CN108530302A - 2`, 3`- dihydro spiral shell [cyclopropane -1,1`- indenes] -2- amine derivatives and its preparation method and application - Google Patents
2`, 3`- dihydro spiral shell [cyclopropane -1,1`- indenes] -2- amine derivatives and its preparation method and application Download PDFInfo
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- CN108530302A CN108530302A CN201710128575.5A CN201710128575A CN108530302A CN 108530302 A CN108530302 A CN 108530302A CN 201710128575 A CN201710128575 A CN 201710128575A CN 108530302 A CN108530302 A CN 108530302A
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- 0 C*(Cc(cccc1)c1OC)=C Chemical compound C*(Cc(cccc1)c1OC)=C 0.000 description 14
- JDOPPTBYOJWOPT-UHFFFAOYSA-N CC(C)(C)Cc(ccc(OC)c1OC)c1N Chemical compound CC(C)(C)Cc(ccc(OC)c1OC)c1N JDOPPTBYOJWOPT-UHFFFAOYSA-N 0.000 description 1
- WIYSLLDNBMLEPM-UHFFFAOYSA-N CC(C)SCc(c(OC)c1)ccc1F Chemical compound CC(C)SCc(c(OC)c1)ccc1F WIYSLLDNBMLEPM-UHFFFAOYSA-N 0.000 description 1
- KSMVBYPXNKCPAJ-UHFFFAOYSA-N CC(CC1)CCC1N Chemical compound CC(CC1)CCC1N KSMVBYPXNKCPAJ-UHFFFAOYSA-N 0.000 description 1
- QXPLJUBIYJHRAB-UHFFFAOYSA-N CNCc(cccn1)c1OC Chemical compound CNCc(cccn1)c1OC QXPLJUBIYJHRAB-UHFFFAOYSA-N 0.000 description 1
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- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
- C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
Abstract
The invention belongs to pharmaceutical technology fields, disclose formula (I) 2', 3' dihydro spiral shell [cyclopropane 1,1' indenes] 2 amine derivatives and preparation method thereof, including：II is reacted through Witting, obtains III, and acetic acid rhodium catalysis ethyl diazoacetate obtains IV and V with III cyclopropanization reactions, hydrolyzes, and Curtius is reset, and obtains VI and VII, and (1) VI or VII take off Boc, and compound VIII or IX are obtained through reduction amination；Or (2) VI or VII replaces with 2 chlorine, 1 morpholino ethane, 1 ketone, obtains X or XI；Or (3) VI or VII and (4 oxocyclohexyl) t-butyl carbamate, through reduction amination, de- Boc obtains compound XII or XIII；Or (4) VI or VII and substituted aryl boric acid are coupled through Suzuki, de- Boc obtains XIV or XV, and VIII or IX are obtained through reduction amination.Formula (I) derivative of the present invention has preferable inhibitory activity to LSD1, while having preferable selectivity to homology enzymes such as monoamine oxidase and LSD2, is expected to develop into the medicine of the diseases such as acute myeloid leukemia.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of 2', and 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine derives
Object and its preparation method and application, it is alternatively that property LSD1 inhibitor can be used for preparing treatment acute myeloid leukemia drug.
Background technology
Acute myeloid leukaemia (AML) is the heterogeneous malignant tumour occurred in hematopoietic tissue, in marrow and peripheral blood
Original and inmature marrow cell paraplasm is main feature, clinical manifestation is anaemia, bleeding, infection and fever, internal organs infiltrate,
Metabolic disorder etc., the majority of cases state of an illness is suddenly heavy, and prognosis is dangerous, and being such as not treated in time often can threat to life.The illness rate of AML is every
100000 people 3.8, increase to every 100,000 people 17.9 in the adult of over-65s.The standard care example of AML is more than 40
Year-end drawdown level is little, relies on conventional cytotoxic drug, and by " induction " the chemotherapy inducer remission in 1-2 periods, induction includes anthracene
The combination of ring class and cytarabine.Some research approaches have had been incorporated into the third reagent, most commonly thioguanine or according to
Support pool glycosides, but without apparent overall survival advantage.AML type chemotherapy carries substantial toxic feature, most significantly serious
Bone marrow toxicity.
Pass through the research to AML molecular biology in recent years, it was found that new drug target, lysine specificity demethyl
Change enzyme 1 (LSD1).LSD1 is first histone demethylase that 2004 Nian Shi poplars seminars determine, by 852 amino acid
Composition, sequential structure show to form three structural domains：N-terminal SWlRM (Swi3p, Rsc8p and Moira) structural domain, the oxidation of C-terminal amine
The Tower structural domains of enzyme (Amine oxidase like, AOL) structural domain and centralized positioning.LSD1 is the amino oxygen that FAD is relied on
Change enzyme family member, can specificity removal H3K4 and H3K9 single, double methyl, to adjust the mutual of histone and other albumen
Effect, and the processes such as activation, inhibition and x chromosome inactivation for influencing genetic transcription.
LSD1 has been reported as the potential pharmacological target in acute myeloid leukaemia.Research finds LSD1 90.4%
It is overexpressed in the marrow of acute myelogenous leukemia (AML) case and the case of all intractable AML, and only 4.7%
Case complete incidence graph.The mouse model of user's MLL-AF9 leukaemia, Harris etc. prove LSD1 as in MLL leukaemia
Break up the crucial effector blocked, promote the maintenance of LSC (Leukemic stemcells) dryness, while it being inhibited to break up and wither
It dies.It is handled respectively using SiRNA and LSD1 inhibitor, can significantly lower LSD1 levels, the monocyte in LSC can be promoted
To macrophage differentiation, the generation for an one-step inducing apoptosis of going forward side by side, to play effect (the Harris WJet for inhibiting AML
al.CancerCell,2012,21(4):473-487).Binda etc. reports mouse acute promyelocytic leukemia (APL) cell
It is more sensitive to LSD1 inhibitor, and describe LSD1 inhibitor and act synergistically on the induction of APL cells with Vitamin-A Acid (ATRA)
Candidate stem cell breaks up and reduces tumor cell migration (BindaC etal.J.Am.Chem.Soc, 2010,132 (19):6827-
6833)。
The small molecule LSD1 inhibitor studied at present mainly include anti-phenyl cyclopropylamine class, polyamines class, pyrimidine-Thiourea,
Benzoyl hydrazine, miazines.Wherein phenyl cyclopropylamine is a kind of inhibitor of most study, has the drawback that inhibitory activity
It is low, it is bad to the selectivity of the homology enzymes such as monoamine oxidase and LSD2.
The present invention is improved existing inhibitor, using phenyl cyclopropylamine as parent, by conformation limitation and structural modification,
It is proposed a kind of structure novel, it is high to LSD1 inhibitory activity, and to the novel inhibitors of LSD1 homology enzyme high selectivities.
Invention content
The present invention provides a kind of 2' of structure novel, 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives and its
Preparation method, including：It is reacted through Witting using II as raw material, obtains III, acetic acid rhodium catalysis ethyl diazoacetate and III rings third
Alkylation reaction obtains IV and V, and hydrolysis, Curtius is reset, and obtains VI and VII, and (1) VI or VII take off Boc, are obtained through reduction amination
Compound VIII or IX；Or the chloro- 1- morpholinoes ethane -1- ketone of (2) VI or VII and 2- replaces, and obtains X or XI；Or (3) VI
Or VII and (4- oxocyclohexyls) t-butyl carbamate, through reduction amination, de- Boc obtains compound XII or XIII；Or (4)
VI or VII and substituted aryl boric acid are coupled through Suzuki, and de- Boc obtains XIV or XV, and VIII or IX are obtained through reduction amination.
Alternatively property LSD1 inhibitor can be used for 2' prepared by the present invention, 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives
Prepare treatment acute myeloid leukemia drug.
The 2' of the present invention, 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives, shown in structure such as following formula (I)：
Wherein, R1Selected from hydrogen, halogen, aryl, substituted aryl, heterocycle, substituted heterocycle；
R2Selected from hydrogen, alkyl-substituted aryl, methoxyl group and alkyl-substituted aryl, halogen and alkyl-substituted aryl,
Halogen, methoxyl group and alkyl-substituted aryl, alkyl-substituted hetero-aromatic ring, methoxyl group and alkyl-substituted hetero-aromatic ring, halogen and
Alkyl-substituted hetero-aromatic ring, cyclohexylamine, 1- morpholine substituted alkyl -1- ketone.
Preferably, R1Selected from hydrogen, halogen, phenyl, the phenyl of halogen substitution, the alkyl-substituted phenyl of C1~C10, C1~
The alkyl-substituted five-ring heterocycles of C10, the alkyl-substituted hexa-member heterocycles of C1~C10；
R2Selected from hydrogen, the alkyl-substituted phenyl of C1~C10, methoxyl group and the alkyl-substituted phenyl of C1~C10, halogen and C1
The alkyl-substituted phenyl of~C10, halogen, methoxyl group and the alkyl-substituted phenyl of C1~C10, alkyl-substituted five yuan of C1~C10
Heterocycle, the alkyl-substituted hexa-member heterocycles of C1~C10, methoxyl group and the alkyl-substituted five-ring heterocycles of C1~C10, methoxyl group and C1~
The alkyl-substituted hexa-member heterocycles of C10, halogen and the alkyl-substituted five-ring heterocycles of C1~C10, halogen and C1~C10 are alkyl-substituted
Hexa-member heterocycle, cyclohexylamine, 1- morpholine substituted alkyl -1- ketone.Wherein, described five yuan/six former heterocycles are the heterocycle containing N, O, S.
Preferably, R1Selected from hydrogen, bromine, phenyl, 4- fluorophenyls；
R2For hydrogen or following group：
It is further preferred that 2' of the present invention, 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- aminated compounds is selected from：
(1) (anti-) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(2) (suitable) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(3) (anti-)-N- (pyridine -3- methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(4) (suitable)-N- (pyridine -3- methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(5) (anti-)-N- ((2- methoxypyridine -3- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(6) (suitable)-N- ((2- methoxypyridine -3- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(7) (anti-)-N- ((2- fluorine pyridin-3-yl) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(8) (suitable)-N- ((2- fluorine pyridin-3-yl) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(9) (anti-)-N- ((3- fluorine pyridine -2- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(10) (suitable)-N- ((3- fluorine pyridine -2- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(11) (anti-)-N- benzyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(12) (suitable)-N- benzyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(13) (anti-)-N- (2- methoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(14) (suitable)-N- (2- methoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(15) (anti-)-N- (2- luorobenzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(16) (suitable)-N- (2- luorobenzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(17) (anti-)-N- (the bromo- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(18) (suitable)-N- (bromo- 2- methoxy-benzyls -2', the 3'- dihydro spiral shells of 5- [cyclopropane -1,1'- indenes] -2- amine
(19) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(20) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(21) (anti-)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(22) (suitable)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(23) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 4-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(24) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 4-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(25) (anti-)-N- (3,4- dimethoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(26) (suitable)-N- (3,4- dimethoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(27) (anti-)-N-2- ((2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) amino) -1- morpholinoes ethane -
1- ketone
(28) (suitable)-N-2- ((2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) amino) -1- morpholinoes ethane -
1- ketone
(29) (anti-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(30) (suitable) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(31) (anti-) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(32) (suitable) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(33) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -
2- amine
(34) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -
2- amine
(35) (anti-)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -5'- phenyl -2', 3'- dihydro spiral shells [cyclopropane -1,1'-
Indenes] -2- amine
(36) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,
1'- indenes] -2- amine
(37) (anti-)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers
1)
(38) (anti-)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers
2)
(39) (suitable)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers
3)
(40) (suitable)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers
4)。
The present invention also provides a kind of 2', the preparation method of 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives,
Shown in the method such as following formulas (A)：
Reaction equation (A)
Wherein, R1Selected from hydrogen, halogen, aryl, substituted aryl, heterocycle, substituted heterocycle；
R2Selected from hydrogen, alkyl-substituted aryl, methoxyl group and alkyl-substituted aryl, halogen and alkyl-substituted aryl,
Halogen, methoxyl group and alkyl-substituted aryl, alkyl-substituted hetero-aromatic ring, methoxyl group and alkyl-substituted hetero-aromatic ring, halogen and
Alkyl-substituted hetero-aromatic ring, cyclohexylamine, 1- morpholine substituted alkyl -1- ketone.
