CN111471010A - Indoleamine-2, 3-dioxygenase (IDO) inhibitors - Google Patents

Indoleamine-2, 3-dioxygenase (IDO) inhibitors Download PDF

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CN111471010A
CN111471010A CN202010446383.0A CN202010446383A CN111471010A CN 111471010 A CN111471010 A CN 111471010A CN 202010446383 A CN202010446383 A CN 202010446383A CN 111471010 A CN111471010 A CN 111471010A
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alkyl
radical
amino
alkoxy
alkylamino
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CN111471010B (en
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李磐
温俏冬
王骥
甘泉
路杨
杨东晖
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Xiamen Baotai Biotechnology Co ltd
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Hangzhou Arnold Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
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Abstract

The invention relates to a preparation method of a compound shown in formula I, and the compound prepared by the method has activity of inhibiting indoleamine 2, 3-dioxygenase.

Description

Indoleamine-2, 3-dioxygenase (IDO) inhibitors
The application is a divisional application, and the Chinese application number of the parent case is as follows: 201880057640.2, International application number PCT/CN2018/124110, International application date 12/27 of 2018.
The present invention claims priority from chinese patent applications CN201711478307.2 and CN201810754253.6, and the contents of the specification, drawings and claims of this priority document are incorporated in their entirety into the specification of the present invention and are included as a part of the original description of the present invention. Applicants further claim that applicants have the right to amend the description and claims of this invention based on this priority document.
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of an indoleamine-2, 3-dioxygenase (IDO) inhibitor.
Background
Tryptophan (TRP) is an α -amino acid used for protein biosynthesis, it contains α -amino, α -carboxylic acid groups and side chain indoles, which are essential in humans, the human body is unable to synthesize it, but must be obtained from the diet tryptophan is also a precursor for the synthesis of the neurotransmitter 5-hydroxytryptamine (serotonin) and the hormone N-acetyl-5-methoxytryptamine (melatonin), the heme-dependent enzyme indoleamine 2, 3-dioxygenase (also called IDO, or IDO1) is a metabolic enzyme outside the liver responsible for the conversion of tryptophan to N-formyl-kynurenine, which is the first step in the tryptophan metabolism process and is also the rate-limiting step of the overall process N-formyl-kynurenine is a precursor for the various bioactive molecules kynurenine (kynurine, or Kyn 2012), which has an immunomodulatory function (schwarccz et al, Nat rev.13; neosci.465).
Indoleamine 2, 3-dioxygenase (IDO) is widely expressed in solid tumors (Uyttenhove et al, natmed. 2003; 10:1269), also expressed in primary and metastatic cancer cells IDO in tumors induced by pro-inflammatory factors, including type I and type II interferons produced by infiltrating lymphocytes (Tnani and baard, Biochim biophysis acta.1999; 1451(l): 59; Mellor and Munn, Nat Rev Immunol 2004; 4(10): mun; Munn, Front biosci.2012; 4:734) and transforming growth factor- β (TGF- β) (pallototta et al, natimmunol.2011; 12(9):870), there is increasing evidence that IDO has been an inducible enzyme as an inducible enzyme, a major role in immune cell regulation, and plays a role in tretinoin the regulation of tryptophan levels, and thus has been a significant role in immune cell transplantation, tumor cell suppression, and immune receptor mediated by immune deficiency, and immune receptor mediated immune response to the development of immune receptor mediated immune diseases, and subsequent immune responses to the development of immune receptor mediated immune system, and immune suppression, and subsequent immune suppression.
Numerous published preclinical data also further confirm the role of IDO in anti-tumor immune responses forcing induction of IDO in Cancer cells was demonstrated to have a survival advantage (Uyttenhove et al, Nat med. 2003; 10:1269) in Cancer cells forcing IDO induction by decreasing kynurenine levels in tumor growth has also shown that IDO inhibitors reduce lymphocyte dependence by reducing kynurenine levels (L iu et al, blood.2010; 115(17):3520) preclinical studies also show that IDO inhibitors have synergistic effects if combined with other tumor drugs, such as radiation therapy, chemotherapy or vaccines, etc. (Koblish et al, Mol Cancer ther. 2010; 9(2):489, Hou et al, Cancer et al (67; 2007; 2): 792; sham 792 et al, blood 24.2009).
