CN110156786A - Pyrimido cycle compound and its preparation method and application - Google Patents

Pyrimido cycle compound and its preparation method and application Download PDF

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Publication number
CN110156786A
CN110156786A CN201810144135.3A CN201810144135A CN110156786A CN 110156786 A CN110156786 A CN 110156786A CN 201810144135 A CN201810144135 A CN 201810144135A CN 110156786 A CN110156786 A CN 110156786A
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base
compound
decane
azaspiro
pyrimidine
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CN201810144135.3A
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CN110156786B (en
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邹斌
张睿
付贤磊
马世超
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Shanghai Blueray Biopharma Co ltd
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Shanghai Qing Yu Medical Science And Technology Co Ltd
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Priority to CN202210427468.3A priority Critical patent/CN115448923B/en
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Priority to CN201810144135.3A priority patent/CN110156786B/en
Priority to KR1020207026395A priority patent/KR102614939B1/en
Priority to US16/969,392 priority patent/US11498930B2/en
Priority to MA051845A priority patent/MA51845A/en
Priority to AU2019222026A priority patent/AU2019222026B2/en
Priority to PCT/CN2019/074685 priority patent/WO2019158019A1/en
Priority to JP2020543947A priority patent/JP7335882B2/en
Priority to SG11202007740TA priority patent/SG11202007740TA/en
Priority to EP19754599.9A priority patent/EP3753941B1/en
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract

The invention discloses pyrimido cycle compound, its pharmaceutically acceptable salt and its solvates.Present invention provides the preparation methods of such compound, the purposes containing the composition of such compound and such compound in terms of preparation treatment with the drug of the abnormal related disease of SHP2 activity or illness.

Description

Pyrimido cycle compound and its preparation method and application
Technical field
The invention discloses pyrimido cycle compound, its pharmaceutically acceptable salt and its solvates.The present invention also mentions It supplied the preparation method of such compound, prepared treatment and SHP2 containing the composition of such compound and such compound Purposes in terms of the drug of active exception related disease or illness.
Background technique
Tyrosine phosphatase SHP2 is by two homologous 2 structural domains of the end N- Src (N-SH2 and C-SH2) and an albumen junket Propylhomoserin phosphatase catalytic structural domain (PTP) is constituted.Under base state, N-SH2 can form a cyclic annular knot in conjunction with PTP Structure, so that the combination of PTP and substrate is hindered, so that enzymatic activity is suppressed；When the tyrosine of upstream receptor protein is by phosphoric acid After change, N-SH2 is in conjunction, and PTP catalytic domain is released to play phosphatase activity.
On a cellular level, SHP2 is participated in by the function in the cytoplasm downstream of many receptor tyrosine kinases Multiple tumour cell signal transduction pathway, such as RTK/Ras/MAPK, JAK/STAT and PI3K/Akt.By to these kinases with And the regulating and controlling effect of signal path, SHP2 and many important cell activities are closely related, such as cell Proliferation, migration, divide Change, the dead, regulation of cell factor and tumour generation etc..
Meanwhile SHP2 also assists in the immune system inhibition of programmed death receptor 1 (PD1) mediation.The PD-1 of T cell with After PD-L1 is combined, it can do recruit a large amount of SHP2 in the cell.SHP2 can be by T cell endoantigen receptor pathway albumen dephosphorization Acidification, to inhibit the activation of T cell.Therefore, immunosupress can be reversed in tumor microenvironment by inhibiting the activity of SHP2.
SHP2 is important a member in Protein-tyrosine-phosphatase family, related to a variety of diseases of the mankind, such as exerts southern synthesis Levy (Noonan Syndrome), leopard syndrome (Leopard Syndrome), teenager's myelomonocytic leukemia, at nerve Cytoma, melanoma, acute myeloid leukaemia, breast cancer, cancer of the esophagus, lung cancer, colon cancer, head cancer, neuroblastoma, head Squamous cell carcinoma, gastric cancer, primary cutaneous type and spongioblastoma of neck etc..
A series of patents delivered at no distant date, such as WO2018/013597A1, WO2017/210134A1, WO2017/ 211303A1、WO 2017/216706A1、WO 2016/203406A1、WO 2016/203405A1、WO 2016/203404A1、 It is novel as one to show SHP2 by WO2015/107495A1, WO2015/107494A1 and WO2015/107493A1 etc. Can patent medicine target spot, cause more and more concerns.Around the exploitation of SHP2 inhibitor, there is the PTP catalysis region for SHP2 Inhibitor exploitation and non-catalytic regions the big strategy of allosteric inhibitor exploitation two；Since PTP catalysis region inhibitor has selection Property and druggability difference problem, more researchs tend to the exploitation of allosteric inhibitor at present.Above-mentioned patent disclosure is allosteric Inhibit, but most of, such as WO 2015/107493 A1 disclosed in compound SHP099s not high to the inhibitory activity of tumour cell (6- (4- amino -4- methyl piperidine -1- base) -3- (2,3- dichlorophenyl) pyrazine -2- amine) etc., up for further development structure SHP2 inhibitor novel and that bioactivity is good, druggability is high.
Summary of the invention
Pyrimido cycle compound provided by the invention is a kind of completely new SHP2 inhibitor, is shown fine to tumour cell Inhibitory activity and druggability it is good, have wide drug development prospect.And the preparation method of such compound is simple, favorably In industrialized production.
In a first aspect, the present invention provides pyrimido cycle compound shown in formula (I), its pharmaceutically acceptable salt or its is molten The solvate of agent compound or the salt.
Wherein
Z1、Z2Simultaneously be C or in which one of be N；
X independently is S or is not present；
Y independently is C or N；
N independently is 0,1 or 2；
R1Independently 0 to 4 R1aSubstituted phenyl, 0 to 4 R1aWhat is replaced contains 1-4 azepine aryl, 0 to 4 R1aSubstituted naphthalene, 0 to 4 R1aWhat is replaced contains 1-4 azanaphthalene aryl, 0 to 4 R1aSubstituted or unsubstituted benzo is miscellaneous Ring, 0 to 4 R1aIt is substituted or unsubstituted to contain 1-4 azepine virtue and ring, 0 to 4 R1aWhat is replaced contains 1-4 N, NR1b、O Or the heteroatomic hetero-aromatic ring, R such as S (O) m1cSubstituted or unsubstituted C1-8Alkyl, R1cSubstituted or unsubstituted C1-8Halogenated alkyl； Wherein m is selected from 0,1 and 2；
R1aIt independently is halogen, R1a1Substituted or unsubstituted C1-4Alkoxy, R1a1Substituted or unsubstituted C1-4Alkyl, three Methyl fluoride, C (=O) OR1a2、NR1a2R1a3, NHC (=O) R1a4、R1a1Substituted or unsubstituted C3-8Naphthenic base；R1a1It independently is Halogen or C1-4Alkyl；R1a2、R1a3It independently is hydrogen, C1-4Alkyl；R1a4It independently is C1-4Alkyl, substituted or unsubstituted alkene Base, amide, C3-12Single or multiple heterocycle；
R1bIt independently is hydrogen, R1a1Substituted or unsubstituted C1-4Alkyl；
R1cIt independently is hydrogen ,-C (=O) OR1a2、R1a1Substituted or unsubstituted C1-4Alkyl；
R2a、R2b、R3aAnd R3bIt independently is hydrogen, R1a1Substituted or unsubstituted C1-4Alkyl；
As Y=N, R4It independently is hydrogen, R1a1Substituted or unsubstituted C1-4Alkyl；R5It is not present；
As Y=C, R4、R5It independently is hydrogen, aryl, C1-4Alkyl, C1-4Alkoxy ,-O-C1-4Alkyl, amino, C1-4Alkane Base substituted-amino ,-O-C1-4Alkyl-substituted amino or R4And R50 to 3 R is formed together with Y4aReplace 3 to 7 yuan saturation or The unsaturated loop coil in part, the ring can be optionally containing 1 to 3 independently selected from hetero atoms or the groups such as N, C (=O) and/or O；
R4aIt independently is hydrogen, halogen, R1a1Substituted or unsubstituted C1-4Alkoxy, R1a1Substituted or unsubstituted C1-4Alkane Base, hydroxyl, amino, C1-4Alkyl amino.
In one of preference, pyrimido cycle compound structure of the present invention is formula (II)
In another preferred example, R1Selected from flowering structure:
Wherein, 0,1,2,3 or 4 o；Ring A is the heteroaryl containing 1 to 4 N atom；Ring B is to contain 1 to 4 N, S, O Etc. heteroatomic heteroaryl；G independently is hetero atoms or the groups such as C, C (=O), N, S or O；R1aa、R1abIt independently is R1a；R1ac It independently is R1cSubstituted or unsubstituted C1-8Alkyl, R1cSubstituted or unsubstituted C1-8Alkyl halide；
In another preferred example, R2a、R2b、R3aAnd R3bIt independently is hydrogen or methyl；
In another preferred example, as Y=N, R4It independently is hydrogen, methyl；R5It is not present；
In another preferred example, as Y=C, R4、R5Independently be hydrogen, methyl, ethyl, phenyl, amino, methylamino or Ethylamino；
In another preferred example, as Y=C, R4And R5It is selected from the ring that Y is formed together with flowering structure:
Wherein, 0,1,2 or 3 p；R4aAs defined above；
In another preferred example, as Y=C, R4And R5Following configuration is selected from the ring that Y is formed together:
Wherein, p, R4aAs defined above；
In another preferred example, the compound is selected from following any compound:
On the other hand, the present invention provides pyrimido cycle compound shown in formula (I), its pharmaceutically acceptable salt or its is molten The compound isotopically labelled of agent compound.The atom that can be isotopically labeled in compound shown in formula (I) includes but does not limit to Yu Qing, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine etc..They can be respectively by isotope2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl and125I etc. is replaced.
On the other hand, the present invention provides the preparation method of pyrimido cycle compound shown in formula (I) and its intermediate, mainly Including following aspect:
The present invention provides the preparation method of formula (I), includes the following steps:
Halogenated intermediates compoundAfter carrying out coupling reaction with boric acid, mercaptan or sulphur sodium (F) Formula (I) is obtained, reaction equation is as follows:
Wherein, W1Represent halogen, preferably Br, I；Z1、Z2、X、Y、n、R1、R2a、R2b、R3a、R3b、R4And R5It is as defined above institute It states.
One of preferred embodiment, the preparation method of formula (II), includes the following steps:
Halogenated intermediates compound A and boric acid, mercaptan or sulphur sodium (F) obtain formula (II), reaction side after carrying out coupling reaction Formula is as follows:
Wherein, W1Represent halogen, preferably Br, I；X,Y,n,R1、R2a、R2b、R3a、R3b、R4And R5It is as defined above.
The present invention also provides compound A,
Wherein, W1Represent halogen, preferably Br, I；R2a、R2b、R3a、R3b、R4、R5, Y, n it is as defined above.
The present invention also provides the preparation methods of compound A comprising the steps of:
Halogenated intermediates E is replaced to obtain midbody compound A under alkaline condition by intermediate amine C, and reaction equation is such as Under:
Wherein, W1Represent halogen, preferably Br, I；W2Represent halogen, preferably Cl, Br, I；Y,n,R2a、R2b、R3a、R3b、R4With R5It is as defined above.
The present invention also provides compound C-1,
Wherein, U independently is C or O；Q is selected from 0,1 or 2；Pg is selected from protecting group Boc, Ac, S (=O)tBu；n,R2a、R2b、 R3a、R3bAnd R4aIt is as defined above.
The present invention also provides the preparation methods of compound C-1 comprising the steps of:
Loop coil ketone compound C-1a reduction amination obtains intermediate C-1b；C-1 is obtained after C-1b selectively deprotection, is reacted Equation is as follows:
Wherein, Pg1 is selected from protecting group Boc, benzoyl, benzyl；Pg,U,q,n,R2a、R2b、R3a、R3bAnd R4aDefinition As described above.
The present invention also provides compound C-2,
Wherein, R6It independently is C1-8Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl；U,q,Pg, n、R2a、R2b、R3a、R3bAnd R4aIt is as defined above.
The present invention also provides the preparation methods of compound C-2 comprising the steps of:
Loop coil ketone compound C-1a and R6Substituted nucleopilic reagent addition obtains hydroxy compounds C-2a；Compound C-2a turns It is melted into amino-compound C-2b, then obtains C-2 after its protecting group of selectively removing Pg1, reaction equation is as follows:
Wherein, R6、U、q、Pg1、Pg、n、R2a、R2b、R3a、R3bAnd R4aIt is as defined above.
The present invention also provides compound C-3,
Wherein, R6、Pg、n、R2a、R2b、R3aAnd R3bIt is as defined above.
The present invention also provides the preparation methods of compound C-3 comprising the steps of:
The ester group ortho position dehydrogenation of compound C-3a and R6Substituted electrophilic reagent obtains compound C-3b after replacing；Compound C-3b hydrolysis ester group obtains sour C-3c；Amine C-3d is obtained after sour C-3c is rearranged, then selectively removing protecting group Pg1 obtains C- 3, reaction equation is as follows:
Wherein, R6、Pg1、Pg、n、R2a、R2b、R3aAnd R3bIt is as defined above.
The present invention also provides compound C-4,
Wherein, R6、Pg、n、R2a、R2b、R3aAnd R3bIt is as defined above.
The present invention also provides the preparation methods of compound C-4 comprising the steps of:
Cyano compound C-4a is restored and is obtained intermediate C-4b after protecting amino, then selectively removing protecting group Pg1 C-4 is obtained, reaction equation is as follows:
Wherein, Pg1, Pg, R6、n、R2a、R2b、R3aAnd R3bIt is as defined above.
The present invention also provides compound E,
Wherein, W1Represent halogen, preferably Br, I；W2Represent halogen, preferably Cl, Br, I；
The present invention also provides the preparation methods of compound E comprising the steps of:
Double halogen substituted compound E are obtained after hydroxy intermediate B-3 halogenation, reaction equation is as follows:
Wherein, W1Represent halogen, preferably Br, I；W2Represent halogen, preferably Cl, Br, I；
The present invention also provides compound F-1, F-2,
Wherein, V independently is C or N；R1aIt is as defined above.
The present invention also provides compound F-1 preparation methods comprising the steps of:
Halogenated compound F-1a and mercapto-propionate obtain intermediate F-1b under the conditions of catalytic coupling, then in alkalinity Under the conditions of obtain corresponding sulphur sodium compound F-1；
The present invention also provides compound F-2 preparation methods comprising the steps of:
Halogenated compound F-1a and mercaptan are condensed to yield intermediate F-2b, then obtain thiol compounds in acid condition F-2。
The above-mentioned reaction equation for preparing F-1, F-2 is as follows:
Wherein, W3For halogen, preferably Br, I；V,R1aIt is as defined above.
The present invention also provides another preparation methods of pyrimido cycle compound shown in formula (I), comprise the following steps:
IntermediateFormula (I) is obtained after replacing with amine C, reaction equation is as follows:
Wherein, W2Represent halogen, preferably Cl, Br, I；Z1、Z2、X、Y、n、R1、R2a、R2b、R3a、R3b、R4And R5Definition such as It is upper described.
One of preferred embodiment, the preparation method of formula (II), includes the following steps:
Halogenated intermediates compound B and amine C obtains formula (II) after replacing, and reaction equation is as follows:
Wherein, W2Represent halogen, preferably Cl, Br, I；X,Y,n,R1、R2a、R2b、R3a、R3b、R4And R5It is as defined above institute It states.
The present invention also provides a kind of compound B,
Wherein, W2Represent halogen, preferably Cl, Br, I；R1Definition is as defined above with X；
The present invention also provides the preparation methods of compound B comprising the steps of:
Dichloro pyrimidine compound B-1 is replaced to obtain intermediate B -2 by amine；The condensation and cyclization under strongly acidic conditions of intermediate B -2 And it hydrolyzes and obtains halogenated intermediates B-3；Halogenated intermediates B-3 obtains intermediate B -4 under conditions of catalytic coupling, then converts At intermediate B, reaction equation is as follows:
Wherein W1Represent halogen, preferably Br, I；W2Represent halogen, preferably Cl, Br, I；R1It is as defined above with X.
In another preferred example, the preparation method of compound II-A, comprises the following steps:
Sulphur sodium midbody compound D and halides are coupled to obtain formula (II-A), and reaction equation is as follows:
Wherein, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5It is as defined above.
The present invention also provides a kind of compound D,
Wherein, Y, n, R2a、R2b、R3a、R3b、R4And R5It is as defined above.
