CN106045862A - Cyclopropylamine spiro(hetero)cyclic compound, and pharmaceutical composition and application thereof - Google Patents

Abstract

The invention relates to a preparation method for a cyclopropylamine spiro(hetero)cyclic compound and a composition containing the same, and application of the compound and the composition as an inhibitor for human lysine-specific demethylase (LSD1). The inhibitor is the cyclopropylamine spiro(hetero)cyclic compound as shown in a formula (I) which is described in the specification, or a pharmaceutically acceptable salt, predrug, solvate, polymorphic crystal or stable isotope derivative thereof. The compound can be used for treating or preventing diseases related to human lysine-specific demethylase, e.g., cancers and nerve diseases.

Description

Cyclopropylamine class spiral shell (miscellaneous) cycle compound, its pharmaceutical composition and application

Technical field

The present invention relates to a kind of cyclopropylamine class spiral shell (miscellaneous) cycle compound, its isomer, prodrug or pharmaceutically acceptable salt, stable isotope derivatives, its pharmaceutical composition, preparation method and application.

Background technology

People's lysine specificity demethylase (Human lysine specific demethylasel, LSD1) it is amino oxidase family member, in the presence of flavin adenine dinucleotide (FAD) (FAD), LSD1 the dimethyl on the 4th (H3K4) and the 9th (H3K9) lysine residue and monomethyl can modify on special removal histone H 3.LSD1 can also remove methylate modification, such as p53 and DNMT1 etc. on some other nonhistones substrate.LSD1 has various biological function, mainly includes promoting tumor proliferation, suppression energy metabolism, promoting lipogenesis, suppression steatolysis and regulating cell differentiation etc..Therefore LSD1 is prevention and the potential drug target treating multiple disease.

LSD1 all overexpression in kinds of tumors tissue, such as, carcinoma of prostate, breast carcinoma, neuroblastoma, nonsmall-cell lung cancer and bladder cancer etc. (Cancer cell, 2011,20 (4): 457-71；Carcinogenesis, 2010,31 (3): 512-20).During the generation and development of kinds cancer, the expression of a lot of tumor suppressor genes is suppressed extremely.The inhibitor of LSD1 can make the gene (SFRP1, SFRP4, SFRP5 and GATA5) that in colorectal cancer cells, these are suppressed extremely again express, thus induce apoptosis (Int J Cancer, 2011,128 (3): 574-86), the existing LSD1 of discovery again is closely related with Differentiation of Neuroblastoma；LSD1 high expressed in PD neuroblastoma, after siRNA knocks out LSD1, the growth of oncocyte is suppressed, experiment in vivo confirms that suppression LSD1 can suppress the growth LSD1 of neuroblastoma by changing and the histone methylated state in tumor increment related gene promoter region, thus regulate the expression of associated protein, promote the growth of kinds of tumors further.In some hematologic cancers, LSD1 expression is PD with cell in becoming positive correlation, and in the M1 hypotype acute myeloid leukemia of low side differentiation, LSD1 is overexpression.LSD1 plays an important role for the maintenance of leukemic stem cells increment and dryness, and this conclusion is similarly obtained checking (Cancer cell, 2012,21 (4): 473-87) in gene fusion type leukemia.H3K4me2, as the substrate of LSD1, has been found to its level and memory improvement is related (Nature 2007,447,175), and therefore LSD1 inhibitor is also used as prevention or the therapeutic agent of neurodegenerative disease.

Known to comprise cyclopropylamine structure compound can suppress multiple therapy target, including amino oxidase, such as monoamine oxidase A (MAO-A), monoamine oxidase-B (MAO-A), LSD1.Tranylcypromine is the active component of marketed drug Parnate, can suppress above-mentioned target spot, but owing to suppression MAO-A may result in the generation of adverse side effect, therefore the high selective cyclopropylamine class medicine of exploitation is necessary.

Summary of the invention

Owing to the most selectivity is not for the medicine listing of LSD1 target spot, therefore exploitation LSD1 inhibitor is used for preventing and treat cancer and sacred disease is feasible.

The technical problem to be solved is, it is provided that a kind of have cyclopropylamine class spiral shell (miscellaneous) cycle compound, its stereoisomer, prodrug or the pharmaceutically acceptable salt of regulation effect, its stable isotope derivatives, its pharmaceutical composition, preparation method and application for people's lysine specificity demethylase (LSD1).

On the one hand, the invention provides a kind of compound, its isomer, prodrug, stable isotope derivatives and pharmaceutically acceptable salt shown in formula I；

Wherein, A ring is and cyclic group；In described also cyclic group, at least a ring is saturated rings, and described saturated rings includes cycloalkyl or Heterocyclylalkyl；Described A ring is selected from: C_6-10Aryl C_4-8Cycloalkyl, C_3-5Heteroaryl C_4-8Cycloalkyl, C₆Aryl C_3-7Heterocyclylalkyl or C_3-5Heteroaryl C_3-7Heterocyclylalkyl.

Described A ring forms volution or spiroheterocyclic structure by the saturated C atom in also cyclic group saturated rings and cyclopropylamine group shown in formula I by sharing a C atom.

Described A ring arbitrarily can be replaced selected from the substituent group of R by n, and wherein, n is 0,1,2,3 or 4, and R is selected from hydrogen, R₁Or-L₂-E。

R₁Selected from halogen ,-OH ,-CN ,-NO₂,-SH, carboxyl, amino, alkyl, haloalkyl, halogenated alkoxy, alkyl amino, C_2-6Alkynyl, C_2-6Thiazolinyl, cycloalkyl, cycloalkyl-alkyl, Heterocyclylalkyl, hetercycloalkylalkyl ,-OR₆、-OC(O)R₆、-OC(O)NR₆R_6a、-C(O)OR₆、-C(O)R₆、-C(O)NR₆R_6a、-N(R₆)C(O)R_6a、-N(R₆)C(O)NR₆R_6a、-(CH₂)_rNR₆R_6a、-N(R₆)SO₂R_6a、-S(O)_0-2R₆Or-SO₂NR₆R_6a, r is the integer of 1-5；

-L₂-E is selected from-(CH₂)_m-E、-O(CH₂)_m-E or-N (R₃)(CH₂)_m-E；Wherein, m is 0,1,2,3 or 4；When m is 0 ,-(CH₂)_m-for connecting key, E is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl；When E is replaced, can be by one or more R₁It is substituted in optional position.R₃Selected from hydrogen, alkyl, haloalkyl ,-S (O)_0-2R₆、-C(O)R₆、-C(O)OR₆、-CONR₆R_6a, aminoalkyl or hydroxyalkyl；R is the integer of 1-5；

R₆And R_6aIt is each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, hetercycloalkylalkyl, cycloalkyl-alkyl, aryl alkyl or heteroaryl alkyl, or, R₆And R_6aSingle Heterocyclylalkyl of 3-7 unit is formed together with the atom N being jointly connected with them.

R_x、R_y、R_zIt is each independently selected from hydrogen, deuterium, halogen or alkyl, or, R_xWith R_yThe monocyclic cycloalkyl of 3-7 unit is formed together with the C atom being jointly connected with them.

L₁Selected from-(CR₂R_2a)_m-；Wherein, m is 0,1,2,3 or 4；R₂And R_2aIt is each independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, hydroxyl, amino, monocyclic cycloalkyl, monocyclic cycloalkyl alkyl, alkoxyl, aminoalkyl, single Heterocyclylalkyl, single hetercycloalkylalkyl ,-OC (O) R₇、-OC(O)NR₇R_7a、-NR₇R_7a、-N(R₇)C(O)R_7a、-N(R₇)S(O)₂R_7a、-N(R₇)C(O)NR₇R_7a、-S(O)₂NR₇R_7a、-(CH₂)_rS(O)_0-2R₇、-(CH₂)_rC(O)OH、-C(O)R₇、-C(O)OR₇、-C(O)NR₇R_7a、-(CH₂)_rC(O)NR₇R_7aOr-(CH₂)_rNR₇R_7a；R is the integer of 1-5.

R₇And R_7aIt is each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, hetercycloalkylalkyl, cycloalkyl-alkyl, aryl alkyl or heteroaryl alkyl, or, R₇And R_7aSingle Heterocyclylalkyl of 3-7 unit is formed together with the atom N being jointly connected with them.

M is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl；

In M, described substituted cycloalkyl, substituted Heterocyclylalkyl, substituted cycloalkyl-alkyl, substituted hetercycloalkylalkyl, substituted aryl or substituted heteroaryl can be by following one or more R₅And/or R_5aGroup is substituted in optional position: hydrogen, halogen ,-OR₇、-SR₇、-NO₂,-CN, amino, alkyl, haloalkyl, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, heterocycloalkylalkoxy, cycloalkyl alkoxy, alkoxy aryl, heteroarylalkoxy, aminoalkyl ,-OC (O) R₇、-OC(O)NR₇R_7a、-NR₇R_7a、-N(R₇)C(O)R_7a、-N(R₇)S(O)₂R_7a、-N(R₇)C(O)NR₇R_7a、-S(O)₂NR₇R_7a、-(CH₂)_rS(O)_0-2R₇、-(CH₂)_rCOOH、-C(O)R₇、-C(O)OR₇、-C(O)NR₇R_7a、-(CH₂)_rC(O)NR₇R_7aOr-(CH₂)_rNR₇R_7a；

In M, described substituted cycloalkyl, substituted Heterocyclylalkyl, substituted cycloalkyl-alkyl, substituted hetercycloalkylalkyl also can be by one=R₄Group is substituted in optional position ,=R₄Selected from=O ,=S or=NH；

In M, described R₄And R_5aBy unsubstituted or replaced by following one or more groups further: C_1-3Alkyl, halogen ,-OH ,-CN ,-NO₂, amino, carboxyl, C_1-3Alkoxyl, halo C_1-3Alkoxyl, halo C_1-3Alkyl, C_6-10Aryl, C_3-5Heteroaryl, C_3-8Cycloalkyl or 5-7 unit Heterocyclylalkyl；

In described A ring, described C_6-10Aryl C_4-8Cycloalkyl preferred benzo C_4-7Cycloalkyl or naphthalene nucleus C_4-7Cycloalkyl；Described C₆Aryl C_3-7Heterocyclylalkyl preferred benzo C_3-6Heterocyclylalkyl；Described C_3-5Heteroaryl C_4-8The preferred pyridine ring of cycloalkyl C_4-7Cycloalkyl；Described C_3-5Heteroaryl C_3-7The preferred pyridine ring of Heterocyclylalkyl C_3-6Heterocyclylalkyl.