The research of IDO inhibitor antitumor drugs has made important progress in the world, for example, INCB024360, N L G919 and BMS-986205 have all entered into the clinic, but INCB024360 has toxic side effect problem, so the existing clinical research dosage (50mg bid, or 100mg bid) is about 30% of the optimal dosage (300mg bid,600mg bid), the clinical activity is greatly limited, meanwhile the toxic group of INCB024360 is the pharmacophore, INCB024360 and its derivatives have the problem of high toxicity, N L G919 has better safety, but N L G919 has poorer biological activity, BMS-986205 has entered into the clinic at present, but the clinical data is limited, based on BMS-986205, the research of novel compounds with high biological activity and high safety is carried out, which has very important practical significance for finding novel IDO antitumor immunotherapeutic drugs with better clinical therapeutic activity, such as possible to cure tumor rather than just inhibiting tumor.
Disclosure of Invention
The invention provides a compound shown as a formula I,
Figure BDA0002505919540000041
wherein
Figure BDA0002505919540000042
Represents:
Figure BDA0002505919540000043
or
Figure BDA0002505919540000044
A represents-C (O) -, -S (O)2-or-s (o) -;
wherein each R is1Each is independentSelected from hydrogen atom, halogen, hydroxyl, nitro, cyano, sulfonic acid group and C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy, halo C1-C6Cycloalkyl radical, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, di (C)1-6Alkyl) amino C2-6Alkoxycarbonyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, carbamoyl, C1-6Alkylcarbamoyl, di (C)1-6Alkyl) carbamoyl, di (C)1-6Alkyl) amino C2-6Alkylcarbamoyl, sulfamoyl, C1-6Alkylsulfamoyl, di (C)1-6Alkyl) sulfamoyl, di (C)1-6Alkyl) amino C2-6Alkylsulfamoyl, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl, di (C)1-6Alkyl) phosphono, hydroxy C1-6Alkyl, hydroxy carbonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C1-6Alkylsulfinyl C1-6Alkyl, di (C)1-6Alkyl) phosphono C1-6Alkyl, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, di (C)1-6Alkyl) aminoacetyl, amino C2-6Alkoxy radical, C1-6Alkylamino radical C2-6Alkoxy, di (C)1-6Alkyl) amino C2-6Alkoxy, hydroxy C2-6Alkylamino radical, C1-6Alkoxy radical C2-6Alkylamino radical, amino radical C2-6Alkylamino radical, C1-6Alkylamino radical C2-6Alkylamino radical, di (C)1-6Alkyl) amino C2-6An alkylamino group; or adjacent R1Mutually cyclized to form a 3-8 membered ring, and the ring contains 0, 1,2 and 3 heteroatoms;
Cy1selected from 5-15 membered bridged ring group, 5-15 membered spiro ring group, 5-15 membered bridged heterocyclic group, or 5-15 membered spiro heterocyclic group substituted by any substituent group: halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano;
Ra、Rb、R2each independently selected from hydrogen and C1-C6Alkyl or C3-6A cycloalkyl group;
Cy2is C containing one or more substituents5-C10Aryl radical, C5-C10Heteroaryl group, C5-C10Cycloalkyl radical, C5-C10A heterocycloalkyl group; the substituent can be selected from halogen, hydroxyl, nitro, cyano, sulfonic acid group and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, C1-6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkoxycarbonyl, di (C)1-6Alkyl) amino C2-6Alkoxycarbonyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, carbamoyl, C1-6Alkylcarbamoyl, di (C)1-6Alkyl) carbamoyl, di (C)1-6Alkyl) amino C2-6Alkylcarbamoyl, sulfamoyl, C1-6Alkylsulfamoyl, di (C)1-6Alkyl) sulfamoyl, di (C)1-6Alkyl) amino C2-6Alkylsulfamoyl, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl, di (C)1-6Alkyl) phosphono, hydroxy C1-6Alkyl, hydroxy carbonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C1-6Alkylsulfinyl C1-6Alkyl, di (C)1-6Alkyl) phosphono C1-6Alkyl, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, di (C)1-6Alkyl) aminoacetyl, amino C2-6Alkoxy radical, C1-6Alkylamino radical C2-6Alkoxy, di (C)1-6Alkyl) amino C2-6Alkoxy, hydroxy C2-6Alkylamino radical, C1-6Alkoxy radical C2-6Alkylamino radical, amino radical C2-6Alkylamino radical, C1-6Alkylamino radical C2-6Alkylamino radical, di (C)1-6Alkyl) amino C2-6Alkylamino, -S (O) C1-6An alkyl group; or when two substituents are adjacent, can form a 3-8 membered ring, which 3-8 membered ring may contain 0, 1,2, 3O, S, N atoms; m and n are 0, 1,2, 3 and 4.
