:1) mixed solvent washing (lOO mL), with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] -2- (5,6- diethoxies -1, the fluoro- 3- imino groups of 1- diethyl -4--isoindoline -2- bases) (0.02 g of ethanone hydrobromide 36, yellow solid), yield： 3.0%.
MS m/z (ESI): 582 [M+l]
1H NMR (400 MHz, DMSO- , ppm): δ 7.63 (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, /=7.2 Hz, 6H) embodiment 37
L- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (the fluoro- 3- imino groups of 5,6- diethoxy -1,1- diethyl -4--isoindoline -2- bases) ethanone hydrobromide
The first step
L- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (the fluoro- 3- imino groups of 5,6- diethoxy -1,1- diethyl -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -3, small amine 36d (0.3 g of the fluoro- iso-indoles of 3- diethyl -7-, 1 mmol) and small (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketone 8d (0.39 g of 2- bromines, 1.1 mmol) it is dissolved in 6 mL N, in N- dimethylformamides, 60 °C of lower microwave reactions 60 minutes.100 mL water are added into reaction solution, with n-hexane and ethyl acetate (V/V=5:L) mixed extractant solvent (lOO mL), Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (5,6- diethoxies -1, the fluoro- 3- imino groups of 1- diethyl -4--isoindoline -2- bases) ethyl ketone hydrobromic acid ＆ 37 (0.05 g, yellow solid), yield： 8.8%.
MS m/z (ESI): 568 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.43 (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=7.2 Hz, 2H), 4.15 (q, J=7.2 Hz, 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, /=7.2 Hz, 6H) embodiment 38
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (5,6- diethoxy -1, the 1- diethyl-fluoro- 3- imino groups of 4--different
The first step
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (the fluoro- 3- imino groups of 5,6- diethoxy -1,1- diethyl -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -3, small amine 36d (0.3 g of the fluoro- iso-indoles of 3- diethyl -7-, 1 mmol) and small (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketone 2h (0.41 g of 2- bromines, 1.1 mmol) it is dissolved in 6 mL N, in dinethylformamide, 60 °C of lower microwave reactions 60 minutes.100 mL water are added into reaction solution, with n-hexane and ethyl acetate (V/V=5:1) mixed extractant solvent (100 mL), Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (5,6- diethoxies -1, the fluoro- 3- imino groups of 1- diethyl -4--isoindoline -2- bases) ethanone hydrobromide 38 (0.02 g, yellow solid), yield： 2%.
MS m/z (ESI): 568 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.48 (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=7.2 Hz, 2H), 4.14 (q, J=7.2 Hz, 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, /=7.2 Hz, 6H) embodiment 39
L- [the 3- tert-butyl group -4- methoxyl group -5- [(lR, 5^-8- oxa- -3- azabicyclos [3.2.1] oct-3-yl] phenyl] -2- (the fluoro- 3- imino groups-- two of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
[(2R,5 -5- (methylol) tetrahydrofuran-2Base] methanol
1,5- hexadienes 39a (4.6 g, 56 mmol) is dissolved in 620 mL tetrahydrofurans and dichloromethane (V/V=9:1) in the mixed solvent, adds sodium metaperiodate (26.2 g, 123 mmol), ruthenium trichloride (23 mg, 0.11 mmol), 80 g silica gel and 40 mL water, stirring reaction 8 hours.Reaction solution Jian Ya Nong Shrink, add 100 mL isopropanols, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product [C2R, 5-5- (；Methylol) base of tetrahydrofuran -2] methanol 39M4.34 g, colourless liquid), yield： 58.6 %.
1H NMR (400 MHz, CDC13, ppm):δ 4.08 (m, 2H), 3.76 (m, 2H), 3.73 (m, 4H), 1.92 (m, 2H), 1.79 (m, 2H)
Second step
[(2R,5 -5- (tolysulfonyl oxygen methyl)-tetrahydrofuran-2- yl]-methyl-4- toluene sulfonic acide ester is by [(2R, 5-5- (methylol) tetrahydrofurans-2 base] methanol 39b (3.0 g, 22.7 mmol) it is dissolved in 20 mL dichloromethane, add 4- toluene sulfochlorides (8.6 g, 45.4 mmol) and pyridine (4.4 mL, 54.5 mmol), stirring reaction 12 hours.30 mL water are added into reaction solution, aqueous phase is extracted (20 mLx3) with dichloromethane, merge organic phase, washed (20 mLx2) with saturated sodium carbonate solution (20 mLx2) and saturated nacl aqueous solution respectively, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, gained residue ethyl alcohol recrystallization, obtain title product [(2R, 5-5- (tolysulfonyl oxygen methyl)-tetrahydrofuran-2- bases]-methyl-4- toluene sulfonic acide esters 39c (6.0 g, white solid), yield： 60.0%.
1H NMR (400 MHz, CDC13, ppm):δ 7.79 (d, J=8.0 Hz, 4H), 7.36 (d, /=8.0 Hz, 4H), 4.11 (m, 2H), 3.94 (m, 4H), 2.46 (s, 6H), 1.95 (m, 2H), 1.72 (m, 2H)
3rd step
(lR, 5-3- benzyls-8- oxa--3- azabicyclos [3.2.1] octanes
By [(2R, 5-5- (tolysulfonyl oxygen methyl)-tetrahydrofuran-2- bases]-methyl-4- toluene sulfonic acide ester 39c (4.1 g, 9.32 mmol) and benzylamine (3.56 mL, 32.6 mmol) it is dissolved in 40 mL toluene, 120 °C of lower stirring reactions 12 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product -3- benzyl -8- oxa- -3- azabicyclo [3.2.1] octane 39d (1.58 g, colourless liquid), yield： 83.6 %.
1H NMR (400 MHz, CDC13, ppm):δ 7.32 (m, 5H), 4.28 (m, 2H), 3.47 (s, 2H), 2.56 (d, J=12.0 Hz, 2H), 2.36 (d, /=12.0 Hz, 2H), 2.01 (m, 2H), 1.99 (m, 2H)
4th step
(lWR) -8- oxa-s -3- azabicyclos [3.2.1] octane
By (1 5-3- benzyl-8- oxa--3- azabicyclo [3.2.1] octanes 39d (1.5 g, 7.39 mmol) it is dissolved in 200 mL ethyl acetate, add palladium/carbon (75 mg, 5%), hydrogen is replaced three times, 80 °C of lower stirring reactions 2 hours.Reaction solution Jian Ya Nong Shrink, filtering, filtrate decompression Nong Shrink, obtain title product (, 5R) -8- oxa- -3- azabicyclo [3.2.1] octanes 39e (；347mg, colourless liquid), yield： 83.3 %.
MS m/z (ESI): 114 [M+l]
5th step
1- [the 3- tert-butyl group -4- methoxyl group -5- [GR, 5S) -8- oxa-s -3- azabicyclos [3.2.1] oct-3-yl] phenyl] ethyl ketone is by the 1- tert-butyl groups -5- (1,1- dimethoxy-ethyls) the iodo- 2- methoxybenzenes 2f of -3- (761 mg, 2.01 mmol) and
2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl (79 mg, 0.20 mmol) it is dissolved in 10 mL toluene, add palladium/carbon (76 mg, 10%), potassium tert-butoxide (786 mg, 7.00 mmol) and (1 5R) -8- oxa- -3- azabicyclos [3.2.1] octane 396 (228 1,2.01 11^101), 80 °C of lower stirring reactions 5 hours.20 mL water are added into reaction solution, aqueous phase is extracted with ethyl acetate (5 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, add 5mL acetic acid and ImL water, stirring reaction 1 hour.Add 20 mL water, aqueous phase is extracted with ethyl acetate (5 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl group -4- methoxyl groups
- 5- [(1 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls] phenyl] ethyl ketone 39f (286 mg, yellow solid), yield： 45.0%.
MS m/z (ESI): 318 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.67 (d, J=2.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H),
4.44 (m, 2H), 3.94 (s, 3H), 3.17 (d, /=12.0 Hz, 2H), 3.01 (d, /=12.0 Hz, 2H), 2.57 (s:3H), 2.12 (m, 2H), 2.05 (m, 2H), 1.41 (s, 9H)
6th step
2-bromo--[the 3- tert-butyl group-4- methoxyl groups-5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls] phenyl] ethyl ketone
Under 40 °C, by 1- [the 3- tert-butyl group-4- methoxyl group-5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] octyl- 3- yls]-phenyl]-ethyl ketone 39f (258 mg, 0.81 mmol) it is dissolved in 8 mL chloroforms, add copper bromide (363.6 g, 1.63 mmol), stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl group-4- methoxyl group-5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls] phenyl] ethyl ketone 39g (220 mg, yellow solid yield： 68.3%. 1H NMR (400 MHz, CDC13, ppm):δ 7.70 (d, J=2.4 Hz, 1H), 7.55 (d, /=2.4 Hz, 1H),
4.45 (m, 2H), 4.40 (s, 2H), 3.96 (s, 3H), 3.17 (d, /=12.0 Hz, 2H), 2.99 (d, /=12.0 Hz, 2H), 2.12 (m, 2H), 2.05 (m, 2H), 1.41 (s, 9H)
7th step
L- [the 3- tert-butyl group -4- methoxyl group -5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls] phenyl]-2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide is by 5, 6- diethoxies -7- fluoro- 3, 3- dimethyl-iso-indoles -1- amine 24d (189 mg, 0.71 mmol) the bromo- 1- of standing grain Jie 2- [the 3- tert-butyl group -4- methoxyl group -5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls]-phenyl] ethyl ketone 39g (；310 mg, 0.78 mmol) it is dissolved in 5 mL DMFs, stirring reaction 12 hours.5 mL water are added into reaction solution, are extracted with ethyl acetate (5 mIX3), merge organic phase, washed (10 mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression Nong Shrink, with thin-layered chromatography with solvent
System A purifying gained residues, obtain title product 1- [the 3- tert-butyl group-4- methoxyl group-5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls] phenyl]-2- (5, the fluoro- 3- imino groups-1 of 6- diethoxies-4-, 1- dimethyl-isoindoline-2- bases) (72 mg of ethanone hydrobromide 39, yellow powder), yield： 15.3%.
MS m/z (ESI): 582 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.35 (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=7.2 Hz, 2H), 4.13 (q, J=7.2 Hz, 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, /=7.2 Hz, 3H), 1.39 (s, 9H), 1.31 (t, /=7.2 Hz, 3H) embodiment 40
L- [the 3- tert-butyl group -4- methoxyl groups -5- (2- oxa- -6- azaspiros [3.3] hex- 6- yls) phenyl] -2- (5,6- diethoxy -4- fluorine
2- (p-toluenesulfonyl) -6- oxa-s -2- azepines spiroheptane is by 3- bromo- 2; small alcohol 40a (65.0 g of 2- bis- (bromomethyl) propane; 0.20 mol) and 4- methyl benzenesulfonamides 40b (41.0 g; 0.24 mol) it is dissolved in 600 mL ethanol; add potassium hydroxide (35.84 g; 0.64 mol), 80 °C of lower stirring reactions 12 hours.Filtering, filter cake washs (10 mLx3) with ethanol, is dried in vacuo, and obtains title product cun tosyl) 30.0 g of -6- oxa- -2- azepine spiroheptanes 40c, white solid), yield： 59.2%.
MS m/z (ESI): 254 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.71 (d, /=8.0 Hz, 2H), 7.14 (d, /=8.0 Hz, 2H), 4.59 (s, 4H), 3.91 (s, 4H), 2.44 (s, 3H)
Second step
6- oxa- -2- azaspiros [3.3] heptane oxalate
By 2- (；P-toluenesulfonyl) -6- oxa- -2- azaspiros [3,3] heptane 40c (5.5 g, 22.0 mmol) is dissolved in 120 mL methanol, adds magnesium powder C4.2 g, 174 mmol), ultrasonic response 1 hour.Jian Ya Nong Shrink, 180 mL ether and 30 g Disodium sulfate decahydrates are added, are stirred 1 hour, filtering, the ethanol solution of 5 mL l M oxalic acid is added in filtrate, stirring 0.5 hour, filtering, filter cake is washed (10 mLx3) with ethanol, vacuum drying, obtain title product 6- oxa- -2- azaspiros [3.3] heptane oxalate 40d (2.6 g, white solid), yield： 74.2%.
MS m/z (ESI): 100 [M+l]
3rd step
L- [3- tert-butyl group 1-4- methoxyl groups -5- (6- oxa- -2- azepine spiroheptane -2- bases) phenyl] ethyl ketones are by the 1- tert-butyl groups -5- (1, 1- dimethoxy-ethyls) iodo- 2- methoxybenzenes 2f (8.5 g of -3-, 23 mmol) and 2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl (443 mg, 1.13 mmol) it is dissolved in 120 mL toluene, add palladium/carbon (850 mg, 10%), potassium tert-butoxide (7.6 g, 68 mmol) and 6- oxa- -2- azaspiros [3.3] heptane oxalate 40d (9.0 g, 25 mmol), 60 °C of lower stirring reactions 1 hour.200 mL water are added into reaction solution, aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, add lOO mL acetic acid and 2 mL water, stirring reaction 1 hour.Add 200 mL water, aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [3- tert-butyl group 1-4- methoxyl groups -5- (6- oxa- -2- azepine spiroheptane -2- bases) phenyl] ethyl ketone 40e (6.0 g, gray solid), yield： 88.2%.
MS m/z (ESI): 304 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.46 (d, /=2.0 Hz, 1H), 7.05 (d, /=2.0 Hz, 1H), 4.85 (s, 4H), 4.02 (s, 4H), 3.70 (s, 3H), 2.56 (s, 3H), 1.41 (s, 9H)
4th step
The bromo- l- of 2- [the 3- tert-butyl group -4- methoxyl groups -5- (6- oxa- -2- azepine spiroheptane -2- bases) phenyl] ethyl ketone
Under -78 °C, by two (；Trimethyl silicane) amido lithium (12.7 mL, 12.7 mmol) and 1- [3- tert-butyl group 1-4- methoxyl groups -5- (6- oxa- -2- azepine spiroheptane -2- bases) phenyl] ethyl ketone 40e (3.5 g, 11.6 mmol) it is dissolved in 50 mL tetrahydrofurans, stirring reaction 1 hour, add bromine (1.85 g, 11.6 mmol), stirring reaction 2 hours.30 mL water are added into reaction solution, aqueous phase is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl group -4- methoxyl groups -5- (6- oxa- -2- azepine spiroheptane -2- bases) phenyl] ethyl ketone 40f (820 mg, yellow solid), yield： 18.6%.
MS m/z (ESI): 383 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.49 (d, J=2.4 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 4.85 (s, 4H), 4.41 (s, 2H), 4.02 (s, 4H), 3.71 (s, 3H), 1.40 (s, 9H)
5th step
L- [the 3- tert-butyl group -4- methoxyl groups -5- (2- oxa- -6- azaspiros [3.3] hex- 6- yls) phenyl] -2- (5,6- diethoxies
The fluoro- 3- imino groups -1 of -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide is by 5,6- diethoxies -7- fluoro- 3,3- dimethyl-iso-indoles -1- amine 24d (132 mg, 0.50 mmol) the bromo- 1- of standing grain Jie 2- [the 3- tert-butyl group -4- methoxyl groups -5- (6- oxa- -2- azepine spiroheptane -2- bases) phenyl] ethyl ketone 40f (190 mg, 0.50 mmol) it is dissolved in 2 mL tetrahydrofurans, add triethylamine (1 mL, 0.72 mmol), stirring reaction 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 1- [the 3- tert-butyl group -4- methoxyl groups -5- (2- oxa- -6- azaspiros [3.3] hex- 6- yls) phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide 40 (15 mg, yellow solid), yield： 4.6%.
MS m/z (ESI): 567 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 8.99 (br. s, 1H), 7.45 (s, 2H), 7.13 (s, 1H), 5.42 (s, 2H), 4.71 (m, 4H), 4.25 (q, /=7.2 Hz, 2H), 4.13 (q, /=7.2 Hz, 2H), 4.09 (m, 4H), 3.67 (s, 3H), 1.50 (s, 6H), 1.41 (t, /=7.2 Hz, 3H), 1.38 (s, 9H), 1.31 (t, /=7.2 Hz, 3H) embodiments 41
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
The first step
The bromo- fluoro- benzaldehydes of 3,4- diethoxies -2- of 6-
The fluoro- benzene 23e of bromo- 1, the 2- diethoxies -3- of 5- (15.38 g, 58.5 mmol) are dissolved in 250 mL trifluoroacetic acids, add hexa (16.4 g, 117 mmol), stirring reaction continues reaction 5 hours under 30 minutes, 90 °C.500 mL water are added into reaction solution, it is extracted with ethyl acetate (250 mLx2), merge organic phase, saturated sodium bicarbonate solution (250 mLx5) is used successively, water (200 mL) and saturated nacl aqueous solution washing (200 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain fluoro- benzaldehyde 41a (7.87 g of bromo- 3, the 4- diethoxies -2- of title product 6-, yellow solid), yield： 46.3%.
1H NMR (400 MHz, CDC13, ppm):δ 10.25 (s, 1H), 7.00 (d, /=1.6 Hz, 1H), 4.20 (m, 4H), 1.54 (t, J=7.2 Hz, 3H), 1.43 (t, J=7.2 Hz, 3H)
Second step
The bromo- fluoro- benzoic acid of 3,4- diethoxies -2- of 6-
Under ice bath, by 6- bromo- 3, the fluoro- benzaldehyde 41a (5.5g of 4- diethoxies -2-, 18.8 mmol) it is dissolved in 50 mL tetrahydrofurans, add 50 mL water, sodium hydroxide (1.2 g, 30.1 mmol) and potassium permanganate (3.28 g, 20.7 mmol), react at room temperature 12 hours.Filtering, the dense Shrink of filtrate decompression, is extracted with ethyl acetate (150 mLx3), merges organic phase, washed with saturated nacl aqueous solution (100 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product 6- bromo- 3, the fluoro- benzoic acid 41b of 4- diethoxies -2- (3.8 g, yellow solid), yield： 65.8%.
MS m/z (ESI): 307 [M-l]
1H NMR (400 MHz, CDC13, ppm):δ 13.74 (br. s, 1H), 7.18 (s, 1H), 4.13 (q, /=7.2 Hz. 2H), 4.05 (q, J=7.2 Hz, 2H), 1.34 (t, /=7.2 Hz, 3H), 1.25 (t, /=7.2 Hz, 3H)
3rd step
The bromo- fluoro- methyl benzoates of 3,4- diethoxies -2- of 6-
The fluoro- benzoic acid 41b of bromo- 3, the 4- diethoxies -2- of 6- (3.8 g, 12.4 mmol) are dissolved in 30 mL thionyl chlorides, flowed back 5 hours.45 mL methanol and dichloromethane (V/V=2 are added under Jian Ya Nong Shrink, ice bath:1) mixed solution, is stirred at room temperature 12 hours.Jian Ya Nong Shrink obtain the fluoro- methyl benzoate 41c of bromo- 3, the 4- diethoxies -2- of title product 6- (3.46 g, yellow oil), yield： 86.9%.
1H NMR (400 MHz, CDC13, ppm):δ 6.90 (d, J=2.0 Hz, 1H), 4.10 (m, 4H), 3.94 (s, 3H), 1.46 (t, /=7.2 Hz, 3H), 1.36 (t, /=7.2 Hz, 3H)
4th step
The fluoro- methyl benzoates of 6- cyano group -3,4- diethoxy -2-
By 6- bromo- 3, fluoro- methyl benzoate 41c (3.46 g of 4- diethoxies -2-, 10.8 mmol) it is dissolved in 50 mL N, in dinethylformamide, sequentially add cuprous cyanide (2.9 g, 32.3 mmol) and 1 mL pyridines, 150 °C of lower stirring reactions 3 hours.300 mL water are added into reaction solution, filtering, it is extracted with ethyl acetate (100 mLx3), merge organic phase, washed (200 mL), anhydrous sodium sulfate drying, filtered with water (200 mL) and saturated nacl aqueous solution successively, filtrate decompression Nong Shrink, with eluant, eluent system B purify gained remaining with silica gel column chromatography
Thing, obtains the title product fluoro- methyl benzoate 41d of 6- cyano group -3,4- diethoxies -2- (1.5 g, white solid), yield： 52.1%.
1H NMR (400 MHz, CDC13, ppm):δ 7.08 (d, /=1.2 Hz, 1H), 4.27 (q, /=7.2 Hz, 2H), 4.19 (q, /=7.2 Hz, 2H), 4.03 (s, 3H), 1.54 (t, /=7.2 Hz, 3H), 1.43 (t, /=7.2 Hz, 3H) the 5th step
5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines] under -1'- ketone ice baths, the fluoro- methyl benzoate 41d of 6- cyano group -3,4- diethoxies -2- (2.66 g, 9.96 mmol) are dissolved in 30 mL ether, add tetraisopropyl titanate (3.3 mL, 11.1 mmol) and ethylmagnesium bromide (7.3 mL, 21.9 mmol), stirring reaction 2.5 hours.65 mL methanol are added into reaction solution, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ -one 41e (1.48 g, yellow solid), yield： 56.0%.
MS m/z (ESI): 266 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.02 (s, 1H), 6.25 (s, 1H), 4.12 (m, 4H), 1.63 (m, 2H), 1.48 (t, J=12 Hz, 3H), 1.38 (t, /=7.2 Hz, 3H), 1.35 (m, 2H)
6th step
5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines] -1'- thioketones is by 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ -one 41e (906 mg, 3.42 mmol) is dissolved in 40 mL tetrahydrofurans, adds lawesson reagent C734 mg, 1.81 mmol), 50 °C of lower stirring reactions 12 hours.50 mL unsaturated carbonates potassium solutions and 40 mL ethyl acetate are added into reaction solution, aqueous phase is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 5', 6'- diethoxy -7- fluoro- spiral shell [cyclopropane -1,3'- isoindoline]-Γ-thioketones 41f (338 mg, grey powder), yield： 22.8%.
MS m/z (ESI): 282 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 9.68 (s, 1H), 6.24 (s, 1H), 4.14 (m, 4H), 1.89 (m, 2H), 1.52 (m, 2H), 1.49 (t, /=7.2 Hz, 3H), 1.39 (t, /=7.2 Hz, 3H)
7th step
5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines] -1'- imines is by 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-thioketones 41f (300 mg, 1.07 mmol) is dissolved in 30 mL methanol, adds 12 mL 28% concentrated ammonia liquor and TBHP (0.6 mL, 6 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, add the M of 10 mL 2 hydrochloric acid and 80 mL water, are washed with ethyl acetate (30 mLx3), and aqueous phase adjusts pH with the M sodium hydroxide solutions of 5 mL 5>7, it is extracted with ethyl acetate (30 mLx3), merges organic phase, washed with saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink obtain title product 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (147 mg, gray solid), yield： 52.1%.
MS m/z (ESI): 265 [M+l]
O NMR (400 MHz, CDC13, ppm):δ 6.71 (s, 1H), 6.10 (br. s, 2H), 4.09 (q, /=7.2 Hz, 2H), 4.01 (the Hz of q, J=7.2,2H), 1.49 (m, 2H), 1.42 (m, 2H), 1.35 (t, J=7.2 Hz, 3H):1.26 (t, /=7.2 Hz, 3H)
8th step
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (184 mg, 0.7 mmol) and the bromo- 1- of 2- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketone 2h (370 mg, 0.7 mmol) it is dissolved in 6 mL tetrahydrofurans, add triethylamine (0.15 mL, 1.08 mmol), stirring reaction 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 41 (52 mg, white powder), yield： 11.8%.
MS m/z (ESI): 554 [M+l]
1H NMR (400 MHz, DMSO- , ppm):(the br. s of δ 9.35, 1H), 9.06 (br. s, 1H), 7.62 (d, the Hz of /=2.0, 1H), 7.53 (d, the Hz of J=2.0, 1H), 7.03 (s, 1H), 5.22 (s, 2H), 4.24 (q, the Hz of J=7.2, 2H), 4.13 (q, the Hz of /=7.2, 2H), 3.96 (s, 3H), 3.82 (m, 4H), 3.02 (m, 4H), 1.80 (m, 2H), 1.66 (m, 2H), 1.40 (t, the Hz of /=7.2, 3H), 1.38 (s, 9H), 1.31 (t, the Hz of /=7.2, 3H) embodiment 42
L- (3,5- di-tert-butyl-hydroxy phenyl) -2- (the fluoro- 3'- imino groups-spiral shells of 5', 6'- diethoxy -4'- [cyclopropane -1, Γ-isoindoline -2'- bases) ethanone hydrobromide
The first step
1- (3,5- di-tert-butyl-hydroxy phenyl) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (201 mg, 0.76 mmol) the bromo- 1- of standing grain B 2- (3,5- di-tert-butyl-hydroxy phenyl) ethyl ketone If (327 mg, 0.87 mmol) is dissolved in 6 mL tetrahydrofurans, add triethylamine (0.15 mL, 1.08 mmol), stirring reaction continues reaction 48 hours under 12 hours, 30 °C.Filtering, filter cake n-hexane (lO mL) and water washing (10 mIX3), vacuum drying is obtained
To title product 1- (3,5- di-tert-butyl-hydroxy phenyls) -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) (66 mg of ethanone hydrobromide 42, white powder), yield： 14.7%. MS m/z (ESI): 511 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.06 (br. s, 2H), 7.77 (s, 2H), 7.03 (s, 1H), 5.27 (s, 2H), 4.23 (q, J=7.2 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 1.78 (m, 2H), 1.64 (m, 2H), 1.43 (s, 18H), 1.40 (t, /=7.2 Hz, 3H), 1.31 (t, /=7.2 Hz, 3H) embodiments 43
2- [the 8- tert-butyl groups -6- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Second salt
2- [the 8- tert-butyl groups -6- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetyl group] -2; 3- dihydros -1; 4- benzoxazine -4- bases] ethyl acetate hydrobromate is by 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-; 3'- isoindolines]-Γ-imines 41g (121 mg; 0.46 mmol) and 2- [6- (2- acetyl bromides) -8- tert-butyl groups -2; 3- dihydros -1; 4- benzoxazine -4- bases] ethyl acetate 5e (201 mg; 0.50 mmol) it is dissolved in 4 mL tetrahydrofurans; add triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering; filter cake n-hexane (10 mL) and water washing (10 mIX3); vacuum drying; obtain title product 2- [the 8- tert-butyl groups -6- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] -2; 3- dihydros -1; 4- benzoxazine -4- bases] ethyl acetate hydrobromate 43 (147 mg, yellow powder), yield： 48.4%.