Described A ring is preferably: Or

In described R, described R₁It is selected from: fluorine, chlorine ,-OH ,-CN ,-NO₂,-C (O) OH, amino, C_1-3Alkyl (such as, methyl, ethyl, n-pro-pyl or isopropyl), C_1-3Alkoxyl, halo C_1-3Alkyl and halo C_1-3Alkoxyl.

In described R, described-L₂-E is selected from-(CH₂)_m-E、-O(CH₂)_m-E or-N (R₃)(CH₂)_m-E；M is 0,1 or 2；The preferred substituted or unsubstituted phenyl ring of E or substituted or unsubstituted 5-6 unit hetero-aromatic ring；Described E is more preferably: substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazole radicals, substituted or unsubstituted tetrazole base；Described substituted phenyl, substituted pyrazolyl, substituted imidazole radicals or substituted tetrazole base can be by 1-2 R₁It is substituted in optional position；Described R₃Preferably hydrogen or methyl.

Described R_x、R_yAnd R_zIt is separately: hydrogen, deuterium, methyl or fluorine.Described R_x、R_yAnd R_zMore preferably hydrogen.

Described L₁Selected from-(CH₂)_m-, m is 0,1,2 or 3；When m is 0, L₁For connecting key.

Described M is selected from substituted or unsubstituted C_3-10Cycloalkyl, substituted or unsubstituted C_3-10Cycloalkyl C_1-3Alkyl, substituted or unsubstituted 3-10 unit Heterocyclylalkyl, substituted or unsubstituted 3-10 unit Heterocyclylalkyl C_1-3Alkyl.

Described M, described substituent R₅Preferably C_1-4Alkyl, halo C_1-4Alkyl ,-OR₇、C_6-10Aryl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl, amino ,-NR₇R_7a、-CONR₇R_7a、-(CH₂)_rNR₇R_7a、-C(O)R₇Or-C (O) OR₇；

Described M, described substituent R_5aPreferably hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, C_6-10Aryl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl ,-CONR₇R_7a、-(CH₂)_rNR₇R_7a、-C(O)R₇Or-C (O) OR₇；

Wherein, R₇And R_7aIt is each independently selected from hydrogen, C_1-3Alkyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkyl, phenyl or phenyl C_1-3Alkyl, or R₇And R_7aSingle Heterocyclylalkyl of 3-7 unit is formed together with the atom N being jointly connected with them；R is preferably 1,2 or 3.

The substituent R of described M₅Or R_5aCan be replaced by following one or more groups further: C_1-3Alkyl, C_1-3Alkoxyl, fluorine, chlorine ,-CF₃,-OH, amino, carboxyl, nitro, cyano group or cyclopropyl；

Described M, described substituted C_3-8Cycloalkyl C_1-3Alkyl, 3-8 unit Heterocyclylalkyl C_1-3Alkyl also can be by one=R₄Group is substituted in optional position ,=R₄Selected from=O.

When described M is replaced, preferably by 1-3 R₅And/or R_5aIt is substituted in optional position.Described M is preferably selected from following M₁To M₂₀In any one:

P is 0,1,2 or 3.

Described M is preferably: OrDescribed M is more preferably: Or

Compound, its isomer, prodrug, stable isotope derivatives and pharmaceutically acceptable salt shown in formula I describedly, its general structure is preferably Formulas I A:

In IA, B ring is phenyl ring, pyridine ring or naphthalene nucleus；

X is separately-CH₂-、-C(O)-、-O-、-S(O)_0-2-、-C(O)N(R_1b)-、 -N(R_1b)C(O)N(R_1b)-or N (R_1a)；Q is selected from 0,1 or 2；R is selected from 1 or 2；

R_1aSelected from hydrogen, C_1-6Alkyl, 3-8 unit cycloalkyl, 3-8 unit Heterocyclylalkyl ,-C (O) R₇、-C(O)OR₇Or-C (O) NR₇R_7a；R_1bSelected from hydrogen or C_1-6Alkyl；R₇And R_7aIt is each independently selected from hydrogen, C_1-3Alkyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkyl, phenyl or phenyl C_1-3Alkyl；Or R₇And R_7aSingle Heterocyclylalkyl of 3-7 unit is formed together with the atom N being jointly connected with them；

The definition of remaining each substituent group is all the same described.

Compound, its isomer, prodrug, stable isotope derivatives and pharmaceutically acceptable salt shown in formula I describedly, its general structure is preferably Formulas I A-1 and IA-2:

Wherein, n is selected from 0,1,2 or 3；Q is selected from 0 or 1；R is 1；X is-CH₂-or-O-；The definition of remaining each substituent group is all the same described.

Compound, its isomer, prodrug, stable isotope derivatives and pharmaceutically acceptable salt shown in formula I describedly, its general structure is more preferably Formulas I B:

Wherein, R is worked as_xOr R_yDuring for different substituents, the C of * mark₁、C₂And C₃Being respectively chiral carbon, stereoisomeric configurations presses (C₁, C₂, C₃) sequentially it is respectively as follows: (S, S, S) type, (R, S, R) type, (S, S, R) type, (R, S, S) type, (S, R, S) type, (R, R, R) type, (S, R, R) or (R, R, S) type.

Work as R_xAnd R_yDuring for identical substituent group, the C of * mark₂And C₃Being respectively chiral carbon, stereoisomeric configurations presses (C₂, C₃) sequentially it is respectively as follows: (S, S) type, (S, R) type, (R, R) type or (R, S) type.Compound as shown in Formulas I B can be the stereoisomer of single configuration, it is also possible to for the mixture of the stereoisomer of multiple various configuration.

When M is substituted cycloalkyl, and described substituent R₅?Para-position time, such as, M isTime, then compound as shown in Formulas I B also includes the cis-trans-isomer as shown in Formulas I B-1 (cis) and IB-2 (trans).

Above-mentioned formula method for expressing for compound shown in Formulas I B-1 and IB-2 only illustrates substituent R on cyclohexyl ring₅WithRelative stereochemical structure (cis or trans).Compound as shown in Formulas I B-1 and IB-2 can be single configuration of compound, or spatial configuration mixture.Two kinds of representations of said structure formula IB-1 all represent substituent R on cyclohexyl ring₅WithRelative stereochemical structure be cis, two kinds of representations of general structure IB-2 all represent substituent R on cyclohexyl ring₅WithRelative stereochemical structure be trans；The definition of described each substituent group is all the same described.

Described cyclopropylamine class spiral shell (miscellaneous) cycle compound shown in formula I is following arbitrary compound:

The invention further relates to compound shown in below formula:

Wherein, B ring, R, R_x、R_y、R_z, X, n, q and r defined as described above.

Described compound as shown in Formula II is preferably Formula II A, IIB, IIC or IID:

Wherein, the definition of described each substituent group is all the same described.

Second aspect, the invention still further relates to the preparation method of compound shown in formula I:

Described preparation method comprises the steps: in solvent, and compound as shown in Formula II occurs reductive amination process to obtain compound as shown in Formulas I A in the presence of reducing agent and acid/lewis acid；

Wherein, described aldehyde isL₃For-(CR₂R_2a)_{m ’}-, m ' is 0,1,2 or 3, and wherein M is defined as described above；Described ketone is O=M, and wherein M does not include aryl and/or heteroaryl；

The condition of described reductive amination process and step can be condition and the step of the reductive amination process of this area routine.Following reaction condition specifically preferred according to the invention: the preferred dichloromethane of described solvent or 1,2-dichloroethanes；Described acid preferably acetic acid；The temperature of described reaction preferably 0～30 DEG C；Preferably 1～24 hour described response time.In above-mentioned reductive amination process, as Formula II,Or when there is other amino group in compound shown in O=M, this amino group all should be protected by amino protecting group, has just been avoided that any side reaction.Then need after follow-up deprotection steps if there is above-mentioned amido protecting group, just can obtain compound as shown in Formulas I A.Any suitable amido protecting group, such as: tertbutyloxycarbonyl (BOC) group, all can use.If using BOC as protection group; follow-up deprotection reaction can be in standard conditions, such as, and p-methyl benzenesulfonic acid/methanol system; dichloromethane/trifluoroacetic acid system, saturated ether solution of hydrogen chloride or Trimethylsilyl trifluoromethanesulfonate/2, carried out in 6-lutidines/dichloromethane system.The acid systems such as p-methyl benzenesulfonic acid, hydrochloric acid, hydrogen chloride or trifluoroacetic acid are used in last synthesis step, or in purge process, such as: prepare when there is above-mentioned acid system in the flowing mutually of HPLC, then the described compound as shown in Formulas I A would is that corresponding tosilate, hydrochlorate or trifluoroacetate etc..

Wherein as shown in Formula II, compound can be prepared by method A, from initiation material A₁Start, in non-protonic solvent (preferably oxolane), react with phosphorus ylide reagent obtain intermediate A by Wittig (wittig)₂,；Ethyl diazoacetate forms carbethoxy carbene, with intermediate A under cupric acetylacetonate (II) acts on₂Reaction obtains intermediate A₃, A₃The sour A of correspondence is obtained in the basic conditions through hydrolysis₄After obtain intermediate A through Ku Ertisi (Curtius) rearrangement reaction again₅, A₅Slough tertbutyloxycarbonyl protection in acid condition and obtain II-a；Reaction expression is as follows:

The third aspect, present invention also offers a kind of pharmaceutical composition, it active component including therapeutically effective amount and pharmaceutically acceptable adjuvant；Described active component includes one or more in cyclopropylamine class spiral shell (miscellaneous) cycle compound (I), its isomer, prodrug, stable isotope derivatives and pharmaceutically acceptable salt.

In described pharmaceutical composition, described active component may also include other therapeutic agent that cancer, sacred disease or virus infect.

In described pharmaceutical composition, described pharmaceutically acceptable adjuvant can include pharmaceutically acceptable carrier, diluent and/or excipient.

According to therapeutic purposes, pharmaceutical composition can be made various types of administration unit dosage forms, such as tablet, pill, powder, liquid, suspension, emulsion, granule, capsule, suppository and injection (solution and suspension) etc., preferred liquid, suspension, emulsion, suppository and injection (solution and suspension) etc..