Preferably, R1Selected from hydrogen, halogen, phenyl, the phenyl of halogen substitution, the alkyl-substituted phenyl of C1~C10, C1~
The alkyl-substituted five-ring heterocycles of C10, the alkyl-substituted hexa-member heterocycles of C1~C10；
R2Selected from hydrogen, the alkyl-substituted phenyl of C1~C10, methoxyl group and the alkyl-substituted phenyl of C1~C10, halogen and C1
The alkyl-substituted phenyl of~C10, halogen, methoxyl group and the alkyl-substituted phenyl of C1~C10, alkyl-substituted five yuan of C1~C10
Heterocycle, the alkyl-substituted hexa-member heterocycles of C1~C10, methoxyl group and the alkyl-substituted five-ring heterocycles of C1~C10, methoxyl group and C1~
The alkyl-substituted hexa-member heterocycles of C10, halogen and the alkyl-substituted five-ring heterocycles of C1~C10, halogen and C1~C10 are alkyl-substituted
Hexa-member heterocycle, cyclohexylamine, 1- morpholine substituted alkyl -1- ketone.Wherein, described five yuan/six former heterocycles are the heterocycle containing N, O, S.
Preferably, R1Selected from hydrogen, bromine, phenyl, 4- fluorophenyls；
R2For hydrogen or following group：
It is further preferred that 2' of the present invention, 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- aminated compounds is selected from：
(1) (anti-) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(2) (suitable) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(3) (anti-)-N- (pyridine -3- methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(4) (suitable)-N- (pyridine -3- methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(5) (anti-)-N- ((2- methoxypyridine -3- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(6) (suitable)-N- ((2- methoxypyridine -3- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(7) (anti-)-N- ((2- fluorine pyridin-3-yl) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(8) (suitable)-N- ((2- fluorine pyridin-3-yl) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(9) (anti-)-N- ((3- fluorine pyridine -2- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(10) (suitable)-N- ((3- fluorine pyridine -2- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(11) (anti-)-N- benzyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(12) (suitable)-N- benzyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(13) (anti-)-N- (2- methoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(14) (suitable)-N- (2- methoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(15) (anti-)-N- (2- luorobenzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(16) (suitable)-N- (2- luorobenzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(17) (anti-)-N- (the bromo- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(18) (suitable)-N- (bromo- 2- methoxy-benzyls -2', the 3'- dihydro spiral shells of 5- [cyclopropane -1,1'- indenes] -2- amine
(19) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(20) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(21) (anti-)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(22) (suitable)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(23) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 4-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(24) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 4-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(25) (anti-)-N- (3,4- dimethoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(26) (suitable)-N- (3,4- dimethoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(27) (anti-)-N-2- ((2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) amino) -1- morpholinoes ethane -
1- ketone
(28) (suitable)-N-2- ((2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) amino) -1- morpholinoes ethane -
1- ketone
(29) (anti-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(30) (suitable) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(31) (anti-) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(32) (suitable) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(33) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -
2- amine
(34) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -
2- amine
(35) (anti-)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -5'- phenyl -2', 3'- dihydro spiral shells [cyclopropane -1,1'-
Indenes] -2- amine
(36) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,
1'- indenes] -2- amine
(37) (anti-)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers
1)
(38) (anti-)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers
2)
(39) (suitable)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers
3)
(40) (suitable)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers
4)。
The method specifically includes following steps：
(1) in organic solvent, using formula (II) compound as raw material, with methyltriphenylphosphonium bromide Ph3PCH3Br and t-
BuOK carries out Witting reactions, obtains formula (III) compound；
In step (1), the organic solvent is selected from THF, DMF；Preferably, it is THF.
In step (1), the temperature of the Witting reactions is 0 DEG C -60 DEG C；Preferably, it is 25 DEG C.
In step (1), the time of the Witting reactions is 10h-24h；Preferably, it is 16h.
In step (1), the amount ranging from 1 of the substance of formula (II) compound and methyltriphenylphosphonium bromide:1.2~
2.0；Preferably, it is 1:1.5.
The amount ranging from 1 of the substance of formula (II) compound and t-BuOK:1.2~2.0；Preferably, it is 1:1.5.
(2) in organic solvent, rhodium acetate Rh2(OAc)2It is catalyzed ethyl diazoacetate N2=CHCO2Et changes with formula (III)
It closes object and carries out cyclopropanization reaction, obtain formula (IV) compound and formula (V) compound；
In step (2), the organic solvent is selected from DCM, toluene；Preferably, it is DCM.
In step (2), the temperature of the cyclopropanization reaction is 25 DEG C -60 DEG C；Preferably, it is 45 DEG C.
In step (2), the time of the cyclopropanization reaction is 1h-5h；Preferably, it is 3h.
In step (2), ranging from the 1 of the amount of the substance of formula (III) compound and ethyl diazoacetate:1.2~
2.0；Preferably, it is 1:1.5.
In step (2), rhodium acetate Rh2(OAc)2It is catalyst, formula (III) compound and rhodium acetate Rh2(OAc)2's
Ranging from the 1 of the amount of substance:0.005~0.02；Preferably, it is 1:0.01.
(3) reaction is hydrolyzed in formula (IV) compound and formula (V) compound, and Curtius is reset, and obtains formula (VI) compound
With formula (VII) compound；
Specifically, the method includes：
I) in EtOH and H2The in the mixed solvent of O, using formula (IV) compound and formula (V) compound as raw material, in the mixed of KOH
It closes and is heated to reflux generation hydrolysis under solution, obtain carboxylic acid.
In step i), ranging from the 1 of the amount of formula (IV) compound and the substance of formula (V) compound and KOH:2~4；
Preferably, it is 1:3.
In step i), the time of the hydrolysis is 3h-6h；Preferably, it is 4h.
Ii) in organic solvent, using carboxylic acid as raw material, react at room temperature to obtain nitrine with diphenyl phosphate azide, triethylamine
Compound.
Step ii) in, the organic solvent is selected from benzene, toluene, chloroform；Preferably, it is toluene.
Step ii) in, ranging from the 1 of the amount of the substance of the carboxylic acid and diphenyl phosphate azide:1~3；Preferably, it is
1:2。
Step ii) in, ranging from the 1 of the amount of the substance of the carboxylic acid and triethylamine:2~5；Preferably, it is 1:3.
Iii) in organic solvent, in the tert-butyl alcohol, azide obtains formula (VI) change with tert-butyl alcohol heating reflux reaction
Close object and formula (VII) compound；
Step iii) in, the organic solvent is the tert-butyl alcohol preferably.
Step iii) in, ranging from the 1 of the amount of the substance of the azide and the tert-butyl alcohol:10~20；Preferably, it is 1:
15。
Step iii) in, the temperature of the reaction is 60 DEG C -100 DEG C；Preferably, it is 90 DEG C.
Step iii) in, the time of the reaction is 3h-8h；Preferably, it is 6h.
Formula (VI) compound/formula (VII) compound obtains the 2', 3'- dihydros spiral shell [ring third by following four method
Alkane -1,1'- indenes] -2- amine derivatives：
(4-1) formula (VI) compound/formula (VII) compound takes off Boc protecting groups, through reduction amination, obtains formula (VIII) change
Close object/formula (IX) compound (wherein, formula (VI) compound of formula (VIII) compound, formula (VII) compound of formula (IX)
Compound；
Specifically, the method includes：
I) formula (VI) compound/formula (VII) compound obtains at room temperature in 4M HCl/EtOAc solution removal Boc protecting groups
To hydrochloride.
Ii) in organic solvent, hydrochloride and triethylamine, substituted pyridine aldehydes or benzaldehyde, reducing agent are through reduction amination
Reaction, obtains formula (VIII) compound/formula (IX) compound.
Step ii) in, the organic solvent is selected from DCM, methanol；Preferably, it is methanol.
Step ii) in, the temperature of the reduction amination is 0 DEG C -60 DEG C；Preferably, it is 25 DEG C.
Step ii) in, the time of the reduction amination is 10h-20h；Preferably, it is 16h.
Step ii) in, the reducing agent is selected from NaBH4、NaBH(OAc)3；Preferably, it is NaBH4。
Step ii) in, ranging from the 1 of the amount of the hydrochloride and the substance of substituted pyridine aldehydes or benzaldehyde:1.0~
1.1；Preferably, it is 1:1.0.
Step ii) in, ranging from the 1 of the amount of the substance of the hydrochloride and reducing agent:2~5；Preferably, it is 1:3.
With 2- chloro- 1- morpholinoes ethane -1- ketone substitution reaction occurs for (4-2) formula (VI) compound/formula (VII) compound,
Then Boc protecting groups are removed, formula (X) compound/formula (XI) compound is obtained；
Specifically, the method includes：
I) in DMF, using formula (VI) compound/formula (VII) compound as raw material, with the chloro- 1- morpholinoes ethane -1- ketone of 2-
It is reacted at room temperature with NaH, obtains intermediate.
In step i), the time of the reaction is 1h-4h；Preferably, it is 2h.
In step i), the substance of formula (VI) compound/formula (VII) compound and the chloro- 1- morpholinoes ethane -1- ketone of 2-
Amount ranging from 1:1.0~1.5；Preferably, it is 1:1.2.
Ii) intermediate removes Boc protecting groups in 4M HCl/EtOAc solution at room temperature, obtains formula (X) compound/formula
(XI) compound.
(4-3) formula (VI) compound/formula (VII) compound is restored with (4- oxocyclohexyls) t-butyl carbamate
Then aminating reaction takes off Boc protecting groups, obtains formula (XII) compound/formula (XIII) compound；
Specifically, the method includes：
I) in DCE, using formula (VI) compound/formula (VII) compound as raw material, with (4- oxocyclohexyls) carbamic acid
The tert-butyl ester and acetic acid, reducing agent room temperature react, and obtain intermediate.
In step i), the time of the reaction is 3h-10h；Preferably, it is 6h.
In step i), formula (VI) compound/formula (VII) compound and (4- oxocyclohexyls) t-butyl carbamate
Substance amount ranging from 1:1.0~1.5；Preferably, it is 1:1.2.