In another embodiment of the present invention, Cy is1Selected from 8-12 membered spiro ring group or 8-12 membered spiro ring group, 8-12 membered bridged heterocyclic group, or 8-12 membered spiro heterocyclic group substituted by substituent groups: halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano.
In another embodiment of the present invention, Cy is1Selected from the following groups:
Figure BDA0002505919540000061
the above groups may be selected from halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano.
In another embodiment of the present invention, Cy is1Selected from the following groups:
Figure BDA0002505919540000062
Figure BDA0002505919540000071
the above groups may be selected from halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano.
The invention provides a compound shown as a formula (II),
Figure BDA0002505919540000072
wherein R is1、R2、Ra、Rb、Cy2M, n, A are as defined for formula I; x is selected from (CR)cRd)oWherein is optionally CRcRdMay be substituted by O or NReReplacing; y is selected from CRfOr N; wherein R isc、Rd、Re、RfEach independently selected from hydrogen or C1-6An alkyl group; o is selected from 0, 1,2, 3, 4, 5.
The invention provides a compound shown as a formula (III),
Figure BDA0002505919540000081
wherein W and Q are selected from CRcRdOr NReOr O; A. r1、R2、Ra、Rb、Rc、Rd、Re、Cy2M, n and Y are as defined above for formula (II).
The invention also provides a compound shown as a formula (IV),
Figure BDA0002505919540000082
wherein R is1、R2、Ra、Rb、Cy2M, n, X, Y, A are as defined above for formula (II); z is selected from (CR)g)pWherein CR is arbitrarygMay be replaced by N; rgEach independently selected from hydrogen or C1-6An alkyl group; p is selected from 0, 1,2, 3, 4, 5.
In the preferred technical scheme of the invention, the structure of the compound has the formula (V):
Figure BDA0002505919540000091
wherein R is1、R2、Rc、Rd、Rf、Cy2M and A are as defined above for formula (II).
In the preferred technical scheme of the invention, the structure of the compound has the formula (VI):
Figure BDA0002505919540000092
wherein R is1、R2、Rc、Rd、Cy2M and A are as defined above for formula (II).
In a preferred embodiment of the present invention, the compound has a structure represented by formula (VII):
Figure BDA0002505919540000093
wherein R is1、R2、Re、Rf、Cy2M and A are as defined above for formula (II).
In a preferred technical scheme of the invention, the compound has a structure as shown in a formula (VIII):
Figure BDA0002505919540000101
wherein R is1、R2、Rc、Rd、Rf、Cy2M and A are as defined above for formula (II).
In a preferred technical scheme of the invention, the compound has a structure as shown in a formula (IX):
Figure BDA0002505919540000102
wherein R is1、R2、Rc、Rd、Re、Rf、Cy2M and A are as defined above for formula (II).
In the technical scheme of the invention, the air conditioner is provided with a fan,
Figure BDA0002505919540000103
to represent
Figure BDA0002505919540000104
Or
Figure BDA0002505919540000105
In the technical scheme of the invention, the air conditioner is provided with a fan,
Figure BDA0002505919540000106
preferably, it is
Figure BDA0002505919540000107
In the technical scheme of the invention, A is selected from-C (O) -or S (O)2-。
The invention also provides a preparation method of the compound with the structure of the formula (X):
Figure BDA0002505919540000111
in the route I reaction:
wherein the base used in step (1) is selected from inorganic bases or organic bases, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, tert-butyl lithium, tert-butyl potassium, potassium tert-butoxide, lithium diisopropylamide, barium hydroxide, or any combination thereof;
wherein the organic solvent used in step (1) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof;
wherein the ylide used in step (2) is selected from the group consisting of a sulfur ylide and a phosphorus ylide;
wherein the Grignard reagent used in step (3) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr, or any combination thereof.