In order to make the pharmaceutical composition of tablet form shape, this area can be used any known and widely used excipient.Such as, carrier, such as lactose, white sugar, sodium chloride, glucose, carbamide, starch, calcium carbonate, Kaolin, crystalline cellulose and silicic acid etc.；Binding agent, such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dried starch, sodium alginate, agar powder and Kelp Powder, sodium bicarbonate, calcium carbonate, the fatty acid ester of polyethylene sorbitan, sodium lauryl sulphate, stearic acid monoglycerides, starch and lactose etc.；Disintegrate inhibitor, such as white sugar, glycerol tristearate, Oleum Cocois and hydrogenated oil and fat；Adsorption enhancer, such as quaternary amine alkali and sodium lauryl sulphate etc.；Wetting agent, such as glycerol, starch etc.；Adsorbent, such as starch, lactose, Kaolin, bentonite and colloid silicic acid etc.；And lubricant, such as pure Talcum, stearate, boric acid powder and Polyethylene Glycol etc..Common coated material can also be selected as required to make sugar coated tablet, be coated with gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and multilayer tablet.

In order to make the pharmaceutical composition of pill shape, can use any of and widely used excipient in this area, such as, carrier, such as lactose, starch, Oleum Cocois, hardened vegetable oils, Kaolin and Pulvis Talci etc.；Binding agent, such as gum arabic powder, tragacanth gum powder, gelatin and ethanol etc.；Disintegrating agent, such as agar and Kelp Powder etc..

In order to make the pharmaceutical composition of suppository form shape, this area can be used any known and widely used excipient, such as, Polyethylene Glycol, Oleum Cocois, higher alcohol, the ester of higher alcohol, gelatin and semisynthetic glyceride etc..

In order to prepare the pharmaceutical composition of injection form, after solution or suspension can being sterilized (being preferably added appropriate sodium chloride, glucose or glycerol etc.), make injection isotonic with blood.When preparing injection, it is possible to use carrier any commonly employed in this area.Such as, water, ethanol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol of polyoxy and the fatty acid ester etc. of polyethylene sorbitan.Additionally, common lytic agent, buffer agent and analgesic etc. also can be added.

In the present invention, described compositions content in pharmaceutical composition, without particular restriction, can select in a wide range, generally can be the 10～90% of mass percent, is preferably mass percent 30～80%.

In the present invention, the medication of described pharmaceutical composition is not particularly limited.The preparation of various dosage form can be selected to be administered according to patient age, sex and other condition and symptom.Such as, tablet, pill, solution, suspension, emulsion, granule or capsule oral are administered；Injection can be individually dosed, or is mixed into row vein injection with injection conveying liquid (such as glucose solution and Freamine Ⅲ)；Suppository is for being administered into rectum.

Fourth aspect, the invention still further relates to compound shown in formula I, its pharmaceutically acceptable salt or prodrug, or include compound shown in formula I, its pharmaceutically acceptable salt and/or prodrug, and the application in preparing LSD1 inhibitor of the pharmaceutical composition of pharmaceutically acceptable adjuvant and the application in the medicine of preparation prevention and/or the relevant disease for the treatment of LSD1 mediation.Described disease includes cancer, sacred disease and virus infection etc..Preferred formula I, including compound shown in IA, IA-1, IA-2, IB, IB-1 or IB-2 and their salt and solvate, is suitable for treatment and/or prophylaxis of cancer, and is preferred for treating cancer.

nullWherein，When described disease is cancer，Include but not limited to: hematologic cancer (leukemia)，Including blood、Bone marrow and the cancer of lymph node，As leukemia (includes but not limited to acute myeloid leukaemia (AML)、Acute promyelocytic leukemia (APL)、Chronic myelogenous leukemia (CML)，Chronic neutrophilic granulocyte leukemia、Chronic eosinophilic leukemia、Chronic lymphocytic leukemia (CLL)、Acute lymphoblastic leukemia (ALL) or hairy cell)、Myeloproliferative disease、Multiple myeloma、Myelodysplastic syndrome and lymphoma (include but not limited to hodgkin's lymphomas、Non Hodgkin lymphom)，Colon cancer、Cancer of pancreas、Breast carcinoma、Carcinoma of prostate、Pulmonary carcinoma、The brain cancer、Ovarian cancer、Cervical cancer、Carcinoma of testis、Renal carcinoma、Head and neck cancer、Lymphatic cancer、Or skin carcinoma.

When described disease is sacred disease, include but not limited to: depression, schizophrenia, alzheimer's disease, Huntington Chorea, Parkinson's disease, amyotrophic lateral sclerosis.

Except as otherwise noted, the following term occurred in description of the invention and claims has the meaning that

Term " alkyl " refers to comprise the saturated straight chain of 1-20 carbon atom or branched hydrocarbyl, preferably 1～8 carbon atom, more preferably 1～6 carbon atom, the representative example of alkyl includes but not limited to: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, 4,4-dimethyl amyl group, 2,2,4-tri-methyl-amyls, undecyl, dodecyl, and their various isomers etc..When " alkyl " is as the link group of other group, such as-(CH₂)_m-, it can be side chain or straight chain, and example includes but not limited to-CH₂-、-CH₂CH₂-or-CH₂CH(CH₃)-.Term " C_1-3Alkyl " refer to the alkyl containing 1-3 carbon atom.

Term " cycloalkyl " refers to comprise the saturated of 3-20 carbon atom or the monocycle of part unsaturated (comprising 1 or 2 double bond) or bicyclic radicals." monocyclic cycloalkyl " preferably 3-10 unit monocycle alkyl, more preferably 4-8 unit monocycle alkyl, such as: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring decyl, cyclo-dodecyl, cyclohexenyl group." bicyclic cycloalkyl " includes " dicyclo bridged ring base ", " dicyclo ring cycloalkyl " and " spiro cycloalkyl group ", " dicyclo bridged ring base " refers to that the carbon atom that monocyclic cycloalkyl any two is not linked is connected (that is ,-(CH by the alkylidene bridge between 1-3 extra carbon atom₂)_tThe bridge joint group of-form, wherein t is 1,2 or 3).The representative example of dicyclo bridged ring base includes but not limited to: bornyl, dicyclo [2.2.1] heptenyl, dicyclo [3.1.1] heptane base, dicyclo [2.2.1] heptane base, dicyclo [2.2.2] octyl, dicyclo [3.2.2] nonyl, dicyclo [3.3.1] nonyl, dicyclo [4.2.1] nonyl etc.." dicyclo ring cycloalkyl " comprises the monocyclic cycloalkyl ring being fused on phenyl, monocyclic cycloalkyl, monocyclic heterocycloalkyl or bicyclic heteroaryl, dicyclo ring cycloalkyl include but not limited to: benzocyclobutene, benzocyclobutane, benzocyclohexane, benzo ring heptane, pyrido Tetramethylene., pyrido Pentamethylene., pyrido hexamethylene, 2,3-dihydro-1-H-indenes2,3-cyclopentenopyridine, 5,6-dihydro-4H-cyclopenta [B] thiophene, decahydronaphthalene etc.." spiro cycloalkyl group " refers to that two cycloalkyl share the bicyclic radicals that a carbon atom is formed, and spiro cycloalkyl group includes but not limited to:Deng.Bicyclic cycloalkyl is 6-18 unit, preferably 7-15 unit, more preferably 7-10 unit.Term " C_4-8Cycloalkyl " refer to comprise the cycloalkyl of 4-8 carbon atom.Term " C_3-10Cycloalkyl " refer to comprise the cycloalkyl of 3-10 carbon atom, including monocyclic cycloalkyl and bicyclic cycloalkyl.Monocyclic cycloalkyl or bicyclic cycloalkyl can be received on parent molecule by carbon atom chain arbitrary on ring.

Term " Heterocyclylalkyl " refers to by carbon atom and is selected from the saturated or non-aromatic cyclic radical of part unsaturated (comprising 1 or 2 double bond) that the hetero atoms such as nitrogen, oxygen or sulfur form, this cyclic group can be monocycle or bicyclic radicals, in the present invention, hetero atom number preferably 1,2,3 or 4 in Heterocyclylalkyl, nitrogen, carbon or sulphur atom in Heterocyclylalkyl are the most oxidized.Nitrogen-atoms can be replaced by other groups the most further and form tertiary amine or quaternary ammonium salt." monocyclic heterocycloalkyl " preferably 3-10 unit monocyclic heterocycloalkyl, more preferably 5-8 unit monocyclic heterocycloalkyl.Such as: '-aziridino, oxolane-2-base, oxolane-3-base, morpholine-4-base, thiomorpholine-4-base, thiomorpholine-S-oxide-4-base, piperidin-1-yl, piperidin-2-yl, piperidines-3-base, piperidin-4-yl, N-Alkylpiperidine-4-base, pyrrolidin-1-yl, pyrrolidin-2-yl, N-alkyl pyrrolidine-2-base, piperazine-1-base, 4-alkyl piperazine-1-,Deng.Term " C_3-7Heterocyclylalkyl " refer to monocyclic heterocycloalkyl comprises 3-7 ring carbon atom." bicyclic heterocycloalkyl " includes " dicyclo bridge heterocyclic radical ", " dicyclo ring Heterocyclylalkyl " and " spiro heterocyclic radical ", and " dicyclo bridge heterocyclic radical " refers to that (described straight chain group is selected from, but not limited to, the straight chain group bridging knot that annular atoms that monocyclic heterocycloalkyl any two is not linked formed by the hetero atom that 1-3 extra carbon atom and hetero atom/1-3 extra carbon atom/1 are extra :-CH₂-、-O-、-NH-、-S-、-CH₂CH₂-、-CH₂O-、 -CH₂S-、-CH₂NH-、-CH₂CH₂CH₂-、-CH₂OCH₂-、-CH₂CH₂O-、-CH₂CH₂NH-、-CH₂NH CH₂-), the representative example of dicyclo bridge heterocyclic radical includes but not limited to: Deng." dicyclo ring Heterocyclylalkyl " comprises the monocyclic heterocycloalkyl ring being fused to phenyl, monocyclic cycloalkyl, monocyclic heterocycloalkyl or bicyclic heteroaryl, dicyclo ring Heterocyclylalkyl include but not limited to: 2,3-dihydro benzo furyl, 1,3-dihydroisobenzofuran base, indolinyl, 2,3-dihydrobenzo [b] thienyl, dihydrobenzo piperazine mutter base, 1,2,3,4-tetrahydric quinoline groups, Deng." spiro heterocyclic radical " refers to that two Heterocyclylalkyls or a cycloalkyl and a Heterocyclylalkyl share the bicyclic radicals that a carbon atom is formed, and spiro heterocyclic radical includes but not limited to: Deng.Bicyclic cycloalkyl is 6-18 unit, and preferably 7-15 unit more selects 7-10 unit.Term " C_3-7Heterocyclylalkyl " refer to that Heterocyclylalkyl annular atoms contains 3-7 carbon atom, described C_3-7Heterocyclylalkyl is preferably 4-8 unit Heterocyclylalkyl.Term " C_3-6Heterocyclylalkyl " refer to that Heterocyclylalkyl annular atoms contains 3-6 carbon atom, described C_3-6Heterocyclylalkyl is preferably 4-7 unit Heterocyclylalkyl.Monocyclic heterocycloalkyl and bicyclic heterocycloalkyl can be linked on parent molecule by annular atoms arbitrary on ring.Above-mentioned annular atoms refers in particular to carbon atom and/or the nitrogen-atoms of makeup ring skeleton.