In step i), the reducing agent is selected from NaBH4、NaBH(OAc)3；Preferably, it is NaBH (OAc)3。
Ii) at room temperature, intermediate removes Boc protecting groups in 4M HCl/EtOAc solution, obtain formula (XII) compound/
Formula (XIII) compound.
Suzuki coupling reactions occur for (4-4) formula (VI) compound/formula (VII) compound and substituted aryl boric acid, so
Boc protecting groups are taken off afterwards, obtain formula (XIV) compound/formula (XV) compound, are then occurred also with substituted pyridine aldehydes or benzaldehyde
Former aminating reaction obtains formula (VIII) compound/formula (IX) compound；
Specifically, the method includes：
I) in DMF, using formula (VI) compound/formula (VII) compound as raw material, with substituted phenyl boric acid, Pd (PPh3)4
And Na2CO3Reaction, obtains intermediate.
In step i), the temperature of the reaction is 60 DEG C -110 DEG C；Preferably, it is 80 DEG C.
In step i), the time of the reaction is 5h-10h；Preferably, it is 6h.
In step i), the model of the amount of the substance of formula (VI) compound/formula (VII) compound and substituted aryl boric acid
Enclose is 1:1.0~1.5；Preferably, it is 1:1.2.
In step i), Pd (PPh3)4It is catalyst, formula (VI) compound/formula (VII) compound and Pd (PPh3)4's
Ranging from the 1 of the amount of substance:0.01~0.10；Preferably, it is 1:0.05.
Ii) at room temperature, intermediate removes Boc protecting groups in 4M HCl/EtOAc solution, obtain formula (XIV) compound/
Formula (XV) compound.
Iii) in organic solvent, using formula (XIV) compound/formula (XV) compound as raw material, with triethylamine, substituted pyrrole
Pyridine aldehyde or benzaldehyde, reducing agent obtain formula (VIII) compound/formula (IX) compound through reduction amination；
Step iii) in, the organic solvent is selected from DCM, methanol；Preferably, it is methanol.
Step iii) in, the temperature of the reduction amination is 0 DEG C -60 DEG C；Preferably, it is 25 DEG C.
Step iii) in, the time of the reduction amination is 10h-20h；Preferably, it is 16h.
Step iii) in, the reducing agent is selected from NaBH4、NaBH(OAc)3；Preferably, it is NaBH4。
Step iii) in, the substance of formula (XIV) compound/formula (XV) compound and substituted pyridine aldehydes or benzaldehyde
Amount ranging from 1:1.0~1.1；Preferably, it is 1:1.0.
Step iii) in, ranging from the 1 of the amount of the substance of formula (XIV) compound/formula (XV) compound and reducing agent:
2~5；Preferably, it is 1:3.
In the specific embodiment of the present invention, the 2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine spreads out
Shown in the preparation method following reaction formula (B) of biology：
Reaction equation (B)
The present invention also provides the 2', and 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives are as LSD1's
Application in inhibitor.
The present invention also provides the 2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives are being prepared with LSD1
For the application in the drug of target spot, the treatment to realization to relevant disease.The disease includes but not limited to leukaemia, such as anxious
Property marrow series leukemia.
The beneficial effects of the present invention are 2' of the present invention, 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine derives
The preparation method of object is limited by conformation using phenyl cyclopropylamine as parent and carries out structural modification to have obtained a series of structures new
Clever 2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives.2' of the present invention, 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -
2- amine derivatives can significantly improve its inhibitory activity to LSD1, to LSD1 common manifestations by the combination of improvement and LSD1
Go out higher inhibitory activity, while preferable selectivity is showed to monoamine oxidase and LSD2.Which part compound pair
The inhibitory activity IC of LSD150Value is less than 10nM, and preferable to the selectivity of homology enzyme.In addition, 2' of the present invention, 3'- dihydro spiral shell
[cyclopropane -1,1'- indenes] -2- amine derivatives are better than positive control ORY-1001 to LSD1 inhibitory activity.Therefore, of the invention
2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives, to further apply research and development treatment acute myeloid leukemia
Drug lay a good foundation.
LSD1 is first istone lysine demethylase that 2004 Nian Shiyang seminars find, by 852 amino
Acid composition, encodes the gene serial number (Gene ID) of LSD1 albumen:23028.The gene code contains SWIRM structural domains, FAD knots
Close the nucleoprotein of motif and amine oxidase structural domain.LSD1 is usually present in the same histone with CoEST, BHC80, HDAC and goes
In acetylase compound, CoEST recruits LSD1 after being combined with chromatin, inhibits Neuron-specific base in non-neuronal cells
The expression of cause.
Specific implementation mode
In conjunction with following specific examples, the present invention is described in further detail.Implement the present invention process, condition,
Experimental method etc. is among the general principles and common general knowledge in the art, the present invention does not have in addition to the following content specially referred to
Especially limitation content.
Raw material used in following embodiment is commercially available analysis pure chemicals.
Present invention combination subordinate list and embodiment are described further, rather than are limit the invention in any way.
Embodiment 1：The preparation of 2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine (1)
(a) preparation of 1- methylene -2,3- dihydro -1H- indenes (1a)
By 2,3- dihydro -1H- 1-Indanones (4.00g, 30.30mmol) and triphenylmethylphospbromide bromide phosphine (16.24g,
20mL THF 45.45mmol) are added to, the THF solution of 1.0M potassium tert-butoxides is added under magnetic agitation with constant pressure funnel
(45.45mL, 45.45mmol), reaction solution stir 16 hours at room temperature, solvent are removed in vacuum, residue passes through silica gel chromatographic column
Purify (petrol ether/ethyl acetate=100:1) 1a, colorless oil, 3.42g (87%), are obtained.
(b) (anti-) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- carboxylic acid, ethyl esters (1b) and (suitable) -2', 3'- dihydros
The preparation of spiral shell [cyclopropane -1,1'- indenes] -2- carboxylic acid, ethyl esters (1b')
1a (3.42g, 26.30mmol) and rhodium acetate dimer (115mg, 0.26mmol) are added to 5.0mL dichloromethanes
In alkane, ethyl diazoacetate (2.0mL, 39.45mmol) is added at reflux, solution is stirred 3 hours at 45 DEG C,
It is stirred overnight at room temperature, solvent is removed in vacuum, pass through silica gel chromatograph column purification (petrol ether/ethyl acetate=100:1) 1b, is obtained
And 1b', colorless oil, 3.35g (59%), it is directly used in and reacts in next step.
(c) (anti-) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) t-butyl carbamate (1c) and (suitable) -
2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) t-butyl carbamate t-butyl carbamate (1c') preparation
By 1b and 1b'(3.35g, 15.49mmol) it is added in 10mL EtOH, KOH is added to solution under magnetic agitation
(2.61g, 46.47mmol) is cooled to room temperature after being heated to reflux 3 hours, and 20mL ethyl acetate is added, and is extracted with water (3 × 30mL)
It takes, combining water layer.10% aqueous hydrochloric acid solution is added in water layer, until pH value is down to 5-6, ethyl acetate (3 × 30mL) extraction
It takes, then by combined organic phase saturated common salt water washing, anhydrous Na2SO4It is dry, it is filtered and concentrated in vacuo as grease, directly
It connects for reacting in next step.Under nitrogen protection, grease is dissolved in 20mL dry toluenes, triethylamine is added under ice bath
(6.4mL, 46.47mmol) and diphenyl phosphate azide (6.7mL, 30.98mmol) is warming up to room temperature reaction 4 hours.It will reaction
Mixture is washed with water and saturated brine, anhydrous Na2SO4It is dry, azide is obtained by filtration, vacuum pump drying is directly used in down
Single step reaction.Azide is dissolved in 100mL anhydrous tertiary butanols in a nitrogen atmosphere, is heated to reflux 6 hours, reaction is cooled down
To room temperature, it is concentrated in vacuo, obtains brown oil, be dissolved in ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, nothing
Water Na2SO4It is dry, it is filtered and concentrated in vacuo.Crude product passes through silica gel chromatography (petrol ether/ethyl acetate=30:1) it, obtains
To 1c, white solid, 1.08g (27%)；Obtain 1c', white solid, 763mg (19%).
(d) preparation of (anti-) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine (1)
1c (300mg, 1.16mmol) is dissolved in the ethyl acetate solution of 5mL4M HCl, is stirred at room temperature overnight, mistake
Filter, obtained solid washed and dried with ether, obtains 1, yellow solid, 221mg (98%).1H NMR(400MHz,CD3OD)δ
7.25–7.20(m,1H),7.19–7.10(m,2H),6.79–6.73(m,1H),3.14(t,2H),2.88(dd,1H),2.35–
2.19(m,2H),1.45–1.39(m,1H),1.31–1.25(m,1H).13C NMR(101MHz,CD3OD)δ145.4,144.8,
128.2,128.0,125.5,120.0,35.3,31.9,31.5,29.4,19.9.
Embodiment 2:The preparation of (suitable) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine (2)
2 preparation method is identical as in embodiment 11 preparation method, the difference is that with 1c'(300mg,
1c 1.16mmol) is substituted, obtains 2, yellow solid, 213mg (94%).1H NMR(400MHz,CD3OD)δ7.32(d,1H),
7.27–7.18(m,2H),7.10–7.03(m,1H),3.21–3.06(m,1H),3.02–2.92(m,1H),2.88(dd,1H),
2.40–2.27(m,1H),1.99–1.94(m,1H),1.54–1.47(m,1H),1.43(t,1H).13C NMR(101MHz,
CD3OD)δ147.5,140.4,128.7,127.7,126.3,121.9,36.6,35.0,33.1,31.5,15.7.
Embodiment 3：(anti-)-N- (pyridine -3- methyl) -2', the system of 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine (3)
It is standby
At room temperature, 1 (50mg, 0.26mmol) is dissolved in 2.0mL MeOH, triethylamine (39mg, 0.39mmol) is added,
Generate unhindered amina.Then nicotinoyl aldehyde (28mg, 0.26mmol) is added in solution, magnetic agitation 30min, 4A type molecules is added
Sieve stirs 15min, and sodium borohydride (20mg, 0.52mmol) is added, and reacts 16 hours.Then mixture is filtered, is removed in vacuum molten
Agent obtains crude product, is dissolved in ethyl acetate, is saturated NaHCO3Organic phase, anhydrous Na are collected in washing2SO4Dry, filtering is simultaneously
It is concentrated in vacuo, passes through silica gel chromatography (petrol ether/ethyl acetate=4:1) 3, are obtained, yellow oil, 26mg
(40%).1H NMR(400MHz,CD3OD)δ8.47(d,1H),8.42–8.37(m,1H),7.82–7.76(m,1H),7.35
(dd,1H),7.16–7.10(m,1H),7.07–7.02(m,2H),6.62–6.57(m,1H),3.83(s,2H),3.05–2.83
(m,2H),2.34–2.23(m,2H),2.12–2.03(m,1H),1.15(dd,1H),0.82(t,1H).13C NMR(101MHz,
CD3OD)δ150.3,148.6,148.5,144.6,138.6,137.5,127.4,126.8,125.1,125.1,119.4,
51.8,45.9,34.2,31.6,29.5,22.0.