MS m/z (ESI): 583 [M+l]
1H NMR (400 MHz, DMSO- , ppm):(the br. s of δ 9.72, 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, the Hz of /=7.2, 2H), 4.11 (m, 4H), 3.49 (m, 2H), 1.74 (m, 2H), 1.65 (m, 2H), 1.39 (t, the Hz of /=7.2, 3H), 1.36 (s, 9H), 1.30 (t, the Hz of J=12, 3H), 1.19 (t, the Hz of /=7.2, 3H) embodiment 44
1- 3,5- di-tert-butyl-phenyl) and -2- (the fluoro- 3'- imino groups-spiral shells of 5', 6'- diethoxy -4'- [cyclopropane -1, Γ-isoindoline -2'- bases) ethanone hydrobromide
The first step
1- (3,5- di-tert-butyl-phenyl) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (132 mg, 0.5 mmol) the bromo- 1- (3 of standing grain Jie 2-, 5- di-t-butyls-phenyl) ethyl ketone 22c (178 mg, 0.57 mmol) is dissolved in 4 mL tetrahydrofurans, adds triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 1- (3,5- di-tert-butyl-phenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) (54 mg of ethanone hydrobromide 44, white powder), yield： 18.8%.
MS m/z (ESI): 495 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.38 (br. s, 1H), 9.05 (br. s, 1H), 7.82 (the Hz of d, J=1.6,2H), 7.78 (d, /=1.6 Hz, 1H), 7.03 (s, 1H), 5.25 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 4.13 (q, J=7.2 Hz, 2H), 1.83 (m, 2H), 1.67 (m, 2H), 1.41 (t, J=7.2 Hz, 3H), 1.36 (s, 18H), 1.31 (t, /=7.2 Hz, 3H) embodiments 45
L- (3,5- di-t-butyl -4- methoxyphenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ of 5', 6'- diethoxy -4'-
'-yl) ethanone hydrobromide
The first step
1- (3,5- di-t-butyl -4- methoxyphenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1' of 5', 6'- diethoxy -4'-
Isoindoline] -2'- bases) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (147 mg, 0.56 mmol) the bromo- 1- (3 of standing grain Jie 2-, 5- di-t-butyl -4- methoxyphenyls) ethyl ketone 21c (198 mg, 0.58 mmol) is dissolved in 4 mL tetrahydrofurans, adds triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 1- (3,5- di-t-butyl -4- methoxyphenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) (47 mg of ethanone hydrobromide 45, white powder), yield： 13.9%.
MS m/z (ESI): 525 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.67 (br. s, 1H), 9.12 (br. s, 1H), 7.90 (s, 2H), 7.04 (s, 1H), 5.38 (s, 2H), 4.23 (the Hz of q, J=12,2H), 4.11 (the Hz of q, J=7.2,2H), 3.70 (s, 3H), 1.79 (m, 2H), 1.64 (m, 2H), 1.43 (s, 18H), 1.40 (m, 6H) embodiment 46
L- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (fluoro- 3'- imino groups-spiral shell [rings of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', the fluoro- spiral shells of 6'- diethoxies -7'- [cyclopropane -1,3'- isoindoline]-Γ-imines 41g (160 mg, 0.56 mmol) and the small (small base-phenyl of the 3- tert-butyl group -4- methoxyl group -5- pyrrolidines of 2- bromines）Ethyl ketone 8d (301 mg, 0.58 mmol) is dissolved in 4 mL tetrahydrofurans, adds triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 46 (118 mg, white powder), yield： 31.5%.
MS m/z (ESI): 538 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.36 (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=7.2 Hz, 2H), 4.12 (the Hz of q, J=7.2
2H), 3.18 (m, 4H), 1.93 (m, 4H), 1.80 (m, 2H), 1.66 (m, 2H), 1.40 (t, /=7.2 Hz, 3H) 1.36 (s, 9H), 1.31 (t, /=7.2 Hz, 3H) embodiments 47
L- [3- (l- adamantane) -4- methoxyl group -5- morpholinyl phenyls] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1 1'- isoindolines] -2'- bases) ethanone hydrobromide
The first step
1- [3- (1- adamantane) -4- methoxyl group -5- morpholinyl phenyls] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (156 mg, 0.59 mmol) and 1- [3- (1- adamantyls) -4- methoxyl group -5- morpholinyl phenyls] bromo- ethyl ketone 17h (298 mg of -2-, 0.67 mmol) it is dissolved in 5 mL tetrahydrofurans, add triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 1- [3- (1- adamantane) -4- methoxyl group -5- morpholinyl phenyls] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 47 (126 mg, white powder), yield： 29.9%. MS m/z (ESI): 632 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the br. s of δ 9.74, 1H), 9.16 (br. s, 1H), 7.57 (m, 2H), 7.07 (s, 1H), 5.44 (s, 2H), 4.25 (q, the Hz of J=12, 2H), 4.12 (q, the Hz of J=7.2, 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, the Hz of /=7.2, 3H), 1.31 (t, the Hz of /=7.2, 3H) embodiment 48
1- [3- [(1 5-3- azabicyclos [3 Shang 0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls]-2- (5', fluoro- 3'- imino groups-spiral shell [cyclopropane-1,1'- isoindoline]-2'- bases of 6'- diethoxies-4'-) ethanone hydrobromide
The first step
Cyclopropane -1,2- diethyl dicarboxylate
Under ice bath, by 60% sodium hydride (22.0 g, 0.51 mol) it is dissolved in 150 mL toluene, 2- ethyl acrylates 48a (50.0 g are added dropwise, 0.5 mol) and 2- ethyl chloroacetates 48b (61.3 g, 0.5 mol) mixed solution, stirring reaction 12 hours.A small amount of water quenching is added into reaction solution under ice bath to go out reaction, aqueous phase is extracted with ethyl acetate (50 mLx3), merges organic phase, is washed (50 mL) with water (50 mL) and saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, 65-92 °C of cut is collected in filtering, filtrate decompression Nong Shrink, oil bath vacuum distillation, obtain title product cyclopropane -1,2- diethyl dicarboxylate 48c C39.78 g, colourless liquid), yield： 42.8%.
MS m/z (ESI): 187 [M+l]
Second step
[(1 2R) -2- (hydroxymethyl) cyclopropyl] methanol
Under ice bath, by lithium aluminium hydride reduction (8.98 g, 0.24 mol) it is dissolved in 180 mL tetrahydrofurans, hydrogen is replaced three times, 20 mL cyclopropane -1,2- diethyl dicarboxylates 48c (22.0 g, 0.12 mol) tetrahydrofuran solution is added dropwise, 70 °C of lower stirring reactions 3 hours, room temperature continues stirring reaction 12 hours.22 mL saturated ammonium chloride solutions are added dropwise under ice bath into reaction solution, Jian Ya Nong Shrink, add 200 mL ethyl acetate, filtering, filtrate decompression Nong Shrink, purify gained residue with eluant, eluent system B with silica gel column chromatography, obtain title product [(1 2-2- (hydroxymethyl) cyclopropyl] methanol 48d (1.14 g, yellow liquid), yield：9.4% and [(lS, 2R) -2- (hydroxymethyl) cyclopropyl] methanol 48e (5.3 g, yellow liquid), yield： 43.9%
1H NMR (400 MHz, CDC13, ppm):δ 3.81 (m, 2H), 3.53 (br. s, 2H), 3.10 (m, 2H), 1.03 (m, 2H), 0.45 (m, 2H)
1H NMR (400MHz, CDC13, ppm):δ 4.11 (m, 2H), 3.24 (m, 4H), 1.32 (m, 2H), 0.81 (m:1H), 0.22 (m, 1H)
3rd step
(1R,2^-1,2- two (bromomethyl) cyclopropane
Under ice bath, by triphenylphosphine (28.19 g, 0.107 mol) it is dissolved in 130 mL acetonitriles, bromine (5.4 mL are added dropwise, 0.107 mol), 30 mL [(lS, 2R) -2- (hydroxymethyl) cyclopropyl] methanol 48e (5.22 g are added dropwise at room temperature, 0.051 mol) acetonitrile solution, stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, add 100 mL ethyl acetate, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (1R, 2S) -1, (bromomethyl) cyclopropane of 2- bis- 48f (9.68 g, yellow liquid), yield： 83.9%. 1H NMR ( 400MHz, CDC13, ppm):δ 3.50 (m, 4H), 1.66 (m, 2H), 1.18 (m, 1H), 0.43 (m, 1H)
4th step
1- [3- [(1 5-3- azabicyclos [3 Shang 0] hex- 3- the yls]-5- tert-butyl group-4- methoxyphenyls] ethyl ketone is by l- (the 3- amino-5- tert-butyl group-4- methoxyphenyls)-ethyl ketone 8b (1.0 g, 4.5 mmol) and (1R, 2-1, (bromomethyl) the cyclopropane 48f of 2- bis- (2.06 g, 9.0 mmol) it is dissolved in 20 mL water, add potassium carbonate (680 mg, 4.95 mmol), 120 °C of lower microwave stirring reactions 20 minutes.Add 20 mL ethyl acetate, aqueous phase is extracted with ethyl acetate (30 mLx3), merge organic phase, washed (50 mL) with water (50 mL) and saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [3- [(1 5-3- azabicyclos [3.1.0] hex- 3- the yls]-5- tert-butyl group-4- methoxyphenyls] ethyl ketone 48g (596 mg, yellow liquid), yield： 45.9%.
MS m/z (ESI): 288 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.52 (d, J=2.0 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 3.64 (s, 3H), 3.61 (m, 2H), 3.00 (m, 2H), 2.56 (s, 3H), 1.56 (m, 2H), 1.42 (s, 9H), 0.6 (m, 2H)
5th step
L- [3- [(lR, 5-3- azabicyclos [3 Shang 0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls] under 40 °C of the bromo- ethyl ketones of-2-, by l- [3- [(lR, 5-3- azabicyclos [3 Shang 0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls] ethyl ketone 48g (2.0 g, 6.97 mmol) it is dissolved in 20 mL chloroforms, add copper bromide (3.11 g, 13.94 mmol), stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product l- [3- [GR, 5-3- azabicyclos [3.1.0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls] bromo- ethyl ketone 48h (558 mg of-2-, yellow solid), yield： 21.9%.
MS m/z (ESI): 368 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.55 (d, J=2.0 Hz, 1H), 7.43 (d, J=2.0 Hz, 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)
6th step
1- [3- [(1 5-3- azabicyclos [3 Shang 0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls]-2- (5', fluoro- 3'- imino groups-spiral shell [cyclopropane-1,1'- isoindoline]-2'- bases of 6'- diethoxies-4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane-1 of 6'- diethoxies-7'-, 3'- isoindolines]-Γ-imines 41g (161 mg, 0.61 mmol) and l- [3- [(lR, 5-3- azabicyclos [3 Shang 0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls] bromo- ethyl ketone 48h (246 mg of-2-, 0.67 mmol) it is dissolved in 5 mL tetrahydrofurans, add triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 1- [3- [(1 5-3- azabicyclos [3 Shang 0] hex- 3- the yls]-5- tert-butyl group-4- methoxyphenyls]-2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane-1 of 6'- diethoxies-4'-, 1'- isoindolines]-2'- bases) ethanone hydrobromide 48 (118 mg, white powder), yield： 30.7%.
MS m/z (ESI): 550 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.34 (br. s, 1H), 9.05 (br. s, 1H), 7.49 (d, /=1.6 Hz, 1H), 7.39 (d, /=1.6 Hz, 1H), 7.04 (s, 1H), 5.22 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 4.12 (q, /=7.2 Hz, 2H), 3.61 (s, 3H), 3.54 (d, /=8.8 Hz, 2H), 2.99 (d, /=8.8 Hz:2H), 1.80 (br. s, 2H), 1.66 (m, 4H), 1.40 (t, /=7.2 Hz, 3H), 1.38 (s, 9H), 1.31 (t, /=7.2 Hz, 3H), 0.61 (m, 1H), 0.55 (m, 1H) embodiment 49
2- [the 8- tert-butyl groups -6- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetyl group] -2,3- -1,4- benzoxazine -4- bases] acetonitrile hydrobromate
The first step
2- [the 8- tert-butyl groups -6- [2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) acetyl group] -2, 3- dihydros -1, 4- benzoxazine -4- bases] acetonitrile hydrobromate is by 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (160 mg, 0.61 mmol) and 2- [6- (the bromo- acetyl group of 2-) -8- tert-butyl groups -2, 3- dihydros -1, 4- benzoxazine -4- bases] acetonitrile 16b (320 mg, 0.91 mmol) it is dissolved in 5 mL tetrahydrofurans, add triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering; filter cake n-hexane (10 mL) and water washing (10 mIX3); vacuum drying; obtain title product 2- [the 8- tert-butyl groups -6- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] -2; 3- dihydros -1; 4- benzoxazine -4- bases] acetonitrile hydrobromate 49 (150 mg, yellow powder), yield： 40.2%.
MS m/z (ESI): 535 [M+l]
Ή NMR (400 MHz, DMSO-J6, ppm):δ 9.40 (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=12 Hz, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.36 (m, 2H), 1.85 (m, 2H), 1.65 (m, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.35 (s, 9H), 1.30 (t, J=12 Hz, 3H) embodiments 50
L- (the 8- tert-butyl group -4- methyl -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (the fluoro- 3'- imino groups of 5', 6'- diethoxy -4'- -
The first step
1- (the 8- tert-butyl group -4- methyl -2, 3- dihydros -1, 4- benzoxazine -6- bases) -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide is by 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (157 mg, 0.59 mmol) the bromo- 1- of standing grain B 2- (the 8- tert-butyl group -4- methyl -2, 3- dihydros -1, 4- benzoxazine -6- bases) ethyl ketone 19b (230 mg, 0.71 mmol) it is dissolved in 5 mL tetrahydrofurans, add triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (lO mL) and water washing (10 mIX3), vacuum drying, obtain title product 1- (the 8- tert-butyl group -4- methyl -2,3- dihydro -1,4- benzoxazine -6- bases) -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 50 (164 mg, buff powder), yield： 46.7%
MS m/z (ESI): 510 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):{ the br. s of δ 9.34, 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, the Hz of /=7.2, 2H), 4.13 (q, the Hz of J=1.2, 2H), 3.34 (m, 2H), 2.94 (s, 3H), 1.78 (m, 2H), 1.67 (m, 2H), 1.41 (t, the Hz of /=7.2, 3H), 1.36 (s, 9H), 1.31 (t, the Hz of /=7.2, 3H) embodiment 51
L- (the 8- tert-butyl group -4- ethyls -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
The first step
L- (the 8- tert-butyl group -4- ethyls -2, the 3- dihydro-benzoxazine -6- bases of Isosorbide-5-Nitrae -) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (165 mg, 0.62 mmol) the bromo- 1- of standing grain B 2- (the 8- tert-butyl group -4- ethyl -2,3- dihydro -1,4- benzoxazine -6- bases)-ethyl ketone 6b (255 mg, 0.75 mmol) it is dissolved in 4 mL tetrahydrofurans, add triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (lO mL) and water washing (10 mIX3), vacuum drying, obtain title product 1- (the 8- tert-butyl group -4- ethyl -2,3- dihydro -1,4- benzoxazine -6- bases) -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 51 (133 mg, white powder), yield： 35.2%.
MS m/z (ESI): 524 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the br. s of δ 9.35, 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, the Hz of J=4.4, 2H), 4.24 (q, the Hz of J=7.2, 2H), 4.12 (q, the Hz of /=7.2, 2H), 3.43 (q, the Hz of /=7.2, 2H), 3.37 (t, the Hz of /=4.4, 2H), 1.78 (m, 2H), 1.66 (m, 2H), 1.40 (t, the Hz of /=7.2, 3H), 1.36 (s, 9H), 1.31 (t, the Hz of /=7.2, 3H), 1.12 (t, the Hz of /=7.2, 3H)
L- [the 3- tert-butyl group -4- methoxyl group -5-G- piperidines) phenyl] (7- imino group -2,5- dimethyl -5- phenyl-pyrrols are simultaneously by -2-
[3,4-b] pyridine -6- bases) ethanone hydrobromide
By 2,5- dimethyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 9f (237 mg, 1 mmol) and small [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl]-ethyl ketone 12b (441.6 mg of 2- bromines, 1.2 mmol) it is dissolved in 3 mL N, in dinethylformamide, stirring reaction 12 hours.5 mL water are added into reaction solution, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- [the 3- tert-butyl group -4- methoxyl group -5-G- piperidines) phenyl] -2- (7- imino groups -2, 5- dimethyl -5- phenyl-pyrrols simultaneously [3, 4-b] pyridine -6- bases) (150 mg of ethanone hydrobromide 52, light yellow solid), yield： 24.8%. MS m/z (ESI): 525 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.92 (d, J=7.6 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.46 (m, 7H), 5.43 (d, /=18.8 Hz, 1H), 5.03 (d, /=18.8 Hz, 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
Small (4- methoxyl group -3- -5- trimethyls silicon substrate-phenyl) ethanone hydrobromides of 2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-)
The first step
1- (the iodo- phenyl of 4- hydroxyls -3-) ethyl ketone
By 1- (4- hydroxy phenyls) ethyl ketone 53a (4.0 g, 29.38 mmol) it is dissolved in 250 mL concentrated ammonia liquors, add 300 mL iodine (7.46 g, 29.38 mmol) and KI (23.75 g, 143.08 mmol) the aqueous solution, stir under 50 °C
Mix reaction 48 hours.Filtering, filtrate adjusts pH=1, filtering with the mL of concentrated hydrochloric acid 100, filter cake is washed with water (100 mLx3), vacuum drying, obtains title product 1- (the iodo- phenyl of 4- hydroxyls -3-) ethyl ketone 53M3.75 g, yellow solid), yield： 48.8%.
MS m/z (ESI): 261 [M-l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 11.13 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.70 (dd ,/；= 8.4 Hz, J2=2.0 Hz, 1H), 6.81 (d, J=8.4 Hz, 2H), 2.34 (s, 3H)
Second step
The iodo- 4- methoxyphenyls of ^3-) ethyl ketone
By 1- (the iodo- phenyl of 4- hydroxyls -3-) ethyl ketone 53b (3.52 g, 13 mmol) it is dissolved in 50 mL acetone, power mouthful enters toluene-4-sulfonic acid methyl esters (2 mL, 14 mmol) and potassium carbonate (2.78 g, 20 mmol), 50 °C of lower stirring reactions 6 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain the iodo- 4- methoxyphenyls of title product 1- 3-) ethyl ketone 53c C3.03 g, Off-white solid), yield： 81.6%. MS m/z (ESI): 277 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.39 (d, /=2.4 Hz, 1H), 7.95 (dd ,=8.4 Hz, J2=2.4 Hz, 1H), 6.85 (d, /=8.4 Hz, 1H), 3.96 (s, 3H), 2.55 (s, 3H)
3rd step
L- (4- methoxyl group -3- morpholinyl phenyls) ethyl ketone
By 1- (the iodo- 4- methoxyphenyls of 3-) ethyl ketone 53c (3.03 g, 10.96 mmol) and 2- dicyclohexylphosphino -2'- (^, dimethylamine)-biphenyl (216 mg, 0.55 mmol) it is dissolved in 120 mL toluene, add palladium/carbon (302 mg, 10%), sodium tert-butoxide (2.10 g, 21.91 mmol) and morpholine (1.9 mL, 21.91 mmol), 80 °C of lower stirring reactions 3 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- (4- methoxyl group -3- morpholinyl phenyls) ethyl ketone 53d (1.77 g, pale tan oil), yield： 68.8%.
MS m/z (ESI): 236 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.66 (dd ,/； = 8.4 Hz, J2=2.4 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 6.89 (d, /=8.4 Hz, 1H), 3.94 (s, 3H), 3.90 (m, 4H), 3.10 (m, 4H), 2.56 (s, 3H)
4th step
4- [5- (l, l- dimethoxy-ethyls) -2- methoxyphenyls] morpholine is by 1- (4- methoxyl group -3- morpholinyl phenyls) ethyl ketone 53d (971 mg, 4.13 mmol) and trimethyl orthoformate (1.4 mL, 12.38 mol) it is dissolved in 40 mL methanol, add D (+) -10- camphorsulfonic acids (1.054 g, 4.54 mmol), stirring reaction 12 hours.626 mg potassium carbonate are added into reaction solution, are stirred 0.5 hour, 50 mL water are added, it is extracted with ethyl acetate (50 mLx3), merge organic phase, (50 mLx2), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, obtain title product 4- [5- (1,1- dimethoxy-ethyl) -2- methoxyphenyls] morpholine 53e (1.09 g, brownish black grease), yield： 94.0%.
MS m/z (ESI): 282 [M+l]
Ή NMR (400 MHz, CDC13, ppm):δ 7.13 (dd ,/；= 8.8 Hz, J2=2.0 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.84 (d, /=8.8 Hz, 1H), 3.90 (m, 4H), 3.87 (s, 3H), 3.18 (s, 6H), 3.09 (m, 4H), 1.53 (s, 3H)
5th step
[5- (l, l- dimethoxy-ethyls) -2- methoxyl group -3- morpholinyl phenyls]-trimethyl silane dry ice-propanone bath under, by 4- [5- (1, 1- dimethoxy-ethyls) -2- methoxyphenyls] morpholine 53e (1.09 g, 3.88 mmol) it is dissolved in 40 mL n-hexanes, add tetramethylethylenediamine (116 μ, , 0.78 mmol) and n-BuLi C3.1 mL, 7.76 mmol), reaction 4 hours is stirred at room temperature, trim,ethylchlorosilane (975 μ are added under ice bath, 7.76 mmol), room temperature continues stirring reaction 12 hours.50 mL saturated ammonium chloride solutions are added into reaction solution, are extracted with ethyl acetate (30 mLx3), merge organic phase, with water (20 mL><2) with saturated nacl aqueous solution washing (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product [5- (1,1- dimethoxy-ethyls) -2- methoxyl group -3- morpholinyl phenyls]-trimethyl silane 53f (1.31g, pale tan oil), yield： 95.7%.
MS m/z (ESI): 354 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.14 (d, /=2.0 Hz, 1H), 7.09 (d, /=2.0 Hz, 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)
6th step
2-bromo- 1. (4- methoxyl groups-3- morpholine-5- trimethyls silicon substrate-phenyl) ethyl ketone is by [5- (1,1- dimethoxy-ethyls)-2- methoxyl group-3- morpholinyl phenyls]-trimethyl silane 53f (1.31 g, 3.71 mmol) it is dissolved in 20 mL acetic acid, add pyridinium tribromide Key salt (1.19 g, 3.71 mmol), stirring reaction 2 hours.30 mL saturated nacl aqueous solutions are added into reaction solution, it is extracted with ethyl acetate (30 mIX3), merge organic phase, washed (20 mLx2) with saturated sodium bicarbonate solution (20 mLx2) and saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- (4- methoxyl group -3- morpholine -5- trimethyls silicon substrate-phenyl) ethyl ketone 53g (560 mg, yellow solid), yield： 39.0%.
MS m/z (ESI): 386 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 7.70 (d, /=2.4 Hz, 1H), 7.63 (d, /=2.4 Hz, 1H), 4.42 (s, 2H), 3.97 (s, 3H), 3.90 (m, 4H), 3.11 (m, 4H), 0.32 (s, 9H)
7th step
Small (4- methoxyl group -3- morpholine -5- trimethyls silicon substrate-phenyl) ethanone hydrobromides of 2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-)
By 5', the fluoro- spiral shells of 6'- diethoxies -7'- [cyclopropane -1,3'- isoindoline]-Γ-imines 41g (156 mg, 0.59 mmol) and the bromo- 1- of 2- (4- methoxyl group -3- morpholine -5- trimethyls silicon substrate-phenyl）Ethyl ketone 53g (298 mg, 0.67 mmol) is dissolved in 5 mL tetrahydrofurans, adds triethylamine (0.1 mL, 0.72 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 2- (5', fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 6'- diethoxies -4'-) small (4- first
Epoxide -3- morpholine -5- trimethyls silicon substrate-phenyl) ethanone hydrobromide 53 (126 mg, yellow powder), yield： 29.9%.