Term " aryl " refers to any stable 6-10 unit monocycle or bicyclic aromatic groups, such as: phenyl, naphthyl, tetralyl, 2,3-indanyl or xenyl etc..Term " C_6-10Aryl " refer to 6-10 unit monocycle or bicyclic aromatic groups.

Term " heteroaryl " refers to that the carbon atom at least 1 ring is selected from the aromatic group that the hetero atom displacement of nitrogen, oxygen or sulfur is formed, and it can be 5-7 unit single ring architecture or 7-12 unit twin nuclei, preferably 5-6 unit heteroaryl.In the present invention, hetero atom number preferably 1,2 or 3, including: pyrazolyl, pyrrole radicals, imidazole radicals, 1,2,4-triazol radical, 1,2,3-triazol radicals, tetrazole base, indazolyl, iso indazolyl, indyl, isoindolyl, benzofuranyl, benzothienyl, benzo [d] [1,3] dioxolanyl, benzothiazolyl, benzoxazolyl group, quinolyl, isoquinolyl, quinazolyl etc..Term " C_3-5Aryl " refer to comprise 1 or 2 heteroatomic 5-6 unit bicyclic heteroaryl.

Term " and cyclic group " refers to that at least two circulus shares the condensed ring structure that two adjacent atoms are formed each other, and circulus can comprise aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl.In indication of the present invention cyclic group, at least a ring is aromatic rings.In the present invention, C_6-10Aryl C_4-8The specific embodiment of cycloalkyl includes but not limited to: benzocyclobutene, 2,3-dihydro-1-H-indenes, 1,2,3,4-naphthanes, benzocyclobutane, benzo ring heptane,C_3-5Heteroaryl C_4-8The specific embodiment of cycloalkyl includes but not limited to: 2,3-cyclopentenopyridine, 5,6-dihydro-4H-cyclopenta [b] thiophene or 5,6-dihydro-4H-cyclopenta [b] furan 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinolines,C₆Aryl C_3-7The specific embodiment of Heterocyclylalkyl includes but not limited to: 2,3-Dihydrobenzofuranes, 1,3-dihydroisobenzofuran, indoline, 2,3-dihydrobenzo [b] thiophene, dihydrobenzo piperazine mutter, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-Isosorbide-5-Nitrae-benzdioxan, 3,4-dihydro-2H-1,4-benzimidazole dihydrochloride, C_3-5Heteroaryl C_3-7The specific embodiment of Heterocyclylalkyl includes but not limited to: naphthyridines,Or

Described " and ring group " is preferably by any saturated carbon atom on non-aromatic ring and the cyclopropylamino group shown in Formulas I structureShare a carbon atom and form spiro-compound or spiroheterocyclic compound, the preferred cycloalkyl of non-aromatic ring or Heterocyclylalkyl.Heretofore described " and cyclic group " includes above-mentioned for " aryl ", " Heterocyclylalkyl ", " cycloalkyl " and the definition of " heteroaryl ".

Term " cycloalkyl-alkyl " refers to be connected by alkyl between cycloalkyl with mother nucleus structure.Thus, " cycloalkyl-alkyl " comprises the definition of abovementioned alkyl and cycloalkyl.Further, described " cycloalkyl-alkyl " can be by=R₄Group is substituted in optional position, includes but not limited to:

Term " hetercycloalkylalkyl " refers to be connected by alkyl between Heterocyclylalkyl with mother nucleus structure.Thus, " hetercycloalkylalkyl " comprises the definition of abovementioned alkyl and Heterocyclylalkyl.Further, described " hetercycloalkylalkyl " can be by=R₄Group is substituted in optional position, includes but not limited to:

Term " alkoxyl " refers to that described carbon number purpose is ring-type or acyclic alkyl groups by having of connecing of oxygen bridging, comprises alkyl oxy, cycloalkyl oxy and Heterocyclylalkyl epoxide.Thus, " alkoxyl " comprises the definition of abovementioned alkyl, Heterocyclylalkyl and cycloalkyl.

The group of the hydrogen evolution that term " cycloalkyl alkoxy " refers in cycloalkyl substituted alkoxyl on alkyl.Thus, " cycloalkyl alkoxy " comprises the definition of above-mentioned cycloalkyl and alkoxyl.

The group of the hydrogen evolution that term " heterocycloalkylalkoxy " refers in Heterocyclylalkyl substituted alkoxy on alkyl.Thus, " heterocycloalkylalkoxy " comprises the definition of above-mentioned Heterocyclylalkyl and alkoxyl.

Term " thiazolinyl " refers to the straight chain containing at least 1 carbon-carbon double bond, side chain or ring-type non-aromatic alkyl.Wherein can there is 1-3 carbon-carbon double bond, preferably there is 1 carbon-carbon double bond.Term " C_2-4Thiazolinyl " refer to the thiazolinyl with 2-4 carbon atom, term " C_2-6Thiazolinyl " refer to the thiazolinyl with 2-6 carbon atom, including vinyl, acrylic, cyclobutenyl, 2-methyl butene base and cyclohexenyl group.Described thiazolinyl can be replaced.

Term " alkynyl " refers to the straight chain containing at least 1 triple carbon-carbon bonds, side chain or cyclic hydrocarbon group.Wherein can there is 1-3 triple carbon-carbon bonds, preferably there is 1 triple carbon-carbon bonds.Term " C_2-6Alkynyl " refer to the alkynyl with 2-6 carbon atom, including acetenyl, propinyl, butynyl and 3-methylbutynyl.

Term " aryl alkyl " refers to be connected by alkyl between aryl with mother nucleus structure.Thus, " aryl alkyl " comprises the definition of abovementioned alkyl and aryl.

Term " heteroaryl alkyl " refers to be connected by alkyl between Heterocyclylalkyl with mother nucleus structure.Thus, " heteroaryl alkyl " comprises the definition of abovementioned alkyl and heteroaryl.

The group of the hydrogen evolution that term " alkoxy aryl " refers in aryl substituted alkoxy on alkyl.Thus, " alkoxy aryl " comprises the definition of above-mentioned aryl and alkoxyl.

The group of the hydrogen evolution that term " heteroarylalkoxy " refers in heteroaryl substituted alkoxy on alkyl.Thus, " heteroarylalkoxy " comprises the definition of above-mentioned heteroaryl and alkoxyl.

Term " halogen " represents fluorine, chlorine, bromine or iodine.

Term " haloalkyl " refers to the alkyl arbitrarily replaced by halogen.Thus, " haloalkyl " comprises the definition of above halogen and alkyl.

Term " halogenated alkoxy " refers to the alkoxyl arbitrarily replaced by halogen.Thus, " halogenated alkoxy " comprises the definition of above halogen and alkoxyl.

Term " amino " refers to-NH₂, term " alkyl amino " refers to that on amino, at least one hydrogen atom is replaced by alkyl.Term " aminoalkyl " refers to that on alkyl, an oxygen atom is replaced by amino.Thus, " alkyl amino " and " aminoalkyl " comprises the definition of abovementioned alkyl and amino.

Term " carboxyl " refers to-C (O) OH.Term " cyano group " refers to-CN.Term " nitro " refers to-NO₂。

Term " cyclopropyl amino " refers toDescribed cyclopropylamino can be replaced；Term " cyclopropylamine class spiral shell (miscellaneous) cycle compound " refers to as shown in Formulas I, IA, IA-1, IA-2, IB, IB-1, IB-2 and II, and cyclopropyl amino and other circulus are by sharing the compound containing spiral shell (miscellaneous) ring structure that a ring C atom is formed.

Symbol "=" represent double bond；

" room temperature " of the present invention refers to 15-30 DEG C.

Described isotope substitutive derivative includes: in Formulas I arbitrary hydrogen atom replaced by 1-5 D-atom obtain isotope substitutive derivative, arbitrary carbon atom is replaced the isotope substitutive derivative that in the isotope substitutive derivative or Formulas I obtained, arbitrary oxygen atom is obtained by the replacement of 1-3 oxygen 18 atom by 1-3 carbon 14 atom in Formulas I.

Described " prodrug " is converted into original activity compound after referring to compound metabolism in vivo.Saying typically, prodrug is inert matter, or specific activity parent compound activity is little, but can provide convenient operation, be administered or improve metabolic characteristic.