The present invention also provides the preparation methods of compound D comprising the steps of:
Midbody compound A and mercapto-propionate obtain intermediate D-1 under the conditions of catalytic coupling, then in alkaline item Corresponding sulphur sodium compound D is obtained under part, reaction equation is as follows:
Wherein, W1Represent halogen, preferably Br, I；Y,n,R2a、R2b、R3a、R3b、R4And R5It is as defined above.
In another preferred example, the preparation method of compound II-B, comprises the following steps:
The amino protecting group for removing intermediate II-B1 under acid or alkaline conditions obtains compound II-B, reactional equation Formula is as follows:
Wherein, Pg is selected from protecting group Boc, Ac, S (=O)tBu；R4Pg、R5PgTogether with connection carbon, selected from flowering structure:
R4、R5Together with connection carbon, selected from flowering structure:
X、n、R1、R2a、R2b、R3a、R3b、R4、R5And R4aAs defined above；P is 0,1,2 or 3.
In another preferred example, the preparation method of compound II-C, comprises the following steps:
Compound II-C is obtained after the amino group of intermediate II-C1, reaction equation is as follows:
Wherein, X, Y, n, R1、R2a、R2b、R3a、R3b、R4、R5、R1aAnd R1a4It is as defined above.
It is involved in the present invention to solvent be selected from: methylene chloride, chloroform, 1,2- dichloroethanes, dioxane, DMF, second Nitrile, DMSO, NMP, THF or combinations thereof.
It is involved in the present invention to alkali include organic base and inorganic base.
The organic base involved in the present invention arrived is preferred are as follows: TEA, DIPEA or combinations thereof.
The inorganic base involved in the present invention arrived is preferred are as follows: sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, uncle Sodium butoxide, LiHMDS, LDA, butyl lithium or combinations thereof.
The compound isotopically labelled of pyrimido cycle compound shown in formula (I) of the present invention can by with unmarkedization Prepared by synthetic method as closing species, except that unlabelled starting material and/or reagent are changed into isotope labelling Starting material and/or reagent.
On the other hand, the present invention also provides a kind of pharmaceutical composition, comprising formula (I) pyrimido cycle compound, its pharmaceutically Acceptable salt or its solvate or formula (I) pyrimido cycle compound, its pharmaceutically acceptable salt or its solvate Compound isotopically labelled and pharmaceutically acceptable auxiliary material.The pharmaceutically acceptable auxiliary material be preferably selected from diluent, Absorbent, wetting agent, adhesive, disintegrating agent, lubricant.
On the other hand, the present invention also provides pyrimido cycle compound shown in the formula (I), its is pharmaceutically acceptable Salt or its solvate be used to prepare the drug for the treatment of and the abnormal related disease of SHP2 activity or illness in terms of purposes.As It is preferred that the disease or illness include exerting southern syndrome, leopard syndrome, the white blood of teenager's Myelomonocyte Disease, neuroblastoma, melanoma, acute myeloid leukaemia, breast cancer, cancer of the esophagus, lung cancer, colon cancer, head cancer, at nerve Cytoma, the squamous cell carcinoma of neck, gastric cancer, primary cutaneous type or spongioblastoma.
On the other hand, the present invention also provides a kind of pharmaceutical preparations, are cyclized and close comprising pyrimido shown in the formula (I) Object, its pharmaceutically acceptable salt or its solvate, can take in an appropriate manner, for example as tablet, capsule (as continued Release or time controlled released capsule), pill, powder, particle (such as little particle), elixir, tincture, suspension (such as nanosuspension, Fine suspension) and spray drying the forms such as suspended matter, syrup, lotion, the solution of forms such as dispersion, can be used for taking orally, tongue Under injection buccal, including forms such as subcutaneous injection, intravenous injection, intramuscular injection, breastbone inner injection, injections, nose take (ratio Such as nose film suck), local surfaces (such as creams and ointment), rectally (such as suppository) mode.Chemical combination disclosed by the invention Object can individually be taken or take together with pharmaceutical carrier appropriate.
On the other hand, the present invention also provides the pharmaceutical preparation described in previous aspect can be formulated into drug dose appropriate with Facilitate and control the dose of drug.The dosage of compound disclosed by the invention is different according to specific factor, than Such as pharmacodynamics and the mode taken, the weight for taking object, gender, age, health status and object of taking medicine, state of an illness feature, Other while situation of taking medicine, the frequency of medication, hepatic and renal function and want the effect reached etc..Compound disclosed by the invention can With taking for daily single dose, (such as daily two to four times) can also be taken several times with accumulated dose.
On the other hand, the present invention also provides pyrimido cycle compound shown in formula (I), its pharmaceutically acceptable salt or Its solvate is used in combination with other drugs, and the other drugs are selected from: anticarcinogen, antiallergic, stops tumour immunity drug Medicine, antalgesic, cell-protecting medicines etc. are spat, combination has better effect together.It should be understood that within the scope of the present invention, Above-mentioned each technical characteristic of the invention and specifically described in below (e.g. embodiment) can be mutual between each technical characteristic Combination, to form a new or preferred technical solution.Due to space limitations, I will not repeat them here.
The present invention has the advantage that
1, pyrimido cycle compound disclosed by the invention is a kind of novel allosteric inhibitor, can by with SHP2 is non-urges The combination for changing region, which simultaneously " is locked ", lives the very weak base state of SHP2 activity, inhibits its active purpose to reach.It is of the invention public The pyrimido cycle compound opened overcomes the disadvantages of PTP catalysis region inhibitor universal selectivity and poor druggability, is demonstrated by Good bioactivity and can druggability, there is good drug development prospect.
2, in the experiment of SHP2 inhibition of enzyme activity, phosphorylated protein kinase (p-ERK) cell experiment and MOLM- of the same terms In the appraisement systems such as 13 cell proliferation experiments, the present invention and 2015/107493 A1 of WO and document (Nature 2016,535, Compound SHP099 (6- (4- amino -4- methyl piperidine -1- base) -3- (2,3- dichlorophenyl) pyrazine-disclosed in 148-152) 2- amine) it compares, show more superior activity.
Term explanation
Unless otherwise defined, otherwise whole technologies used herein and scientific term all have such as fields of the present invention The normally understood identical meanings of those of ordinary skill.As used herein, in use, term in mentioning the numerical value specifically enumerated " about " mean that the value can change not more than 1% from the value enumerated.For example, as used herein, statement " about 100 " includes 99 Hes 101 and between whole values (for example, 99.1,99.2,99.3,99.4 etc.).
As used herein, term " containing " or " including (including) " can be open, semi-enclosed and enclosed.It changes Yan Zhi, the term also include " substantially by ... constitute " or " by ... constitute ".
Group definition
It can be in bibliography (including Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY 4TH ED. " Vols.A (2000) and B (2001), Plenum Press, New York) in find definition to standard chemistry terms. Unless otherwise stated, using the conventional method within the scope of art technology, as mass spectrum, NMR, IR and UV/VIS spectroscopic methodology and Pharmacological method.Unless proposing to be specifically defined, otherwise herein in analytical chemistry, Synthetic Organic Chemistry and drug and pharmaceutical chemistry Related description in the term that uses be known in the art.It in chemical synthesis, chemical analysis, medicine preparation, preparation and can pass Send, and in the treatment of patient use standard technique.For example, using manufacturer to the operation instruction of kit, or according to Mode well known in the art or explanation of the invention are implemented to react and be purified.Usually can according in this specification reference and The description in multiple summary and more specific document discussed, according to conventional method well known in the art implement above-mentioned technology and Method.In the present specification, group and its substituent group can be selected by those skilled in the art with provide stable structure division and Compound.When the conventional chemical formulas by writing from left to right describes substituent group, which similarly includes from right to left Write obtained equivalent substituent group in chemistry when structural formula.For example ,-CH2O- is equal to OCH2-。
Chapter title used herein is only used for the purpose of organizational, and is not necessarily to be construed as the limit to the theme System.All documents or literature department quoted in the application point include but is not limited to patent, patent application, article, books, manipulator Volume and paper are integrally incorporated herein by reference.
The certain chemical groups defined herein indicate carbon atom present in the group previously by symbol is simplified Sum.For example, C1-6Alkyl refers to the alkyl as defined below with 1 to 6 carbon atom in total.Simplify the carbon in symbol Total atom number does not include the carbon being likely to be present in the substituent group of the group.
In addition to aforementioned, when being used in the description of the present application and claims, unless otherwise specified, otherwise Following term has meaning as follows.
In this application, term " halogen " refers to fluorine, chlorine, bromine or iodine.
" hydroxyl " refers to-OH group.Alkoxy " refers to the alkyl as defined below replaced by hydroxyl (- OH).
" carbonyl " refers to-C (=O)-group." cyano " refers to-CN.
" amino " refers to-NH2.
" substituted amino " refers to by one or two alkyl as defined below, alkyl-carbonyl, aralkyl, heteroaryl alkane The amino that base replaces, for example, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl alkyl amino, heteroarylalkyl amino.
" carboxyl " refers to-COOH.
In this application, a part as group or other groups (is used for example in the groups such as the alkyl of halogen substitution In), term " alkyl " refers to the hydrocarbon chain base of fully saturated linear chain or branched chain, is only made of carbon atom and hydrogen atom, has example Such as 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atom, and connected by the rest part of singly-bound and molecule, For example including but be not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, 2- Methyl butyl, 2,2- dimethyl propyl, n-hexyl, heptyl, 2- methylhexyl, 3- methylhexyl, octyl, nonyl and decyl etc.. For the present invention, term " alkyl " refers to the alkyl containing 1 to 6 carbon atom.
In this application, a part as group or other groups, term " alkenyl " mean only by carbon atom and hydrogen Atom composition contains at least one double bond, has such as 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms And the hydrocarbon chain radical of the linear chain or branched chain by the connection of the rest part of singly-bound and molecule, such as, but not limited to vinyl, propylene Base, allyl, but-1-ene base, but-2-ene base, amyl- 1- alkenyl, amyl- 1,4- dialkylene etc..
In this application, a part as group or other groups, term " cyclic hydrocarbon radical " mean only by carbon atom and The stable non-aromatic monocyclic or multi-ring alkyl of hydrogen atom composition, may include condensed ring system, bridged-ring system or loop coil body System has 3 to 15 carbon atoms, preferably has 3 to 10 carbon atoms, more preferably has 3 to 8 carbon atoms, and it is saturation Or rest part connection unsaturated and that singly-bound and molecule can be passed through via any suitable carbon atom.Unless another in this specification It specializes outside, the carbon atom in cyclic hydrocarbon radical can be optionally oxidized.The example of cyclic hydrocarbon radical includes but is not limited to cyclopropyl, ring Butyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cyclooctyl, 1H- indenyl, 2,3- bis- Hydrogenated indenyl, 1,2,3,4- tetrahydro-naphthalenyl, 5,6,7,8- tetrahydro-naphthalenyl, 8,9- dihydro -7H- benzo ring heptene -6- base, 6,7, 8,9- tetrahydro -5H- benzocyclohepta alkenyl, 5,6,7,8,9,10- hexahydro-benzo ring octenyl, fluorenyl, two rings [2.2.1] heptyl, - two ring of 7,7 dimethyl [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl, two rings [3.1.1] heptyl, Two rings [3.2.1] octyl, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, adamantyl, octahydro -4,7- methylene - 1H- indenyl and octahydro -2,5- methylene-pentalene base etc..
In this application, a part as group or other groups, term " heterocycle " mean by 2 to 14 carbon originals Son and 1 to 6 selected from nitrogen, phosphorus, oxygen and sulphur hetero atom composition stable 3 yuan to 20 yuan of non-aromatic cyclic groups.It removes It is in addition specialized in non-this specification, otherwise heterocycle can be the ring system of monocycle, bicyclic, tricyclic or more, can Including condensed ring system, bridged-ring system or spiro ring system；Nitrogen, carbon or sulphur atom in its heterocycle are optionally oxidized；Nitrogen Atom is optionally quaternized；And heterocycle can be partially or completely to be saturated.Heterocycle can be via carbon atom or miscellaneous original Son is simultaneously connect by singly-bound with molecule rest part.In the heterocycle comprising condensed ring, one or more rings can be hereafter institute The aryl or heteroaryl of definition, it is non-aromatic annular atom that condition, which is with the tie point of molecule rest part,.With regard to mesh of the invention For, heterocycle preferably includes 1 to 3 heteroatomic 4 yuan to 11 yuan stable nonaro-maticity list selected from nitrogen, oxygen and sulphur Ring, bicyclic, bridged ring or spiro-cyclic groups, more preferably comprising 1 to 3 selected from nitrogen, heteroatomic stable 4 yuan to 8 of oxygen and sulphur First non-aromatic monocyclic, bicyclic, bridged ring or spiro-cyclic groups.The example of heterocycle includes but is not limited to: pyrrolidinyl, morpholinyl, Piperazinyl, high piperazine base, piperidyl, thio-morpholinyl, 2,7- diaza-spiro [3.5] nonane -7- base, 2- oxa- -6- azepine - Spiral shell [3.3] heptane -6- base, 2,5- diaza-bicyclic [2.2.1] heptane -2- base, azetidinyl, pyranose, oxinane Base, thiapyran base, tetrahydrofuran base, oxazines base, dioxy cyclopenta, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, imidazolinyl, miaow Oxazolidinyl, quinazinyl, thiazolidinyl, isothiazole alkyl, isoxazolidinyl, indolinyl, octahydro indyl, octahydro iso-indoles Base, pyrrolidinyl, pyrazolidinyl, phthaloyl imino etc..
In this application, a part as group or other groups, term " aryl " mean there is 6 to 18 carbon originals The conjugated hydrocarbon ring system group of son (preferably with 6 to 10 carbon atoms).For purposes of the invention, aryl can be single The ring system of ring, bicyclic, tricyclic or more, can also be condensed with naphthenic base defined above or heterocycle, and condition is virtue Base is connected via the atom on aromatic rings by the rest part of singly-bound and molecule.The example of aryl include but is not limited to phenyl, Naphthalene, anthryl, phenanthryl, fluorenyl, 2,3- dihydro -1H isoindolyl, 2- benzoxazoles quinoline ketone, 2H-1,4- benzoxazine -3 (4H) - Ketone -7- base etc..
In this application, term " aryl alkyl " refers to the alkane defined above replaced aryl defined above Base.
In this application, a part as group or other groups, term " heteroaryl " mean there is 1 to 15 in ring A carbon atom (preferably with 1 to 10 carbon atom) and 1 to 6 heteroatomic 5 yuan to 16 yuan conjugate ring selected from nitrogen, oxygen and sulphur It is group.Unless in addition specializing in this specification, otherwise heteroaryl can be the ring body of monocycle, bicyclic, tricyclic or more System, can also be condensed with naphthenic base defined above or heterocycle, and condition is that heteroaryl passes through via the atom on aromatic rings The connection of the rest part of singly-bound and molecule.Nitrogen, carbon or sulphur atom in heteroaryl are optionally oxidized；Nitrogen-atoms is optionally It is quaternized.For purposes of the invention, heteroaryl preferably includes 1 to 5 heteroatomic stabilization selected from nitrogen, oxygen and sulphur 5 yuan to 12 yuan aromatic radicals, more preferably comprising 1 to 4 selected from nitrogen, heteroatomic stable 5 yuan to 10 of oxygen and sulphur First aromatic radical or heteroatomic 5 yuan to the 6 yuan aromatic radicals that nitrogen, oxygen and sulphur are selected from comprising 1 to 3.Heteroaryl Example include but is not limited to thienyl, imidazole radicals, pyrazolyl, thiazolyl, oxazolyl, oxadiazoles base, isoxazolyl, pyridyl group, Pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrene oxazolyl, indyl, furyl, pyrrole radicals, triazolyl, tetrazolium Base, triazine radical, indolizine base, isoindolyl, indazolyl, iso indazolyl, purine radicals, quinolyl, isoquinolyl, phenodiazine naphthalene, naphthalene Piperidinyl, quinoxaline base, pteridyl, carbazyl, carboline base, phenanthridinyl, phenanthroline, acridinyl, phenazinyl, isothiazolyl, benzene Benzothiazolyl, benzothienyl dislike triazolyl, are cinnoline base, quinazolyl, thiophenyl, indolizine base, phenanthrolene base, different Oxazolyl, phenoxazine base, phenothiazinyl, 4,5,6,7- tetrahydro benzo [b] thienyl, naphtho- pyridyl group, [1,2,4] triazol [4,3-b] pyridazine, [1,2,4] triazol [4,3-a] pyrazine, [1,2,4] triazol [4,3-c] pyrimidine, [1,2,4] triazol [4,3-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine etc..