The invention also provides a preparation method of the compound with the structure of the formula (XI):
Figure BDA0002505919540000112
in the route II reaction:
wherein the catalyst used in step (1) is selected from methyl titanate, ethyl titanate, n-propyl titanate, isopropyl titanate, butyl titanate or any combination thereof;
wherein the base used in step (2) is selected from inorganic bases or organic bases, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, tert-butyl lithium, tert-butyl potassium, potassium tert-butoxide, lithium diisopropylamide, barium hydroxide, or any combination thereof;
wherein the organic solvent used in step (2) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof;
wherein the ylide used in step (2) is selected from the group consisting of a sulfur ylide and a phosphorus ylide;
wherein the hydrolysis of step (3) is carried out under acidic conditions, said acid being selected from, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid or any combination thereof;
wherein the organic solvent used in step (4) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof.
The invention also provides a preparation method of the compound with the structure of the formula (XII):
Figure BDA0002505919540000121
in path III:
wherein the catalyst used in step (1) is selected from methyl titanate, ethyl titanate, n-propyl titanate, isopropyl titanate, butyl titanate or any combination thereof;
wherein the step (2) is carried out under the action of non-nucleophilic strong base selected from the group consisting of but not limited to lithium diisopropylamide, lithium diethylamide, lithium isopropylcyclohexylamide, lithium dicyclohexylamide, lithium 2,2,6, 6-tetramethylpiperidino and lithium hexamethyldisilazide;
wherein the hydrolysis reaction of step (3) is carried out under acidic conditions, and the acid is selected from, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid, or any combination thereof;
wherein the Grignard reagent used in step (4) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr or any combination thereof;
wherein, when the alkylation reaction in the step (5) is performed, the alkylation reaction reagent is selected from halogenated alkyl, the reaction is performed under the condition of Lewis acid as a catalyst, and the Lewis acid is preferably AlCl3、FeCl2、CuCl2。
The invention also provides a preparation method of the compound with the structure of the formula (XIII):
Figure BDA0002505919540000131
in path IV
Wherein the base used in step (1) and step (3) is selected from inorganic bases or organic bases, including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, tert-butyl lithium, tert-butyl potassium, potassium tert-butoxide, lithium diisopropylamide, barium hydroxide, or any combination thereof;
wherein the organic solvent used in steps (1) to (3) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof;
wherein the oxidant used in step (2) is selected from but not limited to m-chloroperoxybenzoic acid, CrO3、KMnO4、MnO2、NaCr2O7、HIO4、PbAc4、OsO4Hydrogen peroxide or any combination thereof;
wherein the hydrolysis reaction of step (4) is carried out under acidic conditions, and the acid is selected from, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid, or any combination thereof;
wherein the Grignard reagent used in step (5) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr, or any combination thereof.
The invention also provides a preparation method of the compound with the structure of the formula (XIV):
Figure BDA0002505919540000141
in path V:
wherein step (1) is carried out in the presence of an alkali metal fluoride or an alkaline earth metal fluoride selected fromBut are not limited to L iF, NaF, KF, MgF2、CaF2；
Wherein the reduction reaction in the step (2) can be palladium carbon catalytic hydrogenation reduction or Na/liquid ammonia reduction;
wherein the Grignard reagent used in step (3) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr or any combination thereof;