" pharmaceutically acceptable salt " of the present invention is at Berge, et al., " Pharmaceutically acceptable salts ", J.Pharm.Sci., it is discussed in 66,1-19 (1977), and is apparent for Pharmaceutical Chemist, described salt is the most avirulent, and be provided that required pharmacokinetic property, palatability, absorb, be distributed, metabolism or excretion etc..nullCompound of the present invention can have acidic-group、Basic group or amphiprotic group，Typical pharmaceutically acceptable salt includes the salt prepared by the compounds of this invention and acid reaction，Such as: hydrochlorate、Hydrobromate、Sulfate、Pyrosulfate、Disulfate、Sulphite、Bisulfites、Phosphate、Dibasic alkaliine、Dihydric phosphate、Metaphosphate、Pyrophosphate、Nitrate、Acetate、Propionate、Caprate、Caprylate、Formates、Acrylates、Isobutyrate、Caproate、Enanthate、Oxalates、Malonate、Succinate、Suberate、Benzoate、Ar-Toluic acid salt、Phthalate、Maleate、Mesylate、Tosilate、(D，L)-tartaric acid，Citric acid，Maleic acid，(D，L)-malic acid，Fumaric acid，Succinic acid、Succinate、Lactate、Fluoroform sulphonate、Naphthalene-1-sulfonate、Mandelate、Pyruvate、Stearate、Ascorbate、Salicylate.When the compounds of this invention contains acidic-group, its pharmaceutically acceptable salt can also include: alkali metal salt, such as sodium or potassium salt；Alkali salt, such as calcium or magnesium salt；Organic alkali salt, the salt such as formed with ammonia, alkyl Ammonia, hydroxy alkyl Ammonia, aminoacid (lysine, arginine), N-METHYL-ALPHA-L-GLUCOSAMINE etc..

Pharmaceutically acceptable salt of the present invention can pass through general being chemically synthesized.

Generally, the preparation of salt can react prepared by free alkali or acid with waiting chemical equivalent or excess acid (mineral acid or organic acid) or alkali in suitable solvent or solvent compositions.

" isomer " of the present invention refers to that stereoisomer, described stereoisomer include: enantiomer and diastereomer, and wherein cis-trans-isomer is the one of diastereomer.Therefore, the compound of formula I of the present invention can be enantiomer, diastereomer and their any mixture, and all these stereoisomers are included in the present invention.In the present invention, compound of formula I or its salt are with stereomeric form (such as, it contains one or more asymmetric carbon atom) in the presence of, single stereoisomer (enantiomer and diastereomer) and their mixture (enantiomeric mixture and diastereomeric mixtures) are included within the scope of the invention.Present invention additionally comprises compound or the independent stereoisomer of salt that Formulas I represents, and the mixture of the isomer inverted with wherein one or more chiral centres.Scope of the invention include that the mixture of stereoisomer, and the mixture that the enantiomer of purification or enantiomer/diastereomer are enriched with.The present invention includes that the mixture of the stereoisomer of all enantiomers and all possible various combination of non-corresponding isomer, described non-corresponding isomer include cis-trans-isomer.The present invention includes whole combinations and the subset of the stereoisomer of all concrete groups defined above.

Each independent stereoisomer of the compounds of this invention can be prepared by separating from the mixture of stereoisomer, and the separation method of enantiomer and diastereomer is the method known to those skilled in the art.Such as, diastereomeric mixture can be separated by conventional isolation technics such as recrystallization or chromatography.The mixture of enantiomer can be by being converted into non-corresponding isomer, then recrystallization or chromatography is used to separate, or utilize chiral chromatographic column directly to separate, or use any chiral separation method known in the art to carry out being isolated the compound of single configuration.

Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtain the preferred embodiments of the invention.

Agents useful for same of the present invention and raw material are the most commercially.

Detailed description of the invention

Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.

The structure of all compounds of the present invention can pass through nuclear magnetic resonance, NMR (¹H NMR) and/or Mass Spectrometer Method (MS) qualification.

¹H nmr chemical displacement (δ) records (10 with PPM^-6).NMR is carried out by Bruker AVANCE-400 spectrogrph.Suitably solvent is deuterochloroform (CDCl₃), deuterated methanol (CD₃OD), deuterated dimethyl sulfoxide (DMSO-d₆), tetramethylsilane is as internal standard (TMS).

Algorithm (MS) is measured by Utimate 3000HPLC-MSQ Plus MS mass spectrograph, use Kinetex 2.6u C18 100A (50*4.6mm) LCMS-02-001, condition of gradient elution: 95% solvent orange 2 A and 5% solvent B (less than 1.5 minute hands or more than 3 minutes), then 5% solvent orange 2 A and 95% solvent B (1.5 minutes to 3 minutes), percent is the percentage by volume that a certain solvent accounts for total solvent volume.The ammonium bicarbonate aqueous solution of solvent orange 2 A: 10Mm；Solvent B: acetonitrile；

Intermediate involved in the present invention or compound can be by preparations HPLC (pre-HPLC) or supercritical fluid chromatograph (SFC) is isolated and purified or by silica gel plate or silica gel column chromatography separating purification.

Supercritical fluid chromatograph uses SFC-80 (Thar, Waters), chiral separation condition A: chiral column CHIRALPAK AD-H 20 × 250mm, 5um (Daicel), flowing is mutually for carbon dioxide: methanol (methanolic ammonia solution of the 7M containing 0.2%)=90: 10 (percent is percentage by volume), and flow velocity is 70g/min, and column temperature is 35 DEG C, sample concentration: 4g sample/95mL methanol, sample size: 0.3mL；Chiral separation condition B: chiral column CHIRALPAK OJ-H 20 × 250mm, 5um (Daicel), flowing is mutually for carbon dioxide: methanol (methanolic ammonia solution of the 7M containing 0.2%)=90: 10 (percent is percentage by volume), flow velocity is 70g/min, column temperature is 35 DEG C, sample concentration: 3.5g sample/21mL methanol, sample size: 0.4mL.

Preparation HPLC (pre-HPLC) uses Shimadzu LC-20 preparative liquid chromatography, and chromatographic column is: waters xbridge Pre C18,10um, 19mm*250mm.Condition of gradient elution: 20-80% solvent orange 2 A and 80%-20% solvent B；Mobile phase A: 0.05% trifluoroacetic acid aqueous solution (percent is percentage by volume), Mobile phase B: acetonitrile；Detection wavelength: 214nm&254nm；Flow velocity: 1.0mL/ minute.

Thin-layer silicon offset plate is Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate.Silica gel column chromatography generally uses Yantai Huanghai Sea 200-300 mesh silica gel as carrier.

The chiral analysis of the compounds of this invention uses supercritical fluid chromatography analyser SFC Method Station (Thar, Waters), chiral analysis condition A: chiral column CHIRALPAK OJ-H4.6 × 250mm, 5um (Daicel), flowing is mutually for carbon dioxide: methanol (methanolic ammonia solution of the 7M containing 0.2%)=90: 10 (percent is percentage by volume), flow velocity is 3mL/min, and column temperature is 40 DEG C.

The synthesis of intermediate 1:II-1

Step 1: compound A₂-1

By methyltriphenylphosphonium bromide (40.5g, 114mmol) it is dissolved in oxolane (100mL) solution, after being stirred at room temperature 1 hour with potassium tert-butoxide (12.7g, 114mmol), add compound 2,3-bihydrogen-1-indenone (A₁-1) (5.0g, 37.8mmol), reaction is stirred at room temperature 2 hours, add ethyl acetate (50mL) cancellation reaction, washing organic facies with water (100mL), aqueous phase is extracted with ethyl acetate (50mL × 3), merges organic facies and washs with water and saturated aqueous common salt, anhydrous sodium sulfate is dried, and filtering and concentrating also obtains A with silica gel column chromatography (petroleum ether) purification₂-1 (4.3g, productivity: 92%) is oil product.

Step 2: compound A₃-1

By compound A₂-1 (4.3g, 33mmol) with cupric acetylacetonate (II) (3.4g, 29.7mmol) it is dissolved in dichloromethane (100mL), it is warming up to backflow and drips ethyl diazoacetate (3.4g the most slowly, dichloromethane solution (100mL) 29.7mmol), within 2 hours, finishing, 40 DEG C of reactions are overnight.Reactant liquor concentrates and uses silica gel column chromatography (petrol ether/ethyl acetate=20/1) purification gained compound A₃-1 (2.0g, productivity: 28%) is oil product.

Step 3: compound A₄-1

Compound A₃-1 (1.3g, 6mmol) it is dissolved in methanol (20mL), being dissolved in 10mL water by one hydronium(ion) lithium oxide (758mg, 18mmol) drops in above-mentioned solution, stirred overnight at room temperature, vacuum rotary steam removes methanol, the hydrochloric acid liquid of aqueous phase 2N adjusts PH=3, is extracted with ethyl acetate (30mL × 3), merges organic facies and washs with saturated aqueous common salt, anhydrous sodium sulfate is dried, and filtering and concentrating obtains compound A₄-1 (1.05g, productivity: 93%) is oily liquids.

Step 4: compound A₅-1

By compound A₄-1 (1.05g, 5.6mmol) with diphenyl phosphate azide (2.31g, 8.4mmol) it is dissolved in the tert-butyl alcohol (15mL), room temperature adds triethylamine (1.7g, 16.8mmol), then heating to 90 DEG C and stir 6 hours, vacuum rotary steam removes the tert-butyl alcohol, and crude product silica gel column chromatography (petrol ether/ethyl acetate=20/1～10/1) purification obtains compound A₅-1 (605mg, productivity: 42%) is white solid.

¹HNMR(DMSO-d₆, 400Hz): δ 7.16-7.21 (m, 2H), 7.08-7.10 (m, 2H), 7.60-7.72 (m, 1H), 2.90-2.94 (m, 2H), 1.93-1.97 (m, 2H), 1.39 (s, 9H), 1.24-1.27 (m, 2H), 0.94-0.96 (m, 1H).

Step 5: the synthesis of intermediate II-1

By compound A₅-1 (100mg, 0.38mmol) He 2, 6-lutidines (82mg, 0.77mmol) it is dissolved in (1mL) anhydrous methylene chloride, Trimethylsilyl trifluoromethanesulfonate (171mg is dripped under ice bath, 0.77mmol), stirring 5 minutes is continued under condition of ice bath, the cancellation that adds water is reacted and is layered, aqueous phase dichloromethane extracts, merge organic facies, with saturated sodium bicarbonate aqueous solution and brine It, it is dried, concentrate and use silica gel column chromatography (methylene chloride/methanol=10/1) purification to obtain compound II-1 (20mg, productivity: 33%) it is yellow oily liquid.

M/z:[M+H]⁺160

¹HNMR(DMSO-d₆, 400Hz): δ 7.13-7.15 (m, 1H), 7.02-7.07 (m, 2H), 6.61-6.63 (m, 1H), 2.94 (t, J=7.6Hz, 2H), 2.87-2.40 (m, 2H), 1.89-1.96 (m, 3H), 1.07 (dd, J₁=4.8Hz, J₂=7.6Hz, 1H), 0.64 (t, J=4.8Hz, 1H).