Embodiment 4：(suitable)-N- (pyridine -3- methyl) -2', the system of 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine (4)
It is standby
4 preparation in embodiment 33 prepare it is identical, the difference is that with 2 (50mg, 0.26mmol) substitute 1, obtain
To 4, yellow oil, 38mg (60%).1H NMR(400MHz,CD3OD)δ8.32–8.29(m,1H),8.20(d,1H),
7.52–7.47(m,1H),7.24–7.19(m,1H),7.16–7.05(m,4H),3.56(d,1H),3.26(d,1H),2.97–
2.83(m,2H),2.41(dd,1H),2.21–2.11(m,1H),1.82–1.75(m,1H),1.08–1.00(m,2H).13C NMR
(101MHz,CD3OD)δ150.0,148.4,146.3,144.5,138.3,137.4,126.9,126.6,125.0,124.8,
123.0,51.4,46.0,36.7,34.8,31.5,19.6.
Embodiment 5：(anti-)-N- ((2- methoxypyridine -3- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'-
Indenes] -2- amine (5) preparation
5 preparation in embodiment 33 prepare it is identical, the difference is that with 2- methoxyl group nicotine aldehyde (47mg,
Nicotine aldehyde 0.34mmol) is substituted, obtains 5, yellow oil, 59mg (61%).1H NMR(400MHz,CDCl3)δ8.08–8.04
(m,1H),7.47(d,1H),7.22–7.17(m,1H),7.12–7.07(m,2H),6.84–6.79(m,1H),6.62–6.57
(m,1H),3.91(s,3H),3.84–3.72(m,2H),3.10–2.91(m,2H),2.41–2.34(m,1H),2.29–2.25
(m,1H),2.21–2.07(m,3H),1.17–1.14(m,1H).13C NMR(101MHz,CDCl3)δ162.1,147.8,
145.3,143.7,137.8,126.3,125.8,124.2,122.6,118.4,116.7,53.3,48.7,44.5,33.5,
30.8,28.3,22.0.
Embodiment 6：(suitable)-N- ((2- methoxypyridine -3- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'-
Indenes] -2- amine (6) preparation
6 preparation in embodiment 44 prepare it is identical, the difference is that with 2- methoxyl group nicotine aldehyde (38mg,
Nicotine aldehyde 0.28mmol) is substituted, obtains 6, yellow oil, 39mg (50%).1H NMR(400MHz,CDCl3)δ8.01(d,
1H),7.28(d,1H),7.19–7.18(m,1H),7.15–7.09(m,3H),6.77(t,1H),3.91(s,3H),3.60–
3.38(m,2H),3.05–2.89(m,2H),2.38(t,1H),2.23–2.10(m,1H),1.96(s,1H),1.88–1.79(m,
1H),1.07–0.98(m,2H).13C NMR(101MHz,CDCl3)δ162.1,145.1,143.9,137.8,125.7,125.5,
123.9,122.7,122.3,116.5,53.2,48.2,44.6,35.6,33.8,30.8,20.6.
Embodiment 7：(anti-)-N- ((2- fluorine pyridin-3-yl) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2-
The preparation of amine (7)
7 preparation in embodiment 33 prepare it is identical, the difference is that with 2- fluorine nicotine aldehyde (45mg, 0.36mmol)
Nicotine aldehyde is substituted, obtains 7, yellow oil, 21mg (22%).1H NMR(400MHz,CDCl3)δ8.10(d,1H),7.77–
7.10(m,1H),7.21–7.16(m,1H),7.14–7.07(m,3H),6.63–6.58(m,1H),3.93–3.82(m,2H),
3.10–2.91(m,2H),2.39–2.29(m,2H),2.16–2.08(m,1H),1.90(s,1H),1.17(dd,1H),0.86
(t,1H).13C NMR(101MHz,CDCl3)δ163.0,160.7,147.4,146.0,143.7,140.6,126.1,124.3,
122.2,121.4.118.4,46.9,44.4,33.6,30.8,28.3,22.0.
Embodiment 8：(suitable)-N- ((2- fluorine pyridin-3-yl) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2-
The preparation of amine (8)
8 preparation in embodiment 44 prepare it is identical, the difference is that with 2- fluorine nicotine aldehyde (39mg, 0.31mmol)
Nicotine aldehyde is substituted, obtains 8, yellow oil, 25mg (30%).1H NMR(400MHz,CDCl3)δ8.03(d,1H),7.54–
7.48(m,1H),7.20–7.15(m,1H),7.14–7.00(m,4H),3.70–3.45(m,2H),3.04–2.89(m,2H),
2.41(dd,1H),2.23–2.13(m,1H),1.88–1.80(m,1H),1.76(s,1H),1.09–1.04(m,1H),1.01
(t,1H).13C NMR(101MHz,CDCl3)δ163.0,160.6,145.8,145.1,143.5,140.8,125.7,124.0,
122.1,121.9,121.3,46.4,44.5,35.4,30.7,29.7,20.5.
Embodiment 9：(anti-)-N- ((3- fluorine pyridine -2- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2-
The preparation of amine (9)
9 preparation in embodiment 33 prepare it is identical, the difference is that with 3- fluorine pyridine carboxaldehyde (41mg,
Nicotine aldehyde 0.31mmol) is substituted, obtains 9, yellow oil, 41mg (47%).1H NMR(400MHz,CDCl3)δ8.39–8.37
(m,1H),7.37–7.31(m,1H),7.22–7.17(m,2H),7.14–7.08(m,2H),6.64–6.60(m,1H),4.10–
4.01(m,2H),3.08–3.02(m,2H),2.47–2.35(m,3H),2.20–2.12(m,1H),1.19(dd,1H),0.94
(t,1H).13C NMR(101MHz,CDCl3)δ158.7,156.2,147.8,144.9,143.9,126.3,125.8,124.2,
123.2,122.6,118.5,48.4,44.7,33.5,30.9,28.3,22.1.
Embodiment 10：(suitable)-N- ((3- fluorine pyridine -2- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2-
The preparation of amine (10)
10 preparation in embodiment 44 prepare it is identical, the difference is that with 3- fluorine pyridine carboxaldehyde (41mg,
Nicotine aldehyde 0.31mmol) is substituted, obtains 10, yellow oil, 52mg (59%).1HNMR(400MHz,CDCl3)δ8.30(d,J
=4.8Hz, 1H), 7.26-7.20 (m, 1H), 7.16-7.07 (m, 5H), 3.84-3.70 (m, 2H), 3.06-2.86 (m, 2H),
2.45(dd,1H),2.21(s,1H),2.18–2.08(m,1H),1.89–1.81(m,1H),1.07–1.00(m,2H).13C NMR
(101MHz,CDCl3)δ158.8,156.3,148.1,145.0,144.8,143.9,125.6,123.9,123.1,122.5,
122.3,48.3,44.8,35.6,33.7,30.7,20.8.
Embodiment 11：The preparation of (anti-)-N- benzyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine (11)
11 preparation is identical as preparing for 3 in embodiment 3, the difference is that with benzaldehyde (28mg, 0.26mmol)
Nicotine aldehyde is substituted, obtains 11, yellow oil, 27mg (42%).1H NMR(400MHz,CDCl3)δ7.33–7.27(m,1H),
7.26–7.21(m,1H),7.21–7.16(m,1H),7.14–7.07(m,1H),6.64–6.58(m,1H),3.96–3.77(m,
1H),3.08–2.92(m,1H),2.42–2.33(m,1H),2.17–2.09(m,1H),1.93(s,1H),1.16(dd,1H),
0.87(t,1H).13C NMR(101MHz,CDCl3)δ147.8,143.8,140.4,128.4,128.2,127.0,126.3,
125.7,124.2,118.4,53.9,44.8,33.6,30.9,28.4,22.0.
Embodiment 12：The preparation of (suitable)-N- benzyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine (12)
12 preparation is identical as preparing for 4 in embodiment 4, the difference is that with benzaldehyde (32mg, 0.31mmol)
Nicotine aldehyde is substituted, obtains 12, yellow oil, 29mg (39%).1H NMR(400MHz,CDCl3)δ7.27–7.22(s,1H),
7.22–7.17(m,1H),7.16–7.11(m,2H),3.59–3.39(m,2H),3.07–2.91(m,1H),2.44(dd,1H),
2.23–2.14(m,1H),1.90–1.81(m,1H),1.09–1.00(m,1H).13C NMR(101MHz,CDCl3)δ145.2,
143.9,140.5,128.3,128.2,126.8,125.7,125.6,124.0,122.3,53.5,44.8,35.5,33.8,
30.8,20.4.
Embodiment 13：(anti-)-N- (2- methoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine (13)
Preparation
13 preparation is identical as preparing for 3 in embodiment 3, the difference is that with Benzaldehyde,2-methoxy (36mg,
Nicotine aldehyde 0.26mmol) is substituted, obtains 13, yellow oil, 48mg (65%).1H NMR(400MHz,CDCl3)δ7.24–
7.15(m,3H),7.11–7.05(m,2H),6.89–6.84(m,1H),6.82(d,1H),6.61–6.56(m,1H),3.89–
3.73(m,5H),3.08–2.93(m,2H),2.44–2.35(m,1H),2.28(dd,1H),2.16–2.07(m,1H),1.13
(dd,1H),0.86(t,1H).13C NMR(101MHz,CDCl3)δ157.6,148.0,143.8,129.9,128.4,128.2,
126.2,125.6,124.1,120.3,118.4,110.2,55.1,49.2,44.7,33.5,30.9,28.3,22.0.
Embodiment 14：(suitable)-N- (2- methoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine (14)
Preparation
14 preparation is identical as preparing for 4 in embodiment 4, the difference is that with Benzaldehyde,2-methoxy (36mg,
Nicotine aldehyde 0.26mmol) is substituted, obtains 14, yellow oil, 46mg (62%).1H NMR(400MHz,CDCl3)δ7.22–
7.15(m,2H),7.14–7.09(m,3H),7.04–7.01(m,1H),6.87–6.82(m,1H),6.78(d,1H),3.76(s,
3H),3.62–3.43(m,2H),3.06–2.89(m,2H),2.39(dd,1H),2.19–2.10(m,1H),1.87–1.80(m,
2H),1.04–0.97(m,2H).13C NMR(101MHz,CDCl3)δ157.6,145.1,144.2,130.0,128.6,128.0,
125.5,125.5,123.9,122.4,120.2,110.0,55.1,48.7,44.7,35.7,33.7,30.8,20.7.
Embodiment 15：(anti-)-N- (2- luorobenzyls) -2', the system of 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine (15)
It is standby
15 preparation is identical as preparing for 3 in embodiment 3, the difference is that with 2- fluorobenzaldehydes (33mg,
Nicotine aldehyde 0.26mmol) is substituted, obtains 15, yellow oil, 40mg (52%).1H NMR(400MHz,CDCl3)δ7.31–
7.25(m,1H),7.24–7.15(m,2H),7.12–6.97(m,4H),6.62–6.57(m,1H),3.92–3.80(m,2H),
3.08–2.91(m,2H),2.42–2.28(m,2H),2.16–2.06(m,1H),1.80(s,1H),1.15(dd,1H),0.88–
0.83(m,1H).13C NMR(101MHz,CDCl3)δ162.5,160.1,147.8,143.9,130.6,128.8,127.4,
126.2,124.3,124.1,118.5,115.4),47.5,44.7,33.7,31.0,28.4,22.2.