In this application, term " heteroaryl alkyl " refers to defined above replaced heteroaryl defined above Alkyl.In this application, " optionally " or " optionally " indicating that the event then described or situation may occur may not also Occur, and the description includes the case where that the event or situation occur and do not occur simultaneously.For example, " aryl being optionally substituted " Indicate that aryl is substituted or unsubstituted, and the description includes simultaneously substituted aryl and unsubstituted aryl.
Substituent group described in claims of the present invention and specification part " optionally " be selected from alkyl, alkenyl, alkynyl, Halogen, halogenated alkenyl, halo alkynyl, cyano, nitro, the aryl optionally replaced, the heteroaryl optionally replaced, is appointed at halogenated alkyl The cyclic hydrocarbon radical for choosing generation, the heterocyclic hydrocarbyl optionally replaced.
Terms used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " refer in molecule Specific fragment or functional group.Chemical part is typically considered the chemical entities being embedded or attached on molecule.
When containing alkene double bond in the compound of the present invention, unless otherwise stated, the compound of the present invention is intended to wrap Containing E- and Z- geometric isomer.
" tautomer " refers to another atom from an atom transfer of molecule to identical molecule of proton and is formed Isomers.
All tautomeric forms of the compound of the present invention also will within the scope of the present invention.Chemical combination of the invention Object or its pharmaceutically acceptable salt may be containing one or more asymmetric carbon atoms, and therefore can produce enantiomter, non- Enantiomter and other stereoisomeric forms in any ratio.Each asymmetric carbon atom can based on spatial chemistry and be defined as (R)-or (S)-.The present invention is intended to include all possible isomers and its racemic modification and optical voidness forms.The compound of the present invention Preparation can choose racemic modification, diastereoisomer or enantiomter as raw material or intermediate.It is optically active different Structure body can be used chiral synthon or chiral reagent to prepare, or be split using routine techniques, for example, by using crystallization And the methods of chiral chromatogram.
Substituent group of the invention represents symbol, such as Z1、Z2、X、Y、U、V、W1、W2、W3、n、o、p、q、R1、R2a、R2b、R3a、 R3b、R4、R5, Pg1, Pg etc., such as unspecified, identical symbol represents identical definition in different places.
The routine techniques of preparation/separation individual isomeric includes being synthesized by the chirality of suitable optical voidness precursor, or make With such as chiral hplc resolution of racemic body (or racemic modification of salt or derivative), Gerald see, for example, Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols, Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations, Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128.
In this application, term " pharmaceutically acceptable salt " includes pharmaceutically acceptable acid-addition salts and pharmaceutically may be used The base addition salts of receiving.
" pharmaceutically acceptable acid-addition salts " be refer to retain free alkali biological effectiveness and without other side effects , salt is formed by with inorganic acid or organic acid.Inorganic acid salt includes but is not limited to hydrochloride, hydrobromate, sulfate, nitric acid Salt, phosphate etc.；Acylate includes but is not limited to formates, acetate, 2,2 dichloroacetates, trifluoroacetate, propionic acid Salt, caproate, caprylate, caprate, undecylenate, glycollate, gluconate, lactate, sebacate, adipic acid Salt, glutarate, malonate, oxalates, maleate, succinate, fumarate, tartrate, citrate, palm Hydrochlorate, stearate, oleate, cinnamate, laruate, malate, glutamate, pyroglutamate, aspartic acid Salt, benzoate, mesylate, benzene sulfonate, tosilate, alginate, ascorbate, salicylate, 4- ammonia Base salicylate, napadisilate etc..These salt can be prepared by method known in the art.
" pharmaceutically acceptable base addition salts " refer to the biological effectiveness for being able to maintain free acid and without other side effects , with inorganic base or organic base be formed by salt.Salt derived from inorganic base includes but is not limited to sodium salt, sylvite, lithium salts, ammonium Salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc..Preferred inorganic salts are ammonium salt, sodium salt, sylvite, calcium salt and magnesium Salt.Salt derived from organic base includes but is not limited to salt below: primary amine class, secondary amine class and tertiary amines, substituted amine, packet Include natural substituted amine, cyclic amine and deacidite, such as ammonia, isopropylamine, trimethylamine, diethylamine, three Ethamine, tripropyl amine (TPA), ethanol amine, diethanol amine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2- lignocaine second Alcohol, dicyclohexyl amine, lysine, arginine, histidine, caffeine, procaine, choline, glycine betaine, ethylenediamine, gucosamine, Methyl glucose osamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamino resin etc..Preferred organic base includes isopropyl Amine, diethylamine, ethanol amine, trimethylamine, dicyclohexylamine, choline and caffeine.These salt can pass through method known in the art Preparation.
In this application, " pharmaceutical composition " refers to that the compounds of this invention is used to live biology with what this field usually received Property compound is delivered to the preparation of the medium of mammal (such as people).The medium includes pharmaceutically acceptable carrier.Drug The purpose of composition is to promote the administration of organism, plays bioactivity in turn conducive to the absorption of active constituent.
Terms used herein " pharmaceutically acceptable " refers to the bioactivity or property for not influencing the compounds of this invention Substance (such as carrier or diluent), and relative nontoxic, the i.e. substance can be applied to individual without causing undesirable biological respinse Or it is interacted in a manner of bad with any component for including in composition.In this application, " pharmaceutically acceptable figuration It by the reason department license of relevant government is the acceptable adjuvant used for the mankind or domestic animal that agent ", which includes but is not limited to any, carrier, Excipient, glidant, sweetener, diluent, preservative, dyestuff/colorant, corrigent, surfactant, wetting agent, dispersion Agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
" tumour " of the present invention includes but is not limited to that brain tumor includes neuroblastoma, glioma, glioblastoma With astrocytoma, sarcoma, melanoma, joint chondroma, cholangioma, leukaemia, gastrointestinal stromal tumor, diffusion large B cell leaching Lymph cancers, histiocytic lymphoma, non-small cell lung cancer, Small Cell Lung Cancer, cancer of pancreas, the lungs such as bar cancer, follicular lymphoma Squamous carcinoma, adenocarcinoma of lung, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, cervical carcinoma, oophoroma, intestinal cancer, nasopharyngeal carcinoma, The cancer of the brain, osteocarcinoma, cancer of the esophagus, melanoma, kidney, carcinoma of mouth, Huppert's disease, celiothelioma, Malignant Rhabdoid Tumor, uterus The diseases such as endometrial carcinomas, head and neck cancer, thyroid cancer, parathyroidoma, cervix tumor and soft tissue sarcoma.
Terms used herein " prevention ", " prevention " and " preventing " includes the generation or evil for so that sufferer is reduced disease or illness A possibility that change.
The term as used herein " treatment " includes following meanings with other similar synonyms:
(i) prevent disease or illness to occur in mammals, especially when this kind of mammal be susceptible to the disease or Illness, but when being not yet diagnosed as having suffered from the disease or illness；
(ii) inhibit disease or illness, that is, contain its development；
(iii) alleviate disease or illness, even if the state of the disease or illness subsides；Or
(iv) mitigate symptom caused by the disease or illness.
Term " effective quantity ", " therapeutically effective amount " or " pharmacy effective dose " used herein, which refers to, takes metapedes at certain Alleviate at least one medicament of one or more symptoms of treated disease or illness or the amount of compound in degree.Its result It can be sign, the abatement of symptom or the cause of disease and/or alleviation or any other required variation of biosystem.For example, for controlling " effective quantity " treated is the composition needed for clinically providing significant remission effect comprising compound is disclosed herein Amount.The technology of such as dose escalation trial can be used to measure the effective quantity being suitable in any individual case.Art used herein Language " taking ", " application ", " administration " etc. are to refer to for compound or composition to be delivered to the required site for carrying out biological effect Method.These methods include but is not limited to oral route, through intraduodenal routes, parental injection (including intravenous, skin Under, peritonaeum is interior, intramuscular, intra-arterial injection or infusion), local administration and per rectum administration.Those skilled in the art are known to be used In the application technique of Compounds and methods for described herein, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Those of discussed in Sciences (current edition), Mack Publishing Co., Easton, Pa.Preferred In embodiment, the compound and composition being discussed herein pass through oral administration.
Term " pharmaceutical composition " used herein, " drug combination ", " applying other treatments ", " applies it at " drug combination " Its therapeutic agent " etc. refers to the drug therapy obtained and mixing or combining more than one active constituent comprising active constituent Fix and be not fixed combination.Term " fixed Combination ", which refers to, to be administered simultaneously in the form of single entity or single dosage form to patient At least one compound as described herein and at least one collaboration medicament.Term " being not fixed combination " refers to the shape with corpus separatum Formula is administered simultaneously to patient, share or sequentially apply at least one compound as described herein and at least with variable interval time A kind of collaboration preparation.These are also applied in cocktail therapy, such as apply three or more active constituents.Art technology Personnel are also understood that in method discussed below that midbody compound functional group may need to be protected by protecting group appropriate Shield.Such functional group includes hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protection base include trialkylsilkl or Diarylalkyl-silyl (such as t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl first silicon Alkyl), THP trtrahydropyranyl, benzyl etc..The protecting group of suitable amino, amidino groups and guanidine radicals includes tertbutyloxycarbonyl, benzyloxycarbonyl group Deng.Suitable sulfhydryl protected base includes-C (O)-R " (wherein R " is alkyl, aryl or aralkyl), to methoxy-benzyl, triphen Methyl etc..Suitable carboxyl-protecting group includes alkyl, aryl or aralkyl esters.Protecting group can be according to those skilled in the art Standard technique knowing and as described herein is introduced and is removed.The use of protecting group is specified in Greene, T.W. with P.G.M.Wuts, Protective Groups in Organi Synthesis, (1999), in 4th Ed., Wiley.Protection Base can also be fluoropolymer resin.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.
Starting material as used in the following examples can by chemicals retailer such as Aldrich, TCI, Alfa Aesar, finish , An Naiji etc. buys, or can be synthesized by known method.
In following embodiments, ice bath refers to -5 degrees Celsius to 0 degree Celsius, and room temperature refers to 10 degrees Celsius to 30 degrees Celsius, returns Stream temperature generally refers to solvent reflux temperature under solvent normal pressure.Reaction refers to that the time is 8-15 hours overnight.In following embodiments, Concrete operations temperature is not limited, is carried out at room temperature.
In following embodiments, the separating-purifying of intermediate and final product be by positive or reverse-phase chromatography post separation or Other suitable methods.Positive flash chromatography column is to use ethyl acetate and n-hexane or methanol and methylene chloride etc. as flowing Phase.Reverse phase preparative high pressure liquid chromatography (HPLC) is detected with C18 column and with UV 214nm and 254nm, mobile phase A (water and 0.1% formic acid), B (acetonitrile) or mobile phase A (water and 0.1% ammonium hydrogen carbonate), B (acetonitrile).
In each embodiment: LCMS instrument: 1260 UV detector of Pump Agilent: Agilent 1260DAD Mass Spectrometer API 3000
Chromatographic column: Waters sunfire C18,4.6 × 50mm, 5um
Mobile phase: A-H2O (0.1%HCOOH)；B- acetonitrile NMR
Instrument: Bruker Ascend 400M (1H NMR:400MHz；13C NMR:100MHz)。
Embodiment 1: the preparation of the chloro- 8- of intermediate 5- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine (B1)
Step 1: the chloro- N- of 2- (2,2- dimethoxy-ethyl) -5- iodine pyrimidine -4- amine
The chloro- 5- iodine pyrimidine (110g, 400mmol) of 2,4- bis- and 2,2- dimethoxy are sequentially added into dry 2L flask Ethamine (84g, 800mmol) and dehydrated alcohol (1.2L).Under 0 DEG C of condition of nitrogen gas, be slowly added dropwise thereto triethylamine (109mL, Reaction 10 hours is stirred at room temperature in mixture after 800mmol).After completion of the reaction, it is concentrated in vacuo, obtained concentrate adds Enter the water of 1L, and extracted using methylene chloride (3 × 300mL), saturated common salt water washing simultaneously mixes organic layer, through anhydrous sodium sulfate It is dried, filtered and concentrated, uses dehydrated alcohol washing (3 × 50mL) to obtain brown solid 2- obtained brownish black solid chloro- N- (2,2- dimethoxy-ethyl) -5- iodine pyrimidine -4- amine (110g, yield: 78%).
1H NMR (400MHz, DMSO-d6) δ 8.35 (s, 1H), 4.58 (t, J=5.4Hz, 1H), 3.47 (t, J= 5.6Hz,2H),3.29(s,6H)ppm；LC-MS:m/z 344.1[M+H]+。
Step 2: 8- iodine imidazo [1,2-c] pyrimidine -5- alcohol
Sequentially added into dry 2L flask the chloro- N- of 2- (2,2- dimethoxy-ethyl) -5- iodine pyrimidine -4- amine (110g, 317mmol) and the 800mL concentrated sulfuric acid.Under a nitrogen atmosphere, 65 DEG C are heated the mixture to be stirred to react 2 hours.End of reaction Afterwards, reaction solution is cooled to room temperature, and mixture is poured slowly into ice water, then adjusts pH about to 6.0 with the NaOH solution of 4M, and It is extracted using ethyl acetate (3 × 300mL), mix organic layer and uses saturated common salt water washing, be dried over anhydrous sodium sulfate, mistake It filters and is concentrated to get 8- iodine imidazo [1,2-c] pyrimidine -5- alcohol (70g, yield 84.5%).
1H NMR (400MHz, DMSO-d6) δ 11.80 (s, 1H), 7.92 (d, J=1.5Hz, 1H), 7.60 (d, J= 3.9Hz, 1H), 7.40 (d, J=1.5Hz, 1H)；LC-MS:m/z 262.1[M+H]+。
Step 3: 8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- alcohol
Sequentially added in dry 250mL three-necked flask bottle 8- iodine imidazo [1,2-c] pyrimidine -5- alcohol (2.61g, 10mmol), cuprous iodide (190mg, 1mmol), 1,10- phenanthroline (360mg, 2mmol), 2,3- thiophenol dichlorobenzene (2.15g, 12mmol), the dioxane solvent of potassium phosphate (4.2g, 20mmol) and 50mL.The mixture heats instead under the protection of nitrogen It answers 3 hours.After reaction, saturation NH is added4Cl solution (200mL).It is extracted with ethyl acetate (3x200mL).Merge Organic phase Na2SO4Dry, filter, filtrate decompression concentration, obtained residue is purified by silica gel chromatography (0 to The methanol of 10% gradient: ethyl acetate), it is phonetic to obtain faint yellow solid 8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] Pyridine -5- alcohol (2.3g, yield: 74%).
LC-MS:m/z 312.1[M+H]+.
Step 4: the chloro- 8- of 5- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine (B1)
It is phonetic that 8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] is sequentially added into dry 100mL single-necked flask Pyridine -5- alcohol (2.3g, 7.3mmol) and phosphorus oxychloride (30mL), then under a nitrogen atmosphere, to N, N- diisopropyl is slowly added dropwise Ethamine (1mL) heats the mixture to 120 DEG C later and stirs 4 hours.After completion of the reaction, mixture is cooled to room temperature and again will Mixture vacuum concentration, and saturated sodium bicarbonate solution quenching reaction, are extracted, saturated common salt using ethyl acetate (3 × 30mL) Water washing simultaneously mixes organic layer, and anhydrous sodium sulfate is dried, filtered and concentrated, and obtained residue is purified by silica gel chromatography (methanol of 0 to 10% gradient: ethyl acetate) obtain the chloro- 8- of white solid 5- ((2,3- dichlorophenyl) is thio) imidazo [1, 2-c] pyrimidine B1 (660mg, yield: 27.4%).
1H NMR (400MHz, DMSO-d6) δ 8.18 (d, J=1.4Hz, 1H), 8.07 (s, 1H), 7.76 (d, J= 1.4Hz, 1H), 7.52 (dd, J=8.0,1.3Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 7.00 (dd, J=8.1,1.2Hz, 1H)ppm；LC-MS:m/z 330.1[M+H]+.