wherein, when the alkylation reaction in the step (4) is carried out, the alkylation reaction reagent is selected from halogenated alkyl, the reaction is carried out under the condition of Lewis acid as a catalyst, and the Lewis acid is preferably AlCl3、FeCl2、CuCl2。
Detailed Description
Design and reaction examples
All synthesized compounds can be analytically verified by, but are not limited to, L CMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance) determined by Bruker AVANCE-500 NMR, the deuterated solvent used in the determination being deuterated dimethyl sulfoxide (d-dimethyl sulfoxide)6-DMSO), deuterated chloroform (CDCl)3) Tetramethylsilane (TMS) was used as an internal standard. The following abbreviations represent various types of split peaks: singlet(s), doublet (d), triplet (t), multiplet (m), broad (br). Mass Spectrometry (MS) was measured using a Thermo Fisher-MSQ Plus LC Mass spectrometer. General synthetic analysis and examples are described below:
example 1
N- (4-chlorophenylyl) -6- (6-fluoroquinolin-4-yl) spiro [2.5] octane-1-carboxamid eN- (4-chlorophenyl) -6- (6-fluoroquinolin-4-yl) spiro [2.5] octane-1-carboxamide
Figure BDA0002505919540000161
The first step is to dissolve 1, 4-cyclohexanedione monoethylene glycol ketal (10.0g,64.03mmol) in 250m L methyl tert-butyl ether, add N-phenyl bis (trifluoromethanesulfonyl) imide (22.9g,64.03mmol), cool the reaction to-78 ℃, add dropwise sodium bis (trimethylsilyl) amide (2 mol/L tetrahydrofuran solution) (32m L, 64.03mmol) to the reaction under nitrogen atmosphere, after the dropwise addition, continue stirring at that temperature for 60 minutes, then raise the reaction to room temperature, stir overnight until T L C detects that the reaction raw material is completely consumed, quench the reaction with 3m L aqueous potassium hydrogen sulfate solution, filter to remove solids, concentrate the filtrate, add 3m L methyl tert-butyl ether to the residual solution, wash the organic layer three times with 45m L sodium hydroxide (5%), wash 50m L saturated saline once, dry the organic layer with anhydrous sodium sulfate, filter, concentrate to obtain compound 1a (17.23g), orange oily yield.1H NMR(500MHz,CDCl3)5.66(J＝4.0Hz,1H),4.01–3.96(m,4H),2.56–2.52(m,2H),2.42–2.40(m,2H),1.90(t,J＝6.5Hz,2H).
In the second step, compound 1a (13g,45.1mmol) was dissolved in 100m L dioxane, and pinacol diboron (14.9g,58.64mmol), potassium acetate (13.3g,135.3mmol) and Pd (dppf) Cl were added sequentially2(1.65g,2.26 mmol). The reaction mixture was refluxed overnight under nitrogen atmosphere. Then the reaction solvent dioxane was evaporated to dryness, ethyl acetate was added, celite was filtered, the filtrate was concentrated and then separated by flash column chromatography to give compound 1b (7.6g) as a pale yellow solid in 63% yield.1HNMR(500MHz,CDCl3)6.48–6.45(m,1H),3.98(s,4H),2.40–2.34(m,4H),1.73(t,J＝6.5Hz,2H),1.25(s,12H).
The third step was to dissolve Compound 1b (5.7g,21.48mmol) in 60M L/15M L dioxane/water, add 4-chloro-6-fluoroquinoline (3.0g,16.53mmol), potassium carbonate (6.8g,49.56mmol) and Pd (PPh3)4(954mg,0.83mmol) in that order, reflux the reaction mixture under nitrogen atmosphere overnight, then concentrate the reaction mixture, extract it with ethyl acetate, concentrate the organic phase and separate it with flash column chromatography to give Compound 1c (2.42g), pale yellow liquid, yield 51%. MS (ESI): M/z286.1(M + H)+.1H NMR(500MHz,CDCl3)8.81(d,J＝4.5Hz,1H),8.15(dd,J＝9.0,5.5Hz,1H),7.65(dd,J＝10.0,2.5Hz,1H),7.49(td,J＝9.0,2.5Hz,1H),7.26(d,J＝4.5Hz,1H),5.77(t,J＝3.5Hz,1H),4.08–40.6(m,4H),2.65–2.60(m,2H),2.56–2.53(m,2H),2.00(t,J＝6.5Hz,2H).
The fourth step was to dissolve Compound 1c (2.42g,8.49mmol) in 45M L isopropanol, add 10% Palladium on carbon (300mg) and heat the reaction mixture to 55 deg.C under hydrogen atmosphere overnight, then filter off the Palladium on carbon with Celite and concentrate the filtrate to give crude Compound 1d (2.04g) as a syrup in 84% yield for use directly in the next reaction MS (ESI) M/z288.1(M + H)+.