Embodiment 16：(suitable)-N- (2- luorobenzyls) -2', the system of 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine (16)
It is standby
16 preparation is identical as preparing for 4 in embodiment 4, the difference is that with 2- fluorobenzaldehydes (33mg,
Nicotine aldehyde 0.26mmol) is substituted, obtains 16, yellow oil, 42mg (60%).1H NMR(400MHz,CDCl3)δ7.22–
7.08(m,6H),7.04–6.92(m,2H),3.67–3.47(m,2H),3.08–2.88(m,2H),2.41(dd,1H),2.21–
2.12(m,1H),1.88–1.80(m,1H),1.65(s,1H),1.07–0.98(m,2H).13C NMR(101MHz,CDCl3)δ
162.5,160.1,145.2,143.9,130.8,128.6,127.4,125.7,124.1,123.9,122.5,115.2,46.8,
44.6,35.6,33.9,30.9,20.8.
Embodiment 17：(anti-)-N- (the bromo- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(17) preparation
17 preparation is identical as preparing for 3 in embodiment 3, the difference is that with the bromo- Benzaldehyde,2-methoxies of 5-
(56mg, 0.26mmol) substitutes nicotine aldehyde, obtains 17, yellow oil, 53mg (57%).1H NMR(400MHz,CDCl3)δ
7.34–7.28(m,2H),7.21–7.16(m,1H),7.12–7.07(m,2H),6.69(d),6.62–6.58(m,1H),3.87–
3.67(m,5H),3.09–2.93(m,2H),2.40–2.32(m,1H),2.27(dd),2.16–2.07(m,1H),2.06–1.97
(m,1H),1.15(dd,1H),0.86(t,1H).13C NMR(101MHz,CDCl3)δ156.6,147.8,143.8,132.4,
130.8,130.7,126.3,125.7,124.2,118.4,112.7,111.9,55.4,48.6,44.6,33.6,30.8,
28.3,22.0.
Embodiment 18：(suitable)-N- (bromo- 2- methoxy-benzyls -2', the 3'- dihydro spiral shells of 5- [cyclopropane -1,1'- indenes] -2- amine
(18) preparation
18 preparation in embodiment 44 prepare it is identical, the difference is that with the bromo- Benzaldehyde,2-methoxies of 5-
(56mg, 0.26mmol) substitutes nicotine aldehyde, obtains 18, yellow oil, 62mg (67%).1H NMR(400MHz,CDCl3)δ
7.26–7.22(m,1H),7.19–7.16(m,1H),7.14–7.06(m,4H),6.61(d,1H),3.72(s,3H),3.62–
3.34(m,2H),3.06–2.89(m,2H),2.36(dd,1H),2.20–2.11(m,1H),1.88–1.79(m,2H),1.07–
0.97(m,2H).13C NMR(101MHz,CDCl3)δ156.5,145.1,143.9,132.5,130.8,130.4,125.6,
125.5,123.9,122.3,112.4,111.7,55.3,48.2,44.6,35.5,33.8,30.7,20.5.
Embodiment 19：(anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(19) preparation
19 preparation is identical as preparing for 3 in embodiment 3, the difference is that with the fluoro- Benzaldehyde,2-methoxies of 5-
(48mg, 0.31mmol) substitutes nicotine aldehyde, obtains 19, yellow oil, 60mg (65%).1H NMR(400MHz,CDCl3)δ
7.20–7.16(m,1H),7.12–7.06(m,2H),7.00–6.94(m,1H),6.91–6.85(m,1H),6.73(dd,1H),
6.62–6.57(m,1H),3.88–3.68(m,5H),3.09–2.92(m,2H),2.42–2.34(m,1H),2.28(dd,1H),
2.16–2.07(m,1H),1.93(s,1H),1.14(dd,1H),0.86(t,1H).13C NMR(101MHz,CDCl3)δ158.1,
155.7,153.6,147.9,143.8,130.3,126.0,124.2,118.5,116.5,113.6,110.9,55.6,48.8,
44.6,33.6,30.9,28.3,22.0.
Embodiment 20：(suitable)-N- (the fluoro- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(20) preparation
20 preparation is identical as preparing for 4 in embodiment 4, the difference is that with the fluoro- Benzaldehyde,2-methoxies of 5-
(48mg, 0.31mmol) substitutes nicotine aldehyde, obtains 20, yellow oil, 64mg (70%).1H NMR(400MHz,CDCl3)δ
7.25–7.20(m,1H),7.19–7.12(m,3H),6.90–6.79(m,2H),6.74–6.67(m,1H),3.76(s,3H),
3.67–3.37(m,2H),3.11–2.93(m,2H),2.42(dd,1H),2.25–2.14(m,1H),1.90–1.77(m,2H),
1.10–1.02(m,2H).13C NMR(101MHz,CDCl3)δ158.0,155.6,153.6,145.1,144.0,130.4,
125.6,124.0,122.4,116.6,113.4,110.7,55.7,48.3,44.7,35.6,33.8,30.8,20.7.
Embodiment 21：(anti-)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -
The preparation of 2- amine (21)
21 preparation is identical as preparing for 3 in embodiment 3, the difference is that with chloro- 3, the 4- dimethoxy benzenes first of 2-
Aldehyde (51mg, 0.26mmol) substitutes nicotine aldehyde, obtains 21, yellow oil, 51mg (64%).1H NMR(400MHz,CDCl3)δ
7.23–7.18(m,1H),7.15–7.08(m,2H),7.02(d,1H),6.76(d,1H),6.64–6.59(m,1H),3.94–
3.82(m,8H),3.11–2.93(m,2H),2.45–2.36(m,1H),2.31(dd,1H),2.19–2.09(m,1H),1.91
(s,1H),1.17(dd,1H),0.89(t,1H).13C NMR(101MHz,CDCl3)δ151.8,146.7,144.6,142.7,
129.7,127.2,125.3,124.7,123.9,123.2,117.4,109.2,59.5,55.1,50.3,43.4,32.6,
29.8,27.3,21.0.
Embodiment 22：(suitable)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -
The preparation of 2- amine (22)
22 preparation is identical as preparing for 4 in embodiment 4, the difference is that with chloro- 3, the 4- dimethoxy benzenes first of 2-
Aldehyde (51mg, 0.26mmol) substitutes nicotine aldehyde, obtains 22, yellow oil, 54mg (68%).1H NMR(400MHz,CDCl3)δ
7.21–7.17(m,1H),7.14–7.10(m,1H),6.81(d,1H),6.71(d,1H),3.83(s,3H),3.66–3.46(m,
1H),3.09–2.90(m,1H),2.39(dd,1H),2.22–2.11(m,1H),1.90–1.81(m,1H),1.76(s,1H),
1.06–0.99(m,1H).13C NMR(101MHz,CDCl3)δ152.6,145.4,145.1,144.0,130.9,128.2,
125.7,125.6,125.1,123.9,122.5,110.2,60.6,56.1,50.7,44.5,35.6,33.8,30.8,20.8.
Embodiment 23：(anti-)-N- (the fluoro- 2- methoxy-benzyls of 4-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(23) preparation
23 preparation is identical as preparing for 3 in embodiment 3, the difference is that with the fluoro- Benzaldehyde,2-methoxies of 4-
(39mg, 0.26mmol) substitutes nicotine aldehyde, obtains 23, yellow oil, 53mg (71%).1H NMR(400MHz,CDCl3)δ
7.20–7.16(m,1H),7.15–7.06(m,3H),6.60–6.55(m,2H),6.54(s,1H),3.84–3.67(m,5H),
3.09–2.91(m,2H),2.41–2.32(m,1H),2.25(dd,1H),2.15–2.06(m,1H),1.97(s,1H),1.13
(dd,1H),0.85(t,1H).13C NMR(101MHz,CDCl3)δ163.1,160.7,157.6(d),146.9,142.7,
129.6,125.3,124.6,123.1,117.4,105.3,97.7,54.3,47.5,43.6,32.5,29.8,27.2,20.9.
Embodiment 24：(suitable)-N- (the fluoro- 2- methoxy-benzyls of 4-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(24) preparation
24 preparation is identical as preparing for 4 in embodiment 4, the difference is that with the fluoro- Benzaldehyde,2-methoxies of 4-
(36mg, 0.23mmol) substitutes nicotine aldehyde, obtains 24, yellow oil, 46mg (66%).1H NMR(400MHz,CDCl3)δ
7.21–7.15(m,1H),7.15–7.05(m,3H),6.95–6.90(m,1H),6.55–6.45(m,2H),3.72(s,3H),
3.61–3.34(m,2H),3.04–2.86(m,2H),2.37(dd,1H),2.21–2.10(m,1H),1.92(s,1H),1.86–
1.77(m,1H),1.05–0.98(m,2H).13C NMR(101MHz,CDCl3)δ163.0,160.5,157.5,144.1,
143.0,129.6,124.5,123.0,122.9,121.2,105.1,105.1,54.3,47.1,43.6,34.6,32.7,
29.7,19.4.
Embodiment 25：(anti-)-N- (3,4- dimethoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(25) preparation
25 preparation is identical as preparing for 3 in embodiment 3, the difference is that using Veratraldehyde
(44mg, 0.26mmol) substitutes nicotine aldehyde, obtains 25, yellow oil, 38mg (46%).1H NMR(400MHz,CDCl3)δ
7.21–7.15(m,1H),7.13–7.07(m,2H),6.85–6.76(m,3H),6.64–6.58(m,1H),3.85(s,3H),
3.79–3.73(m,5H),3.09–2.89(m,2H),2.38–2.28(m,2H),2.18–2.07(m,1H),1.96(s,1H),
1.17(dd,1H),0.86(t,1H).13C NMR(101MHz,CDCl3)δ148.8,148.0,147.8,143.7,133.0,
126.3,125.7,124.2,120.3,118.4,111.6,111.1,55.9,55.7,53.7,44.8,33.5,30.8,28.3,
21.9.
Embodiment 26：(suitable)-N- (3,4- dimethoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(26) preparation
26 preparation is identical as preparing for 4 in embodiment 4, the difference is that using Veratraldehyde
(44mg, 0.26mol) substitutes nicotine aldehyde, obtains 26, yellow oil, 42mg (51%).1H NMR(400MHz,CDCl3)δ
7.24–7.19(m,1H),7.17–7.12(m,3H),6.75(d,1H),6.69–6.65(m,2H),3.86–3.82(m,6H),
3.56–3.24(m,2H),3.09–2.92(m,2H),2.46(dd,1H),2.27–2.17(m,1H),1.90–1.80(m,2H),
1.11–1.03(m,2H).13C NMR(101MHz,CDCl3)δ148.8,147.9,145.2,143.8,132.9,125.7,
125.4,124.0,122.2,120.3,111.7,110.8,55.9,55.7,53.3,44.8,35.5,33.8,30.8,20.0.