Embodiment 2: the preparation of chloro- 8- iodine imidazo [1,2-c] pyrimidine (E1) of intermediate 5-
8 iodine imidazo [1,2-c] pyrimidine -5- alcohol (5g, 19.1mmol) are sequentially added into dry 250mL single-necked flask N,N-diisopropylethylamine (1mL) is slowly added dropwise, later adds mixture under the protection of nitrogen with phosphorus oxychloride (50mL) Heat to 120 DEG C stir 4 hours.After completion of the reaction, reaction solution is cooled to room temperature and will be concentrated in vacuo, and unsaturated carbonate hydrogen is then added Sodium solution is quenched, and is extracted using ethyl acetate (3 × 100mL), mixes organic layer and uses saturated common salt water washing, through anhydrous sulphur Sour sodium is dried, filtered and concentrated, be purified by silica gel chromatography by the residue that column chromatographic purifying obtains to obtain (0 to The methanol of 10% gradient: ethyl acetate) obtain 5- chloro- 8- iodine imidazo [1,2-c] pyrimidine E1 (1.6g, yield: 29.8%).
1H NMR (400MHz, Methanol-d4) δ 8.28 (s, 1H), 8.16 (d, J=1.6Hz, 1H), 7.81 (d, J= 1.6Hz,1H)ppm；LC-MS:m/z 280.1[M+H]+.
Embodiment 3: intermediate (R) -2- methyl-N- ((R) -8- azaspiro [4.5] decane -1- base) propane -2- sulfenyl The preparation of amine (C-1A)
Step 1: (R) -1- ((R) -1,1- dimethyl ethyl sulfonamido) -8- azaspiro [4.5] decane -8- carboxylic acid The tert-butyl ester
1- carbonyl -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester is sequentially added in dry 100mL single port bottle (2.53g, 10mmol), the tetrahydrofuran of purity titanium tetraethoxide (6.84g, 30mmol) and 50mL, is stirred to react 4 in the case where being heated to reflux Hour.After being cooled to room temperature, methanol (10mL) is added, lithium borohydride (0.65g, 30mmol) then is added.The mixture that will be obtained Reaction 3 hours is stirred at room temperature.Methanol is slowly added to salt water is then added so that excessive boron hydride is quenched.It will obtain Mixture stir 15 minutes then by diatomite filtering.Aqueous mixture is extracted with ethyl acetate (3x 50mL).It will Organic phase MgSO4It dries, filters, and removes volatile matter under reduced pressure.Obtained residue is purified by silica gel chromatography (ethyl acetate of 0 to 50% gradient: petroleum ether) obtains white solid (R) -1- ((R) -1,1- dimethyl ethyl sulfenyl ammonia Base) -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (2.86g, yield: 80%).
LC-MS:m/z 359.1[M+H]+.
Step 2: (R) -2- methyl-N- ((R) -8- azaspiro [4.5] decane -1- base) propane -2- sulfenamide (C-1A)
By (R) -1- ((R) -1,1- dimethyl ethyl sulfonamido) -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester It is small that reaction 2 is stirred at room temperature in the solution of the dioxane (50mL) of (2.86g, 8mmol) and the concentrated sulfuric acid (2.0mL, 32mmol) When.Na is added2CO3Saturated aqueous solution is extracted until pH 11, and by aqueous mixture with DCM (3x50mL).By having for merging Machine is mutually washed with brine, and uses Na2SO4It dries, filters, and removes volatile matter under reduced pressure, obtain white solid (R) -2- methyl - N- ((R) -8- azaspiro [4.5] decane -1- base) propane -2- sulfenamide C-1A (1.86g, yield: 90%)
1H NMR(400MHz,DMSO-d6) δ 4.82 (d, J=7.5Hz, 1H), 3.04 (d, J=7.6Hz, 1H), 2.81 (ddd, J=12.1,8.0,4.0Hz, 2H), 2.60-2.51 (m, 2H), 1.92-1.14 (m, 10H), 1.12 (s, 9H) ppm；LC- MS:m/z259.1[M+H]+.
According to the synthetic method of embodiment 1, reacted to obtain following intermediate C-1B, C-1C, C- with similar starting material 1D、C-1E、C-1F、C-1G。
Embodiment 4: intermediate (R) -2- methyl-N- ((S) -2- oxa- -8- azaspiro [4.5] decane -4- base) propane -2- The preparation of sulfenamide (C-1H)
Step 1: 4- (2- (benzyloxy) -1- hydroxyethyl) piperidines -1,4- dioctyl phthalate 1- tert-butyl -4- methyl esters
Under nitrogen protection, 1- tert-butyl -4- methyl piperidine-Isosorbide-5-Nitrae-two is sequentially added to dry 500mL three-necked flask Formic acid esters (45g, 180mmol) and tetrahydrofuran (400mL), then solution is cooled to -78 DEG C, and be added dropwise LiHMDS (261mL, 261mmol).It is warmed to room temperature, and is stirred at room temperature 3 hours after being added dropwise.Then -78 DEG C are re-cooled to, is slowly added dropwise Tetrahydrofuran (50mL) solution of benzyloxy ethylhexanal (46g, 300mmol).Reaction solution is slowly warmed to room temperature and stirs 2.5 hours. After completion of the reaction, saturation NH is added4Cl solution (200mL) quenching reaction.It is extracted with ethyl acetate (3x 200mL).Merge Organic phase Na2SO4Dry, filter, filtrate decompression concentration, obtained residue is purified by silica gel chromatography (0 to The ethyl acetate/petroleum ether of 50% gradient), obtain 4- (2- (the benzyloxy) -1- hydroxyethyl) piperidines-Isosorbide-5-Nitrae-tertiary fourth of dioctyl phthalate 1- Base -4- methyl esters (52g, yield: 73.3%).
1H NMR(400MHz,CDCl3)δ7.36-7.30(m,5H),4.50(s,2H),3.97(s,2H),3.73-3.65 (m, 2H), 3.62 (s, 3H), 3.59-3.48 (m, 3H), 2.88 (d, J=6.2Hz, 1H), 2.23 (dd, J=13.7,2.7Hz, 1H), 2.04-1.88 (m, 2H), 1.74 (d, J=14.7Hz, 1H), 1.56 (d, J=4.2Hz, 1H), 1.44 (s, 9H) ppm； LC-MS:m/z 294.1[M+H]+.
Step 2: 4- (2- (benzyloxy) -1- hydroxyethyl) -4- (hydroxymethyl) piperidines -1- t-butyl formate
Successively 4- (2- (the benzyloxy) -1- hydroxyethyl) piperidines -1,4- dioctyl phthalate-into dry 500mL three-necked flask 1- tert-butyl -4- methyl esters (51.4g, 130mmol) and tetrahydrofuran (500mL) solution, are then added LiBH into solution4 (11.44g, 520mmol), and be stirred at room temperature 6 hours.After completion of the reaction, using saturation NaHCO3(200mL) quenching reaction.With Ethyl acetate (3x 200mL) extraction.By combined organic phase Na2S04It dries, filters, filtrate decompression concentration, and will obtain Residue is purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 50% gradient), obtains 4- (2- (benzyloxy) -1- hydroxyl Base ethyl) -4- (hydroxymethyl) piperidines -1- t-butyl formate (27g, yield: 57%).
LC-MS:m/z 266.1[M+H]+.
Step 3: 4- (1,2- dihydroxy ethyl) -4- (methylol) piperidines -1- t-butyl formate
4- (2- (benzyloxy) -1- hydroxyethyl) -4- (hydroxymethyl) is sequentially added into dry 500mL single-necked flask Piperidines -1- t-butyl formate (27g, 74mmol), methanol (270mL) and Pd/C (20g), then three times with hydrogen balloon displacement, room Temperature stirring 12 hours.Reaction solution filtering and concentrating obtains 4- (1,2- dihydroxy ethyl) -4- (methylol) piperidines -1- t-butyl formate (18.9g, yield: 93%).
LC-MS:m/z 176.1[M+H]+.
Step 4: 4- hydroxyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester
4- (1,2- dihydroxy ethyl) -4- (methylol) piperidines -1- formic acid is sequentially added into dry 500mL single-necked flask The tert-butyl ester (18.9g, 69mmol), triphenylphosphine (25.2g, 86.25mmol) and tetrahydrofuran (350mL), reaction solution is cooled to 0 DEG C and be added DEAD (12.46mL, 86mmol) then be warmed to room temperature stirring 5 hours.After completion of the reaction, saturated water is added (200mL) quenching reaction.It is extracted with ethyl acetate (3x 200mL).Merge organic phase, and uses Na2SO4It dries, filters, filters Liquid is concentrated under reduced pressure and obtained residue is purified by silica gel chromatography (ethanol/methylene of 0 to 2% gradient), obtains 4- hydroxyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (13.2g, yield: 74%).
1H NMR(400MHz,CDCl3) δ 4.04 (dd, J=10.0,4.6Hz, 1H), 3.98-3.90 (m, 1H), 3.71- 3.63 (m, 2H), 3.64-3.49 (m, 3H), 3.20 (dt, J=13.4,6.3Hz, 1H), 3.07 (ddd, J=13.2,9.2, 3.5Hz, 1H), 1.95 (d, J=5.2Hz, 1H), 1.74-1.66 (m, 1H), 1.53-1.46 (m, 1H), 1.39 (s, 9H), 1.27-1.11(m,1H)ppm；LC-MS:m/z 202.1[M-56+H]+.
Step 5: 4- carbonyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester
4- hydroxyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid is sequentially added into dry 500mL single-necked flask The tert-butyl ester (13.2g, 51mmol), methylene chloride (280mL) and Dess-Martin oxidant (32.2g, 76.5mmol), ice bath Lower stirring 5 hours.NaHCO is added after completion of the reaction3: Na2S2O3The saturated solution (200mL) of (1:1) separates organic phase, water phase It is extracted with DCM (3x 100mL).Combined organic phase Na2SO4It is dry, filtrate decompression concentration.Obtained residue is passed through into silicon Glue chromatography purifies (ethyl acetate/petroleum ether of 0 to 40% gradient), obtains colorless solid 4- carbonyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (12g, yield: 92.1%).
1H NMR(400MHz,CDCl3) δ 4.05 (d, J=13.6Hz, 4H), 3.87 (d, J=12.9Hz, 2H), 3.09 (ddd, J=13.5,9.8,3.5Hz, 2H), 1.73 (ddd, J=13.9,9.8,4.3Hz, 2H), 1.53 (d, J=15.1Hz, 2H),1.46(s,9H)ppm；LC-MS:m/z 200.0[M-56+H]+。
Step 6: (S) -4- ((R) -1,1- dimethyl ethyl sulfonamido) -2- oxa- -8- azaspiro [4.5] decane - 8- carboxylic acid tert-butyl ester
Use the identical synthetic method of 3 intermediate C-1A step 1 of embodiment, 4- carbonyl -2- oxa- -8- azaspiro [4.5] Decane -8- carboxylic acid tert-butyl ester reduction amination obtains white solid (S) -4- ((R) -1- Methylethyl sulfonamido) -2- oxa- - 8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester.
1H NMR(400MHz,CDCl3) δ 4.14 (dd, J=9.3,6.2Hz, 1H), 3.90 (d, J=13.8Hz, 2H), 3.77 (s, 2H), 3.70 (dd, J=9.2,5.3Hz, 1H), 3.63 (q, J=6.1Hz, 1H), 3.27 (d, J=6.4Hz, 1H), 2.90 (t, J=12.4Hz, 2H), 1.71 (dt, J=16.6,7.9Hz, 2H), 1.51 (s, 2H), 1.45 (s, 9H), 1.22 (s, 9H)ppm；LC-MS:m/z 361.1[M-100]+。
Step 7: (R) -2- methyl-N- ((S) -2- oxa- -8- azaspiro [4.5] decane -4- base) propane -2- sulfenyl Amine (C-1H)
Use the identical synthetic method of 3 intermediate C-1A step 2 of embodiment, (S) -4- ((R) -1- Methylethyl sulfenyl Amino) -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester removing Boc protecting group after obtain white solid (R) -2- Methyl-N- ((S) -2- oxa- -8- azaspiro [4.5] decane -4- base) propane -2- sulfenamide C-1H.
1H NMR(400MHz,DMSO-d6) δ 5.30 (s, 1H), 5.23 (d, J=8.9Hz, 1H), 3.93 (dd, J=8.6, 7.2Hz, 1H), 3.69 (d, J=8.6Hz, 1H), 3.58 (d, J=8.6Hz, 1H), 3.46 (dd, J=8.5,7.0Hz, 2H), 2.89-2.73(m,2H),2.48-2.42(m,1H),1.69-1.50(m,2H),1.39-1.21(m,3H),1.12(s,9H) ppm；LC-MS:m/z261.1[M+H]+.
Embodiment 5:(R) -2- methyl-N- ((R) -1- oxa- -8- azaspiro [4.5] decane -4- base) propane -2- sulfenyl The preparation of the synthesis (C-1I) of amine
Step 1: 3- methoxy propyl -1- alkynes
50%NaOH aqueous solution is added into water (40mL) solution of the propyl- 2- alkynes -1- alcohol (50g, 892.8mmol) of stirring Reaction mixture is heated to 70 DEG C by (98.2g).It is at lower than 70 DEG C that dimethyl suflfate (67.4g, 535.7mmol) is slow It is added in reaction mixture.Reaction mixture is in 60 DEG C of stirring 2h.Product is distilled and is collected from reaction mass at 60 DEG C Into cooling receiving bottle at -70 DEG C.The distillate is dried overnight with calcium chloride, redistillation obtains 3- methoxy propyl -1- (30g, yield: 48%), being colourless liquid to alkynes.
1H NMR(CDCl3, 400MHz) δ 4.10 (d, J=2.0Hz, 2H), 3.39 (s, 3H), 2.43 (t, J=2.0Hz, 1H)ppm.
Step 2: 1- methoxyl group -1,2- allene
The suspension of potassium tert-butoxide (3.9g, 35.7mmol) and 3- methoxy propyl -1- alkynes (50g, 714.2mmol) is at 70 DEG C Stirring 2 hours.By product from distilling and be collected at -70 DEG C in cooling receiver to obtain in reaction mass at 50 DEG C Colourless liquid 1- methoxy propyl -1,2- diene (35g, yield: 70%).The compound is dry with KOH and is maintained at 0 DEG C of storage.
1H NMR(CDCl3, 400MHz) δ 6.76 (t, J=8.0Hz, 1H), 5.48 (d, J=6.0Hz, 2H), 3.41 (s, 3H)ppm。
Step 3: 4- hydroxyl -4- (1- methoxy propyl -1,2- diene -1- base) piperidines -1- t-butyl formate
At -78 DEG C, to stirring 1- methoxy propyl -1,2- diene (0.527g, 7.5mmol) in THF (10mL) It is slowly added dropwise in solution and n-BuLi (THF solution of 2.5M) (2.8mL, 7.0mmol) is added, reaction solution continues at this temperature Stirring 30 minutes.Then THF (5mL) solution of 4- carbonyl piperidines -1- t-butyl formate (1.0g, 5.0mmol) is added to instead It answers in mixture, and continues stirring 4 hours at -78 DEG C.Reaction mixture saturation NaHCO3Aqueous solution is quenched, and with acetic acid second Ester (3 × 10mL) extraction.Combined organic layer is washed with salt water (50mL), anhydrous sodium sulfate is dry.It filters and depressurizes down dense Contracting, obtaining yellow gum object 4- hydroxyl -4- (1- methoxy propyl -1,2- diene -1- base) piperidines -1- t-butyl formate, (1.0g is received Rate: 90%)
Step 4: 4- methoxyl group -1- oxa- -8- azaspiro [4.5] decane -3- alkene -8- carboxylic acid tert-butyl ester
To 4- hydroxyl -4- (1- methoxy propyl -1,2- diene -1- base) piperidines -1- t-butyl formate (6.0g, 22.3mmol) Potassium tert-butoxide (12.5g, 111.5mmol) and dicyclohexyl -18- crown- 6 are added in the agitating solution in the tert-butyl alcohol (60mL) (0.42g, 1.1mmol).Reaction mixture return stirring 9 hours.Reaction mixture is cooled to 10 DEG C, with 5%HCl (pH= 7.0) it neutralizes, is extracted with ethyl acetate (3 × 150mL).Combined organic layer is washed with salt water (200mL), uses anhydrous slufuric acid Sodium dries, filters, and filtrate decompression is concentrated to get 4- methoxyl group -1- oxa- -8- azaspiro [4.5] decane -3- alkene -8- carboxylic acid The tert-butyl ester (4.0g), the compound are directly used in next step without purifying.
1H NMR(CDCl3,400MHz)δ4.56(s,2H),3.97(s,1H),3.69(s,3H),3.08(s,1H),1.79- 1.74(m,1H),1.52(s,9H),1.45-1.26(m,1H)ppm；LCMS:m/z 214[M-55]+.