The fifth step is to dissolve compound 1d (2.04g,7.11mmol) in 36M L acetone, add 9M L4 mol/L hydrochloric acid, heat the reaction mixture to 45 ℃ overnight, then evaporate the solvent, neutralize the aqueous solution with 6 mol/L sodium hydroxide to pH 9, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, isolate the residue on flash column chromatography to give compound 1e (1.17g), a pale yellow solid, 67% yield ms esi M/z 244.3(M + H)+.1H NMR(500MHz,CDCl3)8.85(d,J＝4.5Hz,1H),8.22(dd,J＝9.0,5.5Hz,1H),7.74(dd,J＝10.0,2.5Hz,1H),7.57–7.50(m,1H),7.33(d,J＝4.5Hz,1H),3.74–3.66(m,1H),2.72–2.58(m,4H),2.41–2.34(m,2H),2.11–2.00(m,2H).
Sixthly, triethyl phosphonoacetate (968mg,4.32mmol) is dissolved in 16M L ultra-dry tetrahydrofuran, sodium tert-butoxide (415mg,4.32mmol) is added at 0 ℃ in ice bath for 10 minutes, then a solution of compound 1e (1g,4.12mmol) in tetrahydrofuran (4M L) is added to the reaction mixture, after 2 hours of reaction, quenched with water, the aqueous solution is extracted three times with 20M L ethyl acetate, the organic phases are combined, washed with 20M L saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by flash column chromatography to give compound 1f (1.18g), a white solid, yield 92%, (MS ESI) M/z 314.0(M + H)+.1H NMR(500MHz,CDCl3)8.81(d,J＝4.5Hz,1H),8.17(dd,J＝9.0,5.5Hz,1H),7.72(dd,J＝10.0,2.5Hz,1H),7.53–7.47(m,1H),7.28(d,J＝4.5Hz,1H),5.75(s,1H),4.19(q,J＝7.0Hz,2H),3.52–3.42(m,1H),2.54–2.48(m,2H),2.26–2.11(m,4H),1.80–1.68(m,2H),1.30(t,J＝7.0Hz,3H).
Seventh step, NaH (383mg,9.57mmol) was added to 15M L dimethylsulfoxide, trimethyl sulfoxide iodide (2.11g,9.57mmol) was added to the suspension, the mixture was stirred at room temperature for 1.5 hours, then a solution of Compound 1f (1.0g,3.19mmol) in dimethylsulfoxide (5M L) was added to the reaction solution, the reaction was stirred at room temperature overnight, then quenched with water, extracted with ethyl acetate, and separated by flash column chromatography to give Compound 1g (820mg), a colorless oily liquid, yield 78%. MS ESI M/z 328.1(M + H)+.1HNMR(500MHz,CDCl3)8.83(d,J＝4.5Hz,1H),8.24(dd,J＝9.0,5.5Hz,1H),7.71(dd,J＝10.0,2.5Hz,1H),7.55–7.49(m,1H),7.35(d,J＝4.5Hz,1H),4.19(q,J＝7.0Hz,2H),3.32–3.24(m,1H),2.17(td,J＝13.0,3.5Hz,1H),2.07–1.90(m,4H),1.87–1.78(m,1H),1.58(dd,J＝8.0,5.5Hz,1H),1.46–1.37(m,1H),1.30(t,J＝7.0Hz,3H),1.28–1.24(m,2H),1.16–1.11(m,1H),1.00(dd,J＝8.0,4.5Hz,1H).
Eighth step 4-chloroaniline (94mg,0.73mmol) was dissolved in 5M L tetrahydrofuran, 2 mol/L mol isopropyl magnesium chloride in tetrahydrofuran (0.4M L, 0.73mmol) was added at 0 ℃ in an ice bath, the mixture was stirred at room temperature for 5 minutes, 1g (60mg,0.18mmol) of tetrahydrofuran (2M L) was added to the mixture, the reaction was stirred at room temperature overnight and then quenched with saturated ammonium chloride solution, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse phase preparative chromatography to give compound 1(16.04mg), a white solid, yield 21%. MS (ESI): M/z 408.9(M + H)+.1H NMR(500MHz,d6-DMSO)10.37(s,1H),8.81(s,1H),8.11–8.05(m,1H),8.02(d,J＝11.0Hz,1H),7.69–7.63(m,3H),7.38–7.31(m,3H),3.48–3.40(m,1H),2.20(t,J＝12.0Hz,1H),1.97–1.84(m,4H),1.78(d,J＝12.5Hz,1H),1.72(t,J＝6.5Hz,1H),1.35–1.26(m,1H),1.17–1.08(m,2H),0.96–0.90(m,1H).