MS m/z (ESI): 632 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.46 (br. s, 2H), 7.67 (d, J=2.4 Hz, 2H), 7.07 (s, 1H), 5.49 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 4.11 (q, /=7.2 Hz, 2H), 3.91 (s, 3H), 3.79 (m, 4H), 3.05 (m, 4H), 1.79 (m, 2H), 1.66 (m, 2H), 1.39 (t, /=7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H), 0.29 (s, 9H) embodiment 54
L- [the 3- tert-butyl group -4- methoxyl groups -5- (l-piperidines) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
The first step
1- [3- the tert-butyl group-4- methoxyl groups-5- (1-piperidines) phenyl]-2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy-4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (198 mg, 0.75 mmol) the bromo- 1- of standing grain B 2- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] ethyl ketone 12b (324 mg, 0.88 mmol) it is dissolved in 5 mL tetrahydrofurans, add triethylamine (0.15 mL, 1.08 mmol), 25 °C of lower stirring reactions 12 hours.Filtering, filter cake n-hexane (10 mL) and water washing (10 mLx3), vacuum drying, obtain title product 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 54 (257 mg, white powder), yield： 54.2%. MS m/z (ESI): 552 [M+l]
1H NMR (400 MHz, DMSO- , ppm):{ the br. s of δ 9.36, 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, the Hz of J=7.2, 2H), 4.12 (q, the Hz of J=7.2, 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, the Hz of /=7.2, 3H), 1.38 (s, 9H), 1.31 (t, the Hz of /=7.2, 3H) embodiment 55
L- [3- [(lR, 5-3- azabicyclos [3.1.0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls]-2- (5,6- diethoxies
- 4- fluorate
The first step
L- [3- [(lR, 5-3- azabicyclos [3.1.0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls]-2- (5,6- diethoxies
The fluoro- 3- imino groups-1 of-4-, 1- dimethyl-isoindoline-2- bases) ethanone hydrobromide is by 5,6- diethoxies-7- fluoro- 3, small amine 24d (258 mg of 3- dimethyl-iso-indoles, 0.97 mmol) it is dissolved in 4 mL N, in dinethylformamide, addition 1- [3- [(1 5-3- azabicyclos [3 Shang 0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls] bromo- ethyl ketone 48h (558 mg of-2-, 1.07 mmol), stirring reaction 12 hours.10 mL water and 10 mL ethyl acetate are added into reaction solution, merge organic phase, washed (5 mLx3) with water (5 mLx3) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product l- [3- [GR, 5-3- azabicyclos [3.1.0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls]-2- (5, the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) (36 mg of ethanone hydrobromide 55, yellow solid), yield： 5.9%.
MS m/z (ESI): 552 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.34 (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, /=7.2 Hz, 3H), 1.39 (s, 9H):1.31 (t, /=7.2 Hz, 3H), 0.60 (m, 2H) embodiment 56
L- [3- [(lR, 5-3- azabicyclos [3.1.0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls]-2- (5', 6'- diethoxies
- 3'- imino groups-spiral shell [ring -1,1'- isoindoline] -2'- bases) ethanone hydrobromide
The first step
L- [3- [(lR, 5-3- azabicyclos [3.1.0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls]-2- (5', 6'- diethoxies
- 3'- imino groups-spiral shell [cyclopropane -1, 1'- isoindolines] -2'- bases) ethanone hydrobromide is by 5', 6'- diethoxy spiral shell [cyclopropane -1, 3'- isoindolines]-Γ-imines hydrobromate 7d (172 mg, 0.70 mmol) it is dissolved in 4 mL tetrahydrofurans, add l- [3- [(lR, 5-3- azabicyclos [3.1.0] hex- 3- yls]-5- the tert-butyl group-4- methoxyphenyls] bromo- ethyl ketone 48h (360 mg of-2-, 0.98 mmol) and triethylamine (0.1 mL, 0.72 mmol), stirring reaction 12 hours.Filtering, filter cake uses n-hexane (10 mLx2) and water washing (10 mLx3) successively, vacuum drying, obtain title product 1- [3- [(1 5-3- azabicyclos [3.1.0] hex- 3- the yls]-5- tert-butyl group-4- methoxyphenyls]-2- (5', 6'- diethoxies-3'- imino groups-spiral shell [cyclopropane-1,1'- isoindolines]-2'- bases) ethanone hydrobromide 56 (27 mg, white powder), yield： 6.3%
MS m/z (ESI): 532 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the br. s of δ 9.64, 1H), 9.08 (br. s, 1H), 7.87 (s, 1H), 7.500, 1H), 7.40 (s, 1H), 7.05 (s, 1H), 5.18 (s, 2H), 4.17 (q, the Hz of /=7.2, 2H), 4.11 (q, the Hz of /=7.2, 2H), 3.61 (s, 3H), 3.55 (d, the Hz of /=8.8, 2H), 2.99 (d, the Hz of /=8.8, 2H), 1.72 (m, 2H), 1.63 (m, 4H), 1.38 (m, 15H), 0.62 (d, the Hz of /=4.4, 1H), 0.55 (d, the Hz of /=4.4, 1H) embodiment 57
Small (4- methoxyl groups-3--5-trimethyl silicanes-phenyl) ethanone hydrobromides of 2- (fluoro- 3- imino groups-1, the 1- dimethyl of 5,6- diethoxy-4--isoindoline-2- bases)
The first step
Small (4- methoxyl group -3- morpholines -5- trimethyl silicanes-phenyl) ethanone hydrobromides of 2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases)
By 5,6- diethoxies -7- fluoro- 3,3- dimethyl-iso-indoles -1- amine 24d (266 mg, 1.0 mmol) and small (4- methoxyl group -3- morpholine -5- trimethyls silicon substrate-phenyl) the ethyl ketone 53g (425 mg, 1.1 mmol) of 2- bromines are dissolved in 5
In mLN, dinethylformamide, stirring reaction 12 hours.5 mL water are added into reaction solution, aqueous phase is extracted with ethyl acetate (5 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, filtering, filter cake n-hexane (10 mL) and water washing (10 mL), vacuum drying, obtain title product 2- (5, the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) -1- (4- methoxyl group -3- morpholines -5- trimethyl silicanes-phenyl) (84 mg of ethanone hydrobromide 57, yellow powder), yield： 12.0%.
MS m/z (ESI): 572 [M+l]
1H NMR (400 MHz, DMS0-d6, ppm):δ 9.35 (br. s, 1H), 8.99 (br. s, 1H), 7.67 (m, 2H), 7.46 (s, 1H), 5.47 (s, 2H), 4.26 (q, /=7.2 Hz, 2H), 4.10 (q, /=7.2 Hz, 2H), 3.93 (s, 3H), 3.89 (m, 4H), 3.05 (m, 4H), 1.51 (s, 6H), 1.41 (t, /=7.2 Hz, 3H), 1.31 (t, /=7.2 Hz, 3H), 0.31 (s, 9H) embodiment 58
L- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-- b] pyridine -6- bases) ethanone hydrobromide
The first step
1- (6- methoxyl group -3- pyridines) -1- benzyl carbinols
Under dry ice-propanone bath, by the bromo- 2- methoxyl group-B of 5- than pyridine 58a (21.0 g, 111 mmol) it is dissolved in 120 mL ether, 2.5M n-BuLis (49.1 mL are added dropwise, 123 mmol) hexane solution, stirring reaction 1 hour adds acetophenone G4.4 mL, 123 mmol), continue stirring reaction 1 hour.50 mL saturated ammonium chloride solutions are added into reaction solution, aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (6- methoxyl group -3- pyridines) -1- benzyl carbinols 58b (19.3 g, white solid), yield： 75.4%.
MS m/z (ESI): 230 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.26 (s, 1H), 7.63 (m, 6H), 6.72 (m, 1H), 3.96 (s,
3H), 1.99 (s, 3H)
Second step
5- (l- nitrine -1- phenyl-ethyl groups) -2- methoxypyridines
Under ice bath, by 1- (6- methoxyl group -3- pyridines) -1- phenyl-ethanols 58b (14.4 g, 63 mmol) and sodium azide C12.3 g, 189 1^^1) it is dissolved in 72 11^ water, 56 mL concentrated hydrochloric acids, stirring reaction 12 hours are added dropwise.It is 78 that 800 mL saturated sodium bicarbonate solutions regulation pH is added into reaction solution, it is extracted with ethyl acetate (200 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product 5- (1- nitrine -1- phenyl-ethyl groups) -2- methoxypyridines 58c (16.0 g, yellow oil) crude product.
1H NMR (400 MHz, DMS0- , ppm):δ 8.23 (s, 1H), 7.51 (d, /=9.2 Hz, 1H), 7.38 (m, 5H), 6.73 (d, J=9.2 Hz, 1H), 3.98 (s, 3H), 2.05 (s, 3H)
3rd step
5-G- nitrine -1- phenyl-ethyl groups) -2- methoxv-pyridine 1- oxides by 5- (1- nitrine -1- phenyl-ethyl groups) -2- methoxyl group-B than pyridine 58c (16.0 g, 63 mmol) it is dissolved in 200 mL dichloromethane, add metachloroperbenzoic acid (21.7 g, 126 mmol), stirring reaction 13 hours.Reaction solution Jian Ya Nong Shrink, add 300 mL ethyl acetate, washed with saturated sodium bicarbonate solution (100 mLx3), aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 5- (1- nitrine -1- phenyl-ethyl groups) -2- methoxv-pyridine 1- oxides 58d (12.0 g, light yellow oil), yield： 70.6%.
MS m/z (ESI): 271 [M+l]
4th step
(l- nitrine -1- phenyl-ethyl group 6- methoxv-pyridine -2- nitriles are by 5- (1- nitrine -1- phenyl-ethyl groups) -2- methoxyl group-B than pyridine 1- oxides 58d (8.9 g by 3-, 33 mmol) it is dissolved in 120 mL acetonitriles, add cyano group trimethyl silane (17.6 mL, 132 mmol) and dimethylaminoethyl chloride (3.63 mL, 39.5 mmol), stirring reaction 24 hours.100 mL dichloromethane are added into reaction solution, merge organic phase, washed (20 mLx3) with saturated sodium bicarbonate solution (20 mLx3) and with saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 3- (1- nitrine -1- phenyl-ethyl groups) -6- methoxv-pyridine -2- nitriles 58e (4.5 g, light yellow oil), yield： 48.9%.
MS m/z (ESI): 280 [M+l]
5th step
2- methoxyl group -5- methyl -5- phenyl -6H- pyrroles [3,4-b] pyridine -7- imines is by 3- (1- nitrine -1- phenyl-ethyl groups) -6- methoxv-pyridine -2- nitriles 58e (4.4 g, 15.7 mmol) it is dissolved in 120 mL tetrahydrofurans, add 6 mL water and triphenylphosphine (8.26 mg, 31.5 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain
Title product 2- methoxyl groups -5- methyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 58f (3.0 g, white solid), yield： 75.2%.
MS m/z (ESI): 254 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.95 (d, J=8.4 Hz, 1H), 7.48 (m, 2H), 7.28 (m, 2H), 7.20 (m, 1H), 6.84 (d, /=8.4 Hz, 1H), 3.95 (s, 3H), 1.71 (s, 3H)
6th step
L- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrolo- [3,4-b] pyridine -6- bases) ethanone hydrobromide
By 2- methoxyl group -5- methyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 58f (253 mg, 1 mmol) and the bromo- 1- of 2- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) ethyl ketone 8d (424.8 mg, 1.2 mmol) it is dissolved in 5 mL methanol, add triethylamine (0.166 mL, 1.2 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system C purify gained residue, obtain title product 1- (the 3- tert-butyl group -4- methoxyl groups -5- pyrrolidin-1-yls-phenyl) -2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols simultaneously [3,4-b] pyridine -6- bases) (65 mg of ethanone hydrobromide 58, light yellow solid), yield： 10.7%.
MS m/z (ESI): 527 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.92 (d, J=8.8 Hz, 1H), 7.36 (m, 7H), 7.22 (d, J=8.4 Hz, 1H), 5.46 (d, /=18.4 Hz, 1H), 5.04 (d, /=18.4 Hz, 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
(7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols are simultaneously by l- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2-
3,4-b] pyridine -6- bases) ethanone hydrobromide
The first step
(7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols are simultaneously by 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2-
[3,4-b] pyridine -6- bases) ethanone hydrobromide
By 2- methoxyl groups -5- methyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 58f (253 mg, 1 mmol)
With the bromo- l- of 2- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketone 2h (444 mg, 1.2 mmol) it is dissolved in 4 mL tetrahydrofurans, add triethylamine (0.166 mL, 1.2 mmol), stirring reaction 12 hours.Reacting liquid filtering, filtrate decompression Nong Shrink, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols simultaneously [3,4-b] pyridine -6- bases) (120 mg of ethanone hydrobromide 59, light yellow solid), yield： 19.3%.
MS m/z (ESI): 543 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.96 (d, /=8.8 Hz, 1H), 7.38 (m, 7H), 7.25 (d, J=8.4 Hz, 1H), 5.53 (d, /=18.8 Hz, 1H), 5.10 (d, /=18.8 Hz, 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
(7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols are simultaneously [3,4-b] by l- (3,5- di-tert-butyl-hydroxy phenyl) -2-
The first step
1- (3,5- di-tert-butyl-hydroxy phenyl) -2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols [3,4-b] mouths are than pyridine -6- bases) ethanone hydrobromide
By 2- methoxyl group -5- methyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 58f (64 mg, 0.25 mmol) the bromo- 1- (3 of standing grain B 2-, 5- di-tert-butyl-hydroxy phenyls) ethyl ketone If (248 mg, 0.76 mmol) it is dissolved in 2 mL methanol, add triethylamine (0.105 mL, 0.76 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with thin-layered chromatography with solvent system C purify gained residue, obtain title product 1- (3,5- di-t-butyls -4- hydroxy phenyls) -2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols simultaneously [3,4-b] pyridine -6- bases) (30 mg of ethanone hydrobromide 60, yellow solid), yield： 23.8%.
MS m/z (ESI): 500 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.95 (d, /=8.4 Hz, 1H), 7.69 (s, 2H), 7.39 (m, 5H), 7.25 (d, J=8.8 Hz, 1H), 5.43 (d, /=18.4 Hz, 1H), 5.06 (d, /=18.4 Hz, 1H), 4.04 (s, 3H), 1.98 (s, 3H), 1.40 (s, 18H)
Embodiment 61
L- [the 3- tert-butyl group -4- methoxyl groups -5- (l-piperidines) phenyl] -2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols
4-b] pyridine -6- bases) ethanone hydrobromide
The first step
1- [3- the tert-butyl group-4- methoxyl groups-5- (1-piperidines) phenyl]-2- (7- imino group-2- methoxyl group-5- methyl-5- phenyl-pyrrols simultaneously [3,4-b] pyridine-6- bases) ethanone hydrobromide
By 2- methoxyl group -5- methyl -5- phenyl -6H- pyrrolo-es [3,4-b] pyridine -7- imines 58f (253 mg, 1 mmol) and small [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] ethyl ketone 12b (441.6 mg of 2- bromines, 1.2 mmol) it is dissolved in 3 mL N, in dinethylformamide, stirring reaction 12 hours.5 mL water are added into reaction solution, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtaining title product 1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] -2-, (7- imino group -2- methoxyl group -5- methyl -5- phenyl-B ratios cough up simultaneously [3, 4-b] pyridine -6- bases) (180 mg of ethanone hydrobromide 61, light yellow solid), yield： 30.0%
MS m/z (ESI): 541 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.96 (s, 2H), 7.94 (d, /=8.8 Hz, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.37 (m, 5H), 7.22 (d, J=8.4 Hz, 1H), 5.45 (d, J=18.4 Hz, 1H), 5.07 (d, /=18.4 Hz, 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
2- [[the 3- tert-butyl groups -5- [2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols simultaneously [3,4-b] pyridine -6- bases) acetyl group] -2- methoxyphenyls] amino] acetonitrile hydrobromate
The first step
2- [[the 3- tert-butyl groups -5- [2- (7- [3,4-b] pyridine -6- bases) acetyl
By 2- methoxyl group -5- methyl -5- phenyl -6H- pyrrolo-es [3; 4-b] pyridine -7- imines 58f (253 mg; 1 mmol) and 2- [[5- (2- the acetyl bromides) -3- tert-butyl group -2- methoxyphenyls] amino] acetonitrile 14b (406.8 mg; 1.2 mmol) it is dissolved in 3 mL N; in dinethylformamide, stirring reaction 12 hours.5 mL water are added into reaction solution, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 2- [[the 3- tert-butyl groups -5- [2- (7- imino group -2- methoxyl group -5- methyl -5- phenyl-pyrrols simultaneously [3, 4-b] pyridine -6- bases) acetyl group] -2- methoxyphenyls] amino] (150 mg of acetonitrile hydrobromate 62, light yellow solid), yield： 25.3%.
MS m/z (ESI): 512 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.90 (s, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.37 (m, 7H), 7.10 (d, /=6.8 Hz, 1H), 6.09 (t, /=6.8 Hz, 1H), 5.50 (d, /=18.8 Hz, 1H), 5.05 (d, /=18.8 Hz, 1H), 4.38 (d, /=7.2 Hz, 2H), 4.03 (s, 3H), 3.72 (s, 3H), 1.99 (s, 3H), 1.36 (s, 9H) embodiment 63
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (3- imino groups -1- methyl isophthalic acids-phenyl-pyrrol simultaneously [3,4-b] quinoline
- 2- ethanone hydrobromides
The first step
1- phenyl-l- (3- quinoline) ethanol
Under dry ice-propanone bath, by bromo- quinoline 63a (20.0 g of 3-, 96.6 mmol) it is dissolved in 120 mL ether, 2.5 M n-BuLis (42.5 mL are added dropwise, 106 mmol) hexane solution, stirring reaction 1 hour adds acetophenone (12.4 mL, 106 mmol), continue stirring reaction 12 hours.50 mL saturated ammonium chloride solutions are added into reaction solution, aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, (20 mLx3), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- phenyl -1- (3- quinoline) ethanol 63b (9.3 g, light yellow oil), yield： 38.8%.
MS m/z (ESI): 250 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.90 (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-G- nitrine -1- phenyl-ethyl groups) quinoline
Under ice bath, 1- phenyl -1- (3- quinoline) ethanol 63b (7.0 g, 28 mmol) and sodium azide (5.5 g, 84 mmol) are dissolved in 35 mL water, 35 mL concentrated hydrochloric acids, stirring reaction 12 hours are added dropwise.It is 78 that 450 mL saturated sodium bicarbonate solutions regulation pH is added into reaction solution, aqueous phase is extracted with ethyl acetate (150 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 3- (1- nitrine -1- phenyl-ethyl groups) quinoline 63c (6.8 g, light yellow oil), yield： 88.3%.
1H NMR (400 MHz, CDC13, ppm):δ 8.82 (s, 1 Η), 8.24 (s, 1H), 8.13 (d, /=8.8 Hz, 1H), 7.88 (d, /=8.0 Hz, 1H), 7.77 (t, /=8.8 Hz, 1H), 7.63 (t, /=8.0 Hz, 1H), 7.43 (m: 5H), 2.19 (s, 3H)
3rd step
3- (l- nitrine -1- phenyl-ethyl groups) quinoline 1- oxides
3- (1- nitrine -1- phenyl-ethyl groups) quinoline 63c (6.2 g, 22.6 mmol) are dissolved in 60 mL dichloromethane, metachloroperbenzoic acid (4.8 g, 27 mmol), stirring reaction 3 hours is added.50 mL saturated sodium bicarbonate solutions are added into reaction solution, aqueous phase is extracted (50 mLx3) with dichloromethane, merge organic phase, use saturated sodium-chloride
Solution washs (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 3- (1- nitrine -1- phenyl-ethyl groups) quinoline 1- oxides 63d (6.0 g, yellow oil), yield： 91.0%.
MS m/z (ESI): 291 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.70 (d, J=8.0 Hz, 1H), 8.49 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.45 (m, 5H), 2.15 (s, 3H)
4th step
3-G- nitrine -1- phenyl-ethyl groups)-quinoline -2- nitriles
By 3-G- nitrine -1- phenyl-ethyl groups) quinoline 1- oxides 63d (5.95 g, 20 mmol) it is dissolved in 120 mL acetonitriles, add cyano group trimethyl silane (4.65 mL, 35 mmol) and dimethylaminoethyl chloride (2.82 mL, 30 mmol), 80 °C of lower stirring reactions 4 hours.Reaction solution Jian Ya Nong Shrink, add 100 mL ethyl acetate and 50 mL saturated sodium bicarbonate solutions, aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 3- (1- nitrine -1- phenyl-ethyl groups)-quinoline -2- nitriles 63e (3.3 g, light yellow oil), yield： 54.1%.
MS m/z (ESI): 300 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 8.65 (s, 1H), 7.87 (m, 4H), 7.45 (m, 5H), 2.34 (s, 3H)
5th step
I methyl-I-phenyl -2H- pyrrolo-es [3,4-b] quinoline -3- imines is by 3- (1- nitrine -1- phenyl-ethyl groups)-quinoline -2- nitriles 63e (2.1 g, 7 mmol) it is dissolved in 100 mL tetrahydrofurans, add 0.5 mL water and triphenylphosphine (3.68 mL, 14 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- methyl isophthalic acids-phenyl -2H- pyrrolo-es [3,4-b] quinoline -3- imines 63f (1.6 g, light yellow solid), yield： 83.5%. 1H NMR (400 MHz, CDC13, ppm):δ 8.53 (s, 1 Η), 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
L- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (3- imino groups -1- methyl isophthalic acids-phenyl-pyrrol simultaneously [3,4-b] quinoline
- 2- bases) ethanone hydrobromide
By 1- methyl isophthalic acids-phenyl -2H- pyrrolo-es [3,4-b] quinoline -3- imines 63f (273 mg, 1 mmol) and the bromo- 1- of 2- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) ethyl ketone 2h (444 mg, 1.2 mmol) be dissolved in 5 mL methanol and tetrahydrofuran (V/V=3:2) in the mixed solvent, adds triethylamine (0.166 mL, 1.2 mmol), stirring reaction 24 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system C purify gained residue, obtain title product 1- (the 3- tert-butyl group -4- methoxyl group -5- morpholinyl phenyls) -2- (3- imino groups -1- methyl isophthalic acids-phenyl-pyrrols simultaneously [3,4-b] quinoline -2- bases) (120 mg of ethanone hydrobromide 63, light yellow solid), yield： 18.7%.
MS m/z (ESI): 563 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 8.29 (m, 12H), 5.60 (d, /=18.0 Hz, 1H), 5.19 (d, J=18.0 Hz, 1H), 3.95 (s, 3H), 3.80 (m, 4H), 2.99 (m, 4H), 2.12 (s, 3H), 1.36 (s, 9H) embodiment 64
L- [the 3- tert-butyl group -4- methoxyl groups -5- (l- piperidines) phenyl] -2- (3- imino groups -1- methyl isophthalic acids-phenyl-pyrrol simultaneously [3,4-b] quinolines
- 2- bases) ethanone hydrobromide
The first step
1- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl] -2- (3- imino groups -1- methyl isophthalic acids-phenyl-pyrrol simultaneously [3,4-b] quinoline -2- bases) ethanone hydrobromide
By 1- methyl isophthalic acids-phenyl -2H- pyrrolo-es [3,4-b] quinoline -3- imines 63f (273 mg, 1 mmol) and the bromo- 1- of 2- [the 3- tert-butyl group -4- methoxyl groups -5- (1- piperidines) phenyl]-ethyl ketone 12b (441.6 mg, 1.2 mmol) it is dissolved in 3 mL N, in N-dimethylformamide, stirring reaction 12 hours.5 mL water are added into reaction solution, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- [the 3- tert-butyl group -4- methoxyl group -5-G- piperidines) phenyl] -2- 3- imino groups -1- methyl isophthalic acid-phenyl-mouth ratios and cough up simultaneously [3, 4-b] quinoline -2- bases) (160 mg of ethanone hydrobromide 64, light yellow solid), yield： 25.0%. MS m/z (ESI): 561 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 8.64 (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, /=18.4 Hz, 1H), 5.06 (d, /=18.4 Hz, 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
N- [the 3- tert-butyl groups -5- [2- (7- imino group -2,5- dimethyl -5- phenyl-pyrrols simultaneously [3,4-b] pyridine -6- bases) acetyl group] -2- methoxyphenyls] acetamide hydrobromate
The first step
N- [the 3- tert-butyl groups -5- [2- (7- imino group -2,5- dimethyl -5- phenyl-pyrrols simultaneously [3,4-b] pyridine -6- bases) acetyl group] -2- methoxyphenyls] acetamide hydrobromate
By 2; 5- dimethyl -5- phenyl -6H- pyrrolo-es [3; 4-b] pyridine -7- imines 9f (237 mg; 1 mmol) and N- [5- (the bromo- acetyl group of the 2-) -3- tert-butyl group -2- methoxyphenyls] acetamide 13b (410.4 mg; 1.2 mmol) it is dissolved in 3 mL N; in dinethylformamide, stirring reaction 12 hours.5 mL water are added into reaction solution, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N- [the 3- tert-butyl groups -5- [2- (7- imino groups -2, 5- dimethyl -5- phenyl-pyrrols simultaneously [3, 4-b] pyridine -6- bases) acetyl group] -2- methoxyphenyls] (120 mg of acetamide hydrobromate 65, light yellow solid), yield： 20.7%.