Step 5: 4- carbonyl -1- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester
By 4- methoxyl group -1- oxa- -8- azaspiro [4.5] decane -3- alkene -8- carboxylic acid tert-butyl ester (38.0g, 141.3mmol) and p-TSAH2O (29.6g, 155.4mmol), the mixture of acetone (400mL) are stirred at room temperature 1 hour, The NaHCO of reaction mixture saturation3Aqueous solution is quenched, and is extracted with ethyl acetate (3 × 500mL), combined organic phase salt Water (1000mL) washing, anhydrous sodium sulfate is dry and filters, and is concentrated under reduced pressure to give yellow gum 4- carbonyl -1- oxa- -8- azepine Spiral shell [4.5] decane -8- carboxylic acid tert-butyl ester (25g), which is directly used in reacts in next step.
LCMS:m/z 278[M+Na]+.
Step 6 and seven: (R) -2- methyl-N- ((R) -1- oxa- -8- azaspiro [4.5] decane -4- base) propane -2- is sub- The synthesis (C-1I) of sulfonamide
According to the identical synthetic method of 3 intermediate C-1A of embodiment, ketone intermediate 4- carbonyl -1- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester obtains (R) -2- methyl-N- ((R) -1- oxygen through reduction amination and after removing Boc protecting group Miscellaneous -8- azaspiro [4.5] decane -4- base) propane -2- sulfenamide synthesis (C-1I).LCMS:m/z 261[M+Na]+.
Embodiment 6:(R) -2- methyl-N- ((3S, 4S) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -4- base) third The preparation of alkane -2- sulfenamide (C-1J)
Step 1: (S) -2- ((t-butyldimethylsilyl) oxygroup) ethyl propionate
Imidazoles is added into methylene chloride (300mL) solution of (S) -2 hydroxy propanoic acid ethyl ester (30g, 254mmol) (2.75g, 304.9mmol) and it is cooled to 0 DEG C.Be added portionwise into the solution tert-butyldimethylsilyl chloride (46.0g, 304.9mmol), it and is stirred at room temperature 16 hours.It is analyzed and determined by TLC after the reaction was completed, by reaction mixture water quenching It goes out and methylene chloride (2 × 100mL) is used to extract.Combined organic layer is dry with anhydrous sodium sulfate.It filters and is concentrated under reduced pressure, obtain It is colourless liquid to (S) -2- ((t-butyldimethylsilyl) oxygroup) ethyl propionate (50g, yield 84%).
1H NMR(400MHz,CDCl3) δ 4.32-4.27 (m, 1H), 4.21-4.12 (m, 2H), 1.37 (d, J=6.8Hz, 3H), 1.27 (d, J=7.2Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H) ppm.
Step 2: (S) -2- ((t-butyldimethylsilyi) oxygroup) propionic aldehyde
To (S) -2- ((t-butyldimethylsilyl) oxygroup) ethyl propionate (25g, 107.6mmol) at -78 DEG C Diethyl ether (500mL) solution in be slowly added dropwise be added diisobutylaluminium hydride (1M hexane solution) (129mL, 129.1mmol), And it is stirred 1 hour at -78 DEG C.It is analyzed to identify after the reaction was completed by TLC, so that reaction mixture is warmed to -40 DEG C, reaction is used The saturated aqueous solution of Rochelle salt (1L) is quenched, and ether (500mL) then is added.It is small that gained mixture is stirred at room temperature 2 When.Then it is extracted with ether (200mL).Organic layer is washed with saturated brine (250mL), uses Na2SO4It dries, filters and depressurizes dense Contracting, obtains (S) -2- ((t-butyldimethylsilyi) oxygroup) propionic aldehyde (19g, yield: 94%).
1H NMR(400MHz,CDCl3) δ 9.61 (s, 1H), 4.12-4.06 (m, 1H), 1.27 (d, J=6.8Hz, 3H), 0.91(s,9H),0.10(s,6H)ppm.
Step 3: 4- ((2S) -2- ((t-butyldimethylsilyl) oxygroup) -1- hydroxypropyl) piperidines -1,4- two Formic acid 1- (tert-butyl)
To the 1- of stirring (tert-butyl) -4- ethyl piperidine-Isosorbide-5-Nitrae-dicarboxylic ester (30g, 116.6mmol) THF at 0 DEG C Lithium diisopropylamide (2M, in THF) (93.3mL, 186.6mmol) is added in (250mL) solution, and continues to stir at 0 DEG C It mixes 30 minutes.Then the THF of (S) -2- ((t-butyldimethylsilyi) oxygroup) propionic aldehyde (22g, 116.6mmol) is added (50mL) solution.Gained reaction mixture stirs 1 hour at 0 DEG C, is then kept for 1 hour at room temperature.Sentenced by TLC analysis Break after the reaction was completed, by reaction mixture saturation NH4Cl solution is quenched and ethyl acetate (2 × 250mL) is used to extract.It will merge Organic layer with water (150mL), salt water (150mL) washing, anhydrous sodium sulfate is dry.It filters and is concentrated under reduced pressure.Crude product passes through Silica gel (60-120 mesh) is column chromatography eluting, uses Solvent Gradient mixture of 25% ethyl acetate in petroleum ether as elution Agent obtains 4- ((2S) -2- ((t-butyldimethylsilyl) oxygroup) -1- hydroxypropyl) piperidines-Isosorbide-5-Nitrae-dioctyl phthalate 1- (uncle Butyl) (17g, yield: 32%), being light-red oil.
1H NMR(400MHz,CDCl3)δ4.29-4.09(m,2H),3.96-3.94(m,2H),3.86-3.80(m,1H), 3.56-3.54 (m, 1H), 2.86-2.76 (m, 2H), 2.46 (d, J=5.2Hz, 1H), 2.16-2.13 (m, 1H), 2.13-2.04 (m, 1H), 1.77-1.60 (m, 2H), 1.46 (s, 9H), 1.29-1.24 (m, 3H), 1.12 (d, J=4Hz, 3H), 0.89 (s, 9H),0.05(s,6H)ppm；LCMS:m/z 346[M-100]+.
Step 4: ((2S) -2- ((t-butyldimethylsilyl) oxygroup) -1- hydroxypropyl) -4- (hydroxymethyl) Piperidines -1- t-butyl formate
4- ((2S) -2- ((t-butyldimethylsilyl) oxygroup) -1- hydroxypropyl) is added into the solution of stirring LiBH is added portionwise in the solution in THF (50mL) in piperidines-Isosorbide-5-Nitrae-dioctyl phthalate 1- (tert-butyl) (5g, 11.21mmol)4 It (0.73g, 33.65mmol) and is stirred at room temperature 16 hours.After completion of the reaction, by reaction mixture at 0 DEG C with saturation NaHCO3Solution is quenched, and is stirred at room temperature 15 minutes.The solid of precipitating is filtered out, water phase is extracted with ethyl acetate (2 × 50mL). Combined organic layer is dry with anhydrous sodium sulfate.The crude product being filtered, and concentrated under reduced pressure to give passes through silica gel (100-200 mesh) column Chromatogram purification uses the petroleum ether solution gradient mixture of 25% ethyl acetate as eluent, obtains ((2S) -2- ((tertiary fourth Base dimetylsilyl) oxygroup) -1- hydroxypropyl) -4- (hydroxymethyl) piperidines -1- t-butyl formate (3g, yield: 66%).
1H NMR(400MHz,CDCl3) δ 4.55 (t, J=4.8Hz, 1H), 4.43 (d, J=6.4Hz, 1H), 3.52-3.47 (m,5H),3.31-3.28(m,1H),3.05-3.01(m,2H),1.58-1.49(m,2H),1.42-1.38(m,11H),1.11 (d, J=6.4Hz, 3H), 0.85 (m, 9H), 0.04 (s, 6H) ppm；LC-MS:m/z 404.3[M+H]+。
Step 5: 4- ((2S) -1,2- dihydroxypropyl) -4- (hydroxymethyl) piperidines -1- t-butyl formate
((2S) -2- ((t-butyldimethylsilyl) oxygroup) -1- hydroxypropyl) -4- (hydroxymethyl) piperidines -1- In THF (500mL) solution of t-butyl formate (25g, 61.93mmol) be added tetrabutyl amine fluoride (1M is in THF) (93mL, 92.89mmol), and by gained reaction mixture it is stirred at room temperature 2 hours.It is analyzed and determined after the reaction was completed by TLC, it will be anti- The NaHCO for answering mixture to be saturated3Solution is quenched and ethyl acetate (2 × 500mL) is used to extract.The anhydrous sulphur of combined organic phase Sour sodium is dry.The crude product being filtered, and concentrated under reduced pressure to give silica gel (60-120 mesh) column chromatography eluting crude product, uses 70- Solvent Gradient mixture of 90% ethyl acetate in petroleum ether obtains 4- ((2S) -1,2- dihydroxypropyl)-as eluent (12g, yield: 67%), being colourless liquid to 4- (hydroxymethyl) piperidines -1- t-butyl formate.
1H NMR(400MHz,DMSO-d6) δ 4.72 (t, J=4.8Hz, 1H), 4.61 (d, J=5.2Hz, 1H), 4.50 (d, J=7.2Hz, 1H), 3.72-3.68 (m, 1H), 3.53-3.44 (m, 4H), 3.11-2.98 (m, 3H), 1.68-1.53 (m, 2H), 1.42-1.35 (m, 11H), 1.10 (d, J=6.4Hz, 3H) ppm；LC-MS:m/z 290.1[M+H]+。
Step 6: (3S) -4- hydroxy-3-methyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester
To THF (30mL) suspension of the NaH of stirring (60%, in mineral oil) (1.45g, 60.5mmol) at 0 DEG C Middle addition 4- ((2S) -1,2- dihydroxypropyl) -4- (hydroxymethyl) piperidines -1- t-butyl formate (5g, 17.3mmol) and right In THF (20mL) solution of toluene sulfochloride (3.29g, 17.3mmol), and obtained reaction mixture is small in 0 DEG C of reaction 3 When.After the reaction was completed, reaction mixture is used to saturation NH at -20 DEG C4Cl solution (250mL) is quenched, and with ethyl acetate (2 × 50mL) extraction.Combined organic layer is dry with anhydrous sodium sulfate.The crude product silica gel being filtered, and concentrated under reduced pressure to give (100-200 mesh) is column chromatography eluting, uses Solvent Gradient mixture of 40% ethyl acetate in petroleum ether as eluant, eluent, Obtain (3S) -4- hydroxy-3-methyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (2.1g, yield: 44%).
1H NMR(400MHz,CDCl3) δ 3.83-3.62 (m, 5H), 3.43 (d, J=6.0,1H), 3.07-2.97 (m, 2H), 1.72-1.55 (m, 3H), 1.51-1.42 (m, 11H), 1.33 (d, J=6.4Hz, 3H) ppm；LC-MS:m/z 172.2 [M-100]+。
Step 7: (S)-tert-butyl -3- methyl -4- carbonyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylate
By (3S) -4- hydroxy-3-methyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (2.1g, It 7.74mmol) is added in tetrahydrofuran (50mL) solution, and is kept stirring 1 hour.After completion of the reaction, vacuum distillation removes molten Agent.Gained residual product is purified by silica gel (100-200 mesh) column chromatography, uses solvent of 30% ethyl acetate in petroleum ether For gradient mixture as eluant, eluent, the purified by flash chromatography for then using 0.1% formic acid and acetonitrile as eluant, eluent obtains (S)- Tert-butyl -3- methyl -4- carbonyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylate (1.2g, yield: 57%).
1H NMR(400MHz,CDCl3) δ 4.20 (d, J=9.5Hz, 1H), 3.94-3.90 (m, 4H), 3.16-3.10 (m, 1H),3.03-2.97(m,1H),1.81-1.75(m,1H),1.67-1.62(m,1H),1.61-1.57(m,1H),1.42-1.45 (m, 10H), 1.32 (d, J=6.0Hz, 3H) ppm；LC-MS:m/z 214.1[M-55]+。
Step 8: (3S, 4S) -4- ((R)-terf-butylsulfinyl) amino) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate
(S)-tert-butyl -3- methyl -4- carbonyl -2- oxa- -8- azaspiro [4.5] decane -8- carboxylate (1.2g, 4.46mmol) agitating solution in THF (15mL) be respectively be added (R) -2- methylpropane -2- sulfenamide (1.07g, 8.91mmol) and tetraethyl titanate (4.07g, 17.84mmol).Gained reaction mixture stirs 20 hours at 90 DEG C.It will be anti- It answers mixture to be cooled to -4 DEG C, is added MeOH (2mL), LiBH is then added portionwise4(282mg, 12.99mmol) and in Xiang Tongwen It is kept stirring under degree 1 hour.After completion of the reaction, reaction mixture is quenched at 0 DEG C with saturated brine solution, and at room temperature Stirring 15 minutes.Filtering, solution are extracted with ethyl acetate (2 × 50mL).Combined organic layer is dry with anhydrous sodium sulfate.Filtering And the crude product being concentrated under reduced pressure to give uses 0.1% formic acid and acetonitrile as the GRACE purified by flash chromatography crude product of eluent, Obtain (3S, 4S) -4- ((R)-terf-butylsulfinyl) amino) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -8- first Tert-butyl acrylate (1.2g, yield: 72%).
1H NMR(400MHz,CDCl3)δ4.20-4.15(m,1H),3.90-3.84(m,2H),3.63-3.59(m,1H), 3.49-3.43(m,1H),3.31-3.29(m,1H),2.95-2.81(m,2H),1.90-1.71(m,2H),1.49-1.40(m, 11H), 1.25 (s, 9H), 1.19 (d, J=6.5Hz, 3H) ppm；LC-MS:m/z 375.2[M+H]+。
Step 9: (R) -2- methyl-N- ((3S, 4S) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -4- base) third Alkane -2- sulfenamide (C-1J)
To (3S, 4S) -4- ((R)-terf-butylsulfinyl) amino) -3- methyl -2- oxa- -8- azaspiro [4.5] last of the ten Heavenly stems In methylene chloride (10mL) solution of alkane -8- t-butyl formate (1.1g, 2.936mmol) be added dropwise trifluoroacetic acid (1.12mL, 14.68mmol) and it is stirred at room temperature 6 hours.After completion of the reaction, crude product reaction mixture being concentrated under reduced pressure to give is used The chromatography purification of crude product of 0.1% formic acid and acetonitrile obtains (R) -2- methyl-N- ((3S, 4S) -3- methyl -2- oxa- -8- Azaspiro [4.5] decane -4- base) propane -2- sulfenamide C-1J (850mg, yield: 72%).
1H NMR(400MHz,DMSO-d6)δ8.40(brs,D2O Exchangeable,1H),8.30(brs, D2OExchangeable, 1H), 5.28 (d, J=12.0Hz, 1H), 4.13-4.09 (m, 1H), 3.77 (d, J=9.0Hz, 1H), 3.50-3.45(m,2H),3.29-3.26(m,1H),3.19-3.15(m,1H),2.94-2.85(m,2H),1.87-1.80(m, 2H), 1.69-1.59 (m, 2H), 1.17 (s, 9H), 1.08 (d, J=6.0Hz, 3H) ppm；LC-MS:m/z 275.2[M+H]+。
Embodiment 7: intermediate (R) -2- methyl-N- ((1R) -2- methyl -8- azaspiro [4.5] decane -1- base) propane - The preparation of 2- sulfenamide (C-1K)
Step 1: 2- methyl-1-carbonyl-8- azaspiro [4.5] decane-8- carboxylic acid tert-butyl ester
At 0 DEG C, under conditions of nitrogen protection, 1- carbonyl -8- azaspiro is sequentially added into the drying single-necked flask of 100mL [4.5] it in decane -8- carboxylic acid tert-butyl ester (1g, 3.95mmol) and dry tetrahydrofuran (15mL), is then slowly added dropwise LiHMDS (3.95ml, 3.95mmol), at such a temperature stir 1 hour after, thereto be added iodomethane (0.25mL, 3.95mmol), and continue stirring 2 hours.After completion of the reaction, using saturated sodium bicarbonate solution quenching reaction, ethyl acetate (3 × 20mL) extraction, combined organic phase Na2SO4It is dry, filtrate decompression be concentrated and pass through column Silica gel chromatography (0 to The ethyl acetate/petroleum ether of 20% gradient) obtain 2- methyl-1-carbonyl-8- azaspiro [4.5] decane-8- carboxylic acid tert-butyl ester. LCMS:m/z 368.0[M+H]+.