Example 32
N-(4-chlorophenyl)-7-(6-fluoroquinolin-4-yl)spiro[3.5]nonane-1-carboxamide
N- (4-chlorophenyl) -7- (6-fluoroquinolin-4-yl) spiro [3.5] nonane-1-carboxamide
Figure BDA0002505919540000201
Synthesis of compound 32 starting from intermediate 1e in example 1, was prepared via the following steps: the first step is as follows: (cyclopropylmethyl) triphenylphosphine bromide (2.0eq) was added to the ultra-dry tetrahydrofuran, and NaH (2.0eq) was added to the suspension, followed by stirring at room temperature for 2 hours. Further, compound 1e (1.0eq) and tris (3, 6-dioxaheptyl) amine (0.1eq) were added to the reaction solution. The reaction mixture was stirred at room temperature for 10 minutes and then heated to 62 ℃ for 4 hours. The reaction solvent was dried by spinning and the residue was isolated by flash column chromatography to give compound 32a in 75% yield. MS (ESI) M/z 268.3(M + H)+.
The second step is that: compound 32a (1.0eq) was dissolved in dichloromethane and m-chloroperoxybenzoic acid (1.4eq) was added in portions at 0-5 ℃. The reaction mixture was reacted at 0-5 ℃ for 40 minutes and then warmed to room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, and the organic phase was washed successively with a 10% aqueous sodium hydroxide solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash column chromatography to give compound 32b in 35% yield. MS (ESI) M/z284.3(M + H)+.
The third step: compound 32b (1.0eq) and p-toluenesulfonylmethylisocyanitrile (2.0eq) were dissolved in 1, 2-dimethoxyethane and methanol (v/v:16/1), and potassium tert-butoxide (3.0eq) was added at 0-5 ℃. The reaction mixture was stirred at room temperature for 4 hours, then poured into water and neutralized with 1M hydrochloric acid solution to pH 6-7. The aqueous solution was extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash column chromatography to give compound 32c in 20% yield. MS (ESI) M/z 295.3(M + H)+.
The fourth step: compound 32c (1.0eq) was dissolved in ethanol, 40% sodium hydroxide solution (10.0eq) was added, and the mixture was heated at 95 ℃ for reaction for 3 hours. The reaction was diluted with water and neutralized with 4M hydrochloric acid solution to pH 1-2. Extracting the aqueous phase with ethyl acetate and combining the organicsThe phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 32d in 82% yield, which was used in the next step without purification. MS (ESI) M/z 314.3(M + H)+.
The fifth step: compound 32d (1.0eq) was dissolved in ethyl acetate, and pyridine (3.0eq) and tripropyl phosphoric anhydride (2.5eq) were added in this order and stirred at room temperature for 10 minutes. 4-chloroaniline (3.0eq) was then added and the reaction was continued at room temperature with stirring overnight. To the reaction solution was added 2M sodium hydroxide solution, and diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative chromatography to give compound 32 as a white solid.
Synthesis of compounds 33,34,35,36,37 and compound 32.