Embodiment 27：(anti-)-N-2- ((2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) amino) -1- morpholinoes
The preparation of ethane -1- ketone (27)
DEG C at, 1c (100mg, 0.39mmol) is dissolved in 2.0mL anhydrous DMFs, and NaH is added into solution, (28mg,
0.59mmol, 50% mineral oil), the chloro- 1- morpholinoes ethane -1- ketone of 2- is added into mixture for magnetic agitation 0.5 hour
(77mg, 0.47mmol) is warming up to and is stirred at room temperature 2 hours.After the completion of reaction, reaction mixture is poured into ice water, acetic acid second
Ester extracts, and merges organic layer, with water and saturated common salt water washing, anhydrous Na2SO4Dry, filtering is spin-dried for.Crude product passes through silica gel
Column chromatography purifies (methylene chloride/methanol=60:1) yellow solid, is obtained, the ethyl acetate solution of 5mL 4M HCl, room are dissolved in
It is stirred overnight under temperature, filters, washed and dried with ether, obtain 27, yellow solid, 60mg (48%).1HNMR(400MHz,
CD3OD)δ7.28–7.09(m,3H),6.83–6.71(m,1H),4.31(s,2H),3.77–3.55(m,7H),3.48(s,2H),
3.25–2.97(m,3H),2.46–2.25(m,2H),1.45(s,2H).13C NMR(101MHz,CD3OD)δ164.9,145.1,
144.8,128.4,128.0,125.5,120.1,67.5,67.4,46.3,43.5,42.9,33.0,31.7,29.5,19.5.
Embodiment 28：(suitable)-N-2- ((2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) amino) -1- morpholinoes
The preparation of ethane -1- ketone (28)
28 preparation method is identical as 27 preparation method in embodiment 27.The difference is that with 1c'(100mg,
1c 0.39mmol) is substituted, obtains 28, yellow solid, 56mg (45%).1H NMR(400MHz,CD3OD) 7.36 (d, J=of δ
6.4Hz,1H),7.31–7.19(m,3H),4.18–3.74(m,2H),3.67–3.58(m,4H),3.57–3.52(m,2H),
3.38–3.24(m,2H),3.23–3.13(m,1H),3.07(dd,1H),3.03–2.95(m,1H),2.40–2.31(m,1H),
2.00–1.91(m,1H),1.74(dd,1H),1.52–1.42(m,6.8Hz,1H).13C NMR(101MHz,CD3OD)δ164.6,
147.5,140.1,129.0,128.0,126.5,121.7,67.5,67.3,46.2,43.6,42.7,36.7,34.0,31.5,
15.1.
Embodiment 29：The preparation of (anti-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine (29)
(a) preparation of the bromo- 1- methylene -2,3- dihydros -1H- indenes (29a) of 5-
By bromo- 2, the 3- dihydros -1H- 1-Indanones (4.00g, 18.95mmol) of 5- and triphenylmethylphospbromide bromide phosphine (10.08g,
20mL THF 28.43mmol) are added to, the THF solution of 1.0M potassium tert-butoxides is added under magnetic agitation with constant pressure funnel
(28.43mL, 28.43mmol), reaction solution stir 16 hours at room temperature, solvent are removed in vacuum, residue passes through silica gel chromatographic column
Purify (petrol ether/ethyl acetate=100:1) 29a, colorless oil, 3.37g (85%), are obtained.
(b) the bromo- 2' of (anti-) -5'-, 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- carboxylic acid, ethyl esters (29b) and (suitable) -5'-
The preparation of bromo- 2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- carboxylic acid, ethyl esters (29b')
29a (3.37g, 16.12mmol) and rhodium acetate dimer (71mg, 0.16mmol) are added to 5.0mL dichloromethanes
In alkane, ethyl diazoacetate (2.0mL, 39.45mmol) is added at reflux, solution is stirred 3 hours at 45 DEG C,
It is stirred overnight at room temperature, solvent is removed in vacuum, pass through silica gel chromatograph column purification (petrol ether/ethyl acetate=100:1) it, obtains
29b and 29b', colorless oil, 2.90g (61%) are directly used in and react in next step.
(c) (anti-)-(the bromo- 2' of 5'-, 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- bases) t-butyl carbamate (29c)
The bromo- 2' of (suitable) -5'-, 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- bases) t-butyl carbamate (29c') preparation
By 29b and 29b'(2.90g, 9.82mmol) it is added in 10mL EtOH, KOH is added to solution under magnetic agitation
(1.65g, 29.46mmol) is cooled to room temperature after being heated to reflux 3 hours, and 20mL ethyl acetate is added, and is extracted with water (3 × 30mL)
It takes, combining water layer.10% aqueous hydrochloric acid solution is added in water layer, until pH value is down to 5-6, ethyl acetate (3 × 30mL) extraction
It takes, then by combined organic phase saturated common salt water washing, anhydrous Na2SO4It is dry, it is filtered and concentrated in vacuo as grease, directly
It connects for reacting in next step.Under nitrogen protection, grease is dissolved in 20mL dry toluenes, triethylamine is added under ice bath
(4.1mL, 29.46mmol) and diphenyl phosphate azide (4.2mL, 19.64mmol) is warming up to room temperature reaction 4 hours.It will reaction
Mixture is washed with water and saturated brine, anhydrous Na2SO4It is dry, azide is obtained by filtration, vacuum pump drying is directly used in down
Single step reaction.Azide is dissolved in 100mL anhydrous tertiary butanols in a nitrogen atmosphere, is heated to reflux 6 hours, reaction is cooled down
To room temperature, it is concentrated in vacuo, obtains brown oil, be dissolved in ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, nothing
Water Na2SO4It is dry, it is filtered and concentrated in vacuo.Crude product passes through silica gel chromatography (petrol ether/ethyl acetate=30:1) it, obtains
To 29c, white solid, 797mg (24%)；Obtain 29c', white solid, 730mg (22%).
(d) preparation of (anti-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine (29)
Into anhydrous 2.5mLDMF be added 29c (150mg, 0.44mmol) and tetrakis triphenylphosphine palladium (25mg,
0.022mmol), phenylboric acid (65mg, 0.53mmol) is added under magnetic agitation, Na is then added2CO3Aqueous solution (2M, 0.4mL
H2O).It vacuumizes under stream of nitrogen gas, then heats reaction mixture 16 hours at 80 DEG C, after cooling, reaction is mixed
Object is filtered and is extracted with ethyl acetate, and merges organic layer, washing, anhydrous Na2SO4It is dry, it is filtered and concentrated in vacuo, by crude product
Pass through silica gel chromatography (petrol ether/ethyl acetate=25:1) purifying, obtains white solid in.Then by 5mL 4M HCl
Ethyl acetate solution be added in white solid, and be stirred at room temperature overnight, filter, washed and dried with ether, obtained
29, yellow solid, 75mg (63%).1H NMR(400MHz,DMSO-d6)δ8.72(s,3H),7.65–7.59(m,2H),7.51
(s,1H),7.47–7.40(m,3H),7.37–7.31(m,1H),6.93(d,1H),3.18–3.02(m,2H),2.88–2.78
(m,1H),2.38–2.29(m,1H),2.25–2.16(m,1H),1.36(d,2H).13C NMR(101MHz,DMSO-d6)δ
144.4,144.3,140.4,139.0,128.9,127.2,126.6,125.4,122.5,119.8,33.6,30.3,30.1,
28.3,18.8.
Embodiment 30：The preparation of (suitable) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine (30)
30 preparation is identical as preparing for 29 in embodiment 29, the difference is that with 29c'(120mg, 0.35mol)
It substitutes, 29c obtains 30, yellow solid, 60mg (62%).1H NMR(400MHz,DMSO-d6)δ8.36(s,2H),7.66–
7.60(m,2H),7.57(s,1H),7.45(t,3H),7.38–7.31(m,2H),3.13–2.92(m,3H),2.89–2.82(m,
1H),2.28–2.17(m,1H),2.03–1.93(m,1H),1.58–1.52(m,1H),1.35(t,1H).13C NMR(101MHz,
DMSO-d6)δ146.8,140.5,139.9,139.4,129.1,127.5,126.8,125.1,123.2,122.2,35.1,
34.0,31.2,30.5,16.0.
Embodiment 31：(anti-) -5'- (4- fluorophenyls) -2', the system of 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine (31)
It is standby
31 preparation is identical as preparing for 29 in embodiment 29, the difference is that with (4- fluorophenyls) boric acid
(174mg, 0.53mol) substitutes phenylboric acid, obtains 31, yellow solid, 77mg (60%).1HNMR(400MHz,DMSO-d6)δ
8.77(s,2H),7.69–7.62(m,2H),7.49(s,1H),7.40(d,1H),7.26(t,2H),6.92(d,1H),3.18–
3.02(m,2H),2.86–2.79(m,1H),2.40–2.29(m,1H),2.25–2.15(m,1H),1.38–1.31(m,2H).13C
NMR(101MHz,DMSO-d6)δ162.8,160.4,144.2,137.8,136.7,128.5,128.4,125.2,122.4,
119.7,115.6,115.4,33.4,30.2,29.9,28.2,18.6.
Embodiment 32：(suitable) -5'- (4- fluorophenyls) -2', the system of 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine (32)
It is standby
32 preparation is identical as preparing for 30 in embodiment 30, the difference is that with (4- fluorophenyls) boric acid
(174mg, 0.53mol) substitutes phenylboric acid, obtains 32, yellow solid, 44mg (34%).1H NMR(400MHz,DMSO-d6)
δ8.52(s,2H),7.72–7.65(m,2H),7.56(s,1H),7.49–7.41(m,2H),7.28(t,2H),3.46(s,2H),
3.13–2.92(m,2H),2.86(s,1H),2.28–2.16(m,1H),2.05–1.94(m,1H),1.66–1.58(m,1H),
1.34(t,1H).13C NMR(101MHz,DMSO-d6)δ162.8,160.4,146.5,139.7,138.0,136.7,128.5,
128.4,124.7,122.8,122.2,115.7,115.5,34.8,33.7,31.0,30.3,15.8.
Embodiment 33：(anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- phenyl -2', 3'- dihydro spiral shells [cyclopropane -1,1'-
Indenes] -2- amine (33) preparation
At room temperature, 29 (40mg, 0.15mmol) are dissolved in 2.0mL MeOH, triethylamine (23mg, 0.23mmol) are added,
Generate unhindered amina.Then 2- methoxyl group -5- fluorobenzaldehydes (23mg, 0.15mmol) are added in solution, magnetic agitation 0.5 is small
When, 4A type molecular sieves are added, stir 15min, sodium borohydride (23mg, 0.60mmol) is added, react 16 hours.Then filtering is mixed
Object is closed, solvent is removed in vacuum, obtains crude product, is dissolved in ethyl acetate, is saturated NaHCO3Organic phase is collected in washing, anhydrous
Na2SO4It is dry, it is filtered and concentrated in vacuo, passes through silica gel chromatography (petrol ether/ethyl acetate=15:1) 33, are obtained, Huang
Color grease, 40mg (72%).1H NMR(400MHz,CDCl3)δ7.57–7.53(m,2H),7.43–7.37(m,3H),7.35–
7.27(m,2H),7.03–6.98(m,1H),6.93–6.86(m,1H),6.73(dd,1H),6.66(d,1H),3.91–3.70
(m,6H),3.16–2.96(m,2H),2.48–2.39(m,1H),2.34(dd,1H),2.23–2.13(m,1H),1.20(dd,
1H),0.92(t,1H).13C NMR(101MHz,CDCl3)δ157.0,154.7,152.6,146.1,143.5,140.6,
138.2,127.6,126.0,125.8,124.5,122.1,117.7,115.6,112.7,109.9,54.6,47.7,43.6,
32.4,29.8,27.5,21.0.