Intermediate 2:A₅The fractionation of-1

By compound A₅-1 (22.5g), to enantiomeric mixture, first collects the A that polarity is less through silica gel column chromatography purification (petrol ether/ethyl acetate=50/1～10/1) isolated two₅-1a (4.8g, productivity: 21%), after collect the A that polarity is bigger₅-1b (3.5g, productivity: 15%).By A₅-1a (4.8g) splits (chiral separation condition A) with SFC and obtains the A of single configuration₅-1a₁(2.2g, productivity: 46%) and the A of single configuration₅-1a₂(2.1g, productivity: 44%)；By A₅-1b (1.0g) splits (in property splitting condition B) with SFC and obtains the A of single configuration₅-1b₁(250mg, productivity: 25%) and the A of single configuration₅-1b₂(240mg, productivity: 24%).

A₅-1a₁:

¹HNMR(DMSO-d₆, 400Hz): δ 7.21 (br s, 1H), 7.16-7.18 (m, 1H), 7.08-7.10 (m, 2H), 6.70-6.72 (m, 1H), 2.90-2.94 (m, 2H), 1.93-1.97 (m, 2H), 1.39 (s, 9H), 1.24-1.27 (m, 2H), 0.95 (t, J=4.8Hz, 1H).

A₅-1b₁:

¹HNMR(DMSO-d₆, 400Hz): δ 6.81-7.20 (m, 5H), 2.90-3.03 (m, 3H), 2.60-2.65 (m, 1H), 2.10-2.15 (m, 1H), 0.74-1.43 (m, 11H).

Intermediate 3: single spatial configuration intermediate II-1a₁、II-1a₂、II-1b₁And II-1b₂Synthesis

Utilize the synthetic method of compound II-1, use A₅-1a₁、A₅-1a₂、A₅-1b₁, and A₅-1b₁For raw material, synthesize the intermediate II-1a of corresponding single spatial configuration₁、II-1a₂、II-1b₁And II-1b₂。

The synthesis of intermediate 4:II-2a and II-2b

Step 1: compound A₅-2

Utilize intermediate A₅The synthetic method of-1, with 5-bromo-2,3-bihydrogen-1-indenone replacement 2,3-bihydrogen-1-indenone synthesis A₅-2 is white solid.

M/z:[M+H]⁺338

Step 2: compound A₅-2a and A₅The preparation of-2b

By A₅-2 (3.2g) silica gel column chromatography separating purification (petrol ether/ethyl acetate=20/1～10/1) obtains two pairs of enantiomeric mixture, first collects the A that polarity is less₅-2a (1.1g, productivity: 34%), after collect the A that polarity is bigger₅-2b (1.2g, productivity: 38%), is white solid.

Step 3: compound A₅-3a and A₅-3b

Compound A is added in 100 milliliters of single port bottles₅-2a (400mg, 1.18mmol), 1-methyl isophthalic acid H-pyrazoles-4-pinacol borate (369mg, 1.77mmol), cesium carbonate (771mg, 2.36mmol) with [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (Pd (dppf) Cl₂) (48mg; 0.06mmol); add N; dinethylformamide (10mL); nitrogen is protected and is replaced 3 time, is warming up to 90 DEG C and is stirred overnight, and reactant liquor is cooled to room temperature and adds ethyl acetate (20mL) cancellation reaction; filtering, filtrate is successively with water and saturated aqueous common salt washing.Organic solvent rotates and is evaporated, and crude product silica gel column chromatography separation (petrol ether/ethyl acetate=3/1) obtains compound A-45-3a, and (340mg, productivity is: 85%) be white solid.Utilize A₅The synthetic method of-3a, uses A₅-2b is Material synthesis A₅-3b is white solid.

A₅-3a:

¹HNMR(CDCl₃, 400Hz): δ 7.73 (s, 1H), 7.72 (s, 1H), 7.23-7.57 (m, 2H), 6.64-6.66 (d, J=7.61H), 4.77 (s, 1H), 3.96 (s, 3H), 3.06-3.12 (m, 2H), 2.78 (s, 1H), 2.07-2.19 (m, 2H), 1.26-1.48 (m, 10H), 0.92 (m, 1H).

M/z:[M+H]⁺340

Step 4: the synthesis of intermediate II-2a and II-2b

By compound A₅-3a (340mg, 1mmol) it is dissolved in methanol (10mL), add p-methyl benzenesulfonic acid (690mg, 4mmol), it is warming up to 65 DEG C stir 2 hours, methanol is removed with Rotary Evaporators, gained solid is soluble in water, it is cooled to 0 DEG C, adjusts PH=8 with the sodium hydrate aqueous solution of 1M, extract (× 3) with dichloromethane, merge organic facies and be dried with anhydrous sodium sulfate, filtering, (220mg, productivity is: 92%) be oily liquids to be spin-dried for obtaining intermediate II-2a.Utilize the synthetic method of II-2a, use A₅-3b be Material synthesis II-2b be oily liquids.

M/z:[M+H]⁺239

Embodiment 1: the synthesis of compound I-1

Step 1: compound II-1-1

Will be to N-t-butoxycarbonylpiperidin ketone (76mg, 0.38mmol), intermediate II-1 (60mg, 0.38mmol) with glacial acetic acid (23mg, 0.38mmol) it is dissolved in 1, in 2-dichloroethanes (5mL), it is stirred at room temperature 1 hour, ice bath cools down, add acetic acid sodium borohydride (145mg, 0.68mmol), stirred overnight at room temperature, reactant liquor dichloromethane cancellation, organic facies uses 1M citric acid solution successively, saturated aqueous common salt washs, concentration of reaction solution also obtains compound II-1-1 (20mg with silica gel column chromatography (methylene chloride/methanol=20/1) purification, productivity: 15%) it is oily liquids.

M/z:[M+H]⁺343

Step 2: compound I-1

By compound II-1-1 (20mg, 0.06mmol) He 2,6-lutidines (13mg, 0.12mmol) it is dissolved in anhydrous methylene chloride (1mL), Trimethylsilyl trifluoromethanesulfonate (26mg is dripped under condition of ice bath, 0.12mmol), stirring 5 minutes is continued under ice bath, the cancellation that adds water is reacted and is layered, aqueous phase dichloromethane extracts, merging organic facies, concentrating and being prepared into compound I-1 (5mg, productivity: 25%) with pre-HPLC is white solid.

M/z:[M+H]⁺243

¹HNMR(CD₃OD, 400Hz): δ 7.18-7.29 (m, 3H), 6.80-6.82 (m, 1H), 3.57-3.60 (m, 2H), 3.13-3.19 (m, 3H), 2.95-2.98 (m, 1H), 2.52-2.55 (m, 1H), 2.31-2.38 (m, 2H), 1.18-1.19 (m, 1H), 1.53-1.57 (m, 1H), 1.31-1.53 (m, 4H), 0.92-0.97 (m, 1H).

Embodiment 2: utilize the synthetic method of compound I-1, and corresponding aldehydes or ketones compound stereoscopic isomer mixture I-2～I-4:

Embodiment 3: the synthesis of compound I-5

By 1-benzyl-4-piperidinealdehyde (64mg, 0.31mmol), intermediate II-1 (50mg, 0.31mmol) He 2 glacial acetic acid are dissolved in 1, in 2-dichloroethanes (1mL), it is stirred at room temperature 1 hour, ice bath cools down, add acetic acid sodium borohydride (197mg, 0.93mmol), it is stirred at room temperature 16 hours, reactant liquor dichloromethane (20mL) dilutes, organic facies is successively with unsaturated carbonate oxygen sodium solution (10mLx2), saturated aqueous common salt washs, anhydrous sodium sulfate is dried, filtering and concentrating also obtains compound I-5 (25mg with silica gel column chromatography (methylene chloride/methanol=20) purification, productivity: 22%) it is yellow oil.

M/z:[M+H]⁺347

¹HNMR(DMSO-d₆, 400Hz): δ 7.14-7.33 (m, 8H), 7.04-7.14 (m, 1H), 3.44 (s, 2H), 2.23-2.93 (m, 5H), 1.45-2.57 (m, 12H), 1.06-1.17 (m, 2H).

Embodiment 4: single spatial configuration compound I-1a₁Synthesis

Step 1: compound II-1a₁The synthesis of-1

Utilize the synthetic method of compound II-1-1 with single configuration intermediate II-1a₁For raw material, synthesize single spatial configuration compound II-1a₁-1 is white solid.

Step 2: compound I-1a₁Synthesis

By II-1a₁-1 (20mg, 0.056mmol) it is dissolved in methanol (2mL), p-methyl benzenesulfonic acid (39mg, 0.22mmol) joining in reactant liquor, be warming up to 60 DEG C and stir 2 hours in this temperature, decompression removes methanol solution, crude product adds 5mL methyl tertiary butyl ether(MTBE), then add the saturated ether solution of hydrogen chloride of 1mL, stirred overnight at room temperature, be filtrated to get single spatial configuration compound I-1a₁(12mg, yield is: 65%) be white solid.

M/z:[M+H]⁺243

¹HNMR(DMSO-d₆, 400Hz): δ 9.90 (br s, 1H), 9.50 (br s, 1H), 9.02 (br s, 1H), 9.88 (br s, 1H), 7.15-7.26 (m, 3H), 6.84-6.86 (m, 1H), 3.36-3.52 (m, 3H), 2.91-3.17 (m, 4H), 2.26-2.42 (m, 3H), 1.91-2.01 (m, 2H), 0.86-1.51 (m, 4H).

Utilize I-1a₁Synthetic method synthesis I-1a₂、I-1b₁And I-1b₂。

Embodiment 5: single spatial configuration compound I-4a₁-1 and I-4a₁The synthesis of-2

Step 1: utilize the synthetic method of compound II-1-1, with the II-1a of single configuration₁For raw material, synthesize cis-trans-isomer mixtures II-4a₁For off-white color solid.

Step 2:II-4a₁-1 and II-4a₁The preparation of-2

By II-4a₁(200mg) through thin-layer silicon offset plate (methylene chloride/methanol=10/1) isolated single spatial configuration compound II-4a₁-1(R_fValue=0.5) (63mg, productivity: 31%) be off-white color solid and single spatial configuration compound II-4a₁-2(R_fValue=0.6) (59mg, productivity: 29%) be faint yellow solid.