MS m/z (ESI): 499 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 10.20 (br. s, 1H), 9.74 (br. s, 1H), 8.09 (the Hz of d, J=1.6,1H), 7.96 (d, /=8.4 Hz, 1H), 7.69 (the Hz of d, J=8.0,1H), 7.62 (d, /=2.0 Hz, 1H):7.37 (m, 5H), 5.45 (d, /=18.8 Hz, 1H), 5.08 (d, /=18.8 Hz, lH), 4.12 (s, 3H), 2.64 (s:3H), (s, the 9H) embodiment 66 of 2.11 (s, 3H), 2.00 (s, 3H), 1.37
L- [the 3- tert-butyl group -4- methoxyl groups -5- (2- oxa- -6- azaspiros [3.3] hex- 6- yls) phenyl] -2- (the fluoro- 3'- imino groups-spiral shells of 5', 6'- diethoxy -4'- '-isoindoline] -2'- bases) ethanone hydrobromide
The first step
L- [the 3- tert-butyl group -4- methoxyl groups -5- (2- oxa- -6- azaspiros [3.3] hex- 6- yls) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide is by 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (134 mg, 0.51 mmol) and the bromo- 1- of 2- [the 3- tert-butyl group -4- methoxyl groups -5- (6- oxa- -2- azepine spiroheptane -2- bases) phenyl] ethyl ketone 40f (202 mg, 0.53 mmol) it is dissolved in 2 mL tetrahydrofurans, add triethylamine (0.1 mL, 0.72 mmol), stirring reaction 12 hours.Filtering, filter cake n-hexane (lO mL) and water washing (10 mIX3), vacuum drying, obtain title product 1- [the 3- tert-butyl groups -4- methoxyl groups oxa- -6- azaspiros [3.3] hex- 6- yls) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 66 (108 mg, yellow solid), yield： 32.9%.
MS m/z (ESI): 566 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the br. s of δ 9.31, 1H), 9.03 (br. s, 1H), 7.41 (d, the Hz of J=2.0, 1H), 7.07 (d, the Hz of /=2.0, 1H), 7.02 (s, 1H), 5.17 (s, 2H), 4.74 (m, 4H), 4.23 (q, the Hz of J=1.2, 2H), 4.12 (q, the Hz of /=7.2, 2H), 3.99 (m, 4H), 3.67 (s, 3H), 1.77 (m, 2H), 1.65 (m, 2H), 1.40 (t, the Hz of /=7.2, 3H), 1.37 (s, 9H), 1.31 (t, the Hz of /=7.2, 3H) embodiment 67
L- [the 3- tert-butyl group-4- methoxyl group-5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls] phenyl]-2- (5', fluoro- 3'- imino groups-spiral shell [cyclopropane-1,1'- isoindoline]-2'- bases of 6'- diethoxies-4'-) ethyl ketone hydrobromic acid
The first step
L- [the 3- tert-butyl group -4- methoxyl group -5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls] phenyl]-2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethyl ketone hydrobromic acid is by 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (156 mg, 0.56 mmol) and the bromo- 1- of 2- [the 3- tert-butyl group -4- methoxyl group -5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls]-phenyl] ethyl ketone 39g (250 mg, 0.63 mmol) it is dissolved in 5 mL tetrahydrofurans, add triethylamine (0.10 mL, 0.72 mmol), stirring reaction 12 hours.Jian Ya Nong Shrink, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl group-4- methoxyl group-5- [(lR, 5-8- oxa--3- azabicyclos [3.2.1] oct-3-yls] phenyl]-2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane-1 of 6'- diethoxies-4'-, 1'- isoindolines]-2'- bases) ethyl ketone hydrobromic acid 67 (102 mg, light yellow solid), yield： 26.1%.
MS m/z (ESI): 580 [M+l]
1H NMR (400 MHz, DMSO- , ppm):7.63 (d, the Hz of /=1.6, 1H), 7.57 (d, the Hz of /=1.6, 1H), 6.98 (s, 1H), 5.22 (s, 2H), 4.41 (m, 2H), 4.22 (q, the Hz of /=7.2, 2H), 4.11 (q, the Hz of /=7.2, 2H), 3.91 (s, 3H), 3.12 (d, the Hz of J=10.5, 2H), 2.88 (d, the Hz of /=10.5, 2H), 2.07 (m, 2H), 1.92 (m, 2H), 1.73 (m, 2H), 1.58 (m, 2H), 1.40 (t, the Hz of J=7.2, 3H), 1.38 (s, 9H), 1.30 (t, the Hz of /=7.2, 3H) embodiment 68
L- [the 3- tert-butyl group -4- methoxyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
The 1- tert-butyl groups -2- methoxyl groups-benzene
2- t-butyl-phenols 2a (15 g, 100 mmol) is dissolved in 200 mL acetone, potassium carbonate (20.70 g, 150 mmol) and iodomethane (21 g, 150 mmol), stirring reaction 12 hours is added.Filtering, filtrate decompression Nong Shrink add lOO mL water, it is extracted with ethyl acetate (100 mLx2), merge organic phase, (100 mLx2), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the title product 1- tert-butyl groups -2- methoxyl groups-benzene 68a (14.20 g, colorless oil), yield： 86.6%.
Second step
The 3- tert-butyl group -2- Methoxy-benzaldehydes
Under ice bath, by the 1- tert-butyl groups -2- methoxyl groups-benzene 68a (12.50 g, 76 mmol) and Ν, Ν, Ν ', Ν '-tetramethylethylenediamine (12.40 g, 107 mmol) it is dissolved in 200 mL methyl tertiary butyl ether(MTBE)s, 2.5 M n-BuLis (33.40 mL, 84 mmol) are added dropwise, at room temperature stirring reaction 2 hours, N is added dropwise under 0 °C, dinethylformamide (16.60 g, 228 mmol), stirring reaction 2 hours.100 mL frozen water will be poured into reaction solution, it is extracted with ethyl acetate (100 mLx2), merge organic phase, (100 mLx2), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the title product 3- tert-butyl group -2- Methoxy-benzaldehyde 68b C12.10 g, colorless oil), yield： 83.0%.
MS m/z (ESI): 193.1 [M+l]
3rd step
The 3- tert-butyl group -2- methoxy-benzoic acids
Under ice bath, by the 3- tert-butyl group -2- Methoxy-benzaldehydes 68b (8.30 g, 43.20 mmol) it is dissolved in 100 mL acetonitriles, add 50 mL sodium hydroxides (3.80 g, 95 mmol) aqueous solution and TBAB (695 mg, 2.20 mmol), potassium permanganate (8.90 g are added portionwise, 56.20 mmol), stirring reaction 2 hours at room temperature.Under ice bath, 5% hypo solution to reaction solution peony is added in reaction solution to take off, add the M hydrochloric acid of 200 mL 1, it is extracted with ethyl acetate (250 mLx2), merge organic phase, washed with saturated nacl aqueous solution (100 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the title product 3- tert-butyl group -2- methoxy-benzoic acids 68c (5.85 g, white solid), yield： 65.0%.
4th step
(the 3- tert-butyl groups -2- methoxyl groups-phenyl)-morpholinyl-Benzophenone is by the 3- tert-butyl group -2- methoxy-benzoic acids 68c (632 mg, 3.04 mmol) it is dissolved in 10 mL dichloromethane, add I-hydroxybenzotriazole (432 mg, 3.20 mmol) and 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochlorides (613 mg, 3.20 mmol), stirring 10 minutes, add morpholine (265 mg, 3.04 mmol), stirring reaction 12 hours.5 mL water are added in reaction solution, extracted with dichloromethane (5 mLx2), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (the 3- tert-butyl groups -2- methoxyl groups-phenyl)-morpholinyl-Benzophenone 68d (650 mg, colorless oil), yield： 77.0%.
5th step
Small [3- tertiary butyl-4-hydroxies -5- (morpholinyl -4- carbonyls) phenyl] ethyl ketone of 2- bromines is by alchlor (133 mg, 1 mmol) it is dissolved in 2 mL dichloromethane, add 2- bromoacetyl bromides (110 mg, 0.55 mmol), add 2 mL (the 3- tert-butyl groups -2- methoxyl groups-phenyl)-morpholinyl-Benzophenone 68d (139 mg, 0.50 mmol) dichloromethane solution, stirring reaction 12 hours.5 mL frozen water are added in reaction solution, it is extracted with ethyl acetate (5 mLx2), merge organic phase, washed with saturated nacl aqueous solution (2 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system B purify gained residue, obtain the bromo- 1- of title product 2- [3- tertiary butyl-4-hydroxies -5- (morpholinyl -4- carbonyls) phenyl] ethyl ketone 68e (71 mg, Red oil), yield： 39.0%
MS m/z (ESI): 384.1 [M+l]
1H NMR (400 MHz, CDC13, ppm):δ 11.57 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7,87 (d, J=2.0 Hz, 1H), 4.37 (s, 2H), 3.82 (m, 8H), 1.48 (s, 9H)
6th step
Small [the 3- tert-butyl group -4- methoxyl groups -5- (morpholinyl -4- carbonyls) phenyl] ethyl ketone of 2- bromines is by the bromo- 1- of 2- [3- tertiary butyl-4-hydroxies -5- (morpholinyl -4- carbonyls) phenyl] ethyl ketone 68e (30 mg, 0.08 mmol) it is dissolved in 2 mL tetrahydrofurans, the diethyl ether solution of 0.5 mLl M formaldehyde, stirring reaction 2 hours is added dropwise.2 mL frozen water are added in reaction solution, extraction point liquid, organic phase is washed (2 mLx2) with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl group -4- methoxyl groups -5- (morpholinyl -4- carbonyls) phenyl] ethyl ketone 68f (32 mg, colorless viscous), yield： 99.9%.
7th step
1- [the 3- tert-butyl group -4- methoxyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (19.70 mg of 3- dimethyl-iso-indoles, 0.08 mmol) it is dissolved in 0.5 mL N, in dinethylformamide, add 2- bromo- 1- [the 3- tert-butyl group -4- methoxyl groups -5- (morpholinyl -4- carbonyls) phenyl] ethyl ketone 68f (30 mg, 0.08 mmol), stirring reaction 12 hours.2 mL water are added into reaction solution, it is extracted with ethyl acetate (5 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl group -4- methoxyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (5, the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) (13 mg of ethanone hydrobromide 68, white solid), yield： 26.0%.
MS m/z (ESI): 584.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.35 (br, 1H), 8.99 (br, 1H), 7.93 (d, /=2.2 Hz, 1H), 7.90 (d, /=2.0 Hz, 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) embodiments 69
L- [the 3- tert-butyl groups -5- (l- hydroxyl -1- methyl-ethyls) phenyl] -2- (fluoro- 3- imino groups -1,1- dimethyl of 5,6- diethoxy -4--isoindoline -2- base ethanone hydrobromides
The first step
The 3- tert-butyl groups -5- methoxycarbonyls-benzoic acid
By 5- tert-butyl benzene -1,3- dibenzoic acids 69a (12 g, 54 mmol) and the concentrated sulfuric acid (；2 mL, cat.) it is dissolved in 360 mL tetrahydrofurans and methanol (V/V=10:L) in the mixed solvent, 80 °C of lower stirring reactions 4 hours.Reaction solution Jian Ya Nong Shrink, silica gel filtering, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain the title product 3- tert-butyl groups -5- methoxycarbonyls-g of benzoic acid 69b 3.08, white solid), yield： 24.3%. MS m/z (ESI): 237.2 [M+l]
Second step
The 3- tert-butyl groups -5- (methoxyl group (methyl) carbamoyl) methyl benzoates are by the 3- tert-butyl groups -5- methoxycarbonyls-benzoic acid 69b (2.85 g; 12 mmol) it is dissolved in 16.4 mL thionyl chlorides, 85 °C of lower stirring reactions 2 hours.Reaction solution Jian Ya Nong Shrink, add 30 mL dichloromethane, sequentially add N- methyl methylamine (1.87 g, 19.20 mmol) and DIPEA (6.30 mL, 36 mmol), and reaction 0.5 hour is stirred at room temperature.Reaction solution Jian Ya Nong Shrink; add the mL of ethyl acetate 50; it is washed with water (50 mLx2); anhydrous sodium sulfate drying; filtering, filtrate decompression Nong Shrink obtain the crude title product 3- tert-butyl groups -5- (methoxyl group (methyl) carbamoyl) methyl benzoate 69c C3.27 g; yellow viscous liquid), yield： 97.6%.
MS m/z (ESI): 280.1 [M+l]
3rd step
Under l- [the 3- tert-butyl groups -5- (the small methyl-ethyl of l- hydroxyls) phenyl] ethyl ketone ice bath; by the crude product 3- tert-butyl groups -5- (methoxyl group (methyl) carbamoyl) methyl benzoate 69c (2.86 g; 10.25 mmol) it is dissolved in 42 mL tetrahydrofurans; the diethyl ether solution of the M methyl-magnesium-bromides of 5.20 mL 3 is added dropwise
Stirring 10 minutes, at room temperature stirring reaction 3.5 hours.Under ice bath, 1 M salt acid for adjusting pH is added in reaction solution for 3-5, it is extracted with ethyl acetate (100 mLx2), merges organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (1- hydroxyl -1- methyl-ethyls) phenyl] ethyl ketone 69d (0.38 g, orange liquid), yield： 15.8%.
MS m/z (ESI): 235.2 [M+l]
4th step
Small [the 3- tert-butyl groups -5- (the small methyl-ethyl of the l- hydroxyls) phenyl] ethyl ketone of 2- bromines is by 1- [the 3- tert-butyl groups -5- (1- hydroxyl -1- methyl-ethyls) phenyl] ethyl ketone 69d (420 mg, 1.79 mmol) standing grain mouthful phenyltrimethyl-ammonium tribromide (672 mg, 1.79 mmol) it is dissolved in 42 mL tetrahydrofurans, stirring reaction 3 hours, stands 12 hours.50 mL water are added in reaction solution, it is extracted with ethyl acetate (50 mLx2), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl groups -5- (1- hydroxyl -1- methyl-ethyls) phenyl] ethyl ketone 69e (287 mg, yellow oily), yield： 51.3%.
MS m/z (ESI): 315.0 [M+l]
5th step
1- [the 3- tert-butyl groups -5- (1- hydroxyl -1- methyl-ethyls) phenyl] -2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (85 mg of 3- dimethyl-iso-indoles, 0.32 mmol) it is dissolved in 3 mL N, in dinethylformamide, add 2- bromo- 1- [the 3- tert-butyl groups -5- (1- hydroxyl -1- methyl-ethyls) phenyl] ethyl ketone 69e (100 mg, 0.32 mmol), stirring reaction 2 hours.10 mL water are added into reaction solution, it is extracted with ethyl acetate (10 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (1- hydroxyl -1- methyl-ethyls) phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide 69 (61 mg, yellow solid), yield： 38.4%.
MS m/z (ESI)499.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.37 (br, 1H), 8.98 (br, 1H), 7.97 (s, 1H), 7.89 (d, /=1.5 Hz, 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
L- [the 3- tert-butyl groups -5- (the small methyl-ethyl of l- hydroxyls) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
The first step
1- 3,5- di-tert-butyl-hydroxy phenyl) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (91 mg, 0.35 mmol) and the bromo- 1- of 2- [the 3- tert-butyl groups -5- (1- hydroxyl -1- methyl-ethyls) phenyl] ethyl ketone 69e (108 mg, 0.35 mmol) it is dissolved in 2 mL tetrahydrofurans, add triethylamine (51 mg, 0.52 mmol), stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (1- hydroxyl -1- methyl-ethyls) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 70 (22 mg, yellow solid), yield： 11.0%.
MS m/z (ESI): 497.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.43 (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
L- [3- (the small base of 4- the Acetylpiperazines) -5- tert-butyl groups -4- methoxyl groups-phenyl] -2- (fluoro- 3'- imino groups of 5', 6'- diethoxy -4'--spiral shell [ring hydrobromate
The first step
L- [3- (the small base of 4- the Acetylpiperazines) -5- tert-butyl groups -4- methoxyl groups-phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide is by 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (112 mg, 0.27 mmol) it is dissolved in 1 mL N, in dinethylformamide, add 1- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl group -4- methoxyphenyls] -2 bromo- ethyl ketone 20c (60 mg, 0.23 mmol), stirring reaction 12 hours.4 mL saturated nacl aqueous solutions and 4 mL ethyl acetate are added into reaction solution, extraction point liquid, aqueous phase is extracted with ethyl acetate (2 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl groups -4- methoxyl groups-phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) (14.50 mg of ethanone hydrobromide 71, white solid), yield： 7.9%.
MS m/z (ESI): 595.4 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.64 (s, 1H), 7.54 (s, lH), 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
L- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl groups -4- methoxyl groups-phenyl] -2- (fluoro- 3- imido of 5,6- diethoxy -4-
L- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl groups -4- methoxyl groups-phenyl] -2- (5, the fluoro- 3- imino groups-i J-dimethyl-isoindoline -2- bases of 6- diethoxies -4-) ethanone hydrobromide is by 5, 6- diethoxies -7- fluoro- 3, small amine 24d (100 mg of 3- dimethyl-iso-indoles, 0.24 mmol) it is dissolved in 1 mL tetrahydrofurans, add 1- [3- (the small base of 4- the Acetylpiperazines) -5- tert-butyl group -4- methoxyphenyls] -2 bromo- ethyl ketone 20c (61 mg, 0.24 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink; with thin-layer chromatography chromatography with solvent system A purify gained residue; obtain title product 1- [3- (4- Acetylpiperazine -1- the bases) -5- tert-butyl groups -4- methoxyl groups-phenyl] -2- (5; the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) (80 mg of ethanone hydrobromide 72; light yellow solid), yield： 48.5%.
MS m/z (ESI): 597.4 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm): δ 9.27 (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) embodiments 73
The 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] benzene
730 73
The first step
3- acetyl group -5- t-butyl-benzoic acid methyl esters
Under ice bath; by the crude product 3- tert-butyl groups -5- (methoxyl group (methyl) carbamoyl) methyl benzoate 69c (2.86 g; 10.25 mmol) it is dissolved in 42 mL tetrahydrofurans, the diethyl ether solution of the M methyl-magnesium-bromides of 5.20 mL 3 is added dropwise
Stirring 10 minutes, at room temperature stirring reaction 3.5 hours.Under ice bath; 1 M salt acid for adjusting pH is added in reaction solution for 3-5; it is extracted with ethyl acetate (100 mLx2); merge organic phase; anhydrous sodium sulfate drying; filtering; filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 1- [the 3- tert-butyl groups -5- (the small methyl-ethyl of 1- hydroxyls) phenyl] ethyl ketone 3- acetyl group -5- t-butyl-benzoic acid methyl esters 73a (1.37 g; white solid), yield： 57.1%.
MS m/z (ESI): 235.2 [M+l]
Second step
3- (2- acetyl bromides) -5- t-butyl-benzoic acid methyl esters
By 1- [the 3- tert-butyl groups -5- (the small methyl-ethyl of 1- hydroxyls) phenyl] ethyl ketone 3- acetyl group -5- t-butyl-benzoic acid methyl esters 73a (598 mg; 2.60 mmol) and phenyltrimethyl-ammonium tribromide (978 mg; 2.60 mmol) it is dissolved in 60 mL tetrahydrofurans, stirring reaction 12 hours.50 mL water are added in reaction solution; it is extracted with ethyl acetate (50 mLx2); merge organic phase; anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 3- (2- the acetyl bromides) -5- tert-butyl groups-methyl benzoate 73b (693 mg, yellow liquid), yield： 85.1%.
MS m/z (ESI): 313.0 [M+l]
3rd step
The 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] methyl benzoate hydrobromate
By 5; 6- diethoxies -7- fluoro- 3; small amine 24d (380 mg of 3- dimethyl-iso-indoles; 1.44 mmol) it is dissolved in 12 mL N; in dinethylformamide; add 3- (2- acetyl bromides) -5- t-butyl-benzoic acid methyl esters 73b (450 mg, 1.44 mmol), stirring reaction 4 hours.30 mL water are added into reaction solution, it is extracted with ethyl acetate (40 mLx2), merge organic phase, water washing (20 mLx2) and saturated nacl aqueous solution washing (20 mLx2), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, separate out white solid, water washing (10 mLx2), obtain the crude title product 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases）Acetyl group] methyl benzoate hydrobromate 73c (229 mg, white solid), yield： 27.5%.
4th step
The 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] benzoate hydrochlorate
By the crude product 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group] methyl benzoate hydrobromate 73c (193 mg; 0.33 mmol) it is dissolved in 8 mL methanol; 4 mL lithium hydroxides (70 mg are added dropwise; 1.67 mmol) the aqueous solution, stirring reaction 4 hours.Reaction solution Jian Ya Nong Shrink; add the mL of water 4; 3 M salt acid for adjusting pH are added for 1-2; C10 mLx2 are washed with water in filtering, gained residue), vacuum drying; obtain the title product 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group] benzoic acid hydrobromate 73 (148 mg, yellow solid), yield： 85.5%. MS m/z (ESI): 483.2 [M-l]
1H NMR (400 MHz, DMSO-J6, ppm): δ 13.37 (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), (m, the 3H) embodiment 74 of 1.52 (s, 6H), 1.44 (m, 3H), 1.39 (s, 9H), 1.33
L- [the 3- tert-butyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--different B draws diindyl quinoline -2- bases) acetophenone hydrochloride
The first step
1- [the 3- tert-butyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetophenone hydrochloride
By the 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups -1 of 6- diethoxies -4-; 1- dimethyl-isoindoline -2- bases) acetyl group] (52 mg of benzoic acid hydrobromate 73; 0.10 mmol) it is dissolved in 2 mL dichloromethane; add I-hydroxybenzotriazole (14 mg; 0.10 mmol) standing grain B 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochlorides (38 mg; 0.20 mmol); stirring reaction 45 minutes; add morpholine (18 mg; 0.20 mmol), stirring reaction 3.5 hours.Reaction solution Jian Ya Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (19 mg of acetophenone hydrochloride 74, white solid), yield： 32.2%.
MS m/z (ESI): 554.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.42 (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) embodiments 75
3- tert-butyl-N-cyclopropyls -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases）Acetyl group] benzamide hydrochloride salt
The first step
3- tert-butyl-N-cyclopropyls -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases）Acetyl group] benzamide hydrochloride salt
By the 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups -1 of 6- diethoxies -4-; 1- dimethyl-isoindoline -2- bases) acetyl group] (52 mg of benzoic acid hydrobromate 73; 0.10 mmol) it is dissolved in 2 mL N; in dinethylformamide; add cyclopropylamine (11 mg; 0.20 mmol) and 2- (7- azos BTA)-Ν; Ν; Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester C46 mg, 0.12 mmol); stirring reaction 2 hours, add N- isobutyl group propyl group -2- amine (；24 mg, 0.24 mmol), stirring reaction 4 hours.10 mL saturated nacl aqueous solutions are added into reaction solution, it is extracted with ethyl acetate (10 mLx3), merge organic phase, saturated nacl aqueous solution washs (10 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 3- tert-butyl-N-cyclopropyls -5- [2- (5, the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group] (13 mg of benzamide hydrochloride salt 75, white solid), yield： 23.2%.
MS m/z (ESI): 524.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.34 (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- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] benzoate hydrochlorate
The first step
The 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] methyl benzoate hydrobromate
By 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-; 3'- isoindolines]-Γ-imines 41g (395 mg; 1.50 mmol) it is dissolved in 12 mL N; in dinethylformamide; add 3- (2- acetyl bromides) -5- t-butyl-benzoic acid methyl esters 73b (540 mg, 1.50 mmol), 30 °C of lower stirring reactions 1.5 hours.100 mL saturated nacl aqueous solutions are added into reaction solution, ethyl acetate extracts (100 mLx3), merge organic phase, washed with saturated nacl aqueous solution (100 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, residue obtained by ethyl acetate washing (5 mLx3), vacuum drying, obtain the title product 3- tert-butyl groups -5- [2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) acetyl group] methyl benzoate hydrobromate 76a (231 mg, white solid), yield： 26.7%.
MS m/z (ESI): 497.3 [M+l]
Second step
The 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] benzoate hydrochlorate
By the 3- tert-butyl groups -5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; 1'- isoindolines] -2'- bases) acetyl group] methyl benzoate hydrobromate 76a (226 mg; 0.39 mmol) it is dissolved in 20 mL methanol; 4 mL lithium hydroxide C164 mg are added dropwise; 3.92 mmol) the aqueous solution, stirring reaction 6 hours.Reaction solution Jian Ya Nong Shrink; add the mL of water 50; 3 M salt acid for adjusting pH are added for 1-2, filtering, gained residue is washed with water (10 mLx3); vacuum drying; obtain the title product 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] (136 mg of benzoate hydrochlorate 76; white solid), yield： 67.0%
MS m/z (ESI): 483.2 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.09 (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) embodiments 77
2- [[the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] acetonitrile hydrobromates
77f 77g
The first step
2,6- two bromo- 4- tertbutyl-anilines
Under ice bath, 4- tert-butyl group aniline 77a (50 g, 335.60 mmol) is dissolved in 300 mL dichloromethane, bromine (118 g, 738.30 mmol) is added dropwise to, at room temperature stirring reaction 1.5 hours.Under ice bath, it is 9-10 that 1 M sodium hydroxide solutions regulation pH value is added into reaction solution, extraction point liquid, aqueous phase is extracted (30 mLx3) with dichloromethane, merge organic phase, successively with 1 M sodium hydroxide solutions (30 mLx3), water (30 mLx3) and saturated nacl aqueous solution washing (30 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain crude title product 2, bromo- 4- tertbutyl-anilines 77b (107 g of 6- bis-, bronzing liquid), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 307.9 [M+l]
Second step
The bromo- 5- tert-butyl groups-benzene of i, 3- bis-
2- methyl -2- nitro-propanes (53.90 g, 522.80 mmol) are dissolved in 200 mL DMFs, it is added dropwise 2, the bromo- 4- tertbutyl-anilines 77b of 6- bis- (107 g, 348.50 mmol), 65 °C of lower stirring reactions 12 hours.400 mL water are added into reaction solution, ethyl acetate extracts (300 mLx4), merge organic phase, washed (100 mLx3) with water (100 mLx3) and saturated nacl aqueous solution successively, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product
1, the 3- bis- bromo- 5- tert-butyl groups-benzene 77c (80.60 g, colourless liquid), yield： 79.2%.