Step 2 and three: (R) -2- methyl-N- ((1R) -2- methyl -8- azaspiro [4.5] decane -1- base) propane -2- is sub- Sulfonamide (C-1K)
According to the identical synthetic method of 3 intermediate C-1A of embodiment, ketone intermediate 2- methyl-1-carbonyl-8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester obtains (R) -2- methyl-N- ((1R) -2- first through reduction amination and after removing Boc protecting group Base -8- azaspiro [4.5] decane -1- base) propane -2- sulfenamide C-1K.
1H NMR(400MHz,CDCl3)δ5.07-4.97(m,1H),3.32-3.20(m,1H),3.01-2.84(m,2H), 2.81-2.61(m,2H),2.20-2.11(m,1H),2.02-1.34(m,8H),1.25-1.20(m,9H),1.06-0.99(m, 3H)ppm；LCMS:m/z 273.0[M+H]+.
Embodiment 8:(R)-N- ((R) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- base) -2- methyl-prop The preparation of alkane -2- sulfenamide (C-1L)
Step 1: 3,3- dimethyl -4- carbonyl -1- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester
Under nitrogen protection, to -78 DEG C 4- carbonyl -1- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl esters (5g, It is slowly added dropwise in THF (50mL) solution 19.6mmol) and LiHMDS (1M, in THF is added；19.6mL, 19.6mmol) and protect It holds and is stirred 2 hours at -78 DEG C.Then be warmed to room temperature to reaction mixture, be added portionwise thereto iodomethane (1.22mL, 19.6mmol).Resulting reaction mixture is continued to stirring 2 hours at room temperature.Reaction mixture is with ethyl acetate (150mL) Dilute and use the NaHCO of saturation3Solution (150mL) is quenched, and is then extracted with ethyl acetate (2 × 300mL).Combined organic phase It is dry with anhydrous sodium sulfate.It filters and depressurizes lower concentration.Obtained residue is purified by silica gel chromatography (0 to 15% ladder The ethyl acetate/petroleum ether of degree), obtain the tertiary fourth of 3,3- dimethyl -4- carbonyl 1- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid (1g, yield: 18%) (0.7g is received ester with 3- methyl -4- carbonyl -1- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate Rate: 14%)
3,3- dimethyl -4- carbonyl -1- oxa- -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester:
1HNMR(400MHz,CDCl3)δ3.94(brs,2H),3.89(s,2H),3.16-3.10(m,2H),1.70-1.61 (m,4H),1.48(s,9H),1.14(s,6H)ppm；LCMS:m/z 306[M+Na]+.
3- methyl -4- carbonyl -1- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate:
1H-NMR(400MHz,CDCl3) δ 4.38 (t, J=8.8Hz, 1H), 3.96 (brs, 2H), 3.67 (t, J=9.6Hz, 1H), 3.14-3.09 (m, 2H), 2.65-2.58 (m, 1H), 1.75-1.46 (m, 13H), 1.15 (d, J=7.2Hz, 3H) ppm； LCMS:m/z 292[M+Na]+.
Step 2: (S) -4- ((terf-butylsulfinyl) imino group) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] Decane -8- t-butyl formate
To stirring 3,3- dimethyl -4- carbonyl -1- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate (2.0g, (R) -2- methylpropane -2- sulfenamide (2.56g, 21.2mmol) and metatitanic acid are added in THF (5.0mL) solution 7.1mmol) Tetra-ethyl ester (8.05g, 35.3mmol).Gained reaction mixture stirs 48 hours at 90 DEG C.Reaction mixture methanol (10mL) is quenched, and is diluted with ethyl acetate (50mL), and then diatomite filters, and the crude product being concentrated to get is by using 0.1% Formic acid and acetonitrile are separated as the reverse phase flash chromatography of eluant, eluent, obtain (S) -4- ((terf-butylsulfinyl) imino group) -3, 3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate (1.5g, yield: 55%).
1HNMR(400MHz,CDCl3)δ4.10-3.88(brs,2H),3.80-3.72(m,2H),3.04(brs,2H), 1.70-1.59(m,5H),1.46-1.41(m,14H),1.24-1.14(m,9H)ppm；LCMS:m/z 331[M-55]+.
Step 3: (R) -4- (((R)-terf-butylsulfinyl) amino) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate and (S) -4- (((R)-terf-butylsulfinyl) amino) -3,3- dimethyl -1- oxa- -8- Azaspiro [4.5] decane -8- t-butyl formate)
To (S) -4- ((terf-butylsulfinyl) imino group) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane - 8- t-butyl formate (1.5g, 3.88mmol) is in MeOH:THF (3:1；NaBH is added in the mixed solvent 30mL)4(886mg, 23.3mmol) then it is heated to reflux stirring 16 hours.After being cooled to room temperature, lower concentrating part solvent is depressurized to 10mL, is then mixed Object is closed to pour into ice water (100mL) and stir 10 minutes.Be filtered to remove generation solid precipitating after be extracted with ethyl acetate (3 × 50mL), the dry concentration of combined organic phase.(R) -4- (((R)-tert-butyl sulfenyl is obtained after the purified separation of obtained crude product Base) amino) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate (and 350mg, yield: 23%) and (S) -4- (((R)-terf-butylsulfinyl) amino) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -8- formic acid uncle And the mixture of both of the above (400mg, yield: 28%) butyl ester (350mg, yield: 23%).
(S) -4- (((R)-terf-butylsulfinyl) amino) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane - 8- t-butyl formate:1HNMR(400MHz,CDCl3) δ 3.94 (brs, 2H), 3.61 (d, J=9.2Hz, 1H), 3.54 (d, J= 9.2Hz, 1H), 3.22 (d, J=10Hz, 1H), 3.07-3.00 (m, 3H), 1.54-1.49 (m, 4H), 1.45 (s, 9H), 1.24 (s,9H),1.21(s,3H),1.03(s,3H)ppm；LCMS:m/z 411[M+Na]+；[α]25 D=+19.62 (c 0.25, MeOH)；retention time:1.835min
(R) -4- (((R)-terf-butylsulfinyl) amino) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane - 8- t-butyl formate:1HNMR(400MHz,CDCl3)δ4.03-3.93(m,2H),3.62-3.58(m,1H),3.50-3.47(m, 1H),3.30(brs,1H),3.11-2.96(m,3H),1.91-1.76(m,2H),1.54-1.56(m,merged in DMSO, 2H)1.43(s,9H),1.25(s,9H),1.03(s,3H),0.99(s,3H)ppm；LCMS:m/z 411[M+Na]+；[α]25 D =-43.56 (c 0.25, MeOH)；retention time:2.009min.
Step 4: (R)-N- ((R) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- base) -2- methyl-prop Alkane -2- sulfenamide (C-1L)
Use the identical synthetic method of 6 intermediate C-1J step 9 of synthetic example, (R) -4- (((R)-tert-butyl Asia sulphur Acyl group) amino) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate removing Boc protecting group after To (R)-N- ((R) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- base) -2- methylpropane -2- sulfenamide C-1L。
1H-NMR(400MHz,DMSO-d6)δ4.92(d,D2O Exchangeable, J=11.5Hz, 1H), 3.50 (d, J =9.0Hz, 1H), 3.43 (d, J=9.0Hz, 1H), 3.20-3.14 (m, 2H), 3.09 (d, J=12.0,1H), 3.00-2.89 (m,2H),1.92-1.86(m,1H),1.82-1.80(m,2H),1.73-1.70(m,1H),1.19(s,9H),0.97(s,3H), 0.94(s,3H)ppm；LCMS:m/z 289[M+H]+。
Embodiment 9:(R)-N- ((S) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- base) -2- methyl-prop The preparation of alkane -2- sulfenamide (C-1M)
Use the identical synthetic method of 6 intermediate C-1J step 9 of synthetic example, (S) -4- (((R)-tert-butyl Asia sulphur Acyl group) amino) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -8- t-butyl formate removing Boc protecting group after To (R)-N- ((S) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- base) -2- methylpropane -2- sulfenamide C-1M。
1HNMR(400MHz,DMSO-d6)δ8.40(brs,D2O Exchangeable,1H),8.40(brs,D2O Exchangeable, 1H), 5.27 (d, J=11.0Hz, 1H), 4.12-4.10 (m, 1H), 3.77 (d, J=8.5Hz, 1H), 3.47-3.44(m,2H),3.28-3.24(m,1H),3.17-3.15(m,1H),2.95-2.87(m,2H),1.86-1.82(m, 2H), 1.69-1.59 (m, 2H), 1.17 (s, 9H), 1.08 (d, J=6.0Hz, 3H) ppm；LCMS:m/z 289[M+H]+.
Embodiment 10: intermediate (R) -2- methyl-N- ((1R) -3- methyl -8- aza-spiro [4.5] decane -1- base) third The preparation of alkane -2- sulfenamide (C-1N)
Step 1: 4- allyl -4- formyl piperidine -1- t-butyl formate
4- formyl piperidine -1- t-butyl formate (35.0g, 164mmol), tertiary fourth are sequentially added into dry 1L flask Lithium alkoxide (15.77g, 197mmol) and allyl bromide, bromoallylene (11.54mL, 189mmol) and DMF (328mL), the mixture stir at 0 DEG C It mixes 1 hour.After completion of the reaction, it pours the mixture into containing saturation NH4Cl aqueous solution: the separatory funnel of H2O (1:1,500mL) In, used Et2O (5x 50mL) extraction.By combined organic phase MgSO4It dries, filters, filtrate decompression concentration.It will obtain Residue be purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 25% gradient), obtain colorless oil 4- allyl Base -4- formyl piperidine -1- t-butyl formate (24g, yield: 48%).
1H NMR(400MHz,CDCl3)δ9.52(s,1H),5.53-5.76(m,1H),4.96-5.19(m,2H),3.80 (br.s., 2H), 2.97 (t, J=11.49Hz, 2H), 2.26 (d, J=7.33Hz, 2H), 1.95 (dt, J=13.71, 3.13Hz,2H),1.38-1.58(m,11H)ppm.
Step 2: 4- allyl -4- (1- hydroxyl allyl) piperidines -1- carboxylic acid tert-butyl ester (C-1N-c)
Sequentially added into dry 1L three-necked flask 4- allyl -4- formyl piperidine -1- t-butyl formate (24g, 95mmol) and THF (300mL), which is cooled under -78 DEG C and protection under a nitrogen and vinyl magnesium bromide is slowly added dropwise (1M in THF, 118mL, 118mmol).In 1 hour, the solution made is to slowly warm up to room temperature.After completion of the reaction, will Mixture is poured into containing saturation NH4In the separatory funnel of Cl aqueous solution (250mL), it is extracted with EtOAc (4x 50mL).It will Combined organic phase MgSO4It dries, filters, filtrate decompression concentration obtains 4- allyl -4- (1- hydroxyl allyl) piperidines - 1- t-butyl formate (26.7g), be not further purified will the compound in next step.
1H NMR(400MHz,CDCl3)δ6.05-5.83(m,2H),5.32-5.21(m,2H),5.12(s,1H),5.08 (d, J=3.5Hz, 1H), 4.05-3.97 (m, 1H), 3.71 (s, 2H), 3.12 (ddd, J=13.8,10.4,3.6Hz, 2H), 2.33 (dd, J=14.3,7.8Hz, 1H), 2.20 (dd, J=14.3,7.2Hz, 1H), 1.60 (q, J=4.3Hz, 2H), 1.57- 1.50(m,2H),1.45(s,9H)ppm.
Step 3: 4- allyl acyl group -4- allylpiperidin -1- t-butyl formate
4- allyl -4- (1- hydroxyl allyl) tertiary fourth of piperidines -1- formic acid is sequentially added into dry 1L three-necked flask Ester (26.7g, 95mmol), Dess-Martin oxidant (44.3g, 105mmol) and anhydrous methylene chloride (380mL), the mixing Object is stirred at room temperature 1 hour.It is poured the mixture into after completion of the reaction containing NaHCO3:Na2SO3Saturated aqueous solution (1:1, In separatory funnel 300mL), then extracted with DCM (4x 50mL).By combined organic phase MgSO4It dries, filters, filtrate It is concentrated under reduced pressure, obtains white solid.White solid is suspended in petroleum ether (250mL) and ultrasound 20 minutes.By white suspension It is filtered by diatomite bed course and is removed under reduced pressure, filtrate decompression is concentrated to get yellow oily 4- allyl acyl group -4- allyl Piperidines -1- t-butyl formate (25g, two step yields: 94%).
1H NMR(400MHz,CDCl3) δ 6.80 (dd, J=16.8,10.3Hz, 1H), 6.39 (dd, J=16.8,1.9Hz, 1H), 5.70 (dd, J=10.3,1.9Hz, 1H), 5.55 (ddt, J=17.5,10.2,7.4Hz, 1H), 5.09-4.98 (m, 2H), 3.77 (s, 2H), 2.94 (s, 2H), 2.31 (d, J=7.4Hz, 2H), 2.08 (d, J=13.8Hz, 2H), 1.47-1.41 (m,11H)ppm。
Step 4: 1- carbonyl -8- azaspiro [4.5] decane -2- alkene -8- carboxylic acid tert-butyl ester
Sequentially added into dry 1L three-necked flask 4- allyl acyl group -4- allylpiperidin -1- t-butyl formate (25g, 89.6mmol), toluene (degassing, 850mL) and Grubbs ' two generations catalyst (2.02g, 2.38mmol) toluene (degassing, 100mL) solution.By obtained mixture 85 DEG C stirred under nitrogen atmosphere 45 minutes.After completion of the reaction, the lower removing of decompression is molten Agent, and obtained residue is purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 40% gradient), obtain 1- carbonyl Base -8- azaspiro [4.5] decane -2- alkene -8- t-butyl formate (19g, 83mmol) is brown solid.By the compound and DDQ Toluene (540mL) solution of (565mg, 2.49mmol) is stirred at room temperature 15 minutes.Obtained shiny red solution is passed through into silicon The filtering of diatomaceous earth bed course.It is added charcoal (100g), and obtained suspension is stirred at room temperature 2 hours.Mixture is passed through into diatom Soil padding filtering, the residue that filtrate decompression is concentrated to get be purified by silica gel chromatography (ethyl acetate of 0 to 40% gradient/ Petroleum ether), obtain white solid 1- carbonyl -8- azaspiro [4.5] decane -2- alkene -8- carboxylic acid tert-butyl ester (12g, yield: 53.3%).
Step 5: 3- methyl-1-carbonyl-8- azaspiro [4.5] decane-8- carboxylic acid tert-butyl ester
CuI (3.8g, 20mmol) and anhydrous tetrahydro furan are sequentially added into the dry three-necked flask of the 250mL of nitrogen protection (100mL), the solution are cooled to -20 DEG C, and MeLi (THF solution of 1.6M, 25mL, 40mmol) is slowly added dropwise into solution, Rear reaction solution is added dropwise in -20 DEG C of reactions until solution is clarified.Then 1- carbonyl -8- azaspiro is slowly added dropwise at such a temperature [4.5] tetrahydrofuran solution (20mL) of decane -2- alkene -8- carboxylic acid tert-butyl ester (2.51g, 10mmol).After reaction, it will mix Object is closed to pour into containing saturation NH4In the separatory funnel of Cl aqueous solution, it is extracted with ethyl acetate (3x 15mL).By merging Organic phase MgSO4Dry, filter and filtrate decompression be concentrated by Silica gel chromatography (ethyl acetate of 0 to 50% gradient/ Petroleum ether), obtain 3- methyl-1-carbonyl-8- azaspiro [4.5] decane-2- alkene-8- t-butyl formate (1.6g, yield: 60%).
1H NMR(400MHz,CDCl3) δ 3.92 (s, 1H), 3.81 (s, 1H), 3.55 (d, J=5.0Hz, 1H), 3.13- 3.04 (m, 1H), 2.96 (t, J=10.9Hz, 1H), 2.56-2.46 (m, 1H), 2.31-2.21 (m, 2H), 1.94-1.75 (m, 2H), 1.62-1.49 (m, 1H), 1.45 (s, 9H), 1.41-1.35 (m, 2H), 1.15 (d, J=6.0Hz, 3H), 0.90 (t, J= 6.9Hz,3H)ppm.
Step 6 and seven: (R) -2- methyl-N- ((1R) -3- methyl -8- aza-spiro [4.5] decane -1- base) propane -2- Sulfenamide (C-1N)
Use synthetic intermediate C-1J step 8 and nine identical synthetic method, ketone intermediate 3- methyl-1-carbonyl-8- nitrogen Miscellaneous spiral shell [4.5] decane -2- alkene -8- t-butyl formate obtains (R) -2- methyl-N- through reduction amination and after removing Boc protecting group ((1R) -3- methyl -8- aza-spiro [4.5] decane -1- base) propane -2- sulfenamide C-1N.