Embodiment 34：(suitable)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- phenyl -2', 3'- dihydro spiral shells [cyclopropane -1,1'-
Indenes] -2- amine (34) preparation
34 preparation is identical as preparing for 33 in embodiment 33, the difference is that being substituted with 30 (40mg, 0.15mol)
29, obtain 34, yellow oil, 30mg (55%).1H NMR(400MHz,CDCl3)δ7.61–7.56(m,2H),7.44–7.39
(m,3H),7.38–7.34(m,1H),7.33–7.28(m,1H),7.17(d,1H),6.87–6.79(m,2H),6.66(dd,
1H),3.72(s,3H),3.69–3.43(m,2H),3.10–2.93(m,2H),2.43(dd,1H),2.25–2.15(m,1H),
1.97(s,1H),1.94–1.83(m,1H),1.11–1.02(m,2H).13C NMR(101MHz,CDCl3)δ157.9,155.6,
153.5,145.7,143.4,141.7,139.0,130.2,128.6,127.1,126.8,124.7,122.7,116.6,
113.5,110.7,55.6,48.4,44.8,35.7,33.7,30.8,20.8.
Embodiment 35：(anti-)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -
1,1'- indenes] -2- amine (35) preparation
35 preparation with the 33 of in embodiment 33 prepare it is identical, the difference is that with chloro- 3, the 4- dimethoxy benzenes of 2-
Formaldehyde (33mg, 0.16mol) substitutes the fluoro- Benzaldehyde,2-methoxies of 5-, obtains 35, yellow oil, 34mg (51%).1HNMR
(400MHz,CDCl3)δ7.57–7.53(m,2H),7.43–7.36(m,4H),7.35–7.27(m,2H),7.06(d,1H),
6.76(d,1H),6.66(d,1H),3.98–3.87(m,2H),3.84(s,6H),3.15–2.97(m,2H),2.49–2.40(m,
1H),2.37(dd,1H),2.24–2.15(m,1H),1.21(dd,1H),0.96(t,1H).13C NMR(101MHz,CDCl3)δ
153.0,146.9,145.6,144.5,141.6,139.3,130.1,128.7,128.4,127.1,126.8,125.6,
125.3,123.1,118.7,110.4,60.6,56.1,51.1,44.2,33.4,30.9,28.6,21.9.
Embodiment 36：(anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [ring third
Alkane -1,1'- indenes] -2- amine (36) preparation
36 preparation with the 33 of in embodiment 33 prepare it is identical, the difference is that with 31 (40mg, 0.14mol) substitute
29, obtain 36, yellow oil, 25mg (54%).1H NMR(400MHz,CDCl3)δ7.52–7.47(m,2H),7.36(s,
1H),7.27(d,1H),7.12–7.05(m,2H),7.04–6.99(m,1H),6.93–6.88(m,1H),6.74(dd,1H),
6.65(d,1H),3.93–3.75(m,2H),3.73(s,3H),3.14–2.96(m,2H),2.61(s,1H),2.49–2.40(m,
1H),2.36(dd,1H),2.24–2.14(m,1H),1.20(dd,1H),0.97(t,1H).13C NMR(101MHz,CDCl3)δ
163.4,161.0,158.0,155.7,153.7,147.0,144.6,138.3,137.7,128.5,125.4,123.0,
118.8,116.8,115.5,114.0,111.0,110.9,55.7,48.6,44.4,33.3,30.9,28.5,21.8.
Embodiment 37：(anti-)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines are (different
Structure body 1) preparation
29c (110mg, 0.63mmol) and acetic acid (40mg, 0.68mmol) are added to 10mL 1,2- dichloros at 0 DEG C
(4- oxocyclohexyls) t-butyl carbamate (160mg, 0.72mmol) is added under magnetic agitation, is stirred at room temperature for ethane
Then sodium triacetoxy borohydride (267mg, 1.26mmol) is added into reaction mixture, and is stirred at room temperature by 10min
6 hours.After the completion of reaction, 50ml dichloromethane is added, with saturated sodium bicarbonate solution and brine It, anhydrous MgSO4It is dry
It is dry, it filters, is concentrated in vacuo.Crude product passes through silica gel chromatography (petroleum ether:Ethyl acetate=9:1) white solid, is obtained
(intermediate 1 and intermediate 2).Then Isosorbide-5-Nitrae-dioxane of 5mL 4M HCl is added in intermediate 1, and at room temperature
It is stirred overnight, filters, washed and dried with ether, obtained (isomers 1), yellow solid, 20mg (14%).1H NMR
(400MHz,D2O)δ7.37(d,1H),7.33–7.25(m,2H),6.88(d,1H),3.60-3.52(m,1H),3.21–3.11
(m,2H),3.04–2.96(m,1H),2.40-2.26(m,2H),2.21-2.09(m,2H),2.03–1.83(m,5H),1.71–
1.55(m,2H),1.47–1.39(m,1H).13C NMR(101MHz,D2O)δ143.91,143.85,127.48,127.05,
124.72,119.19,56.48,46.44,39.47,30.76,30.19,28.13,25.49,25.46,23.35,22.80,
18.35.
Embodiment 38：(anti-)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines are (different
Structure body 2) preparation
The preparation of (isomers 2) with the 37 of in embodiment 37 prepare it is identical, the difference is that, with intermediate 2 substitute
Intermediate 1 takes off Boc reactions, obtains (isomers 2), yellow solid, 25mg (18%).1H NMR(400MHz,D2O)δ7.38(d,
1H),7.34–7.25(m,2H),6.88(d,1H),3.45-3.39(m,1H),3.31-3.25(m,1H),3.22–3.11(m,
2H),3.04-2.97(m,1H),2.48-2.43(m,1H),2.38–2.16(m,5H),1.74–1.51(m,5H),1.43-1.40
(m,1H).13C NMR(101MHz,D2O)δ143.92,143.82,127.45,127.03,124.71,119.16,57.01,
48.49,39.32,30.57,30.13,28.13,28.00,27.97,26.83,26.27,18.57.
Embodiment 39：(suitable)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines are (different
Structure body 3) preparation
The preparation of (isomers 3) with the 38 of in embodiment 38 prepare it is identical, the difference is that with 29c'(110mg,
29c 0.63mol) is substituted, white solid (intermediate 3 and intermediate 4) is obtained, Isosorbide-5-Nitrae-dioxanes of 5mL 4M HCl is added to
It in intermediate 3, and is stirred at room temperature overnight, filters, washed and dried with ether, obtained (isomers 3), yellow oil,
25mg (18%).1H NMR(400MHz,D2O)δ7.46(d,1H),7.41–7.31(m,2H),7.19(d,1H),3.40(s,
1H),3.20–3.09(m,2H),3.06-3.00(m,1H),2.96-2.94(m,1H),2.48–2.33(m,1H),2.28-2.18
(m,1H),2.04–1.94(m,2H),1.92–1.78(m,3H),1.76–1.65(m,3H),1.63-1.59(m,1H),1.54-
1.48(m,2H).13C NMR(101MHz,D2O)δ146.58,139.16,128.15,126.84,125.75,120.22,
56.14,46.60,39.30,35.07,32.25,30.10,25.17,25.01,23.37,22.78,13.44.
Embodiment 40：(suitable)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines are (different
Structure body 4) preparation
The preparation of (isomers 4) is identical as with preparing for 39 in embodiment 39, the difference is that, it is replaced with intermediate 4
Boc reactions are taken off for intermediate 3, are obtained (isomers 4), yellow solid, 21mg (15%).1HNMR(400MHz,D2O)δ7.46(d,
1H),7.39-7.30(m,2H),7.15(d,1H),3.19–3.10(m,2H),3.09–2.99(m,2H),2.91-2.86(m,
1H),2.43-2.34(m,1H),2.28-2.25(m,1H),2.17-2.13(m,1H),2.06–1.90(m,3H),1.68-1.65
(m,1H),1.61-1.50(m,2H),1.46–1.26(m,3H).13C NMR(101MHz,D2O)δ146.52,139.21,
128.04,126.71,125.61,120.33,57.01,48.32,38.96,35.07,32.14,30.08,27.87,27.85,
26.46,25.96,13.73.
Embodiment 41：Inhibition test of the compounds of this invention to LSD1
Experimental method：Utilize the LANCE Ultra LSD1Histone H3-Lysine of Perkin Elmer companies
4DemethylaseAssay kits detection LSD1 goes histone H 3 K4 active.Reaction system:50mM Tris-HCl pH9.0,
DTT, 0.01%Tween-20,10 μM of FAD of 50mM NaCl, 1mM, the H3K4me peptide substrates of 200nM biotin labelings,
2 multiple holes are arranged in 20nM GST-LSD1, each gradient, and not enzyme reacting hole is as blank control wells, and ORY-1001 is as positive
Reference material, test sample are diluted with 10%DMSO, from 500 μM of startings of maximum concentration according to three times gradient dilution.Reaction one
The H3K4 backgrounds antibody and ULight-Streptavidin of Eu labels are added after a hour, final concentration is respectively 2nM and 50nM,
Final detection volume is 20 μ L.It waits for after reaction, being put into Envision and being read, excitation wavelength 320nm, two transmittings
Wavelength is respectively 620nm and 665nm.Under the single concentration conditions of just selection, such as 20 μ g/ml, the activity of sample is tested.It is right
In showing active sample under certain condition, for example, suppression rate %Inhibition big by 50, test agents amount dependence,
That is IC50Value carries out Nonlinear Quasi to sample concentration by sample activity and obtains, and it is Graphpad Prism to calculate software used
4, it is sigmoidaldose-response (varible slope) to be fitted used model, by matched curve bottom and top
Portion is set as 0 and 100.
Embodiment 42：The bioluminescence coupling of monoamine oxidase measures (MAO Glo assay)
Experimental method：1 × reaction buffer, 10 μM of MAOA substrates, a concentration of 100 μ U of MAOA albumen test compound pair
It is diluted with DMSO, from 40 μM of startings of maximum concentration, according to three times gradient dilution, a concentration of 4%, TCP of DMSO are as positive
After reacting 60min, the mixture of follow-up methyl esterase and luciferase is added in reference material, is read using Envision after reacting 20min
Number.Under the single concentration conditions of primary dcreening operation selection, such as 20 μ g/ml, the activity of sample is tested.For showing under certain condition
Go out active sample, such as inhibiting rate %Inhibition is more than 50, test agents amount dependence, i.e. IC50 values pass through
Sample activity carries out Nonlinear Quasi to sample concentration and obtains, and it is Graphpad Prism 4 to calculate software used, and fitting is made
Model is sigmoidaldose-response (varible slope), and matched curve bottom and top are set as 0 He
100。
Monoamine oxidase B activity test method is same as above.
The inhibitory activity data of 1 compound of table and positive control ORY-1001 to LSD1, MAOA, MAOB and LSD2.
αNT:not tested.