3rd step
1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone
Under the dry ice bath, the bromo- 5- tert-butyl groups-benzene 77c of 1,3- bis- (10 g, 34.25 mmol) are dissolved in 80 mL tetrahydrofurans, 13.40 mL2.5 M n-butyllithium solutions, stirring reaction 0.5 hour are added dropwise.Add DMA (4.47 g, 51.37 mmol), stirring reaction 0.5 hour.30 mL water and 30 mL saturated ammonium chloride solutions are added into reaction solution, ethyl acetate extracts (30 mLx5), merge organic phase, washed (30 mLx3) with water (30 mLx3) and saturated nacl aqueous solution successively, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone 77d (3.60 g, yellow liquid), yield： 41.2%.
MS m/z (ESI): 255.0 [M+l]
4th step
L- (3- amino -5- tbutyl-phenyls) ethyl ketone
By 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone 77d (1.02 g, 4 mmol), cuprous oxide (60 mg, 0.40 mmol) and cuprous iodide (76 mg, 0.40 mmol) it is dissolved in the mL of 1-METHYLPYRROLIDONE 2.60, add ammoniacal liquor 2.60 mL, 110 °C of lower microwave stirring reactions 2 hours.20 mL water are added into reaction solution, ethyl acetate extracts (20 mLx3), merge organic phase, washed (20 mLx3) with water (20 mLx3) and saturated nacl aqueous solution successively, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (3- amino -5- tbutyl-phenyls) ethyl ketone 77e (1.38 g, yellow liquid), yield： 90.3%.
MS m/z (ESI): 192.1 [M+l]
5th step
2- [(3- acetyl group -5- tbutyl-phenyls) amino] acetonitrile
By 1- (3- amino -5- tbutyl-phenyls) ethyl ketone 77e (760 mg, 3.98 mmol) it is dissolved in 10 mLN, in N- dimethylformamides, add potassium carbonate (825 mg, 5.97 mmol) and 2- bromoacetonitriles (955 mg, 7.96 mmol), 70 °C of lower stirring reactions 3 hours.30 mL water are added into reaction solution; ethyl acetate extracts (30 mLx3); merge organic phase; successively with water (15 mLx3) and washing saturated nacl aqueous solution (15 mLx3); anhydrous magnesium sulfate is dried; filtering; filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 2- [(3- acetyl group -5- tbutyl-phenyls) amino] acetonitrile 77f (950 mg; yellow liquid), yield： 99.9%.
MS m/z (ESI): 248.2 [M+l 8]
6th step
2- [[3- (2- acetyl bromides) -5- tbutyl-phenyls] amino] acetonitriles are by 2- [(3- acetyl group -5- tbutyl-phenyls) amino] acetonitrile 77f (200 mg; 0.87 mmol) it is dissolved in 25 mL tetrahydrofurans; phenyltrimethyl-ammonium tribromide (327 mg are added portionwise; 0.87 mmol), stirring reaction 20 hours.Filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system B purify obtained by residue,
Obtain title product 2- [[3- (2- acetyl bromides) -5- tbutyl-phenyls] amino] acetonitrile 77g (95 mg, red liquid), yield： 35.3%.
MS m/z (ESI): 310.1 [M+l]
7th step
2- [[the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] phenyl] amino] acetonitrile hydrobromate
By 5; 6- diethoxies -7- fluoro- 3; small amine 24d (77 mg of 3- dimethyl-iso-indoles; 0.29 mmol) it is dissolved in 3 mL N; in dinethylformamide; add 2- [[3- (2- acetyl bromides) -5- tbutyl-phenyls] amino] acetonitrile 77g (90 mg, 0.29 mmol), stirring reaction 1 hour.10 mL water are added into reaction solution, ethyl acetate extracts (10 mLx3), merge organic phase, washed (10 mLx3) with water (10 mLx3) and saturated nacl aqueous solution successively, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 2- [[the 3- tert-butyl groups -5- [2- (5, the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group] phenyl] amino] (35 mg of acetonitrile hydrobromate 77, yellow solid), yield： 21.1%.
MS m/z (ESI): 495.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.38 (br, 1H), 8.96 (br, 1H), 7.45 (s, 2H), 7.21 (s, 1H), 7.12 (s, 1H), 6.52 (the Hz of t, J=6.8,1H), 5.39 (s, 2H), 4.40 (d, J=6.8 Hz, 2H), 4.25 (m, 2H), 4.12 (m, 2H), 1.51 (s, 6H), 1.42 (m, 3H), 1.40 (m, 12H) embodiment 78
N- [the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] phenyl] acetamide hydrobromate
HBr
78
The first step
N-C3- acetyl group -5- tbutyl-phenyls) acetamide
By l-O amino -5- tbutyl-phenyls) ethyl ketone 77e (600 mg, 3.14 mmol) is dissolved in 15 mL dichloromethane, adds triethylamine (635 mg, 6.28 mmol), chloroacetic chloride (495 mg, 6.28 mmol), stirring is added dropwise
Reaction 0.5 hour.30 mL water are added into reaction solution; dichloromethane extracts (20 mIX3); merge organic phase; washed (15 mLx3) with water (15 mLx3) and saturated nacl aqueous solution successively; anhydrous magnesium sulfate is dried; filtering; filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product N- (3- acetyl group -5- tbutyl-phenyls) acetamide 78a (700 mg; yellow liquid), yield： 95.6%.
MS m/z (ESI): 234.2 [M+l]
Second step
N- [3- (2- acetyl bromides) -5- tbutyl-phenyls] acetamides are by N-0 acetyl group -5- tbutyl-phenyls) acetamide 78a (200 mg; 0.86 mmol) it is dissolved in 25 mL tetrahydrofurans; phenyltrimethyl-ammonium tribromide (323 mg are added portionwise; 0.86 mmol), stirring reaction 1 hour.Filtering; filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system B purify gained residue, obtain title product N- [3- (2- acetyl bromides) -5- tbutyl-phenyls] acetamide 78b (110 mg; yellow liquid), yield： 41.0%.
MS m/z (ESI): 311.1 [M-l]
3rd step
N- [the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetyl group] phenyl] acetamide hydrobromate
By 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-; 3'- isoindolines]-Γ-imines 41g (50 mg; 0.19 mmol) it is dissolved in 1.50 mL tetrahydrofurans; add N- [3- (2- acetyl bromides) -5- tbutyl-phenyls] acetamide 78b (60 mg; 0.19 mmol), stirring reaction 3 hours.Filtering; obtain white solid; washed with tetrahydrofuran (0.3 mLx3); obtain title product N- [the 3- tert-butyl groups -5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; 1'- isoindolines] -2'- bases) acetyl group] phenyl] acetamide hydrobromate 78 (50 mg, white solid), yield： 45.9%.
MS m/z (ESI): 496.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 10.16 (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
N- [the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group:
79
The first step
N- [the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group:
Phenyl] acetamide hydrobromate
By 5; 6- diethoxies -7- fluoro- 3; small amine 24d (47 mg of 3- dimethyl-iso-indoles; 0.18 mmol) it is dissolved in 1 mL tetrahydrofurans; add N- [3- (2- acetyl bromides) -5- tbutyl-phenyls] acetamide 78b (55 mg; 0.18 mmol), stirring reaction 2 hours.Filtering; obtain white solid; washed with tetrahydrofuran (0.2 mIX3); vacuum drying; obtain title product N- [the 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group] phenyl] acetamide hydrobromate 79 (55 mg, white solid), yield： 53.9%. MS m/z (ESI): 498.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 10.16 (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
3- tert-butyl-N-cyclopropyls -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] -2- methoxy-b enzamide hydrobromates
The first step
5- acetyl group -3- the tert-butyl group -2- hydroxy-benzoic acids
By the 3- tert-butyl group -2- methoxy-benzoic acids 68c (1.60 g, 7.70 mmol) it is dissolved in 20 mL dichloromethane, chloroacetic chloride (0.72 g is added dropwise, 9.23 mmol) and alchlor (2.55 g, 19.25 mmol), 40 °C of lower stirring reactions 6 hours.20 mL frozen water are added into reaction solution; add lOOmL ethyl acetate; extraction point liquid; aqueous phase is extracted with ethyl acetate (20 mLx2); merge organic phase; washed with saturated nacl aqueous solution (20 mLx3); anhydrous magnesium sulfate is dried; filtering, filtrate decompression Nong Shrink separate out solid; with residue obtained by system B recrystallization purifyings; obtain the title product 5- acetyl group -3- tert-butyl group -2- hydroxy-benzoic acids 80a (1.21 g, gray solid), yield： 62.7%.
Second step
5- acetyl group -3- tert-butyl-N-cyclopropyl -2- hydroxy-benzoyIamides are by the 5- acetyl group -3- tert-butyl group -2- hydroxy-benzoic acids 80a (1.20 g; 5.08 mmol) it is dissolved in 15 mL dichloromethane; add I-hydroxybenzotriazole (720 mg, 5.33 mmol) and 1- ethyls -3- (3- dimethylaminopropyls）Carbodiimide hydrochloride (1.02 g, 5.33 mmol), stirring and dissolving adds cyclopropylamine (290 mg, 5.08 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 5- acetyl group -3- tert-butyl-N-cyclopropyl -2- hydroxy-benzoyIamides 80b (600 mg, colorless viscous solid), yield： 42.8%.
3rd step
5- acetyl group -3- tert-butyl-N-cyclopropyl -2- methoxy-b enzamides are by 5- acetyl group -3- tert-butyl-N-cyclopropyl -2- hydroxy-benzoyIamides 80b (275 mg; 1 mmol) it is dissolved in 3 mL acetone; add potassium carbonate (207 mg; 1.50 mmol) and iodomethane (0.3 mL; 6 mmol), 40 °C of lower stirring reactions 12 hours.Filtering; filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system B purify gained residue, obtain title product 5- acetyl group -3- tert-butyl-N-cyclopropyl -2- methoxy-b enzamides 80c (230 mg; colorless oil), yield： 79.0%.
MS m/z (ESI): 290.2 [M+l]
4th step
5- (2- acetyl bromides) -3- tert-butyl-N-cyclopropyl -2- methoxy-b enzamides are by 5- acetyl group -3- tert-butyl-N-cyclopropyl -2- methoxy-b enzamides 80c (230 mg; 0.79 mmol) it is dissolved in 3 mL chloroforms; add copper bromide (355 mg; 1.59 mmol), 40 °C of lower stirring reactions 12 hours.Filtering; filtrate decompression Nong Shrink; with thin-layer chromatography chromatography with solvent system B purify gained residue; obtain title product 5- (2- acetyl bromides) -3- tert-butyl-N-cyclopropyl -2- methoxy-b enzamides 80d (190 mg; thick white solid), yield： 65.0%.
MS m/z (ESI): 369.1 [M+l]
5th step
3- tert-butyl-N-cyclopropyls -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] -2- methoxy-b enzamide hydrobromates
By 5; 6- diethoxies -7- fluoro- 3; small amine 24d (31.80 mg of 3- dimethyl-iso-indoles; 0.12 mmol) it is dissolved in l mL tetrahydrofurans; add 5- (2- acetyl bromides) -3- tert-butyl-N-cyclopropyl -2- methoxy-b enzamides 80d (44 mg; 0.12 mmol), stirring reaction 12 hours.Filtering; obtain white solid; washed with tetrahydrofuran (0.2 mLx3); vacuum drying; obtain title product 3- tert-butyl-N-cyclopropyls -5- [2- (5; the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group] -2- methoxy-b enzamides hydrobromate 80 (38 mg, white solid), yield： 50.0%.
MS m/z (ESI): 554.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):(the s of δ 9.26, 1H), 8.96 (s, 1H), 8.51 (d, the Hz of /=4.2, 1H), 7.96 (d, the Hz of J=2.0, 1H), 7.93 (d, the Hz of J=2.0, 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
3- tert-butyl-N-cyclopropyls -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases acetyl group of 5', 6'- diethoxy -4'-] -2- methoxy-b enzamide hydrobromates
The first step
3- tert-butyl-N-cyclopropyls -5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; Γ-isoindoline] -2'- bases) acetyl group] -2- methoxy-b enzamides hydrobromate is by 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-; 3'- isoindolines]-Γ-imines 41g (44.50 mg; 0.17 mmol) it is dissolved in 1 mL tetrahydrofurans, addition 5- (2- acetyl bromides) -3- tert-butyl-N-cyclopropyl -2- methoxy-b enzamides 80d (；62 mg, 0.17 mmol), stirring reaction 12 hours.Filtering; obtain white solid; washed with tetrahydrofuran (0.2 mLx3); vacuum drying; obtain (55 mg of title product 3- tert-butyl-N-cyclopropyls -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] -2- methoxy-b enzamides hydrobromate 81; white solid), yield： 51.6%.
MS m/z (ESI): 552.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.36 (s, 1H), 9.06 (s, 1H), 8.51 (d, /=4.3 Hz, 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- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl
- N- (2,3- dihydroxypropyl) benzamide hydrochloride salt
The 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group]-N- (2,3- dihydroxypropyl) benzamide hydrochloride salt
By the 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups -1 of 6- diethoxies -4-; 1- dimethyl-isoindoline -2- bases) acetyl group] (104 mg of benzoic acid hydrobromate 73; 0.20 mmol) it is dissolved in 4 mL N; in dinethylformamide; add 3- aminopropanes -1; 2- glycol (36 mg; 0.40 mmol); 2- (7- azos BTA) ^^; ^, ^- tetramethylurea hexafluorophosphoric acid ester C93 mg, 0.24 mmol) and N- isopropyl propane -2- amine (；49 mg, 0.48 mmol), stirring reaction 5 hours.10 mL saturated nacl aqueous solutions, ethyl acetate extraction (15 are added into reaction solution
MLx3), merge organic phase, washed with saturated nacl aqueous solution (15 mLx2), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain the title product 3- tert-butyl groups -5- [2- (5, fluoro- 3- imino groups -1, the 1- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group]-N- (2,3- dihydroxypropyl) benzamide hydrochloride salts 82 (31 mg, white solid), yield： 26.1%. MS m/z (ESI): 558.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.36 (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
3- tert-butyl-N-cyclopropyls -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] benzamide hydrochloride salt
The first step
The 3- tert-butyl groups-Ν-cyclopropyl -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] benzamide hydrochloride salt
By the 3- tert-butyl groups -5- [2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) acetyl group] (51 mg of benzoate hydrochlorate 76, 0.10 mmol) it is dissolved in 2 mL N, in dinethylformamide, add cyclopropylamine (11 mg, 0.20 mmol), 2- (7- azos BTA)-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (46 mg, 0.12 mmol) and N- isopropyl propane -2- amine (24 mg, 0.24 mmol), stirring reaction 3 hours.10 mL saturated nacl aqueous solutions are added into reaction solution, ethyl acetate extracts (10 mIX3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 3- tert-butyl-N-cyclopropyls -5- [2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) acetyl group] (48 mg of benzamide hydrochloride salt 83, white solid), yield： 87.3%.
MS m/z (ESI): 522.3 [M+l]
Ή NMR (400 MHz, DMSO-J6, ppm):(the br of δ 9.51, 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
L- [the 3- tert-butyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- base acetophenone hydrochlorides
The first step
1- [the 3- tert-butyl groups -5- (morpholine -4- carbonyls) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- base acetophenone hydrochlorides
By the 3- tert-butyl groups -5- [2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) acetyl group] (48 mg of benzoate hydrochlorate 76, 0.09 mmol) it is dissolved in 2 mL N, in dinethylformamide, add morpholine (16 mg, 0.19 mmol), 2- (7- azos BTA)-^, ^- tetramethylurea hexafluorophosphoric acid esters (43 mg, 0.11 mmol) and N- isopropyl propane -2- amine (22 mg, 0.22 mmol), stirring reaction 3 hours.10 mL saturated nacl aqueous solutions are added into reaction solution, ethyl acetate extracts (10 mIX3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl group-5-(morpholine-4- carbonyls) phenyl]-2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] 84 (52 mg of -2'- bases acetophenone hydrochloride, white solid), yield： 96.3%.
MS m/z (ESI): 552.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.70 (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- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group]-N- 2- hydroxyethyls) benzamide hydrochloride salt
The first step
The 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group]-N- (2- hydroxyethyls) benzamide hydrochloride salt
By 2- ethylaminoethanol C13 mg; 0.20 mmol) it is dissolved in 2 mL dichloromethane; add DMAP (37 mg; 0.30 mmol); the 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups -1 of 6- diethoxies -4-; 1- dimethyl-isoindoline -2- bases) acetyl group] (52 mg of benzoic acid hydrobromate 73; 0.10 mmol) and double (2- oxo -3- oxazoles alkyl) secondary phosphonic chloride (51 mg; 0.20 mmol), stirring reaction 3 hours.Reaction solution Jian Ya Nong Shrink; with thin-layer chromatography chromatography with solvent system A purify gained residue; obtain the title product 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups-U- dimethyl of 6- diethoxies -4--isoindoline -2- bases) acetyl group]-N- (2- hydroxyethyls) benzamide hydrochloride salts 85 (32 mg; white solid), yield： 57.1%.
MS m/z (ESI): 528.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.40 (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
2- [[the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Second salt
HBr
86
77g 86
The first step
2- [[the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetyl group] phenyl] amino] acetonitrile hydrobromate
By 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-; 3'- isoindolines]-Γ-imines 41g (38 mg; 0.15 mmol) it is dissolved in 1 mL tetrahydrofurans; add 2- [[3- (2- acetyl bromides) -5- tbutyl-phenyls] amino] acetonitrile 77g (45 mg; 0.15 mmol), stirring reaction 2 hours.With thin-layer chromatography chromatography with solvent system A purify gained residue; obtain yellow solid; l mL tetrahydrofurans are added to stir 10 minutes; filtering, vacuum drying, obtains title product 2- [[the 3- tert-butyl groups -5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; 1'- isoindolines] -2'- bases) acetyl group] phenyl] amino] acetonitrile hydrobromate 86 (12 mg, white solid), yield： 14.6%.
MS m/z (ESI): 512.6 [M+23]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.48 (br, 1H), 9.07 (br, 1H), 7.41 (s, 1H), 7.13 (m, 2H), 7.03 (s, 1H), 6.97 (s, 1H), 6.52 (the Hz of t, J=7.2,1H), 5.21 (s, 2H), 4.38 (d, J=7.2 Hz, 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- tert-butyl groups -5- [double (2- hydroxyethyls) benzamide hydrochloride salts of 2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group-N, N-
The first step
Double (2- hydroxyethyls) benzamide hydrochloride salts of the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group]-N, N-
By the 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups -1 of 6- diethoxies -4-; 1- dimethyl-isoindoline -2- bases) acetyl group] (104 mg of benzoic acid hydrobromate 73; 0.20 mmol) it is dissolved in 4 mL N; in dinethylformamide; add 2- (2- hydroxyethyls amine) ethanol (42 mg; 0.40 mmol) and 2- (7- azos BTA)-Ν; Ν; Ν '; Ν '-tetramethylurea hexafluorophosphoric acid ester C93 mg, 0.24 mmol), add N- isopropyl propane -2- amine (；48 mg, 0.48 mmol), stirring reaction 1 hour.20 mL saturated nacl aqueous solutions are added into reaction solution, ethyl acetate extracts (10 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain the title product 3- tert-butyl groups -5- [2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) acetyl group]-N, double (2- hydroxyethyls) benzamide hydrochloride salt 87 (35 mg of N-, white solid), yield： 28.7%. MS m/z (ESI): 572.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.42 (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- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group]-Ν -2,3- dihydroxypropyls) benzamide hydrochloride salt
The first step
The 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group]-N- (2,3- dihydroxypropyl) benzamide hydrochloride salt
By the 3- tert-butyl groups -5- [2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) acetyl group] (70 mg of benzoate hydrochlorate 76, 0.14 mmol) it is dissolved in 3 mL N, in dinethylformamide, add 3- aminopropanes -1, 2- glycol (25 mg, 0.27 mmol), 2- (7- azos BTA)-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (63 mg, 0.16 mmol) and N- isopropyl propane -2- amine (33 mg, 0.32 mmol), stirring reaction 4 hours.10 mL saturated nacl aqueous solutions, ethyl acetate extraction (15 are added into reaction solution
MLx3); merge organic phase; washed with saturated nacl aqueous solution (15 mLx3); anhydrous magnesium sulfate is dried; filtering; filtrate decompression Nong Shrink; with thin-layer chromatography chromatography with solvent system A purify gained residue; obtain the title product 3- tert-butyl groups -5- [2- (5'; fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 6'- diethoxies -4'-) acetyl group]-N- (2,3- dihydroxypropyl) benzamide hydrochloride salts 88 (45 mg; white solid), yield： 56.3%. MS m/z (ESI): 556.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):(the br of δ 9.45, 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- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl
The first step
The 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group]-Ν-(2- hydroxypropyls) benzamide hydrochloride salt
By the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] benzoate hydrochlorate 76 (70§0.14 11^101) it is dissolved in 3 11^ dichloromethane, add 4- dimethylamino naphthyridines (50 mg, 0.40 mmol) and 2- ethylaminoethanols (16 mg, 0.27 mmol), add double (2- oxo -3- oxazoles alkyl) secondary phosphonic chlorides (69 mg, 0.27 mmol), stirring reaction 4 hours.Reaction solution Jian Ya Nong Shrink; with thin-layer chromatography chromatography with solvent system A purify gained residue; obtain the title product 3- tert-butyl groups -5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; 1'- isoindolines] -2'- bases) acetyl group]-N- (2- hydroxypropyls) benzamide hydrochloride salts 89 (20 mg; white solid), yield： 26.3%.
MS m/z (ESI): 526.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm): δ 9.61 (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),
(m, the 15H) embodiment 90 of 4.20 (m, 2H), 3.63 (m, 2H), 3.40 (m, 2H), 1.93 (s, 2H), 1.73 (s, 2H), 1.44
L- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
The first step
1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] ethyl ketone
By cuprous iodide (573 mg, 3 mmol), L-PROLINE (690 mg, 6 mmol) and cesium carbonate (19.56 g, 60 mmol) be added in reaction bulb, by 5 mL 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone (2.55 g, 10 mmol) dimethyl sulfoxide (DMSO) add reaction system, add ethylene glycol (15 mL, 305 mmol), stirring reaction 12 hours.5 mL saturated ammonium chloride solutions will be poured into reaction solution, add 20 mL ethyl acetate and 20 mL water, extraction point liquid, aqueous phase is extracted with ethyl acetate (20 mL), merge organic phase, washed (30 mLx2) with water (20 mLx2) and saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] ethyl ketone 90a (198 mg, brown oil), yield： 8.4%.
Second step
1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] ethyl ketone 90a (198 mg, 0.84 mmol) is dissolved in 7 mL tetrahydrofurans and methanol (V/V=6 by small [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] ethyl ketone of 2- bromines:1) in the mixed solvent, adds trimethylphenyl tribromide ammonium (404 mg, 0.84 mmol), stirring reaction 3 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] ethyl ketone 90b (190 mg, yellow oily), yield： 71.9%.
3rd step
1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (85 mg, 0.32 mmol) is dissolved in 2 mL tetrahydrofurans, adds 2- bromo- 1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] second
Ketone 90b (100 mg, 0.32 mmol), stirring reaction 12 hours.Filtering, obtain white solid, washed with tetrahydrofuran (0.3 mLx3), vacuum drying, obtain title product 1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) (42 mg of ethanone hydrobromide 90, white solid), yield： 22.9%.
MS m/z (ESI): 499.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm): δ 9.42 (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 (the Hz of t, J=5.2,1H), 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
L- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) -2- (fluoro- 3- imino groups-U- dimethyl-iso-indoles of 5,6- diethoxy -4-
The first step
1- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) ethyl ketone
By 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone (1.53 g; 6 mmol); mesyl sodium (2.45 g; 24 mmol) and copper triflate (I) conjunction benzene (300 mg; 0.40 mmol) it is dissolved in 40 mL dimethyl sulfoxide (DMSO)s, Ν, Ν '-dimethyl-ethylenediamine (108 mg is added dropwise; 0.80 mmol), 150 °C of lower stirring reactions 2.5 hours.50 mL water and 50 mL ethyl acetate are poured into reaction solution; extraction point liquid; aqueous phase is extracted with ethyl acetate (30 mLx2); merge organic phase; washed (30 mLx3) with water (30 mLx3) and saturated nacl aqueous solution; anhydrous magnesium sulfate is dried; filtering; filtrate decompression Nong Shrink; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain the title product 1- 3- tert-butyl group -5- Metlianesulfonyl-phenyls) ethyl ketone 91a (1.16 g, yellow liquid), yield： 76.1%.
Second step
The bromo- 1- of 2- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) ethyl ketone
By 1- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) ethyl ketone 91a (200 mg; 0.79 mmol) it is dissolved in 20 mL tetrahydrofurans; add trimethylphenyl tribromide ammonium (296 mg, 0.79 mmol), stirring reaction 30 minutes.Reaction solution Jian Ya Nong Shrink, with thin-layer chromatography chromatography with solvent system B purify gained residue, obtain title
The bromo- l- of product 2- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) ethyl ketone 91b (210 mg, weak yellow liquid), yield： 80.2%.