Step 3:I-4a₁-1 and I-4a₁The synthesis of-2

By II-4a₁-1 (63mg, 0.17mmol) it is dissolved in methanol (2mL), p-methyl benzenesulfonic acid (87mg, 0.51mmol) joining in reactant liquor, be warming up to 60 DEG C and stir 3 hours in this temperature, decompression removes methanol solution, crude product adds 5mL methyl tertiary butyl ether(MTBE), precipitation solid is collected by filtration, and obtains mesylate compound (35mg, yield: 48%)；Take 10mg tosilate, be dissolved in 0.1mL methanol, then add the saturated ether solution of hydrogen chloride of 2mL, be stirred at room temperature 2 hours, solid is collected by filtration and obtains single spatial configuration compound I-4a₁-1 (3mg, yield: 39%) is faint yellow solid.According to I-4a₁-1 synthetic method, with II-4a₁-2 obtain single spatial configuration compound I-4a for raw material₁-2 (5mg, yield is: 9.5%).

Utilize I-4a₁-1 and I-4a₁Synthetic method synthesis single spatial configuration compound: the I-4a of-2₂-1、I-4a₂-2、I-4b₁-1、I-4b₁-2、I-4b₂-1 and I-4b₂-2 are corresponding hydrochlorate.

Embodiment 6: the synthesis of enantiomeric mixture I-6a-1 and I-6a-2

Step 1: the synthesis of compound II-6a-1 and II-6a-2

By compound II-2a (120mg, 0.5mmol) with 4-N-t-butoxycarbonyl-amino Ketohexamethylene (107mg, 0.5mmol) it is dissolved in 1,2-dichloroethanes (6mL), ice bath is cooled to 0 DEG C, add glacial acetic acid (30mg, 0.5mmol), after half an hour is stirred at room temperature, in reactant liquor, add acetic acid sodium borohydride (192mg, 0.9mmol), continue to be stirred overnight.Reacting with dichloromethane cancellation, and wash with saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate is dried organic facies, filters and concentrated filtrate, and crude product silica gel is prepared plate (methylene chloride/methanol=20/1) purification and obtained compound II-6a-1 (R_fValue=0.4) (12mg, productivity: 10%) and compound II-6a-2 (R_fValue=0.5) (10mg, productivity: 8%) be faint yellow solid.

M/z:[M+H]⁺437

Step 2: the synthesis of compound I-6a-1 and I-6a-2

By compound II-6a-1 (12mg, 0.027mmol) it is dissolved in methanol (2mL), add p-methyl benzenesulfonic acid (16mg, 0.092mmol), it is warming up to 65 DEG C and stirs 2 hours, remove methanol with Rotary Evaporators, gained solid adds saturated ether solution of hydrogen chloride (2mL) and is stirred at room temperature 2 hours, filtering, filter cake also washs with methyl tertiary butyl ether(MTBE), and solid oil pump is vacuum dried.(9.5mg, productivity is: 75%) be white solid to obtain compound I-6a-1.

¹HNMR (DMSO, 400Hz): δ 9.30-9.75 (m, 3H), 8.08-8.15 (m, 3H), 7.82 (s, 1H), 7.34-7.43 (m, 2H), 6.80-6.82 (d, J=7.61H), 3.84 (s, 3H), 2.98-3.06 (m, 4H), 2.20-2.50 (m, 3H), 1.97-2.05 (m, 3H), 1.61-1.72 (m, 2H), 1.41-1.46 (m, 4H), 0.95 (m, 1H).

M/z:[M+H]⁺337

By compound II-6a-2 (10mg, 0.023mmol) it is dissolved in methanol (2mL), add p-methyl benzenesulfonic acid (16mg, 0.092mmol), it is warming up to 65 DEG C and stirs 2 hours, remove methanol with Rotary Evaporators, gained solid adds saturated ether solution of hydrogen chloride (2mL) and is stirred at room temperature 2 hours, filtering, filter cake also washs with methyl tertiary butyl ether(MTBE), and solid oil pump is vacuum dried.(7.4mg, productivity is: 79%) be off-white color solid to obtain compound I-6a-2.

M/z:[M+H]⁺337

Embodiment 7: the synthesis of enantiomeric mixture I-7a

Utilize compound I-1a₁Synthetic method, with enantiomeric mixture II-2a as raw material, synthesis enantiomeric mixture I-7a be off-white color solid.

M/z:[M+H]⁺323

Biological test embodiment:

Embodiment 1:LSD1 enzyme inhibition activity screening test

The compounds of this invention has the ability of suppression LSD1 enzymatic activity, can be tested by tests below: people recombinates LSD1 albumen source for BPS Bioscienc Inc. (catalog number 50100: people recombinates LSD1, the GenBank number of logging in NM_015013, amino acid/11 58-end has N-end GST labelling, MW:103kDa).In order to monitor the suppression speed of LSD1 enzymatic activity and/or testing inhibitor, the H3-K4 peptide (Anaspec) of monomethylation is elected to be substrate.Described demethyl enzymatic activity utilizes AlphaScreen technology, is converted into demethylation H3-K4 peptide by detection monomethylation H3-K4 peptide and weighs.

With the test buffer solution of 3.3%DMSO, test compound is made into the solution of various concentration of 12 kinds of 3-times of serial dilutions (such as, concentration range is from 0 to 30 μMs), being joined by the diluent containing inhibitor of 3 μ L in the reactant liquor of 10 μ L, making DMSO content in final each reaction system is 1%.Select RG6016 as positive control.LSD1 inhibition of enzyme activity test at 10 μ L containing 50mMTrisHCl, PH8.8,50mM sodium chloride, the dithiothreitol, DTT (DTT) of 1mM, the solution of the histone H 3 K4 peptide substrates (ultimate density is 0.5 μM) testing buffer solution, test compound, LSD1 enzymatic solution, monomethylation of 0.01% tween 20 is carried out, 10 μ L reactant liquors are joined 384 orifice plate (OptiPlate^TMPerkinElmer) in, incubation at room temperature 1 hour.It is subsequently adding the Acceptor beads (AlphaLISA of the anti-mouse antibody labeling of 5 μ L, PerkinElmer, the dilution proportion of 1: 500 is pressed with 1x detection buffer (BPS Bioscience)) and the first antibody (BPS of 5 μ L, the dilution proportion of 1: 1600 is pressed with 1x detection buffer), incubated at room half an hour after vibration.It is eventually adding the donor microballon (AlphaScreen of 10 μ L Avidin labellings, Perkin, the dilution proportion of 1: 125 is pressed) with 1x detection buffer (BPS Bioscience), in 30 minutes, it is monitored by AlphaScreen microplate reader (EnSpire Alpha 2390Multilabel Reader, PerkinElmer).

The IC of each inhibitor₅₀Value is all to obtain by GraphPad Prism computed in software.

Compound activity test result of the present invention, IC₅₀Value report in the range of :+represent ＞ 1 μM, ++ represents 0.5-1 μM, +++ represents 0.1-0.5 μM, ++++expression 0.1-0.01 μM, +++ ++ expression ＜ 0.01 μM.

Wherein, what positive control was selected is LSD1 inhibitor that Roche company is in the clinical II phase: RG6016.

Claims (16)

1. a compound shown in formula I, its isomer, prodrug, stable isotope derivatives And pharmaceutically acceptable salt；

Wherein, n is 0,1,2,3 or 4；

A ring is and cyclic group；Described and cyclic group is C_6-10Aryl C_4-8Cycloalkyl, C_3-5Heteroaryl Base C_4-8Cycloalkyl, C₆Aryl C_3-7Heterocyclylalkyl or C_3-5Heteroaryl C_3-7Heterocyclylalkyl；

R is selected from hydrogen, R₁Or-L₂-E；

R₁Selected from halogen ,-OH ,-CN ,-NO₂,-SH, carboxyl, amino, alkyl, haloalkyl, Halogenated alkoxy, alkyl amino, C_2-6Alkynyl, C_2-6Thiazolinyl, cycloalkyl, cycloalkyl-alkyl, heterocycle Alkyl, hetercycloalkylalkyl ,-OR₆、-OC(O)R₆、-OC(O)NR₆R_6a、-C(O)OR₆、-C(O)R₆、 -C(O)NR₆R_6a、-N(R₆)C(O)R_6a、-N(R₆)C(O)NR₆R_6a、-(CH₂)_rNR₆R_6a、-N(R₆)SO₂R_6a、 -S(O)_0-2R₆Or-S (O)₂NR₆R_6a；

-L₂-E is selected from-(CH₂)_m-E、-O(CH₂)_m-E or-N (R₃)(CH₂)_m-E；E is selected from replacing or not taking The aryl in generation or substituted or unsubstituted heteroaryl；When E is replaced, can be by one or more R₁ It is substituted in optional position；

R₃Selected from hydrogen, alkyl, haloalkyl ,-S (O)_0-2R₆、-C(O)R₆、-C(O)OR₆、-CONR₆R_6a、 Aminoalkyl or hydroxyalkyl；

R_x、R_y、R_zIt is each independently selected from hydrogen, deuterium, halogen or alkyl, or, R_xWith R_yWith it The common C atom connected form the monocyclic cycloalkyl of 3-7 unit together.