1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,DMSO-d6)δ3.04-2.95(m,1H),2.75(s, 2H), 2.62-2.53 (m, 2H), 1.93-1.57 (m, 5H), 1.52-1.27 (m, 13H), 0.96 (d, J=6.5Hz, 3H) ppm； LCMS:m/z 273[M+H]+.
Embodiment 11: intermediate: (R) -2- methyl-N- ((1R, 3R) -3- methyl -8- azaspiro [4.5] decane -1- base) The preparation of propane -2- sulfenamide (C-1O)
Step 1: (R) -3- ((t-butyldimethylsilyl) oxygroup) -1- carbonyl -8- azaspiro [4.5] decane -8- Carboxylic acid tert-butyl ester
CuCl (19mg, 0.19mmol), (s)-TolBlNAP are sequentially added into dry 100mL three-necked flask (129mg, 0.19mmol), sodium tert-butoxide (18mg, 0.19mmol) and THF (9mL), mixture are stirred at room temperature 30 minutes. B is added2Pin2THF (2.5mL) solution of (1.78g, 7.01mmol), and obtained mixture is stirred at room temperature 10 minutes. Then the THF (9mL) of 1- carbonyl -8- azaspiro [4.5] decane -2- alkene -8- carboxylic acid tert-butyl ester (1.60g, 6.37mmol) is added Then MeOH (0.53mL, 12.74mmol) is added in solution.Obtained mixture is stirred at room temperature 16 hours.End of reaction Afterwards, H is added2Then sodium perborate (4.84g, 32mmol) is added in O (20mL), and obtained mixture is violent at room temperature Stirring l hours.Obtained green suspension is filtered by diatomite bed course, is poured into containing NaHCO3Saturated aqueous solution: Na2SO3 The separatory funnel of saturated aqueous solution (40mL), and extracted with EtOAc (4x40mL).By combined organic phase MgSO4It is dry, mistake It filters and filtrate decompression is concentrated to get crude product (R) -3- hydroxyl -1- carbonyl -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester.
Crude product (R) -3- hydroxyl -1- carbonyl -8- azaspiro [4.5] decane -8- is sequentially added in the single-necked flask of 100mL Carboxylic acid tert-butyl ester (theoretical amount, 6.37mmol), imidazoles (650mg, 9.56mmol), TBSCl (1.20g, 7.96mmol) and DMF Reaction 16 hours is stirred at room temperature in (16mL), the mixture.After completion of the reaction, reaction mixture is poured into containing saturation NH4In the separatory funnel of Cl aqueous solution (30mL), it is extracted with ethyl acetate (5x 50mL).Combined organic phase is used MgSO4It dries, filters and is purified by silica gel chromatography (the acetic acid second of 0 to 40% gradient in the residue being concentrated under reduced pressure to give Ester/petroleum ether), obtain (R) -3- ((t-butyldimethylsilyl) oxygroup) -1- carbonyl -8- azaspiro [4.5] decane -8- (1.26g, yield: 51.6%), being colorless oil to carboxylic acid tert-butyl ester.
LCMS:m/z 328[M-56+H]+.
Step 2: ((R) -1,1- dimethyl ethyl is sub- by (1R, 3R) -3- ((t-butyldimethylsilyl) oxygroup) -1- Sulfonamido) -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester
Use the identical synthetic method of synthetic intermediate C-1J step 8, ketone intermediate (R) -3- ((tertbutyldimethylsilyl chloride Silylation) oxygroup) after -1- carbonyl -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester reduction amination white solid (1R, 3R) -3- ((t-butyldimethylsilyl) oxygroup) -1- ((R) -1,1- dimethyl ethyl sulfonamido) -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (1.24g, yield: 77%).
1H NMR(400MHz,CDCl3) δ 4.23 (s, 1H), 3.84 (d, J=13.6Hz, 2H), 3.24 (s, 1H), 2.77 (td, J=12.7,12.0,3.0Hz, 2H), 2.27 (d, J=8.8Hz, 1H), 1.72-1.54 (m, 5H), 1.38 (s, 9H), 1.19 (d, J=2.5Hz, 3H), 1.14 (s, 9H), 0.80 (s, 9H), -0.03 (s, 6H) ppm；LCMS:m/z 488.9[M+H ]+.
Step 3: (R)-N- ((1R, 3R) -3- hydroxyl -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- is sub- Sulfonamide (C-1O)
(1R) -3- ((t-butyldimethylsilyl) oxygroup) -1- ((R) -1,1- dimethyl ethyl Asia sulphur under to ice bath Acylamino-) -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (49mg, 0.1mmol) Isosorbide-5-Nitrae-dioxane (1mL) solution in It is added the concentrated sulfuric acid (0.023ml, 0.4mmol).Reaction is stirred at room temperature 2 hours.Reaction solution is adjusted to PH with sodium hydroxide solution =12, then extracted with DCM (4x10mL).Combined organic phase is dried, filtered with anhydrous sodium sulfate, removes wave under reduced pressure Object is sent out, (R)-N- ((1R, 3R) -3- hydroxyl -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide is obtained C-1O (20mg, yield: 70%).LC-MS:m/z 275[M+H]+。
Embodiment 12: fluoro- 8- azaspiro [4.5] decane-of intermediate (R) -1- ((tert-butoxycarbonyl) amino) -3,3- two The preparation of 8- t-butyl formate (C-1P)
Step 1: (1R, 3R) -1- amino) -3- hydroxyl -8- azaspiro [4.5] decane
At room temperature to (1R, 3R) -3- ((t-butyldimethylsilyl) oxygroup) -1- ((R) -1,1- dimethyl ethyl Sulfonamido) -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (100mg, 0.2mmol) methanol (5mL) solution in delay Slow that hydrochloric acid Isosorbide-5-Nitrae-dioxane solution (4M, 2mmol, 0.5mL) is added, reaction solution heats reaction 1 hour at 40 DEG C.Under decompression It is concentrated to get (1R, 3R) -1- amino) -3- hydroxyl -8- azaspiro [4.5] decane, it is directly used in and reacts in next step.
LC-MS:m/z 171.0
Step 2: (1R, 3R) -1- ((tert-butoxycarbonyl) amino) -3- hydroxyl -8- azaspiro [4.5] decane -8- formic acid The tert-butyl ester (C-1P-b)
Will above (1R, the 3R) -1- amino) -3- hydroxyl -8- azaspiro [4.5] decane (0.2mmol) is dissolved into tetrahydrofuran In solution (10mL), (Boc) then is added2Then DIPEA (516mg, 4.0mmol) is added in O (109mg, 0.5mmol), reaction Liquid is stirred at room temperature 16 hours.After completion of the reaction, saturated ammonium chloride quenching reaction is added, is then extracted with ether (5x 50mL), Combined organic phase dried, filtered with anhydrous sodium sulfate and depressurize down be concentrated to get crude product be purified by silica gel chromatography (0 to The ethyl acetate/petroleum ether of 50% gradient), obtain (1R, 3R) -1- ((tert-butoxycarbonyl) amino) -3- hydroxyl -8- azaspiro [4.5] decane -8- t-butyl formate C-1P-b (60mg, two step yields: 80%).
1H NMR(400MHz,CDCl3) δ 5.11 (s, 1H), 4.36 (s, 1H), 3.86-3.62 (m, 3H), 2.94 (t, J= 11.7Hz, 2H), 2.20-2.08 (m, 1H), 1.81 (d, J=8.5Hz, 1H), 1.64-1.55 (m, 3H), 1.49-1.42 (m, 3H), 1.37 (d, J=4.9Hz, 18H) ppm；LC-MS:m/z 393.2[M+H]+.
Step 3: the tertiary fourth of (R) -1- ((tert-butoxycarbonyl) amino) -3- carbonyl -8- azaspiro [4.5] decane -8- formic acid Ester
By (1R, 3R) -1- ((tert-butoxycarbonyl) amino) -3- hydroxyl -8- azaspiro [4.5] decane -8- first at 0 DEG C Tert-butyl acrylate (60mg, 0.16mmol) is dissolved into methylene chloride (5mL), is then slowly added to Dess-Martin at 0 DEG C (76mg, 0.18mmol), reaction solution is kept for 0 DEG C, and the reaction was continued 2 hours.After completion of the reaction, water (4mL) is added to be quenched, then uses Methylene chloride (5x50mL) extraction merges organic phase and is dried, filtered with anhydrous sodium sulfate and depressurize down that be concentrated to get crude product logical Silica gel chromatography (ethyl acetate/petroleum ether of 0 to 80% gradient) is crossed, (R) -1- ((tert-butoxycarbonyl) ammonia is obtained Base) -3- carbonyl -8- azaspiro [4.5] decane -8- t-butyl formate (30mg, yield: 50%).
1H NMR(400MHz,CDCl3) δ 4.46 (d, J=9.4Hz, 1H), 4.07 (d, J=7.0Hz, 1H), 3.92 (s, 2H), 2.73 (t, J=12.7Hz, 2H), 2.63 (dd, J=19.0,8.1Hz, 1H), 2.41 (d, J=18.3Hz, 1H), 2.14- 2.01 (m, 2H), 1.68 (td, J=12.9,4.6Hz, 1H), 1.59 (d, J=4.8Hz, 1H), 1.39 (d, J=2.5Hz, 18H), 1.26 (d, J=2.9Hz, 1H) ppm；LC-MS:m/z 369.1[M+H]+.
Step 4: fluoro- 8- azaspiro [4.5] decane -8- formic acid uncle of (R) -1- ((tert-butoxycarbonyl) amino) -3,3- two Butyl ester
By (R) -1- ((tert-butoxycarbonyl) amino) -3- carbonyl 8- azaspiro [4.5] decane -8- t-butyl formate (80mg, 0.22mmol) is dissolved into methylene chloride (10mL), and DeoxoFluor (162 μ L, 0.88mmol) then is added, reaction Liquid 50 DEG C continuation heating stirring 48 hours.After completion of the reaction, reaction solution is quenched with saturated sodium bicarbonate solution at 0 DEG C, acetic acid Ethyl ester extracts (3x 20mL), and combined organic phase is dried, filtered with anhydrous sodium sulfate sodium, and (R) -1- is concentrated to get under decompression ((tert-butoxycarbonyl) amino) -3,3- bis- fluoro- 8- azaspiro [4.5] decane -8- t-butyl formate (46mg, yield: 54%)
1H NMR(400MHz,CDCl3) δ 4.49 (d, J=9.9Hz, 1H), 3.92 (dd, J=24.5,15.9Hz, 3H), 2.87-2.68 (m, 2H), 2.58-2.42 (m, 1H), 2.21 (td, J=17.7,16.8,9.6Hz, 1H), 2.06-1.86 (m, 2H), 1.60 (t, J=6.6Hz, 1H), 1.38 (d, J=4.0Hz, 21H) ppm；LC-MS:m/z 391.1[M+H]+
Step 5: (R) -1- amino) two fluoro- 8- azaspiro [4.5] decane (C-1P) of -3,3-
At room temperature to fluoro- 8- azaspiro [4.5] decane -8- formic acid of (R) -1- ((tert-butoxycarbonyl) amino) -3,3- two Be slowly added in methanol (5mL) solution of the tert-butyl ester (46mg, 0.12mmol) hydrochloric acid Isosorbide-5-Nitrae-dioxane solution (4M, 1.2mmol, 0.3mL), reaction solution reacts 1 hour at room temperature.(R) -1- amino is concentrated to get under decompression) two fluoro- 8- of -3,3- Azaspiro [4.5] decane (C-1P).LC-MS:m/z 191.1[M+H]+.
Embodiment 13: the preparation of intermediate 1- methyl -8- azaspiro [4.5] decane -1- amine (C-2A)
Step 1: 1- hydroxyl -1- methyl -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester
To the toluene of 1- carbonyl -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (500mg, 2.0mmol) at 0 DEG C The tetrahydrofuran solution (1M, 2.2mmol, 2.2mL) of methyl-magnesium-bromide is slowly added dropwise in (20mL) solution, reaction solution is at 0 DEG C Continue stirring 1 hour.After completion of the reaction, saturated aqueous ammonium chloride is added to be quenched, is then extracted with ethyl acetate (3x 20mL) It takes, combined organic phase is dried, filtered with anhydrous sodium sulfate and depressurized down and is concentrated to get crude product and be purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 50% gradient) obtains the tertiary fourth of 1- hydroxyl -1- methyl -8- azaspiro [4.5] decane -8- carboxylic acid Ester (410mg, yield: 77%).
1H NMR(400MHz,CDCl3)δ4.16-4.04(m,2H),3.12-2.56(m,2H),1.98-1.49(m,8H), 1.49(s,9H),1.42-1.29(m,2H),1.16(s,3H)ppm；LC-MS:m/z 270.2[M+H]+.
Step 2: N- (1- methyl -8- azaspiro [4.5] decane -1- base) acetamide
1- hydroxyl -1- methyl -8- azaspiro [4.5] decane -8- carboxylic acid tert-butyl ester (410mg, 1.52mmol) is dissolved into In acetonitrile (1.82mL), then in 0 DEG C of addition concentrated sulfuric acid (1.56mL), then reaction solution is stirred at room temperature 16 hours.It has reacted Bi Hou pours into reaction solution in ice water, then water-soluble basified to pH=12 with NaOH (50%), then uses ethyl acetate (3x It 20mL) extracts, combined organic phase, which is dried, filtered with anhydrous sodium sulfate and depressurized down, is concentrated to get crude product N- (1- methyl -8- Azaspiro [4.5] decane -1- base) (260mg, yield: 81%), crude product is directly used in reacts acetamide in next step.
LC-MS:m/z 211.0[M+H]+.
Step 3: 1- methyl -8- azaspiro [4.5] decane -1- amine (C-2A)
At room temperature by crude product N- (1- methyl -8- azaspiro [4.5] decane -1- base) acetamide (260mg, 1.23mmol) It is dissolved into 6M hydrochloric acid solution (5mL), reaction solution reacts 4 hours for 120 DEG C under microwave heating condition.After, reaction solution exists The lower concentration of decompression then freeze-drying obtain crude product 1- methyl -8- azaspiro [4.5] decane -1- amine C-2A (200mg, yield: 97%), crude product is not purified to be directly used in and be reacted in next step.
LC-MS:m/z 169.1[M+H]+.
Embodiment 14: the preparation of intermediate (4- ethyl piperidine -4- base) t-butyl carbamate (C-3A)
Step 1: 1- benzyl -4- ethyl piperidine -4- carboxylate methyl ester
To the tetrahydrofuran of 1- benzyl piepridine -4- carboxylate methyl ester (1g, 4.3mmol) at -78 DEG C under nitrogen protection The tetrahydrofuran solution (1M, 5.1mmol, 5.1mL) of LDA is slowly added dropwise in (10mL) solution, reaction solution continues to stir at -78 DEG C It mixes 1 hour, is then slowly added into the tetrahydrofuran (1mL) of iodoethane (795mg, 5.1mmol), reaction solution continues at -78 DEG C Reaction 4 hours.After completion of the reaction, saturated aqueous ammonium chloride is added to be quenched, is then extracted with ethyl acetate (3x30mL), merged Organic phase dried, filtered and depressurized down with anhydrous sodium sulfate and be concentrated to get crude product and be purified by silica gel chromatography (0 to 50% The ethyl acetate/petroleum ether of gradient), obtain 1- benzyl -4- ethyl piperidine -4- carboxylate methyl ester (800mg, yield: 71%).
LC-MS:m/z 262.2[M+H]+.
Step 2: 1- benzyl -4- ethyl piperidine -4- carboxylic acid
1- benzyl -4- ethyl piperidine -4- carboxylate methyl ester (800mg, 3.23mmol) is dissolved into the aqueous solution of ethyl alcohol (second Alcohol: water=4:1,20mL), then plus NaOH (517mg, 12.9mmol), then reaction solution is stirred at room temperature 16 hours.It has reacted Reaction solution is depressurized lower concentration, is then acidified to pH=3 with the hydrochloric acid of 1N, is then extracted with ethyl acetate (3x30mL) by Bi Hou, Combined organic phase, which is dried, filtered with anhydrous sodium sulfate and depressurized down, is concentrated to give product 1- benzyl -4- ethyl piperidine -4- carboxylic acid (720mg, yield: 90%), which is used directly for reacting in next step.