MS m/z (ESI): 350.0 [M+18]
3rd step
L- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5; 6- diethoxies -7- fluoro- 3; small amine 24d (79 mg of 3- dimethyl-iso-indoles; 0.30 mmol) it is dissolved in 1.50 mL tetrahydrofurans; add 2- bromo- 1- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) ethyl ketone 91b (lOO mg; 0.30 mmol), stirring reaction 14 hours.Reaction solution Jian Ya Nong Shrink; with thin-layer chromatography chromatography with solvent system A purify gained residue obtain yellow solid; 2mL tetrahydrofurans are added to stir 5 minutes; filtering; washed with tetrahydrofuran (0.5 mLx3); vacuum drying; obtain title product 1- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) -2- (5; the fluoro- 3- imino groups -1 of 6- diethoxies -4-; 1- dimethyl-isoindoline -2- bases) (30 mg of ethanone hydrobromide 91; white solid), yield： 16.8%.
MS m/z (ESI):519.2 [M+1]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.42 (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
L- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) -2- (fluoro- 3'- imino groups of 5', 6'- diethoxy -4'--spiral shell [cyclopropane -1, Γ-different
- 2'- bases) ethanone hydrobromide
The first step
1- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-; 3'- isoindolines]-Γ-imines 41g (79 mg, 0.30 mmol) is dissolved in 2 mL tetrahydrofurans, adds 2- bromo- 1- (the 3- tert-butyl group -5- Metlianesulfonyl-phenyls) ethyl ketone 91b
(100 mg, 0.30 mmol), stirring reaction 2 hours has white solid precipitation.Filtering; washed with tetrahydrofuran (0.5 mLx2); vacuum drying; obtain the title product 1- 3- tert-butyl group -5- Metlianesulfonyl-phenyls) -2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; 1'- isoindolines] -2'- bases) ethanone hydrobromide 92 (85 mg, white solid), yield： 47.5%.
MS m/z (ESI): 517.2 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.42 (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
L- [the 3- tert-butyl groups -5- (2,3- dihydroxy propoxyl group) phenyl] -2- (fluoro- 3'- imino groups of 5', 6'- diethoxy -4'--spiral shell [ring third
'-isoindoline] -2'- bases) ethanone hydrobromide
The first step
1- [the 3- tert-butyl groups -5- (2,3- dihydroxy propoxyl group) phenyl] ethyl ketone is by cuprous iodide (153 mg, 0.80 mmol), L-PROLINE (184 mg, 1.60 mmol) and cesium carbonate (5.20 g, 16 mmol) add in reaction bulb, 3 mL are added containing 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone 77d (1.02 g, 4 mmol) N, dinethylformamide solution and 27 mL glycerine (11 g, 0.12 mol) DMF solution, 90 °C of lower stirring reactions 48 hours.It is cooled to room temperature, 10 mL saturated ammonium chloride solutions are added into reaction solution reaction is quenched, add 20 mL ethyl acetate and 20 mL water, extraction separates organic phase, aqueous phase is extracted with ethyl acetate (20 mL), merge organic phase, washed (30 mLx2) with water (30 mL) and saturated nacl aqueous solution successively, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (2, 3- dihydroxy propoxyl group) phenyl] ethyl ketone 93a (289 mg, brown liquid), yield： 27.2%.
Second step
The bromo- 1- of 2- [the 3- tert-butyl groups -5- (2,3- dihydroxy propoxyl group) phenyl] ethyl ketone is by copper bromide (103 mg, 0.46 mmol) it is suspended in 1.50 mL ethyl acetate, it is heated to backflow, add 2.50 mL 1- [the 3- tert-butyl groups -5- (2,3- dihydroxy propoxyl group) phenyl] ethyl ketone 93a (61 mg, 0.23 mmol) three
Chloromethanes solution, back flow reaction 3 hours.It is cooled to room temperature, filtering, Jian Ya Nong Shrink filtrates, obtain the small [the 3- tert-butyl groups -5- (2 of crude title product 2- bromines, 3- dihydroxy propoxyl group) phenyl] ethyl ketone 93b (105 mg, dark brown grease), product is not purified directly to carry out next step reaction.
3rd step
1- [the 3- tert-butyl groups -5- (2,3- dihydroxy propoxyl group) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (84 mg, 0.30 mmol) and the bromo- 1- of crude product 2- [the 3- tert-butyl groups -5- (2,3- dihydroxy propoxyl group) phenyl] ethyl ketone 93b (105 mg, 0.30 mmol) it is dissolved in 1.50 mL tetrahydrofurans, stirring reaction 4 hours, separate out a large amount of solids.Suction filtration, filter cake is washed (2 mLx3) with tetrahydrofuran, vacuum drying, prepare, obtain title product 1- [the 3- tert-butyl groups -5- (2,3- dihydroxy propoxyl group) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 93 (38 mg, white solid), yield： 23.7%.
MS m/z (ESI): 529.7 [M+l]
1H NMR (400 MHz, DMSO- , ppm):(the br of δ 9.40, 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- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] benzonitrile hydrobromate
77d 94a 94b
The first step
3- acetyl group -5- the tert-butyl groups-benzonitrile
By 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone 77d (1 g, 3.92 mmol) and copper cyanider (386 mg, 4.31 mmol) it is dissolved in 15 mL METHYLPYRROLIDONEs, 170 °C of lower stirring reactions 2 hours.20 mL ethyl acetate and 20 mL water are added into reaction solution, 10 mL ammoniacal liquor are added, stirred 30 minutes, extraction point
Go out organic phase; aqueous phase is extracted with ethyl acetate (10 mLx3); merge organic phase, wash (15 mLx3), anhydrous sodium sulfate drying with water (15 mLx3) and saturated nacl aqueous solution successively; filtering; filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the title product 3- acetyl group -5- tert-butyl groups-benzonitrile 94a (480 mg; yellow solid), yield： 60.9%.
MS m/z (ESI): 219.1 [M+18]
Second step
3- (2- the acetyl bromides) -5- tert-butyl groups-benzonitrile
3- acetyl group -5- the tert-butyl groups-benzonitrile 94a (300 mg, 1.49 mmol) is dissolved in 15 mL tetrahydrofurans, trimethylphenyl tribromide ammonium (561 mg, 1.49 mmol), stirring reaction 30 minutes is added.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify obtained by residue, obtain title product 3- (2- the acetyl bromides) -5- tert-butyl groups-benzonitrile 94b (345 mg, yellow liquid), yield： 82.5%.
MS m/z (ESI): 299.0 [M+18]
3rd step
The 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group] benzonitrile hydrobromate
By 5; 6- diethoxies -7- fluoro- 3; small amine 24d (95 mg of 3- dimethyl-iso-indoles; 0.36 mmol) it is dissolved in 1.5 mL tetrahydrofurans; add 3- (2- the acetyl bromides) -5- tert-butyl groups-benzonitrile 94b (100 mg; 0.36 mmol), stirring reaction 12 hours.Directly prepare; yellow solid is obtained, 1.5 mL tetrahydrofurans are added, stirred 10 minutes; filter to obtain solid; washed with tetrahydrofuran (0.5 mIX3), be dried in vacuo, obtain the title product 3- tert-butyl groups -5- [2- (5; the fluoro- 3- imino groups -1 of 6- diethoxies -4-; 1- dimethyl-isoindoline -2- bases) acetyl group] benzonitrile hydrobromate 94 (35 mg, white solid), yield： 17.9%.
MS m/z (ESI): 466.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.44 (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) embodiments 95
The 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl
The 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group] benzonitrile hydrobromate
By 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-; 3'- isoindolines]-Γ-imines 41g (94 mg; 0.36 mmol) it is dissolved in 1.5 mL tetrahydrofurans; add 3- (2- the acetyl bromides) -5- tert-butyl groups-benzonitrile 94b (100 mg; 0.36 mmol), stirring reaction 12 hours.Filter to obtain solid; washed with tetrahydrofuran (0.5 mLx2); vacuum drying; obtain the title product 3- tert-butyl groups -5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; 1'- isoindolines] -2'- bases) acetyl group] benzonitrile hydrobromate 95 (100 mg, white solid), yield： 51.5%.
MS m/z (ESI): 464.2 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.40 (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
L- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] -2- (the fluoro- 3'- imino groups-spiral shells of 5', 6'- diethoxy -4'- [cyclopropane -1,1'- isoindoline -2'- bases) ethanone hydrobromide
The first step
1- (the bromo- 5- tbutyl-phenyls of 3-) formaldehyde
The bromo- 5- tert-butyl groups-benzene 77c of 1,3- bis- (17 g, 58.40 mmol) are dissolved in 120 mL tetrahydrofurans, n-BuLi (23.4 mL, 58.40 mmol), stirring reaction 0.5 hour are added dropwise under -78 °C.Add N, N- bis-
NMF (6.40 g, 87.70 mmol), stirring reaction 0.5 hour.120 mL saturated ammonium chloride solutions are added into reaction solution, ethyl acetate extracts (50 mLx2), merge organic phase, washed with saturated nacl aqueous solution (30 mLx3), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the bromo- 5- tbutyl-phenyls of 3-) formaldehyde 96a (11.26 g, yellow solid), yield： 80.0%.
Second step
(the bromo- 5- tbutyl-phenyls of 3-) methanol
1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone 96a (1.20 g, 4.98 mmol) are dissolved in 16 mL absolute ethyl alcohols, sodium borohydride (57 mg, 1.49 mmol), stirring reaction 45 minutes is added portionwise.20 mL water quenchings are added into reaction solution to go out reaction, reaction solution Jian Ya Nong Shrink, aqueous phase is extracted with ethyl acetate (20 mLx2), merges organic phase, is washed with saturated nacl aqueous solution (30 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink obtain title product (the bromo- 5- tbutyl-phenyls of 3-) methanol 96b (l g, white solid), yield： 82.0%.
3rd step
1- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] ethyl ketone
By (the bromo- 5- tbutyl-phenyls of 3-) methanol 96b (790 mg, 3.25 mmol) it is dissolved in 15 mL tetrahydrofurans, n-BuLi (5.20 mL are added dropwise under -78 °C, 13 mmol), stirring reaction 30 minutes, then N, N- dimethyl acetamides (850 mg is added dropwise, 9.75 mmol), drop finishes stirring reaction 30 minutes.60 mL saturated ammonium chloride solutions are added into reaction solution, extraction separates organic phase, aqueous phase is extracted with ethyl acetate (30 mLx2), merge organic phase, washed with saturated nacl aqueous solution (60 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] ethyl ketone 96c (114 mg, colourless liquid), yield： 17.0%.
MS m/z (ESI): 207.1 [M+l]
4th step
Small [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] ethyl ketone of 2- bromines is by 1- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] ethyl ketone 96c (107 mg, 0.52 mmol) it is dissolved in 3 mL tetrahydrofurans, add trimethylphenyl tribromide ammonium (195 mg, 0.52 mmol), stirring reaction 1 hour.Filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] ethyl ketone 96d (90 mg, colourless liquid), yield： 60.8%.
MS m/z (ESI): 287.0 [M+l]
5th step
L- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (73 mg, 0.28 mmol) it is dissolved in 2 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] ethyl ketone 96d (87 mg, 0.30 mmol), stirring reaction 2.5 hours.Solid is filtered to obtain, washed with tetrahydrofuran (；0.5
MLx2), vacuum drying, obtain title product 1- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) (55 mg of ethanone hydrobromide 96, white solid), yield： 34.3%.
MS m/z (ESI): 469.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.42 (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
L- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (fluoro- 3- imino groups -1,1- dimethyl of 5,6- diethoxy -4--isoindoline -2- base ethanone hydrobromides
The first step
1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (76 mg of 3- dimethyl-iso-indoles, 0.29 mmol) it is dissolved in 2 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] ethyl ketone 90b (90 mg, 0.29 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (33 mg of ethanone hydrobromide 97, light yellow solid), yield： 23.1%.
MS m/z (ESI): 501.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm): δ 9.32 (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
L- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] -2- (fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- base ethanone hydrobromides
The first step
1- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (90 mg of 3- dimethyl-iso-indoles, 0.34 mmol) it is dissolved in 3 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] ethyl ketone 96d (116 mg, 0.41 mmol), stirring reaction 16 hours.Filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (hydroxymethyl) phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide 98 (30 mg, white solid), yield： 16.1%.
MS m/z (ESI): 471.1 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.42 (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
L- [the 3- tert-butyl groups -5- (l- methyl-pyrazol-4-yls) phenyl] -2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
The first step
L- [the 3- tert-butyl group -5-0 methyl-pyrazol-4-yls) phenyl] ethyl ketone is by 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone 77d (720 mg, 2.83 mmol) and tetrakis triphenylphosphine palladium
(327 mg, 0.28 mmol) it is dissolved in 50 mL dimethyl ether, stirring reaction 10 minutes, add 7 mLl- methyl-pyrazol-4-yls boric acid (533 mg, 4.23 mmol) and potassium carbonate (1.95 g, 14.10 mmol) the aqueous solution, be warming up to return stirring react 4 hours.Filtering, 20 mL ethyl acetate are added into filtrate, extraction, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (1- methyl-pyrazol-4-yls) phenyl] ethyl ketone 99a (318 mg, light yellow oil), yield： 44.0%.
MS m/z (ESI): 257.1 [M+l]
Second step
1- [the 3- tert-butyl groups -5- (1- methyl-pyrazol-4-yls) phenyl] ethyl ketone 99a (300 mg, 1.17 mmol) is dissolved in by the bromo- l- of 2- [the 3- tert-butyl groups -5- (l- methyl-pyrazol-4-yls) phenyl] ethyl ketones
In 5 mL chloroforms, copper bromide (522 mg, 2.34 mmol) is added, 40 °C of stirring reactions are warming up to 12 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl groups -5- (1- methyl-pyrazol-4-yls) phenyl] ethyl ketone 99b (216 mg, light yellow oil), yield： 55.0%.
3rd step
1- [the 3- tert-butyl groups -5- (1- methyl-pyrazol-4-yls) phenyl] -2- (fluoro- 3- imino groups -1,1- dimethyl of 5,6- diethoxy -4-
- isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (40 mg of 3- dimethyl-iso-indoles, 0.15 mmol) it is dissolved in 1 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- (1- methyl-pyrazol-4-yls) phenyl] ethyl ketone 99b (51 mg, 0.15 mmol), stirring reaction 12 hours.Filter to obtain solid, washed with tetrahydrofuran (0.5 mLx2), vacuum drying, obtain title product 1- [the 3- tert-butyl groups -5- (1- methyl-pyrazol-4-yls) phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide 99 (40 mg, white solid), yield： 44.0%.
MS m/z (ESI): 521.3 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.33 (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) embodiments 100
L- [the 3- tert-butyl groups -5- (l- methyl-pyrazol-4-yls) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1 1'- isoindolines] -2'- bases) ethanone hydrobromide
The first step
1- [the 3- tert-butyl groups -5- (1- methyl-pyrazol-4-yls) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (51 mg, 0.19 mmol) it is dissolved in 0.5 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- (1- methyl-pyrazol-4-yls) phenyl] ethyl ketone 99b C65 mg, 0.19 mmol), stirring reaction 12 hours.It is counter to answer Ye Nong Shrink, prepare, obtain yellow solid, recrystallized with tetrahydrofuran, be dried in vacuo, obtain title product 1- [the 3- tert-butyl groups -5- (1- methylpyrazoles -4- yls) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 100 (11 mg, white solid), yield： 10.0%.
MS m/z (ESI): 519.1 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.59 (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
L- (the 3- tert-butyl group -5- isopropyl-phenyls) -2- (fluoro- 3- imino groups -1,1- dimethyl-isoindolines of 5,6- diethoxy -4-
- 2- ethanone hydrobromides
The first step
The bromo- 3- tert-butyl groups -5- isopropyls-benzene of 1-
Zinc chloride (3.64 g, 26.70 mmol) is dissolved in 20 mL tetrahydrofurans, 2 M isopropylmagnesium chlorides 13.3 mL is added, 50 °C of stirring reactions 3 hours.By 1, the bromo- 5- tert-butyl groups of 3- bis--benzene 77c (5.20 g, 17.80 mmol) add in another reaction bulb, add cuprous iodide (203 mg, 1.07 mmol), 1, Γ-bis- (dibenzyl phosphorus) dichloro diamyl iron palladium (651 mg, 0.89 mmol) and 20 mL tetrahydrofurans, instill the reaction solution of above-mentioned cooling, lucifuge stirring reaction 36 hours.Filtering, filter cake is washed (20 mLx3) with ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 3- tert-butyl groups -5- isopropyls-benzene 101a (433 mg, yellow oil) of title product 1-, yield： 95.0%.
Second step
1- (the 3- tert-butyl group -5- isopropyl-phenyls) ethyl ketone
By the bromo- 3- tert-butyl groups -5- isopropyls of 1--benzene 101a (730 mg, 2.86 mmol) it is dissolved in 5 mL tetrahydrofurans, 2.50 M n-BuLis (1.37 mL are added dropwise under -78 °C, 3.44 mmol), stirring reaction 2 hours, then DMA (0.37 mL is added dropwise, 4.29 mmol), drop finishes stirring reaction 30 minutes.20 mL saturated ammonium chloride solutions are added into reaction solution reaction is quenched, add 5mL water and 20mL ethyl acetate, extraction separates organic phase, washed with saturated nacl aqueous solution (5 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the 3- tert-butyl group -5- isopropyl-phenyls) ethyl ketone 101b (379 mg, colourless liquid), yield： 60.8%.
MS m/z (ESI): 219.1 [M+l]
3rd step
The bromo- l- of 2- (the 3- tert-butyl group -5- isopropyl-phenyls) ethyl ketone
By 1- (the 3- tert-butyl group -5- isopropyl-phenyls) ethyl ketone 101b (326 mg, 1.50 mmol) it is dissolved in 3 mL tetrahydrofurans, add trimethylphenyl tribromide ammonium (562 mg, 1.50 mmol), stirring reaction 1 hour.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain the bromo- 1- of title product 2- (the 3- tert-butyl group -5- isopropyl-phenyls) ethyl ketone 101c (207 mg, colourless liquid), yield： 46.0%.
MS m/z (ESI): 299.9 [M+l]
4th step
L- (the 3- tert-butyl group -5- isopropyl-phenyls) -2- (fluoro- 3- imino groups -1,1- dimethyl-isoindolines of 5,6- diethoxy -4-
- 2- bases) ethanone hydrobromide
The fluoro- small amine 24d of 3,3- dimethyl-iso-indoles (49 mg, 0.18 mmol) of 5,6- diethoxies -7- are dissolved in
In 0.5 mL tetrahydrofurans, 2- bromo- 1- (the 3- tert-butyl group -5- isopropyl-phenyls) ethyl ketone 101c (55 mg, 0.18 mmol), stirring reaction 12 hours are added.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- (the 3- tert-butyl group -5- isopropyl-phenyls) -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (20 mg of ethanone hydrobromide 101, white solid), yield： 19.0%.
MS m/z (ESI): 483.5 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm): δ 7.86 (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
The 1-C3- tert-butyl group -5- isopropyl-phenyls) and -2- (the fluoro- 3'- imino groups of 5', 6'- diethoxy -4'--[cyclopropane -1,1'- is different for spiral shell
'-yl) ethanone hydrobromide
The first step
The 1-C3- tert-butyl group -5- isopropyl-phenyls) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (50 mg, 0.19 mmol) it is dissolved in 0.5 mL tetrahydrofurans, add 2- bromo- 1- (the 3- tert-butyl group -5- isopropyl-phenyls) ethyl ketone 101c (56 mg, 0.19 mmol), stirring reaction 12 hours.Filter to obtain solid, washed with tetrahydrofuran (0.5 mLx2), vacuum drying, obtain title product 1- (the 3- tert-butyl group -5- isopropyl-phenyls) -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 102 (30 mg, white solid), yield： 28.0%.
MS m/z (ESI): 481.6 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.39 (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, /=9.3 Hz, 1H) embodiment 103
L- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] -2- (the fluoro- 3'- imino groups of 5', 6'- diethoxy -4'---1,1'- isoindolines] -2'- bases) ethanone hydrobromide
The first step
1- the bromo- 3- tert-butyl groups -5- (1,1- dimethoxy-ethyl) benzene
By 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone (2.30 g, 9 mmol) it is dissolved in 3 mL methanol, add trimethoxy-methane (2.88 g, 27 mmol) and camphorsulfonic acid (105 mg, 0.45 mmol), stirring reaction 12 hours.500 mg potassium carbonate are added into reaction solution, stirring 10 minutes, add lO mL water and lO mL n-hexanes, extraction point liquid, aqueous phase is with n-hexane extraction (10 mLx2), merge organic phase, saturated nacl aqueous solution washs (10 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain the bromo- 3- tert-butyl groups -5- (1 of crude title product 1-, 1- dimethoxy-ethyls) benzene 103a (2.70 g, light yellow oil), product is not purified directly to carry out next step reaction.
Second step
1- [the 3- tert-butyl groups -5- (1,1- dimethoxy-ethyl) phenyl] piperazine
By the bromo- 3- tert-butyl groups -5- (1 of crude product 1-, 1- dimethoxy-ethyls) benzene 103a (2.70 g, 9 mmol) it is placed in reaction bulb, sequentially add 2- dicyclohexyl phosphorus -2- (N, N- dimethylamino) biphenyl (177 mg, 0.45 mmol), three (dibenzalacetone) two palladium (270 mg, 10%), sodium tert-butoxide (2.60 g, 27 mmol) and piperazine (1.50 g, 18
Mmol), it is eventually adding 40 mL dioxane, 60 °C of lower stirring reactions 3 hours.50 mL water and 20 mL ethyl acetate are added in reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (20 mLx4), merge organic phase, washed with saturated nacl aqueous solution (30 mLx l), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain crude title product 1- [the 3- tert-butyl groups -5- (1,1- dimethoxy-ethyls) phenyl] piperazine 103b (2 g, brown oil), product is not purified directly to carry out next step reaction.
3rd step
1- (the 3- tert-butyl group -5- piperazines -1- bases-phenyl) ethyl ketone
Crude product 1- [the 3- tert-butyl groups -5- (1,1- dimethoxy-ethyl) phenyl] piperazine 103b (2 g, 6.50 mmol) is dissolved in the M hydrogen chloride dioxane solutions of 30 mL 2, stirring reaction 1 hour.Reaction solution Jian Ya Nong Shrink, add 30 mL water and 20 mL ethyl acetate, extraction point liquid, aqueous phase is extracted with ethyl acetate (10 mLx2), merges organic phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink obtain crude title product 1- (the 3- tert-butyl group -5- piperazines-i-base-phenyl) ethyl ketone 103c (1.45 g, yellow oily), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 261.1 [M+l]
4th step
L- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] ethyl ketones are by crude product 1- (the 3- tert-butyl group -5- piperazines -1- bases-phenyl) ethyl ketone 103c (1.40 g, 5.38 mmol) it is dissolved in 10 mL N, in dinethylformamide, add ethylene chlorhydrin (694 mg, 8.60 mmol) and potassium carbonate (1.48 g, 10.76 mmol), it is warming up to 70 °C of stirring reactions 12 hours.30 mL water are added into reaction solution, it is extracted with ethyl acetate (30 mLx4), merge organic phase, saturated nacl aqueous solution washs (50 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] ethyl ketone 103d (630 mg, yellow oil), yield： 39.3%.
MS m/z (ESI): 305.1 [M+l]
5th step
Small [the 3- tert-butyl groups -5- [the small base of 4- (2- hydroxyethyls) piperazines] phenyl] ethyl ketone of 2- bromines is by 1- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] ethyl ketone 103d (103 mg, 0.34 mmol) it is dissolved in 2 mL glacial acetic acid, add pyridinium tribromide Key salt (108 mg, 0.34 mmol), stirring reaction 5 hours.5 mL water are added into reaction solution, pH value is adjusted to 7-8 with sodium acid carbonate, it is extracted with ethyl acetate (10 mLx4), merge organic phase, saturated nacl aqueous solution washs (10 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] ethyl ketone 103e (38 mg, white solid), yield： 29.2%.
MS m/z (ESI): 385.1 [M+l]
6th step
L- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] -2- (the fluoro- 3'- imino groups of 5', 6'- diethoxy -4'- -
Spiral shell [cyclopropane -1, Γ-isoindoline] -2'- bases) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (26 mg, 0.10 mmol) it is dissolved in I mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] ethyl ketone 103e (38 mg, 0.10 mmol), stirring reaction 4 hours.Reaction solution Jian Ya Nong Shrink, with thin-layer chromatography chromatography with eluant, eluent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) (28 mg of ethanone hydrobromide 103, white solid), yield： 43.7%.
MS m/z (ESI): 566.1 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm): δ 8.69 (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
The 1-C3- tert-butyl groups -5- cyclopropyl-phenyl) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
104a 104b 104
The first step
1- (the 3- tert-butyl groups -5- cyclopropyl-phenyl)-ethyl ketone
By 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone (1 g, 3.90 mmol) and tetra-triphenylphosphine palladium (450 mg,
0.39 mmol) it is dissolved in 60 mL dioxane, stirring 10 minutes, again by 10 mL (500 mg containing cyclopropylboronic acid, 5.90 mmol) and cesium carbonate (6.30 g, 19.50 mmol) the aqueous solution add in reaction system, be warming up to 90 °C of lower stirring reactions 5 hours.It is cooled to room temperature, filtering, 50 mL ethyl acetate and 10 mL water are added into filtrate, and extraction separates organic phase, washed with saturated nacl aqueous solution (30 mLx2), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (the 3- tert-butyl groups -5- cyclopropyl-phenyl)-ethyl ketone 104a (600 mg, colourless liquid), yield： 71.2%.