As a result with evaluation：Activity data is shown in table 1,2' prepared by the present invention, 3'- dihydro spiral shell [cyclopropane -1,1'-
Indenes] -2- amine derivatives go out higher inhibitory activity to LSD1 common manifestations, while being showed preferably to monoamine oxidase and LSD2
Selectivity.Especially, embodiment 13, the inhibitory activity IC of 14,15,16,17,22,23,25 couples of LSD150Value is respectively less than 10nM,
And it is preferable to the selectivity of homology enzyme.In addition, being better than positive control ORY-1001 to LSD1 inhibitory activity.Therefore, this hair
Bright 2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives are suitable for preparing the treatment acute myeloid using LSD1 as target spot
The drug of leukaemia.
In conclusion 2' proposed by the present invention, 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives are as LSD1
Inhibitor has potential drug research to be worth in terms for the treatment of acute myeloid leukemia, for the white blood of the acute marrow for the treatment of for finding novel
The drug of disease provides new approaches.
The protection content of the present invention is not limited to above example.Without departing from the spirit and scope of the invention, originally
Field technology personnel it is conceivable that variation and advantage be all included in the present invention, and with appended claims be protect
Protect range.
Claims (13)
1. a kind of 2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives, which is characterized in that its structure such as following formula
(I) shown in：
Wherein, R1For hydrogen, halogen, aryl, substituted aryl, heterocycle, substituted heterocycle；
R2For hydrogen, alkyl-substituted aryl, methoxyl group and alkyl-substituted aryl, halogen and alkyl-substituted aryl, halogen, first
Oxygroup and alkyl-substituted aryl, alkyl-substituted hetero-aromatic ring, methoxyl group and alkyl-substituted hetero-aromatic ring, halogen and alkyl substitution
Hetero-aromatic ring, cyclohexylamine, 1- morpholine substituted alkyl -1- ketone.
2' as described in claim 1,3'- dihydro spiral shell 2. [cyclopropane -1,1'- indenes] -2- amine derivatives, which is characterized in that
In formula (I), R1Selected from hydrogen, bromine, phenyl, 4- fluorophenyls；
R2For hydrogen or following group：
2' as described in claim 1,3'- dihydro spiral shell 3. [cyclopropane -1,1'- indenes] -2- amine derivatives, which is characterized in that its
Selected from following：
(1) (anti-) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(2) (suitable) -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(3) (anti-)-N- (pyridine -3- methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(4) (suitable)-N- (pyridine -3- methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(5) (anti-)-N- ((2- methoxypyridine -3- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(6) (suitable)-N- ((2- methoxypyridine -3- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(7) (anti-)-N- ((2- fluorine pyridin-3-yl) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(8) (suitable)-N- ((2- fluorine pyridin-3-yl) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(9) (anti-)-N- ((3- fluorine pyridine -2- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(10) (suitable)-N- ((3- fluorine pyridine -2- bases) methyl) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(11) (anti-)-N- benzyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(12) (suitable)-N- benzyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(13) (anti-)-N- (2- methoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(14) (suitable)-N- (2- methoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(15) (anti-)-N- (2- luorobenzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(16) (suitable)-N- (2- luorobenzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(17) (anti-)-N- (the bromo- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(18) (suitable)-N- (bromo- 2- methoxy-benzyls -2', the 3'- dihydro spiral shells of 5- [cyclopropane -1,1'- indenes] -2- amine
(19) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(20) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 5-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(21) (anti-)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(22) (suitable)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(23) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 4-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(24) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 4-) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(25) (anti-)-N- (3,4- dimethoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(26) (suitable)-N- (3,4- dimethoxy-benzyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(27) (anti-)-N-2- ((2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) amino) -1- morpholino ethane -1- ketone
(28) (suitable)-N-2- ((2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) amino) -1- morpholino ethane -1- ketone
(29) (anti-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(30) (suitable) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(31) (anti-) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(32) (suitable) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -2- amine
(33) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(34) (suitable)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine
(35) (anti-)-N- (the chloro- 3,4- dimethoxy-benzyls of 2-) -5'- phenyl -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -
2- amine
(36) (anti-)-N- (the fluoro- 2- methoxy-benzyls of 5-) -5'- (4- fluorophenyls) -2', 3'- dihydros spiral shell [cyclopropane -1,1'-
Indenes] -2- amine
(37) (anti-)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers 1)
(38) (anti-)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers 2)
(39) (suitable)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers 3)
(40) (suitable)-N- (2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- bases) cyclohexane-1,4-diamines (isomers 4).
4. a kind of preparation method of 2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine derivatives, which is characterized in that including with
Lower step：
(1) in organic solvent, using formula (II) compound as raw material, with methyltriphenylphosphonium bromide Ph3PCH3Br and t-BuOK into
Row Witting reactions, obtain formula (III) compound；
(2) in organic solvent, rhodium acetate Rh2(OAc)2It is catalyzed ethyl diazoacetate N2=CHCO2Et and formula (III) compound into
Row cyclopropanization reaction obtains formula (IV) compound and formula (V) compound；
(3) reaction is hydrolyzed in formula (IV) compound and formula (V) compound, and Curtius is reset, and obtains formula (VI) compound and formula
(VII) compound；
Target compound is prepared by following four mode in formula (VI) compound/formula (VII) compound of preparation：
(4-1) formula (VI) compound/formula (VII) compound takes off Boc protecting groups, through reduction amination, obtain formula (VIII) compound/
Formula (IX) compound (wherein, formula (VI) compound of formula (VIII) compound, formula (VII) compound of formula (IX) chemical combination
Object)；Or
With 2- chloro- 1- morpholinoes ethane -1- ketone substitution reaction occurs for (4-2) formula (VI) compound/formula (VII) compound, then
Boc protecting groups are removed, formula (X) compound or formula (XI) compound are obtained；Or
With (4- oxocyclohexyls) t-butyl carbamate reduction amination occurs for (4-3) formula (VI) compound/formula (VII) compound
Then reaction takes off Boc protecting groups, obtains formula (XII) compound/formula (XIII) compound；Or
Suzuki coupling reactions occur for (4-4) formula (VI) compound/formula (VII) compound and substituted aryl boric acid, then take off
Boc protecting groups obtain formula (XIV) compound/formula (XV) compound, and reduction ammonia then occurs with substituted pyridine aldehydes or benzaldehyde
Change reaction, obtains formula (VIII) compound/formula (IX) compound；
Shown in the method such as following formulas (A)：
5. method as claimed in claim 4, which is characterized in that the step (3) specifically includes following steps：
I) in EtOH and H2The in the mixed solvent of O, it is molten in the mixing of KOH using formula (IV) compound and formula (V) compound as raw material
It is heated to reflux generation hydrolysis under liquid, obtains carboxylic acid；
Ii) in organic solvent, using carboxylic acid as raw material, react at room temperature to obtain azide with diphenyl phosphate azide, triethylamine；
Iii) in organic solvent, in the tert-butyl alcohol, azide obtains formula (VI) compound with tert-butyl alcohol heating reflux reaction
With formula (VII) compound.
6. method as claimed in claim 4, which is characterized in that (4-1) specifically includes following steps：
I) formula (VI) compound/formula (VII) compound obtains salt at room temperature in 4M HCl/EtOAc solution removal Boc protecting groups
Hydrochlorate；
Ii) in organic solvent, hydrochloride and triethylamine, substituted pyridine aldehydes or benzaldehyde, reducing agent be through reduction amination,
Obtain formula (VIII) compound/formula (IX) compound.
7. method as claimed in claim 4, which is characterized in that (4-2) specifically includes following steps：
I) in DMF, using formula (VI) compound/formula (VII) compound as raw material, with the chloro- 1- morpholinoes ethane -1- ketone of 2- and
NaH is reacted at room temperature, and obtains intermediate；
Ii) intermediate removes Boc protecting groups in 4M HCl/EtOAc solution at room temperature, obtains formula (X) compound/formula (XI) change
Close object.
8. method as claimed in claim 4, which is characterized in that (4-3) specifically includes following steps：
I) in DCE, using formula (VI) compound/formula (VII) compound as raw material, with the tertiary fourth of (4- oxocyclohexyls) carbamic acid
Ester and acetic acid, reducing agent room temperature react, and obtain intermediate；
Ii) at room temperature, intermediate removes Boc protecting groups in 4M HCl/EtOAc solution, obtains formula (XII) compound/formula
(XIII) compound.
9. method as claimed in claim 4, which is characterized in that (4-4) specifically includes following steps：
I) in DMF, using formula (VI) compound/formula (VII) compound as raw material, with substituted aryl boric acid, Pd (PPh3)4With
Na2CO3Reaction, obtains intermediate；
Ii) at room temperature, intermediate removes Boc protecting groups in 4M HCl/EtOAc solution, obtains formula (XIV) compound/formula
(XV) compound；
Iii) in organic solvent, using formula (XIV) compound/formula (XV) compound as raw material, with triethylamine, substituted pyridine aldehydes
Or benzaldehyde, reducing agent obtain formula (VIII) compound/formula (IX) compound through reduction amination.
10. any one of them formula (I) 2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine such as claims 1 to 3 derives
Application of the object in the inhibitor as LSD1.
11. any one of them formula (I) 2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -2- amine such as claims 1 to 3 derives
The application of object, which is characterized in that it is used to prepare the treatment as target spot to realize to disease using LSD1.
12. application as claimed in claim 11, which is characterized in that the disease is leukaemia.
13. application as claimed in claim 12, which is characterized in that the disease is acute myeloid leukemia.
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| CN110041257A (en) * | 2019-04-25 | 2019-07-23 | 河南师范大学 | A method of synthesis indenes spiral shell indenes [1,2-c] isoquinolin trione compounds |
| CN113264816A (en) * | 2021-05-31 | 2021-08-17 | 湖北科技学院 | Spiro [ cyclopropane-1, 2' -indene ] -1',3' -diketone derivative and synthetic method thereof |
| WO2022214303A1 (en) | 2021-04-08 | 2022-10-13 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for treating myeloid cancers |
| WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
| WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
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| US20040077551A1 (en) * | 2002-05-20 | 2004-04-22 | Campbell Jeffrey Allen | Substituted cycloalkyl P1' hepatitis C virus inhibitors |
| WO2016123387A1 (en) * | 2015-01-30 | 2016-08-04 | Genentech, Inc. | Therapeutic compounds and uses thereof |
| CN106045862A (en) * | 2015-04-10 | 2016-10-26 | 上海迪诺医药科技有限公司 | Cyclopropylamine spiro(hetero)cyclic compound, and pharmaceutical composition and application thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110041257A (en) * | 2019-04-25 | 2019-07-23 | 河南师范大学 | A method of synthesis indenes spiral shell indenes [1,2-c] isoquinolin trione compounds |
| CN110041257B (en) * | 2019-04-25 | 2021-08-03 | 河南师范大学 | Method for synthesizing indene spiro indene [1,2-c ] isoquinoline triketone compound |
| WO2022214303A1 (en) | 2021-04-08 | 2022-10-13 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for treating myeloid cancers |
| CN113264816A (en) * | 2021-05-31 | 2021-08-17 | 湖北科技学院 | Spiro [ cyclopropane-1, 2' -indene ] -1',3' -diketone derivative and synthetic method thereof |
| WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
| WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
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