Figure BDA0002505919540000221
Figure BDA0002505919540000231
Figure BDA0002505919540000241
Figure BDA0002505919540000251

Claims (6)

1. A method of preparing a compound having the structure of formula (XIII):
Figure FDA0002505919530000011
wherein, among others,
Figure FDA0002505919530000012
represents: - (O) b,
Figure FDA0002505919530000013
Or
Figure FDA0002505919530000014
Wherein each R is1Each independently selected from hydrogen atom, halogen, hydroxyl, nitro, cyano, sulfonic acid group, C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy, halo C1-C6Cycloalkyl radical, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, di (C)1-6Alkyl) amino C2-6Alkoxycarbonyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, carbamoyl, C1-6Alkylcarbamoyl, di (C)1-6Alkyl) carbamoyl, di (C)1-6Alkyl) amino C2-6Alkylcarbamoyl, sulfamoyl, C1-6Alkylsulfamoyl, di (C)1-6Alkyl) sulfamoyl, di (C)1-6Alkyl) amino C2-6Alkylsulfamoyl, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl, di (C)1-6Alkyl) phosphono, hydroxy C1-6Alkyl, hydroxy carbonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C1-6Alkylsulfinyl C1-6Alkyl, di (C)1-6Alkyl) phosphono C1-6Alkyl, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, di (C)1-6Alkyl) aminoacetyl, amino C2-6Alkoxy radical, C1-6Alkylamino radical C2-6Alkoxy, di (C)1-6Alkyl) amino C2-6Alkoxy, hydroxy C2-6Alkylamino radical, C1-6Alkoxy radical C2-6Alkylamino radical, amino radical C2-6Alkylamino radical, C1-6Alkylamino radical C2-6Alkylamino radical, di (C)1-6Alkyl) amino C2-6An alkylamino group; or adjacent R1Mutually cyclized to form a 3-8 membered ring, and the ring contains 0-3 heteroatoms;
wherein R is2Each independently selected from hydrogen and C1-C6Alkyl or C3-6A cycloalkyl group;
wherein R isc、RdEach independently selected from hydrogen or C1-6An alkyl group;
wherein, Cy2Is C containing one or more substituents5-C10Aryl radical, C5-C10Heteroaryl group, C5-C10Cycloalkyl radical, C5-C10A heterocycloalkyl group; the substituent can be selected from halogen, hydroxyl, nitro, cyano, sulfonic acid group and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, C1-6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkoxycarbonyl, di (C)1-6Alkyl) amino C2-6Alkoxycarbonyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, carbamoyl, C1-6Alkylcarbamoyl, di (C)1-6Alkyl) carbamoyl, di (C)1-6Alkyl) amino C2-6Alkylcarbamoyl, sulfamoyl, C1-6Alkylsulfamoyl, di (C)1-6Alkyl) sulfamoyl, di (C)1-6Alkyl) amino C2-6Alkylsulfamoyl, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl, di (C)1-6Alkyl) phosphono, hydroxy C1-6Alkyl, hydroxy carbonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C1-6Alkylsulfinyl C1-6Alkyl, di (C)1-6Alkyl radical)Phosphono group C1-6Alkyl, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, di (C)1-6Alkyl) aminoacetyl, amino C2-6Alkoxy radical, C1-6Alkylamino radical C2-6Alkoxy, di (C)1-6Alkyl) amino C2-6Alkoxy, hydroxy C2-6Alkylamino radical, C1-6Alkoxy radical C2-6Alkylamino radical, amino radical C2-6Alkylamino radical, C1-6Alkylamino radical C2-6Alkylamino radical, di (C)1-6Alkyl) amino C2-6Alkylamino, -S (O) C1-6An alkyl group; or when two substituents are adjacent, can form a 3-8 membered ring, which 3-8 membered ring may contain 0-3O, S, N atoms;
wherein m is an integer of 0 to 4.
2. The process of claim 1, wherein the base used in step (1) and step (3) is selected from inorganic or organic bases including but not limited to: sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, tert-butyl lithium, tert-butyl potassium, lithium diisopropylamide, barium hydroxide, or any combination thereof.
3. The method of claim 1 or 2, wherein the organic solvent used in steps (1) to (3) includes but is not limited to: 1, 4-dioxane, N-dimethylformamide, dichloromethane, chloroform, DMSO, DMF, THF, acetone, methanol, ethanol, or any combination thereof.
4. A process as claimed in any one of claims 1 to 3 wherein the oxidising agent used in step (2) is selected from but not limited to m-chloroperoxybenzoic acid, CrO3、KMnO4、
MnO2、NaCr2O7、HIO4、PbAc4、OsO4Hydrogen peroxide or any combination thereof.
5. The process of any one of claims 1-4, wherein the hydrolysis reaction of step (4) is carried out under acidic conditions and the acid is selected from, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, citric acid, formic acid, acetic acid, or any combination thereof.
6. The method according to any one of claims 1 to 5, wherein the Grignard reagent used in step (5) is selected from CH3MgCl、CH3MgBr、C2H5MgCl、C2H5MgBr、i-PrMgCl、i-PrMgBr，PhCH2MgCl、PhCH2MgBr, or any combination thereof.
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