MS m/z (ESI): 217.1 [M+l]
Second step
The bromo- l- of 2- (the 3- tert-butyl groups -5- cyclopropyl-phenyl)-ethyl ketone
By 1- (the 3- tert-butyl groups -5- cyclopropyl-phenyl)-ethyl ketone 104a (540 mg, 2.50 mmol) it is dissolved in 7.5 mL tetrahydrofurans, add trimethylphenyl tribromide ammonium (940 mg, 2.50 mmol), stirring reaction 2 hours.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain the bromo- 1- of title product 2- (the 3- tert-butyl groups -5- cyclopropyl-phenyl)-ethyl ketone 104b (510 mg, colourless liquid), yield： 68.9%.
3rd step
The 1-C3- tert-butyl groups -5- cyclopropyl-phenyl) -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (82 mg, 0.31 mmol) the bromo- 1- of standing grain B 2- (the 3- tert-butyl groups -5- cyclopropyl-phenyl)-ethyl ketone 104b (92 mg, 0.31 mmol) it is dissolved in 1 mL tetrahydrofurans, stirring reaction 12 hours, separates out a large amount of solids.Suction filtration, filter cake is washed (0.5 mLx3) with tetrahydrofuran, vacuum drying, obtain the title product 1- 3- tert-butyl groups -5- cyclopropyl-phenyl) -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 104 (139 mg, white solid), yield： 80.0%.
MS m/z (ESI): 479.1 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.36 (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)
L- (the 3- tert-butyl groups -5- cyclopropyl-phenyl) -2- (fluoro- 3- imino groups-U- dimethyl-isoindolines of 5,6- diethoxy -4-
- 2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (62 mg of 3- dimethyl-iso-indoles, 0.21 mmol) it is dissolved in 1 mL tetrahydrofurans, add 2- bromo- 1- (the 3- tert-butyl groups -5- cyclopropyl-phenyl)-ethyl ketone 104b (56 mg, 0.21 mmol), stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- (the 3- tert-butyl groups -5- cyclopropyl-phenyl) -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) ethanone hydrobromide 105 (72 mg, white solid), yield： 61.0%.
MS m/z (ESI): 481.1 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 7.78 (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
L- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
The 3- tert-butyl groups -5- (trifluoromethyl) benzoic acid
Under -78 °C, by 3- bromo- 5- (trifluoromethyl) benzoic acid 106a (5 g, 18.60 mmol) and cuprous iodide (178 mg, 0.93 mmol) it is dissolved in 50 mL tetrahydrofurans, add tert-butyl group magnesium chloride (27.30 mL, 46.50 mmol), stirring reaction 1 hour.20 mL saturated ammonium chloride solutions are added into reaction solution reaction is quenched, add 20 mL ethyl acetate and 20 mL water, pH value is adjusted to 2-3, extraction point with 1 M hydrogen chloride solutions
Liquid, aqueous phase is extracted with ethyl acetate (30 mLx3), merge organic phase, (30 mLx3), anhydrous sodium sulfate drying are washed with water (30 mLx3) and saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain the title product 3- tert-butyl groups -5- (trifluoromethyl) benzoic acid 106b (3.75 g, yellow solid), yield： 82.0%.
MS m/z (ESI): 245.0 [M-l]
Second step
3- fert-Butyl-N-methoxies -5- (trifluoromethyl) benzamides are by the 3- tert-butyl groups -5- (trifluoromethyl) benzoic acid 106b (3.71 g, 15.08 mmol) it is dissolved in 25 mL thionyl chlorides, 85 °C of lower stirring reactions 2 hours.It is counter to answer under Ye Nong Shrink, 0 °C, add 30 mL dichloromethane, N- methoxies amine (2.34 g, 23.98 mmol) is added, N is added dropwise, N- diisopropylethylamine (5.84 g, 45.24 mmol), is warmed to room temperature stirring reaction 12 hours.30 mL water are added into reaction solution, extraction point liquid, aqueous phase is extracted (15 mLx3) with dichloromethane, merges organic phase, with water (15 mL><3) with saturated nacl aqueous solution washing (15 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 3- fert-Butyl-N-methoxies -5- (trifluoromethyl) benzamides 106c (985 mg, yellow liquid), yield： 22.6%.
MS m/z (ESI): 290.0 [M+l]
3rd step
L- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] ethyl ketone
Under 0 °C, by 3- fert-Butyl-N-methoxies -5- (trifluoromethyl) benzamide 106c (900 mg, 3.10 mmol) it is dissolved in 15 mL tetrahydrofurans, add methyl-magnesium-chloride (2.10 mL, 6.23 mmol), stirring reaction 2 hours at room temperature.20 mL saturated ammonium chloride solutions are added into reaction solution reaction is quenched, add 15 mL ethyl acetate and 10 mL water, extraction point liquid, aqueous phase is extracted with ethyl acetate (15 mLx3), merge organic phase, washed (15 mLx3) with water (15 mLx3) and saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] ethyl ketone 106d (720 mg, yellow liquid), yield： 94.7%.
4th step
Small [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] ethyl ketone of 2- bromines
By 1- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] ethyl ketone 106d (300 mg, 1.23 mmol) it is dissolved in 15 mL tetrahydrofurans, add trimethylphenyl tribromide ammonium (462 mg, 1.23 mmol), stirring reaction 1 hour.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] ethyl ketone 106e (290 mg, yellow liquid), yield： 73.0%.
5th step
1- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] -2- (the fluoro- 3- imino groups-U- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
The fluoro- small amine 24d of 3,3- dimethyl-iso-indoles (115 mg, 0.43 mmol) of 5,6- diethoxies -7- are dissolved in
In 5 mL tetrahydrofurans, 2- bromo- l- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] ethyl ketone 106e (140 mg, 0.43 mmol), stirring reaction 1 hour are added.5 mL water and 5mL ethyl acetate are added into reaction solution, extraction point liquid, aqueous phase is extracted with ethyl acetate (5 mLx2), merge organic phase, washed (10 mLx2) with water (10 mLx2) and saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (24 mg of ethanone hydrobromide 106, yellow solid）, yield： 9.4%.
MS m/z (ESI): 509.1 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 9.60 (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) embodiments 107
L- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] -2- (the fluoro- 3'- imino groups-spiral shells of 5', 6'- diethoxy -4'- [cyclopropane -1,1'- '-yl) ethanone hydrobromide
106e 107
1- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (57 mg, 0.22 mmol) it is dissolved in 1 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] ethyl ketone 106e (70 mg, 0.22 mmol), stirring reaction 1 hour.Solid is filtered to obtain, washed with tetrahydrofuran (；0.5 mLx3), vacuum drying, obtain title product 1- [the 3- tert-butyl groups -5- (trifluoromethyl)-phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) (75 mg of ethanone hydrobromide 107, white solid), yield： 59.1%.
MS m/z (ESI): 507.1 [M+l]
1H NMR (400 MHz, DMSO- , ppm): δ 9.38 (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), (m, the 3H) embodiment 108 of 1.66 (m, 2H), 1.39 (m, 12H), 1.31
2- [the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetyl group] phenyl] -2- methyl-propanenitrile hydrobromates
The first step
1- (the bromoethyl) -3- tert-butyl groups -5- methyl-benzene
By the 1- tert-butyl groups -3,5- dimethyl-benzene 108a (5 g, 30.81 mmol), azodiisobutyronitrile (50 mg, 0.30 mmol) and N-bromosuccinimide (4.39 g, 24.65 mmol) it is dissolved in 50 mL carbon tetrachloride, 80 °C of stirring reactions 2 hours.Reaction solution Jian Ya Nong Shrink, add 30 mL water, it is extracted with ethyl acetate (20 mIX3), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain crude title product 1- (the bromoethyl) -3- tert-butyl groups -5- methyl-benzene 108b (6.10 g, colorless oil）, product is not purified directly to carry out next step reaction.
Second step
2- (the 3- tert-butyl group -5- methylphenyls) acetonitrile
By crude product 1- (the bromoethyl) -3- tert-butyl groups -5- methyl-benzene 108b (482 mg, 2 mmol) and cyaniding 4-butyl amine (805 mg, 3 mmol) it is dissolved in 5 mL DMFs, 60 °C of lower stirring reactions 1.5 hours.10 mL water are added in reaction solution, extracted with ether (10 mLx2), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- (the 3- tert-butyl group -5- methylphenyls) acetonitrile 108c (176 mg, pale yellowish oil), yield： 47.0%
3rd step
2- (the 3- tert-butyl group -5- methylphenyls) -2- methyl-propanenitriles
Under -78 °C, by potassium tert-butoxide C198 mg, 1.76 mmol) it is dissolved in 5 mL tetrahydrofurans, 5 mL are added dropwise containing 2- (the 3- tert-butyl group -5- methylphenyls) acetonitrile 108c (150 mg, 0.80 mmol) and iodomethane (342 mg, 2.40 mmol) tetrahydrofuran solution, stirring reaction 0.5 hour, react at room temperature 3 hours.Add 5 mL water, it is extracted with ethyl acetate (5 mLx2), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, crude title product 2- (the 3- tert-butyl group -5- methylphenyls) -2- methyl-propanenitriles 108d (151 mg, yellow oily) is obtained, product is not purified directly to carry out next step reaction.
4th step
The 3- tert-butyl groups -5- (1- cyano group -1- methyl-ethyls) benzoic acid
By the crude product 2-0 tert-butyl group -5- methylphenyls) -2- methyl-propanenitriles 108d (150 mg, 0.69 mmol) it is dissolved in 1.3 mL acetic acid, add the 0.1 mL concentrated sulfuric acids and chromium oxide (206 mg, 2.07 mmol), stirring reaction 2 hours.20 mL water and 10 mL ethyl acetate are added in reaction solution, extraction point liquid, aqueous phase is extracted with ethyl acetate (5 mLx3), merge organic phase, washed (10 mL) with water (10 mLx2) and saturated nacl aqueous solution successively, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain the crude title product 3- tert-butyl groups -5- (1- cyano group -1- methyl-ethyls) benzoic acid 108e (154 mg, yellow oily), product is not purified directly to carry out next step reaction.
5th step
The 3- tert-butyl groups -5- (1- cyano group -1- methyl-ethyls)-N- methoxy-. N-methyls-benzamides are by the crude product 3- tert-butyl group -5-0 cyano group -1- methyl-ethyls) benzoic acid 108e (154 mg, 0.62 mmol) it is dissolved in 2 mL thionyl chlorides, 80 °C of lower stirring reactions 2 hours.Reaction solution Jian Ya Nong Shrink, add 5 mL dichloromethane, under ice bath cooling, add N, 0- dimethyl hydroxylamine hydrochlorides (97 mg, 0.99 mmol), then N is added dropwise, N- diisopropylethylamine (240 mg, 1.86 mmol), stirring reaction 0.5 hour.5 mL water are added in reaction solution, it is extracted with ethyl acetate (10 mLx2), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain the title product 3- tert-butyl groups -5- (1- cyano group -1- methyl-ethyls)-N- methoxy-. N-methyls-benzamide 108f (100 mg, yellow oily）, yield： 55.2%
MS m/z (ESI): 289.1 [M+l]
6th step
2- 3- acetyl group -5- tbutyl-phenyls) -2- methyl-propanenitriles
Under ice bath, by the 3- tert-butyl groups -5- (the small methyl-ethyl of 1- cyano group)-N- methoxy-. N-methyls-benzamide 108f (100 mg, 0.34 mmol) it is dissolved in 2 mL tetrahydrofurans, add 3 M methyl-magnesium-chlorides (0.23 mL, 0.68 mmol), stirring reaction 2 hours.5 mL water are added into reaction solution; pH value is adjusted with 2 mLl M hydrogen chloride solutions; it is extracted with ethyl acetate (5 mLx3); merge organic phase; washed with saturated nacl aqueous solution (20 mLx2); anhydrous magnesium sulfate is dried; filtering; filtrate decompression Nong Shrink; obtain crude title product 2- (3- acetyl group -5- tbutyl-phenyls) -2- methyl-propanenitriles 108g (75 mg; pale solid), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 261.2 [M+l 8]
7th step
2- [3- (2- acetyl bromides) -5- tbutyl-phenyls] -2- methyl-propanenitriles
By crude product 2-0 acetyl group -5- tbutyl-phenyls) -2- methyl-propanenitriles 108g (75 mg; 0.30 mmol) it is dissolved in 10 mL tetrahydrofurans; add trimethylphenyl tribromide ammonium (115 mg, 0.30 mmol), stirring reaction 1.5 hours.Filtering; filtrate decompression Nong Shrink, with thin-layer chromatography chromatography with solvent system B purify gained residue, obtain title product 2- [3- (2- acetyl bromides) -5- tbutyl-phenyls] -2- methyl-propanenitriles 108h (72 mg; colourless liquid), yield： 74.2%.
MS m/z (ESI): 341.1 [M+18]
8th step
2- [the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetyl group] phenyl] -2- methyl-propanenitrile hydrobromates
By 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-; 3'- isoindolines]-Γ-imines 41g (40 mg; 0.15 mmol) it is dissolved in 0.5 mL tetrahydrofurans; add 2- [3- (2- acetyl bromides) -5- tbutyl-phenyls] -2- methyl-propanenitriles 108h (49 mg; 0.15 mmol), stirring reaction 3 hours.Filter to obtain solid; washed with tetrahydrofuran (0.2 mLx3); vacuum drying; obtain title product 2- [the 3- tert-butyl groups -5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; 1'- isoindolines] -2'- bases) acetyl group] phenyl] -2- methyl-propanenitriles hydrobromate 108 (33 mg, white solid), yield： 44.0% o
MS m/z (ESI): 506.1 [M+l]
1H NMR (400 MHz, DMSO- , ppm): δ 7.97 (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) embodiments 109
2- [the 3- tert-butyl groups -5- [2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) acetyl group]
- 2- methyl-propanenitrile hydrobromates
The first step
1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (fluoro- 3- imino groups -1,1- dimethyl of 5,6- diethoxy -4--different
Indoline -2- bases) ethanone hydrobromide
By 5; 6- diethoxies -7- fluoro- 3; small amine 24d (106 mg of 3- dimethyl-iso-indoles; 0.40 mmol) it is dissolved in 5 mL tetrahydrofurans; add 2- [3- (2- acetyl bromides) -5- tbutyl-phenyls] -2- methyl-propanenitriles 108h (129 mg; 0.40 mmol), stirring reaction 4 hours.Reaction solution Jian Ya Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (2- hydroxyl-oxethyls) phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (86 mg of ethanone hydrobromide 109, white solid), yield： 36.5%.
MS m/z (ESI): 508.3 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm): δ 8.01 (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 0,9H), 1.31 (m, 3H) embodiments 110
The 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl
- N, N- bis- (2- hydroxyethyls) benzamide hydrochloride salt
76 110
The first step
The 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) acetyl group]-Ν, Ν-two (2- hydroxyethyls) benzamide hydrochloride salt
By the 3- tert-butyl groups -5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-; 1'- isoindolines] -2'- bases) acetyl group] benzoate hydrochlorate 76 (350 mg, 0.68 mmol) and 2- (2- hydroxyethylaminos) ethanol（142 mg:1.35 mmol) it is dissolved in 3 mLN, dinethylformamide, add the 2- (nitrogen of 7- azos benzo three
Azoles)-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (308 mg, 0.81 mmol), stirring reaction 2 hours.Add 5 mL saturated nacl aqueous solutions, it is extracted with ethyl acetate (20 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain the title product 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- of 5', 6'- diethoxy -4'-
Base) acetyl group]-N, N- bis- (2- hydroxyethyls) benzamide hydrochloride salt 110 (110 mg, light yellow solid), yield： 22.3%.
MS m/z (ESI): 570.1 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):(the s of δ 7.99, 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- tert-butyl groups-5- [2- (5', fluoro- 3'- imino groups-spiral shell [cyclopropane-1, Γ-the isoindoline]-2'- bases of 6'- diethoxies-4'-) acetyl group]-N- [2- hydroxyls-1-(hydroxymethyl) ethyl] benzamide hydrochloride salt
The first step
The 3- tert-butyl groups-5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane-1 of 6'- diethoxies-4'-; 1'- isoindolines]-2'- bases) acetyl group]-N- [2- hydroxyls-1-(hydroxymethyl) ethyl] benzamide hydrochloride salts are by the 3- tert-butyl groups-5- [2- (5'; the fluoro- 3'- imino groups-spiral shell [cyclopropane-1 of 6'- diethoxies-4'-; 1'- isoindolines]-2'- bases) acetyl group] (150 mg of benzoate hydrochlorate 76; 0.29 mmol) and 2- aminopropyl-1,3- glycol（53 mg, 0.58 mmol) it is dissolved in 1 mL DMFs, addition 2- (；The nitrogen of 7- azos benzo three
Azoles)-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (132 mg, 0.35 mmol), stirring reaction 2 hours.Add 5 mL saturated nacl aqueous solutions, it is extracted with ethyl acetate (20 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain the title product 3- tert-butyl groups -5- [2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) acetyl group]-N- [small (hydroxymethyl) ethyl of 2- hydroxyls] (120 mg of benzamide hydrochloride salt 111, light yellow solid), yield： 70.0%.
MS m/z (ESI): 556.2 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm): δ 9.47 (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) embodiments 112
L- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] -2- (fluoro- 3- imino groups -1,1- of 5,6- diethoxy -4-
The first step
1- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] -2- (fluoro- 3- imino groups -1, the 1- dimethyl of 5,6- diethoxy -4--isoindoline -2- bases) ethanone hydrobromide
By 5,6- diethoxies -7- fluoro- 3, small amine 24d (56 mg of 3- dimethyl-iso-indoles, 0.20 mmol) it is dissolved in 5 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] ethyl ketone 1036 (80 1,0.20 1^^1) and triethylamine (80 1,0.20 1^^) is 1), stirring reaction 48 hours.Reaction solution Jian Ya Nong Shrink, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain title product
1- [the 3- tert-butyl groups -5- [4- (2- hydroxyethyls) piperazine -1- bases] phenyl] -2- (5, the fluoro- 3- imino groups -1 of 6- diethoxies -4-, 1- dimethyl-isoindoline -2- bases) (21 mg of ethanone hydrobromide 112, yellow solid), yield： 16.2%.
MS m/z (ESI): 569.7 [M+l]
1H NMR (400 MHz, DMSO- , ppm): δ 7.22 (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), (s, the 6H) embodiment 113 of 1.32 (m, 6H), 1.35 (s, 9H), 1.27
L- [the 3- tert-butyl groups -5- (l, 2- dihydroxy ethyl) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
The first step
L- (the 3- tert-butyl group -5- vinyi-phenyls) ethyl ketone
By 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone (360 mg, 1.41 mmol) and tetrakis triphenylphosphine palladium (163 mg, 0.14 mmol) be dissolved in 4 mL dioxane, stir 10 minutes, add three normal-butyls (；Vinyl) tin (492 mg, 1.55 mmol) and cesium fluoride (428 mg, 2.82 mmol), 90 °C of lower stirring reactions 2 hours.5 mL water and 10 mL ethyl acetate are added into reaction solution, extraction point liquid, organic phase anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain crude title product 1- (the 3- tert-butyl group -5- vinyi-phenyls) ethyl ketone 113a (407 mg, colorless oil), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 203.1 [M+l]
Second step
L- [the 3- tert-butyl group -5- (l, 2- dihydroxy ethyls) phenyl] ethyl ketone is by crude product 1- (the 3- tert-butyl group -5- vinyi-phenyls) ethyl ketone 113a (404 mg, 2 mmol) it is dissolved in the 10 mL tert-butyl alcohols, sequentially add N- methyl-N- morpholine oxides (257 mg, 2.20 mmol) and osmium tetroxide (25 mg, 0.10 mmol), stirring reaction 1 hour.The hypo solutions of 10 mL 5% and 20 mL ethyl acetate are added in reaction solution, divide liquid, organic phase is washed (5 mLx2) with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (1,2- dihydroxy ethyl) phenyl] ethyl ketone 113b (182 mg, colorless oil), yield： 38.0%.
MS m/z (ESI): 237.1 [M+l]
3rd step
1- [the 3- tert-butyl groups -5- (1,2- dihydroxy ethyl) phenyl] ethyl ketone 113b (180 mg, 0.76 mmol) is dissolved in by small [the 3- tert-butyl groups -5- (l, the 2- dihydroxy ethyl) phenyl] ethyl ketone of 2- bromines
In 2 mL tetrahydrofurans, trimethylphenyl tribromide ammonium (287 mg, 0.76 mmol), stirring reaction 4 hours are added.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify obtained by residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl groups -5- (1,2- dihydroxy ethyls) phenyl] ethyl ketone 113c (30 mg, colourless liquid), yield： 12.5%.
4th step
1- [the 3- tert-butyl groups -5- (l, 2- dihydroxy ethyl) phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane of 5', 6'- diethoxy -4'-
- 1,1'- isoindoline] -2'- bases) ethanone hydrobromide
By 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-, 3'- isoindolines]-Γ-imines 41g (25 mg, 0.10 mmol) it is dissolved in 0.5 mL tetrahydrofurans, add the bromo- 1- of 2- [the 3- tert-butyl groups -5- (1,2- dihydroxy ethyls) phenyl] ethyl ketone 118c C30 mg, 0.10 mmol), stirring reaction 12 hours.Suction filtration, solid washed with tetrahydrofuran (；0.5 mLx3), solid is dried in vacuo, collect mother liquor, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 1- [the 3- tert-butyl groups -5- (1,2- dihydroxy ethyl) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide 113 (10 mg, white solid), yield： 18.0%.
MS m/z (ESI): 499.2 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 7.87 (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) embodiments 114
2- [the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1, Γ-the isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetylphenyl] -2- rnethyl-propanoic acid hydrobromates
The first step
2- (3- acetyl group -5- tbutyl-phenyls) -2- methvl-propionic acid methyl estes are by 1- (the bromo- 5- tbutyl-phenyls of 3-) ethyl ketone 77d (4.27 g, 17 mmol), double (dibenzalacetone) palladium (96 mg, 0.17 mmol) and zinc fluoride (866 mg, 8.37 mmol) it is dissolved in 40 mL N, in dinethylformamide, add small (trimethylsiloxy group) propylene (4.35 g of 1- methoxyl group -2- methyl, 25 mmol) and tri-butyl phosphine (1.69 g, 0.84 mmol), 100 °C of lower stirring reactions 16 hours.50 mL water are added into reaction solution; it is extracted with ethyl acetate (50 mLx3); merge organic phase; anhydrous magnesium sulfate is dried; filtering; filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- (the 3- acetyl group -5- tert-butyl groups -
Phenyl) -2- methvl-propionic acid methyl estes 114a (1.68 g, pale tan oil), yield： 36.2%.
Second step
2- [3- (2- acetyl bromides) -5- tbutyl-phenyls] -2- methvl-propionic acid methyl estes are by 2- (3- acetyl group -5- tbutyl-phenyls) -2- methvl-propionic acid methyl estes 114a (276 mg; 1 mmol) it is dissolved in 5 mL tetrahydrofurans; add phenyltrimethylammonium bromide (376 mg; 1 mmol), stirring reaction 1 hour.Filtering; filter cake is washed (10 mL) with ethyl acetate; merge organic phase; Jian Ya Nong Shrink; with thin-layer chromatography chromatography with solvent system B purify gained residue; obtain title product 2- [3- (2- acetyl bromides) -5- tbutyl-phenyls] -2- methvl-propionic acid methyl este 114b C154 mg, light yellow liquid), yield： 43.4%.
3rd step
2- [the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetyl group] phenyl] -2- rnethyl-propanoic acid hydrobromates
By 5'; fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7-; 3'- isoindolines]-Γ-imines 41g (92 mg; 0.35 mmol) it is dissolved in 3 mL tetrahydrofurans; add 2- [3- (2- acetyl bromides) -5- tbutyl-phenyls] -2- methyl-methyl propionate 114b (124 mg; 0.35 mmol) and triethylamine (0.5 mL, 0.35 mmol), stirring reaction 8 hours.Reaction solution Jian Ya Nong Shrink, purified with silica gel column chromatography with eluant, eluent system A, obtain title product 2- [the 3- tert-butyl groups -5- [2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-）Acetyl group] phenyl] -2- rnethyl-propanoic acids hydrobromate 114 (13 mg, yellow solid), yield： 6.2%.
MS m/z (ESI): 525.2 [M+l]
1H NMR (400 MHz, DMSO-J6, ppm):δ 10.98 (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
L- [the 3- tert-butyl groups -5- (2- hydroxyls -1,1- dimethyl-ethyI) phenyl] -2- (fluoro- 3'- imino groups-spiral shells of 5', 6'- diethoxy -4'-
[ring '-different I diindyls quinoline] -2'- bases) ethanone hydrobromide
The first step
2- [the 3- tert-butyl groups -5- (1; 1- dimethoxy-ethyls) phenyl] -2- methvl-propionic acid methyl estes are by 2- (3- acetyl group -5- tbutyl-phenyls) -2- methvl-propionic acid methyl estes 114a (600 mg; 2.17 mmol) it is dissolved in 5 mL methanol; add trimethoxy-methane (714 uL; 6.51 mmol) and camphorsulfonic acid (50 mg; 0.22 mmol), stirring reaction 3 hours.50 mL water and 40 mg potassium carbonate are added into reaction solution, it is extracted with ethyl acetate (30 mLx3), merge organic phase, washed with saturated nacl aqueous solution (100 mLx2), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain crude title product 2- [the 3- tert-butyl groups -5- (1,1- dimethoxy-ethyls) phenyl] -2- methvl-propionic acid methyl estes 115a (676 mg, brownish red grease), product is not purified directly to carry out next step reaction.