L₁Selected from-(CR₂R2_a)_m-；

R₂And R_2aBe each independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, hydroxyl, amino, Monocyclic cycloalkyl, monocyclic cycloalkyl alkyl, alkoxyl, aminoalkyl, single Heterocyclylalkyl, single Heterocyclylalkyl Alkyl ,-OC (O) R₇、-OC(O)NR₇R_7a、-NR₇R_7a、-N(R₇)C(O)R_7a、-N(R₇)S(O)₂R_7a、 -N(R₇)C(O)NR₇R_7a、-S(O)₂NR₇R_7a、-(CH₂)_rS(O)_0-2R₇、-(CH₂)_rC(O)OH、-C(O)R₇、 -C(O)OR₇、-C(O)NR₇R_7a、-(CH₂)_rC(O)NR₇R_7aOr-(CH₂)_rNR₇R_7a；

M is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, replacement or does not takes The cycloalkyl-alkyl in generation, substituted or unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl or take Generation or unsubstituted heteroaryl；When described M is replaced, can be by following one or more R₅With/ Or R_5aGroup is substituted in optional position, described R₅And R_5aSeparately be selected from: hydrogen, halogen, -OR₇、-SR₇、-NO₂,-CN, amino, alkyl, haloalkyl, halogenated alkoxy, aryl, miscellaneous Aryl, cycloalkyl, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl, Heterocyclylalkyl Alkyl, heterocycloalkylalkoxy, cycloalkyl alkoxy, alkoxy aryl, heteroarylalkoxy, ammonia alkane Base ,-OC (O) R₇、-OC(O)NR₇R_7a、-NR₇R_7a、-N(R₇)C(O)R_7a、-N(R₇)S(O)₂R_7a、 -N(R₇)C(O)NR₇R_7a、-S(O)₂NR₇R_7a、-(CH₂)_rS(O)_0-2R₇、-(CH₂)_rCOOH、-C(O)R₇、 -C(O)OR₇、-C(O)NR₇R_7a、-(CH₂)_rC(O)NR₇R_7aOr-(CH₂)_rNR₇R_7a；

When described M is replaced, described substituted cycloalkyl, substituted Heterocyclylalkyl, substituted Cycloalkyl-alkyl, substituted hetercycloalkylalkyl also can be by one=R₄Group is substituted in optional position；

=R₄Selected from=O ,=S or=NH；

In described M, described R₅And R_5aFor unsubstituted, or further by following one or more bases Group is replaced: C_1-3Alkyl, halogen ,-OH ,-CN ,-NO₂, amino, carboxyl, C_1-3Alkoxyl, Halo C_1-3Alkoxyl, halo C_1-3Alkyl, C_6-10Aryl, C_3-5Heteroaryl, C_3-8Cycloalkyl or 5-7 Unit's Heterocyclylalkyl；

R₆And R_6aIt is each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, virtue Base, heteroaryl, hetercycloalkylalkyl, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl, or, R₆And R_6aSingle Heterocyclylalkyl of 3-7 unit is formed together with the atom N being jointly connected with them；

R₇And R_7aIt is each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, virtue Base, heteroaryl, hetercycloalkylalkyl, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl, or, R₇And R_7aSingle Heterocyclylalkyl of 3-7 unit is formed together with the atom N being jointly connected with them；

M is 0,1,2,3 or 4；

R is the integer of 1-5.

Compound the most according to claim 1, its isomer, prodrug or it is pharmaceutically acceptable Salt, it is characterised in that: described A ring is benzo C_4-7Cycloalkyl, benzo C_3-6Heterocyclylalkyl, naphthalene Ring C_4-7Cycloalkyl, pyridine ring C_4-7Cycloalkyl or pyridine ring C_3-6Heterocyclylalkyl.

Compound the most according to claim 1, its isomer, prodrug or it is pharmaceutically acceptable Salt, it is characterised in that: described M is selected from: substituted or unsubstituted C_3-10Cycloalkyl, replacement or Unsubstituted C_3-10Cycloalkyl C_1-3Alkyl, substituted or unsubstituted 3-10 unit Heterocyclylalkyl, replacement or Unsubstituted 3-10 unit Heterocyclylalkyl C_1-3Alkyl.

Compound the most according to claim 3, its isomer, prodrug or it is pharmaceutically acceptable Salt, it is characterised in that: described M is following M₁To M₂₀In any one:

Wherein, R₅Selected from C_1-4Alkyl, halo C_1-4Alkyl ,-OR₇、C_6-10Aryl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl, amino ,-NR₇R_7a、-CONR₇R_7a、 -(CH₂)_rNR₇R_7a、-C(O)R₇Or-C (O) OR₇；

R_5aSelected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, C₆-₁₀Aryl, C_3-8Cycloalkyl, C_3-8Ring Alkyl C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl ,-CONR₇R_7a、-(CH₂)_rNR₇R_7a、-C(O)R₇Or -C(O)OR₇；

Described R₅And R_5aFor unsubstituted, or replaced by following one or more groups further: C_1-3 Alkyl, halogen, halo C_1-3Alkyl ,-OH, carboxyl ,-CN ,-NO₂, amino, C_1-3Alkoxyl, Halo C_1-3Alkoxyl；

R₇And R_7aIt is each independently selected from hydrogen, C_1-3Alkyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkane Base, phenyl or phenyl C_1-3Alkyl；Or R₇And R_7aShape together with the atom N being jointly connected with them Become single Heterocyclylalkyl of 3-7 unit；

P is 0,1,2 or 3.

5. compound shown in formula I as described in any one of Claims 1 to 4, its isomer, front Medicine or pharmaceutically acceptable salt, it is characterised in that: described compound shown in formula I is IA,

Wherein, B ring is phenyl ring, pyridine ring or naphthalene nucleus；

X is-CH₂-、-C(O)-、-O-、-S(O)_0-2-、-C(O)N(R_1b)-、-N(R_1b)C(O)N(R_1b)-、 Or-N (R_1a)-；Q is selected from 0,1 or 2；R is selected from 1 or 2；

R_1aSelected from hydrogen, C_1-6Alkyl, 3-8 unit cycloalkyl, 3-8 unit Heterocyclylalkyl ,-C (O) R₇、-SO₂R₇、 -C(O)OR₇, or-C (O) NR₇R_7a；R_1bSelected from hydrogen or C_1-6Alkyl；

R₇And R_7aIt is each independently selected from hydrogen, C_1-3Alkyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkane Base, phenyl or phenyl C_1-3Alkyl；Or R₇And R_7aShape together with the atom N being jointly connected with them Become single Heterocyclylalkyl of 3-7 unit.

6. compound, its isomer, prodrug or pharmacy shown in formula I as claimed in claim 5 Upper acceptable salt, it is characterised in that: described compound shown in formula I is IA, and wherein, M selects From:

7. compound shown in formula I as described in any one of claim 5, its isomer, prodrug Or pharmaceutically acceptable salt, it is characterised in that: the described compound as shown in Formulas I A be IA-1 or IA-2,

Wherein, n is 0,1,2 or 3；Q is 0 or 1；R is 1；X is-CH₂-or-O-；R_x、R_y And R_zIt is separately: hydrogen, deuterium, methyl or fluorine；

R is selected from hydrogen, R₁Or-L₂-E；

Wherein, R₁It is selected from: fluorine, chlorine ,-OH ,-CN ,-NO₂,-C (O) OH, amino, C_1-3Alkane Base, C_1-3Alkoxyl, halo C_1-3Alkyl and halo C_1-3Alkoxyl；

-L₂-E is selected from-(CH₂)_m-E、-O(CH₂)_m-E or-N (R₃)(CH₂)_m-E；M is 0,1 or 2；E Selected from substituted or unsubstituted phenyl ring or substituted or unsubstituted 5-6 unit hetero-aromatic ring；Described substituted benzene Base and substituted 5-6 unit heteroaryl can be by 1-2 R₁It is substituted in optional position.R₃Preferably hydrogen or methyl；

L₁Selected from-(CH₂)_m-, m is 0,1,2 or 3；

R₅It is selected from: C_1-4Alkyl, halo C_1-4Alkyl ,-OR₇、C_6-10Aryl, C_3-8Cycloalkyl, C_3-8 Cycloalkyl C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl, amino ,-NR₇R_7a、-CONR₇R_7a、 -(CH₂)_rNR₇R_7a、-C(O)R₇Or-C (O) OR₇；R_5aIt is selected from: C_1-4Alkyl, halo C_1-4Alkyl, -OR₇、C_6-10Aryl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl, -CONR₇R_7a、-(CH₂)_rNR₇R_7a、-C(O)R₇Or-C (O) OR₇；

R₇And R_7aIt is each independently selected from hydrogen, C_1-3Alkyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl C_1-3Alkane Base, phenyl or phenyl C_1-3Alkyl, or R₇And R_7aShape together with the atom N being jointly connected with them Becoming single Heterocyclylalkyl of 3-7 unit, r is 1,2 or 3；

R₅And R_5aFor unsubstituted, or replaced by following one or more groups further: C_1-3Alkyl, C_1-3Alkoxyl, fluorine, chlorine ,-CF₃,-OH, amino, carboxyl, nitro, cyano group or cyclopropyl.

8. compound, its isomer, prodrug or pharmacy shown in formula I as claimed in claim 7 Upper acceptable salt, it is characterised in that: the described compound as shown in Formulas I A is Formulas I B,

Wherein, the C of * mark is chiral carbon, works as R_xAnd R_yDuring for different substituents, configuration presses (C₁、 C₂、C₃) order be respectively as follows: (S, S, S) type, (R, S, R) type, (S, S, R) type, (R, S, S) type, (S, R, S) type, (R, R, R) type, (S, R, R) type or (R, R, S) Type；Work as R_xAnd R_yDuring for identical substituent group, configuration presses (C₂、C₃) sequentially it is respectively as follows: (S, S) Type, (S, R) type, (R, S) type, (R, R) type.

9. compound shown in formula I as claimed in claim 1 is following compound:

10. compound as shown in Formula Il,

Wherein, B ring, R, R_x、R_y、R_z, X, n, q and r definition such as claim 5-9 arbitrary Described in.

11. 1 kinds of pharmaceutical compositions, it includes as described in any one of claim 1～9 shown in formula I Compound, its pharmaceutically acceptable salt and/or prodrug, and pharmaceutically acceptable adjuvant.

12. pharmaceutical compositions as claimed in claim 11, it is characterised in that: described pharmaceutically may be used The adjuvant accepted is pharmaceutically acceptable carrier, diluent and/or excipient.

13. compounds shown in formula I as described in any one of claim 1～9, it pharmaceutically can connect The salt being subject to or prodrug, or the pharmaceutical composition as described in any one of claim 11～12 is at preparation LSD1 Application in inhibitor.

14. compounds shown in formula I as described in any one of claim 1～9, it pharmaceutically can connect The salt being subject to or prodrug, or the pharmaceutical composition as described in any one of claim 11～12 preparation prevention and / or treatment LSD1 mediation relevant disease medicine in application.

15. apply as claimed in claim 14, and wherein, described disease is sacred disease, including: Depression, schizophrenia, alzheimer's disease, Huntington Chorea, Parkinson's disease, amyotrophy funiculus lateralis are hard Change disease.

16. apply as claimed in claim 14, and wherein, described disease is cancer, including: knot Intestinal cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, pulmonary carcinoma, the brain cancer, ovarian cancer, cervical cancer, testis Cancer, renal carcinoma, head and neck cancer, lymphatic cancer, leukemia or skin carcinoma.