Second step
1- [the 3- tert-butyl groups -5- (2- hydroxyl-U- dimethyl-ethyIs) phenyl] ethyl ketones are by crude product 2- [the 3- tert-butyl groups -5- (1,1- dimethoxy-ethyls) phenyl] -2- methvl-propionic acid methyl estes 115a (670 mg, 2.08 mmol) it is dissolved in 5 mL tetrahydrofurans, under ice bath, add Li-Al hydrogen (87 mg, 2.29 mmol), stirring reaction 10 minutes.50 mL water are added into reaction solution, it is extracted with ethyl acetate (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (100 mLx2), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, add the dioxane solution of 4 mL1.60 M hydrogen chloride, stirring reaction 5 minutes.50 mL water are added into reaction solution, it is extracted with ethyl acetate (30 mLx3), merge organic phase, washed with saturated nacl aqueous solution (100 mLx2), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain crude title product 1- [the 3- tert-butyl groups -5- (2- hydroxyls -1,1- dimethyl-ethyIs) phenyl] ethyl ketone 115b (471 mg, brownish red grease), product is not purified directly to carry out next step reaction.
3rd step
Small [the 3- tert-butyl groups -5- (2- hydroxyl-U- dimethyl-ethyIs) phenyl] ethyl ketone of 2- bromines is by crude product 1- [the 3- tert-butyl groups -5- (2- hydroxyls -1,1- dimethyl-ethyIs) phenyl] ethyl ketone 115b (471 mg, 1.90 mmol) it is dissolved in 10 mL tetrahydrofurans, add phenyltrimethylammonium bromide (713 mg, 1.90 mmol), stirring reaction 0.5 hour.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain the bromo- 1- of title product 2- [the 3- tert-butyl groups -5- (2- hydroxyl-U- dimethyl-ethyIs) phenyl] ethyl ketone 115c (170 mg, light yellow liquid), yield： 27.4%.
MS m/z (ESI): 327.0 [M+l]
4th step
L- [the 3- tert-butyl groups -5- (2- hydroxyls -1, 1- dimethyl-ethyIs) phenyl] -2- (5', the fluoro- 3'- imino groups-spiral shell [cyclopropane -1 of 6'- diethoxies -4'-, 1'- isoindolines] -2'- bases) ethanone hydrobromide is by 5', fluoro- spiral shell [the cyclopropane -1 of 6'- diethoxies -7'-, 3'- isoindolines]-Γ-imines 41g (120 mg, 0.46 mmol) it is dissolved in 1 mL tetrahydrofurans, add 2- bromo- 1- [the 3- tert-butyl groups -5- (2- hydroxyls -1, 1- dimethyl-ethyIs) phenyl] ethyl ketone 115c (164 mg, 0.50 mmol), stirring reaction 12 hours.Filtering, filter cake is washed (l mL) with tetrahydrofuran, is dried in vacuo, is obtained title product 1- [the 3- tert-butyl groups -5- (2- hydroxyl-U- dimethyl-ethyIs）Phenyl] -2- (fluoro- 3'- imino groups-spiral shell [cyclopropane -1,1'- isoindoline] -2'- bases of 5', 6'- diethoxy -4'-) ethanone hydrobromide 115 (190 mg, white solid), yield： 70.6%.
MS m/z (ESI): 511.2 [M+l]
1H NMR (400 MHz, DMSO- , ppm):δ 9.41 (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：
The calcium ion transport Inhibition test of biological assessment example 1
Following methods can be used to determine inhibitory action of the compounds of this invention to the PARI calcium ion transports mediated.Shanghai Inst. of Life Science, CAS cell resource center (is purchased from by using Chinese hamster ovary cell CHO-K1, catalog number (Cat.No.) GNHa 7), Fluo-4 NW calcium assay kit (invitrogen Cat. No F36206) standing grain mouthful PARI excitement polypeptide thrombin receptor activator peptide 6 (Sigma, T1573-5MG) determine influence of the invention compound to the PARI calcium ion transports mediated.
Probenecid storing solution (probenecid stock solution) and sample-loading buffer (loading buffer) needed for experiment can be prepared according to Fluo-4 NW calcium assay kit kit specifications.Experimental procedure：
CHO-K1 cells are equipped with 10% hyclone with DEME culture mediums (Gibco) and are used as complete medium, and with 25, the concentration of 000 cells/well is inoculated into 96 porocyte culture plates cultivates until converging under 37 °C, 5% carbon dioxide conditions.Culture medium then is discarded, the loading buffer that 100 μ have been configured are added into each hole of culture plate, is incubated 45 minutes under 37 °C, 5 % carbon dioxide conditions.Test compound is dissolved with dimethyl sulfoxide first, then with analysis buffer (assay buffer) (；HBSS containing IX, 20mM HEPES, 2.5mM probenecid) it is diluted to concentration needed for experiment.Then to the test compound sample added in each hole of test group on 96 orifice plates after lOOuL dilutions, negative control group adds the assay buffer of equal volume.Culture plate is then incubated 30 minutes at room temperature, then to adding the exciting polypeptide 6 (thrombin receptor activator peptide 6) of thrombin receptor that 25 μ are diluted to 20 μ Μ with buffer (IX HBSS, 20mM HEPES) in each hole.
The relative intensity of fluorescence in each hole is determined under the nm of excitation wavelength 485, the nm of launch wavelength 525, inhibiting rate of the compound to the PARI calcium ion transports mediated is calculated.
Test compound is calculated PARI inhibiting rate as follows：
FNC:The fluorescence intensity in negative control group hole
FTC:The fluorescence intensity in test compound hole
The half-inhibition concentration IC of test compound5QIt can be calculated by the inhibiting rate under various concentrations.
90 0.01
93 0.013
96 0.033
97 0.035
100 0.058
101 0.077
102 0.038
103 0.046
104 0.03
108 0.029
109 0.042
115 0.025
116 0.003
120 0.014 conclusions：The numerical value of the calcium current inhibiting rate of test compound of the present invention is 0.006 0.099 μ Μ, and the compounds of this invention has obvious inhibitory action to the PARI calcium ion transports mediated.The ex vivo platelet aggregation of example 2 is tested
Following methods can be used to determine inhibitory activity of the compounds of this invention to platelet aggregation.Experimental method is summarized as follows：
With ACD as anti-coagulants, whole blood sample is obtained with the Chinese cavy (being purchased from the g of Shanghai Sheng Wang experimental animals plant X body weight 450 600) of the male of venipuncture mode from health.Then obtained within 20 minutes with 200 X g centrifugations at room temperature and be rich in hematoblastic blood plasma.Blood plasma centrifugation is then obtained into pellet platelets in 10 minutes with 800 X g speed.(contain 140 mM NaCl, 2.7 mM KC1,12 mM NaHC0 with tyrode's solution Tyrode's buffer3, 0.76 mM NaHP04,5.5 mM Glucose, 5 mM HEPES, 2 mg/mL bovine serum albumin, and pH 7.4,20
Apyrase it is suspended and pellet platelets and calculates again after) washing twice, is finally diluted to 2 3x l08Individual/mL is standby.
Aggegation experiment is carried out at ambient temperature.First added into each hole of 96 orifice plates 90, thrombocyte suspension.After concentration needed for the dissolving of test compound dimethyl sulfoxide is configured to test, added into each test group hole 8, compound, negative control group is replaced with the DMSO of same volume.Compound and blood platelet were in 37 °C of lower precincubation 6 minutes, then to adding 2 μ in each hole, the 20 μ Μ exciting peptide T RAP of fibrin ferment, by 96 holes as acutely concussion starts aggegation process on shaking table.Aggegation rate is counted to get by determining the light transmittance in each hole under 405 nm.The agglutinate rate of blood platelet of test compound is calculated as follows：
AR = (Tc -T0)/(T100-T0)
Tc:The light transmittance in test compound hole
TO:The light transmittance of negative control hole
T100:The blood platelet of the light transmittance compound of blank well suppresses aggegation IC5QValue can be calculated by the aggegation rate under various concentrations and obtained.
Conclusion：Test compound of the present invention has obvious inhibitory action to guinea pig platelets aggegation.The pharmacokinetics test of the compounds of this invention of Pharmacokinetic Evaluation test case 1
1st, make a summary
Study after the embodiment of the present invention 24,35,40,44 and 108 compounds drug concentration not in the same time in blood plasma.Pharmacokinetics behavior of the compounds of this invention in rat body is studied, its characteristics of pharmacokinetics is evaluated.
2nd, testing program
2.1 test drug
Embodiment 24,35,40,44 and 108 compounds
2.2 experimental animal
Healthy adult SD rat 20, male and female half and half are divided into 5 groups, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal productiong licensing number：SCXK (Shanghai） 2008-0016.
2.3 medicines are prepared
Appropriate amount of drug is weighed, 0.5% sodium carboxymethylcellulose of addition is ground to sample and is uniformly suspended, sample concentration is that used time preparation is faced in 2.0 mg/mL reservations.
2.4 administration
SD Rat Fasts distinguish gastric infusion after staying overnight, dosage is that 20.0 mg/kg retain（In terms of alkali original shape), the mL/kg of administered volume 10.
2.5 sample collection
Each group animal is respectively at before administration and 1.0,2.0,3.0,4.0,6.0 after administration, 8.0,12.0,24.0,36.0,48.0 hour, by eye socket 0.1 mL of blood sampling, is placed in heparinised tubes, 3500 leave preservation under 10 minutes separated plasmas of the heart, -20 °C.Feed within 2 hours after administration.
3. operation
Each 20 L of rat plasma at each moment after medicine is drawn, adding inner mark solution, (100 ng/mL, methanol is prepared） 50
μ, the μ L of methanol 95, vortex mixed 3 minutes centrifuge 10 minutes (13500 revs/min), take the μ L of supernatant 10 to carry out LC-MS/MS analyses.Main pharmacokinetic parameter is calculated using the softwares of DAS 2.0.
4th, pharmacokinetic parameter result
The pharmacokinetic parameter of the compounds of this invention such as following table:
Conclusion：The compound that the present invention is tested blood concentration and exposure level in rat body is higher, with obvious pharmacokinetic advantage.Efficacy testing
Experiment purpose：
Determine the effect for the guinea pig platelets PAR that the compound of PAR-1 inhibitor embodiment 44 is induced TARP.Experimental drug：
The compound of embodiment 44；Prostaglandin I2, TRAP provides by Sigma companies.
Experimental method：
Drug dose is 50 mg/kg (2.5ml/kg), suspension is made in the Tween-80 for adding 5% with 0.5% sodium carboxymethylcellulose, take the g of 250 g of male guinea pig body weight 350, random packet, gastric infusion, put back to former cage after 2 hours, was anaesthetized with 20% urethane, cavy abdominal aortic blood uses disposable plastic injector, includes 3.8% sodium citrate（1 :10 volumes, a citric acid and nine parts of blood anticoagulants).
The preparation of platelet rich plasma：After the abdominal aorta blood of cavy is centrifuged 10 minutes with 200 g rotating speeds (22 °C), the mL of platelet rich plasma 1.5 on upper strata is taken out.
Hematoblastic washing method：With Tyrode's buffer ' solution (NaCl 129 mM, KC1 2.8 mM, KH2P040.8 mM, MgCl20.8 mM, NaHC03The mM of 8.9 mM, HEPEs 10 mM, glucose 5.5).
Platelet aggregation test：Determined with platelet aggregation instrument, platelet buffer 291 is added in transparent plastic cuvette, 3 buffer solutions and 6 calcium chloride are added in cuvette（50 μ Μ), add magnetic stirring apparatus pre- incubate in 37 °C and bathe 2 minutes, then add 40 μ Μ platelet aggregation TRAP, carry out assembling rate of change in continuous detection 5min（1 minute, 3 minutes, 5 minutes, maximum aggregation rate）, to evaluate medicine to inhibition on platelet aggregation.Experimental result：
Platelet aggregation has very strong inhibitory action in the cavy that induces TRAP of the compound of embodiment 44 5 minutes, is compared with blank control group, the compound of embodiment 85（10 mg/kg) assembled the amplitude of percentage reduction at 3 minutes, 5 minutes for 47.47% and 45.21% (P<0.05, P<0.05);The amplitude that SHR130362 (30 mg/kg) assembles percentage reduction at 3 minutes and 5 minutes is 57.63% and 48.57% (P<0.05, P<0.05);The amplitude that SHR130362 (50 mg/kg) assembled percentage reduction at 1 minute, 3 minutes and 5 minutes is 69.96%, 82.55% and 78.51% (P<0.05, P<0.001, P<0.001).Therefore, the compound of embodiment 44 has preferably blood coagulation resisting function.
Claims (1)
- Claims：1st, a kind of formula（I compound or its pharmaceutically useful salt shown in),( I )Wherein：Ar is selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further by one or more RaSubstituent replaced；Y is selected from-CR12- or N atoms；L is selected from-CR13R14- or-(CH2) m -;R R2And R3It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17Or-C (0) NR16R17Substituent replaced；R1And R2Or R2And R3Aryl is formed together with the carbon atom being connected, wherein described aryl is optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；R4And R5Cyano group, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；Or, R4And R5Cycloalkyl is formed together with the carbon atom being connected, wherein described cycloalkyl is optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical or-NR by one or more16R17Substituent replaced；R6Selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl ,-C (0) OR15、 -C(0)R15Or-C (0) NR16R17, wherein described alkyl, alkoxy, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl or heterocyclic radical；RaHydrogen atom, hydroxyl, halogen, cyano group, nitro, silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR can be each independently selected from identical or different15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR by one or more15、 -OC(0)R15 -0(CH2)nC(0)OR15 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；R12Selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；R13And R14Alkyl or halogen are each independently selected from, wherein described alkyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group or nitro；R15Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group, nitro, alkoxy or alkyl；R16And R17Hydrogen atom, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；Or, R16And R17Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalpHetero atom, and the heterocyclic radical is optionally further by one or more halogens, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19 Substituent replaced；R18And R19It is each independently selected from 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;AndP is selected from 0,1 or 2.2nd, a kind of formula（Compound or its pharmaceutically useful salt shown in Π),Its towel:Y is selected from-CR12- or N atoms；L is selected from-CR13R14- or-(CH2) m -;I 1、 R2And R3It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17Or-C (0) NR16R17Substituent replaced；R1And R2Or R2And R3Aryl is formed together with the carbon atom being connected, wherein described aryl is optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；R4And R5Cyano group, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；Or, R4And R5Cycloalkyl is formed together with the carbon atom being connected, wherein described cycloalkyl is optional Further halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical or-NR are selected from by one or more16R17Substituent replaced；R6Selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl ,-C (0) OR15、 -C(0)R15Or-C (0) NR16R17, wherein described alkyl, alkoxy, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl or heterocyclic radical；R7、 R8、 R9、 R1QAnd R11It is each independently selected from hydrogen atom, hydroxyl, halogen, cyano group, nitro, silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR by one or more15、 -OC(0)R15 -0(CH2)nC(0)OR15 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；Or, R9And R1QHeterocyclic radical, aryl or heteroaryl are formed together with the carbon atom being connected, wherein described heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, silylation, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15, -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；R12Selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, alkenyl, block base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17, wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；R13And R14Alkyl or halogen are each independently selected from, wherein described alkyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group or nitro；R15Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group, nitro, alkoxy or alkyl；R16And R17Hydrogen atom, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl optionally enter One step is selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；Or, R16And R17Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalpHetero atom, and the heterocyclic radical is optionally further by one or more halogens, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；R18And R19It is each independently selected from 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;AndP is selected from 0,1 or 2.3rd, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), wherein Ar are selected from 5 yuan or 6 unit's heteroaryls, preferably pyrrole radicals or pyridine radicals.4th, formula according to claim 1（I compound or its pharmaceutically useful salt, wherein R shown in)4And R5Selected from alkyl or aryl.5th, formula according to claim 1（I compound or its pharmaceutically useful salt, wherein R shown in)4And R5Cyclopropyl is formed together with the carbon atom being connected.6th, formula according to claim 1（I compound or its pharmaceutically useful salt, wherein R shown in)6For hydrogen atom.7th, formula according to claim 1（I compound or its pharmaceutically useful salt, wherein R shown in)12Selected from hydrogen atom or halogen.8th, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), wherein L are selected from-(CH2)m-, m is 1.9th, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), wherein compound are selected from：OSSC.0/llOZN3/X3d 9ε60 /ΐΐΟΖ OAVOSSC.0/llOZN3/X3d 9ε60 /ΐΐΟΖ OAV 90ZOSSC.0/llOZN3/X3d 9ε60 /ΐΐΟΖ OAV20710th, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), its formula of (I) compound exists in the form of free state or pharmaceutically useful acid-addition salts, the acid-addition salts include hydrochloride, hydrobromate, mesylate, sulfate, phosphate, maleate, malate, citrate, acetate or trifluoroacetate, preferably hydrobromate and hydrochloride. 11st, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), the salt of the wherein compound are selected from：OilOSSC.0/llOZN3/X3d 9ε60 /ΐΐΟΖ OAV21112nd, one kind prepares formula（I the method for compound shown in), this method includes:By formula（IA) compound or IB) compoundIt is anti-with formula (IC) compound(IC)Its towel：X is selected from halogen, preferably chlorine atom or bromine atoms；Wherein： L、 Y、 ^〜11Definition as described in claim 18c13rd, a kind of formula（IA) or（IB compound or its pharmaceutically useful salt shown in), it is as preparing formula（I) the intermediate of compound,(IA) (IB)Wherein, R1 、 R2、 R3With Y as defined in claim 1；R4And R5It is each independently selected from cyano group, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, preferably alkyl or aryl, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR16R17、 -OC(0)NR16R17、 -C(0)NR16R17Or-S (0) ONR16R17Substituent replaced；Or, R4And R5Cycloalkyl, preferably cyclopropyl are formed together with the carbon atom being connected, wherein described cycloalkyl is optionally further selected from halogen, hydroxyl, nitro, cyano group, alkyl, alcoxyl by one or more Base, cycloalkyl, heterocyclic radical or-NR16R17Substituent replaced；R6Selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl ,-C (0) OR15、 -C(0)R15Or-C (0) NR16R17Preferably hydrogen atom, is further replaced wherein described alkyl, alkoxy, cycloalkyl, aryl or heteroaryl are optional by one or more substituents selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxy, cycloalkyl or heterocyclic radical.R15Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano group, nitro, alkoxy or alkyl；R16And R17Hydrogen atom, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；Or, R16And R17Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalpHetero atom, and the heterocyclic radical is optionally further by one or more halogens, hydroxyl, cyano group, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, hydroxyalkyl ,-C (0) OR15、 -OC(0)R15、 -0(CH2)nC(0)OR15、 -(CH2)nC(0)OR15、 -C(0)R15、 -NHC(0)R15、 -S(0)pR15、 -NR18R19、 -OC(0)NR18R19、 -C(0)NR18R19Or-S (0) ONR18R19Substituent replaced；R18And R19It is each independently selected from hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；N is selected from 1,2 or 3;AndP is selected from 0,1 or 2.14th, formula according to claim 12（IA) or（IB compound or its pharmaceutically useful salt shown in), wherein compound are selected from：Kind prepare formula (；IA) or (；The method of IB compounds, this method includes: By formula（III) compound is reacted in the presence of a catalyst with cuprous cyanide, obtains formula（IA) or（IB) compound；Wherein described catalyst is preferably Or, by formula（IV) compound dative obtains formula（IA) or（IB) compound;(V)Or, by formula（V) compound is reacted with concentrated ammonia liquor, obtains formula（IA) or（IB) compound;(VI)Or, by formula（VI) compound is reacted in water, obtains formula（ 1 ）Or（IB) compound, wherein R1 、 R2、 R3 、 R4 、 R5With Y as defined in claim 1.16th, a kind of pharmaceutical composition, described pharmaceutical composition contains the formula according to claim 1 for the treatment of effective dose（I compound or its pharmaceutically useful salt and pharmaceutically useful carrier shown in).17th, formula as claimed in claim 1（I compound or its pharmaceutically useful salt shown in), or purposes of the pharmaceutical composition as claimed in claim 13 in calcium ion transport inhibitor is prepared.18th, compound as claimed in claim 1 or its pharmaceutically useful salt, or pharmaceutical composition purposes in thrombin receptor antagonist is prepared as claimed in claim 15.19th, purposes according to claim 18, wherein thrombin receptor antagonist are PARI receptor antagonists Agent.20th, formula as claimed in claim 1（I compound or its pharmaceutically useful salt shown in), or purposes of the pharmaceutical composition in platelet aggregation inhibitor is prepared as claimed in claim 13.21st, formula as claimed in claim 1（I compound or its pharmaceutically useful salt shown in), or purposes of the pharmaceutical composition in inhibitors of smooth muscle cell proliferation is prepared as claimed in claim 13.22nd, formula as claimed in claim 1（I compound or its pharmaceutically useful salt shown in), or purposes of the pharmaceutical composition as claimed in claim 15 in the medicine for preparing the treatment disease relevant with thrombin receptor.23rd, purposes according to claim 22, wherein the disease relevant with thrombin receptor is selected from DVT, reangiostenosis, deep vein thrombosis, pulmonary embolism disease, cerebral infarction, heart disease, sowing property vessel inner blood solidification syndrome, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.
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| CN201010171635XA CN102241621A (en) | 2010-05-11 | 2010-05-11 | 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof |
| CN201010171635.X | 2010-05-11 | ||
| PCT/CN2011/073550 WO2011140936A1 (en) | 2010-05-11 | 2011-04-29 | 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof |
| CN201180002959.3A CN102471264B (en) | 2010-05-11 | 2011-04-29 | 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof |
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| CN201180002959.3A Expired - Fee Related CN102471264B (en) | 2010-05-11 | 2011-04-29 | 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof |
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| CN116003309A (en) * | 2022-08-12 | 2023-04-25 | 深圳微芯生物科技股份有限公司 | Hydrazide compound, preparation method and application thereof |
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| CN103554120B (en) * | 2013-10-16 | 2015-06-24 | 华东师范大学 | Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound |
| CN103554121B (en) * | 2013-10-16 | 2015-06-24 | 华东师范大学 | 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof |
| EP3102576B8 (en) | 2014-02-03 | 2019-06-19 | Vitae Pharmaceuticals, LLC | Dihydropyrrolopyridine inhibitors of ror-gamma |
| CN104086503B (en) * | 2014-07-23 | 2015-10-14 | 张远强 | PAR-1 antagonist and uses thereof |
| CN104072437B (en) * | 2014-07-23 | 2015-10-14 | 张远强 | Disubstituted tetrazole acetophenone compound, Preparation Method And The Use |
| CN104086500B (en) * | 2014-07-23 | 2015-08-26 | 张远强 | A kind of PAR-1 antagonist and uses thereof |
| CN104072435B (en) * | 2014-07-23 | 2015-11-04 | 张远强 | The tetrazole acetophenone compound that two alkyl replaces and purposes |
| CN104072434B (en) * | 2014-07-23 | 2015-12-02 | 张远强 | Between position replace tetrazole acetophenone compound, Preparation Method And The Use |
| PT3207043T (en) | 2014-10-14 | 2019-03-25 | Vitae Pharmaceuticals Llc | Dihydropyrrolopyridine inhibitors of ror-gamma |
| US9663515B2 (en) | 2014-11-05 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9845308B2 (en) | 2014-11-05 | 2017-12-19 | Vitae Pharmaceuticals, Inc. | Isoindoline inhibitors of ROR-gamma |
| CA2988147C (en) | 2015-06-03 | 2023-06-13 | Bristol-Myers Squibb Company | 4-hydroxy-3-(heteroaryl)pyridine-2-one apj agonists for use in the treatment of cardiovascular disorders |
| US10301261B2 (en) | 2015-08-05 | 2019-05-28 | Vitae Pharmaceuticals, Llc | Substituted indoles as modulators of ROR-gamma |
| MA53943A (en) | 2015-11-20 | 2021-08-25 | Vitae Pharmaceuticals Llc | ROR-GAMMA MODULATORS |
| WO2017108737A1 (en) | 2015-12-23 | 2017-06-29 | Chiesi Farmaceutici S.P.A. | 1-(3-tert-butyl-phenyl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro- naphthalen-1-yl)-urea derivatives and their use as p38 mapk inhibitors |
| TW202220968A (en) | 2016-01-29 | 2022-06-01 | 美商維它藥物有限責任公司 | Modulators of ror-gamma |
| US9481674B1 (en) | 2016-06-10 | 2016-11-01 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| WO2019018975A1 (en) | 2017-07-24 | 2019-01-31 | Vitae Pharmaceuticals, Inc. | Inhibitors of ror gamma |
| AU2018307919B2 (en) | 2017-07-24 | 2022-12-01 | Vitae Pharmaceuticals, Llc | Inhibitors of RORϒ |
| CN111094300B (en) * | 2018-01-31 | 2022-09-16 | 江苏恒瑞医药股份有限公司 | Benzo-heteroaryl derivative, preparation method and application thereof in medicine |
| CN110256342B (en) * | 2019-07-16 | 2022-06-07 | 河南省科学院化学研究所有限公司 | Synthetic method of 2-cyano quinoline derivative |
| CN110698352B (en) * | 2019-10-29 | 2023-01-17 | 邢台学院 | Synthetic method of 3-bromo-5-aminocatechol dimethyl ether |
| WO2024046409A1 (en) * | 2022-08-31 | 2024-03-07 | 江苏恒瑞医药股份有限公司 | Heterocyclic compound, preparation method therefor, and pharmaceutical use thereof |
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| CN116003309A (en) * | 2022-08-12 | 2023-04-25 | 深圳微芯生物科技股份有限公司 | Hydrazide compound, preparation method and application thereof |
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| CN102241621A (en) | 2011-11-16 |
| CN102471264B (en) | 2014-04-02 |
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