LC-MS:m/z 248.2[M+H]+.
Step 3: 1- methyl -8- azaspiro [4.5] decane -1- amine
1- benzyl -4- ethyl piperidine -4- carboxylic acid (250mg, 1.0mmol) is dissolved into the tert-butyl alcohol (5mL) at room temperature, so Triethylamine (306mg, 3.0mmol) is added afterwards and diphenyl phosphate azide (330mg, 2.0mmol), following reaction liquid are heated to reflux 8 hours.After completion of the reaction, water quenching reaction is added, is then extracted with ethyl acetate (3x30mL), combined organic phase is with anhydrous Sodium sulphate, which is dried, filtered and depressurized down, is concentrated to give crude product, through Silica gel chromatography (ethyl acetate/stone of 0 to 70% gradient Oily ether), obtain 1- methyl -8- azaspiro [4.5] decane -1- amine (160mg, yield: 50%).
LC-MS:m/z 319.2[M+H]+.
Step 4: (4- ethyl piperidine -4- base) t-butyl carbamate
1- methyl -8- azaspiro [4.5] decane -1- amine (160mg, 0.5mmol) is dissolved into 10mL methanol at room temperature, Then Pd/C (16mg, 10%) is added, reaction solution reacts 16 hours under an atmosphere of hydrogen.Diatomite filtering, then uses acetic acid second Ester washing, is concentrated to get (4- ethyl piperidine -4- base) t-butyl carbamate (110mg, yield: 95%) under decompression.The product It is used directly for reacting in next step.
LC-MS:m/z 229.2[M+H]+.
Step 5: (4- ethyl piperidine -4- base) t-butyl carbamate (C-3A)
(4- ethyl piperidine -4- base) t-butyl carbamate (110mg, 0.5mmol) is dissolved into methanol (3mL) at room temperature In, hydrochloric acid Isosorbide-5-Nitrae-dioxane solution (4N, 5mmol, 1.1Ml) reaction solution is then added and is stirred at room temperature 2 hours, under decompression Being concentrated to get product (4- ethyl piperidine -4- base) t-butyl carbamate (C-3A), (50mg, yield: 95%), the product is direct For reacting in next step.
LC-MS:m/z 128.2[M+H]+.
Embodiment 15: the preparation of intermediate ((4- methyl piperidine -4- base) methyl) t-butyl carbamate (C-4A)
Step 1: 1- benzoyl -4- methyl piperidine -4- formonitrile HCN
Under a nitrogen atmosphere, sequentially added into the drying single-necked flask of 100mL 4- methyl piperidine -4- formonitrile HCN (496mg, 4mmol), DCM (10mL) and triethylamine (611mg, 6mmol), be then slowly added dropwise at room temperature chlorobenzoyl chloride (670mg, 4.8mmol).Mixture is further stirred at room temperature 1 hour, TLC monitoring reaction to raw material end of reaction.It is molten with 1N HCl After liquid quenching reaction, methylene chloride (3 × 20mL) extraction, combined organic phase Na2SO4Dry, filtrate decompression is concentrated and passes through Column Silica gel chromatography (ethyl acetate/petroleum ether of 0 to 40% gradient) obtains 1- benzoyl -4- methyl piperidine -4- first Nitrile (650mg, yield: 70.72%).
LC-MS:m/z 229[M+H]+.
Step 2: 1- benzoyl-((4- methyl piperidine -4- base) methyl) t-butyl carbamate
At 0 DEG C, under condition of nitrogen gas, 1- benzoyl -4- methyl piperidine -4- is sequentially added into the drying flask of 100mL Formonitrile HCN (650mg, 2.85mmol), nickel chloride hexahydrate (135mg, 0.67mmol), di-tert-butyl dicarbonate (1.86g, 8.54mmol) and methanol (12mL), and to sodium borohydride (754mg, 20mmol) is added.Then reaction solution is stirred at room temperature 12 hours, TLC monitoring reaction to raw material end of reaction.After completion of the reaction, reaction solution is concentrated and methylene chloride (3 × 20mL) is used to extract It takes, combined organic phase Na2SO4Dry, filtrate decompression is concentrated and passes through the column Silica gel chromatography (second of 0 to 40% gradient Acetoacetic ester/petroleum ether) obtaining 1- benzoyl-((4- methyl piperidine -4- base) methyl) t-butyl carbamate, (620mg is received Rate: 65.50%)
LC-MS:m/z 333[M+H]+.
Step 3: ((4- methyl piperidine -4- base) methyl) t-butyl carbamate (C-4A)
((1- benzoyl -4- methyl piperidine -4- base) methyl) carbamic acid is sequentially added into the single-necked flask of 100mL The tert-butyl ester (620mg, 1.87mmol), ethyl alcohol (8mL) and 7N NaOH (2mL), then heat mixture under the protection of nitrogen To 90 DEG C stir 8 hours, after mixture is cooled to room temperature, mixture is filtered, after being diluted with water using ethyl acetate (3 × It 20mL) extracts, combined organic phase Na2SO4Dry, filtrate decompression is concentrated and passes through column Silica gel chromatography (0 to 80% The ethyl acetate/petroleum ether of gradient) obtaining ((4- methyl piperidine -4- base) methyl) t-butyl carbamate C-4A, (300mg is received Rate: 70.5%).
1H NMR(400MHz,DMSO-d6) δ 3.97 (q, J=7.0Hz, 2H), 2.80 (d, J=6.4Hz, 2H), 2.65 (d, J=30.3Hz, 2H), 1.38 (s, 9H), 1.27 (dd, J=16.2,7.0Hz, 2H), 1.10 (d, J=12.8Hz, 2H), 0.81 (s,3H)ppm；LC-MS:m/z 229[M+H]+.
Embodiment 16: the preparation of intermediate ((4- Phenylpiperidine -4- base) methyl) t-butyl carbamate (C-4B)
Step 1: 4- cyano -4- Phenylpiperidine -1- t-butyl formate
At 0 DEG C, to (2- chloroethyl) t-butyl carbamate (2g, 8.26mmol) and 2- benzene acetonitrile (968mg, NaH is added portionwise in anhydrous DMF (20mL) solution 8.26mmol) (60% is dispersed in mineral oil, 1.6g, 41.3mmol). Reaction mixture is heated 16 hours at 60 DEG C.After completion of the reaction, water (30mL) on the rocks is quenched, then 3 × 50mL) extraction.It will Combined organic layer is washed with saturated salt solution (2 × 50mL), is then dried, filtered with sodium sulphate and is depressurized lower concentration.It is thick to produce Object obtains 4- cyano -4- Phenylpiperidine -1- by column Silica gel chromatography (ethyl acetate/petroleum ether of 0 to 40% gradient) T-butyl formate (500mg, yield: 21%).
LCMS:m/z 187.2[M-100]+.
Step 2: 4- (amino methyl) -4- Phenylpiperidine -1- t-butyl formate
4- cyano -4- Phenylpiperidine -1- t-butyl formate (0.5g, 1.75mmol) is dissolved into 20mL methanol, then It is added palladium carbon (50mg), reaction solution reacts 16 hours under hydrogen.After completion of the reaction, it filters, 4- (amino is concentrated to get under decompression Methyl) -4- Phenylpiperidine -1- t-butyl formate (0.4g, yield: 80%).
1H NMR(400MHz,CDCl3) δ 7.38 (t, J=7.6Hz, 2H), 7.30 (d, J=7.5Hz, 2H), 7.24 (d, J =7.2Hz, 1H), 3.75 (d, J=7.8Hz, 2H), 3.04 (t, J=11.2Hz, 2H), 2.58 (brs, 2H), 2.21 (d, J= 13.9Hz,2H),1.76-1.61(m,2H),1.44(s,9H)ppm；LC-MS:m/z 191.0[M-100]+.
Step 2: (4- Phenylpiperidine -4- base) methylamine (C-4B)
4- (amino methyl) -4- Phenylpiperidine -1- t-butyl formate (0.4g, 1.37mmol) is dissolved into 10mL methanol In, then it is added hydrochloric acid Isosorbide-5-Nitrae-dioxane solution (4M, 13.7mmol) at room temperature, that the reaction was continued is 2 small in room temperature for reaction solution When.After completion of the reaction, be concentrated to get under decompression (4- Phenylpiperidine -4- base) methylamine C-4B (0.25g, yield: 95%), and crude product It is directly used in and reacts in next step.
LC-MS:m/z 191.2[M+H]+.
Embodiment 17: the preparation of intermediate 6- ((tert-butoxycarbonyl) amino) -2,3- dichloropyridine -4- sodium mercaptides (F-1A)
Step 1: (6- chloropyridine -2- base) t-butyl carbamate
6- chloropyridine -2- amine (8g, 62.2mmol) and THF is added under nitrogen protection into dry 250mL three-necked flask (80mL), mixture stir 10 minutes at 0 DEG C, NaHDMS (124.4mL, 1.0M in THF) then are added, then keeping body It is the tetrahydrofuran solution (50mL) for being slowly added to di-tert-butyl dicarbonate (16.3g, 74.7mmol) at 0 DEG C, continues anti-at 0 DEG C It answers 4 hours.After completion of the reaction, H is added2O (40mL) is then extracted with EtOAc (3x 100mL).Combined organic phase is used MgSO4It dries, filters and is purified by silica gel chromatography (the acetic acid second of 0 to 10% gradient in the residue being concentrated under reduced pressure to give Ester/petroleum ether), obtain (6- chloropyridine -2- base) t-butyl carbamate (7g, yield: 49%).
1H NMR (400MHz, DMSO-d6) δ 10.04 (s, 1H), 7.79-7.58 (m, 2H), 7.02 (dd, J=5.5, 2.9Hz,1H),1.38(s,9H)ppm；LCMS:m/z 288.1[M+H]+.
Step 2: (5,6- dichloropyridine -2- base) t-butyl carbamate
(6- chloropyridine -2- base) t-butyl carbamate (7g, 30.6mmol) is added into dry 100mL round-bottomed flask With n,N-Dimethylformamide (50mL), mixture is stirred at room temperature 10 minutes, and N- chlorosuccinimide is then added (4.50g, 33.67mmol), mixture react 4 hours at 100 DEG C.After completion of the reaction, reaction night temperature, which is cooled to room temperature, adds Enter H2O (50mL) is then extracted with ethyl acetate (3x80mL), then washs (2x40mL) with saturation water lithium chloride solution.It will Organic phase MgSO4It dries, filters and is concentrated under reduced pressure, obtained residue is purified by silica gel chromatography (0 to 5% gradient Ethyl acetate/petroleum ether), obtain (5,6- dichloropyridine -2- base) t-butyl carbamate (5.3g, yield: 65.8%).
1H NMR(400MHz,CDCl3) δ 7.86 (d, J=8.7Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7.24 (s, 1H),1.51(s,9H)；LCMS:m/z 207.1[M-55]+.
Step 3: (the chloro- 4- iodine pyridine -2- base of 5,6- bis-) t-butyl carbamate
(5,6- dichloropyridine -2- base) tertiary fourth of carbamic acid is added under nitrogen protection into dry 100mL round-bottomed flask Ester (5.3g, 20.14mmol) and tetrahydrofuran (50mL), are slowly added dropwise n-BuLi (44.3mmol, 2.5M at -78 DEG C THF), reaction solution stirs 1 hour at this temperature.Then the tetrahydrofuran of iodine (3.07g, 24.17mmol) is slowly added dropwise (20mL) solution, also at -78 DEG C, the reaction was continued 3 hours for this reaction.After completion of the reaction, H is added2O (50mL), then uses EtOAc (3x 80mL) extraction.By combined organic phase MgSO4It dries, filters and is being concentrated under reduced pressure, obtained residue passes through silica gel Chromatography purifies (ethyl acetate/petroleum ether of 0 to 5% gradient), obtains (5,6- bis- chloro- 4- iodine pyridine -2- base) carbamic acid The tert-butyl ester (4.3g, yield: 55%).
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.36(s,1H),1.46(s,9H)ppm；LCMS:m/ z334.1[M-55]+.
Step 4: 3- ((6- ((tert-butoxycarbonyl) amino) -2,3- dichloropyridine -4- base) is thio) methyl propionate
(the chloro- 4- iodine pyridine -2- base of 5,6- bis-) amino is sequentially added under nitrogen protection into dry 100mL round-bottomed flask T-butyl formate (3.2g, 8.22mmol), palladium acetate (92mg, 0.41mmol), Xantphos (285mg, 0.49mmol), DIPEA (2.12g, 16.46mmol) and Isosorbide-5-Nitrae-dioxane (30mL).This reaction mixture 100 DEG C heating stirring 2 hours. It filtering and is concentrated under reduced pressure, obtained residue is purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 30% gradient), Obtain 3- ((6- ((tert-butoxycarbonyl) amino) -2,3- dichloropyridine -4- base) is thio) methyl propionate (3g, yield: 96%).
1H NMR (400MHz, DMSO-d6) δ 10.25 (s, 1H), 7.73 (s, 1H), 3.64 (s, 3H), 3.26 (t, J= 6.9Hz, 2H), 2.82 (t, J=6.9Hz, 2H), 1.46 (s, 9H) ppm；LCMS:m/z 326.3[M-55]+.
Step 5: 6- ((tert-butoxycarbonyl) amino) -2,3- dichloropyridine -4- sodium mercaptides (F-1A)
3- ((6- ((tert-butoxycarbonyl) amino) -2,3- dichloro pyrrole is sequentially added into dry 100mL round-bottomed flask Pyridine -4- base) thio) methyl propionate and tetrahydrofuran (30mL), the ethanol solution of sodium ethoxide is then slowly added dropwise at room temperature again (21%, 6mL), the reaction solution are stirred at room temperature 1 hour.The lower concentration of decompression, is then added methylene chloride (10mL), is precipitated a large amount of Brown solid, filtering, and washed with methylene chloride, 6- ((tert-butoxycarbonyl) amino) -2,3- dichloropyridine-is obtained after dry 4- sodium mercaptides F-1A (2.1g, yield: 84%).
1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.61(s,1H),1.41(s,9H)ppm；LCMS:m/ z262.2[M-55]+.
According to the synthetic method of embodiment 17, with similar intermediate feed react to obtain following intermediate F-1B, F-1C, F-1D、F-1E、F-1F、F-1G、F-1H、F-1I、F-1J、F-1K、F-1L、F-1M、F-1N、F-1O、F-1P。
Embodiment 18: the preparation of intermediate 3- chloro-2-methyl pyridine -4- sodium mercaptides (F-1Q)
Step 1: 3- ((3- chloro-2-methyl pyridin-4-yl) sulfenyl) methyl propionate
((2,3- dichloropyridine -4- base) sulfenyl) methyl propionate of intermediate 3- obtained in synthetic intermediate F-1G process is used In following reaction.
3- ((2,3- dichloropyridine -4- base) sulfenyl) is sequentially added under nitrogen protection into dry 100mL round-bottomed flask Methyl propionate (500mg, 1.88mmol), Pd (PPh3)4(217mg, 0.188mmol), three boroxane of front three basic ring (354mg, 2.82mmol), potassium carbonate (389mg, 2.82mmol) and Isosorbide-5-Nitrae-dioxane (10mL).This reaction mixture is under nitrogen protection 100 DEG C heating stirring 6 hours.It filters and is purified by silica gel chromatography (0 to 40% gradient in the residue being concentrated under reduced pressure to give Ethyl acetate/petroleum ether), obtain 3- ((3- chloro-2-methyl pyridin-4-yl) sulfenyl) methyl propionate (320mg, yield: 69%).
Step 2: 3- chloro-2-methyl pyridine -4- sodium mercaptides (F-1Q)
3- ((3- chloro-2-methyl pyridin-4-yl) sulfenyl) methyl propionate is sequentially added into dry 100mL round-bottomed flask (320mg, 1.30mmol) and tetrahydrofuran (10mL), be then slowly added dropwise at room temperature again sodium ethoxide ethanol solution (21%, 2mL), which is stirred at room temperature 1 hour.The lower concentration of decompression, is then added methylene chloride (10mL), it is solid that a large amount of browns is precipitated Body, filtering, and is washed with methylene chloride, obtained after dry 3- chloro-2-methyl pyridine -4- sodium mercaptides F-1Q (200mg, yield: 85%).
1H NMR (400MHz, DMSO-d6) δ 7.37 (d, J=4.8Hz, 1H), 6.97 (d, J=4.8Hz, 1H), 2.31 (s,3H)ppm；LCMS:m/z 160.0[M+H]+.
According to the synthetic method of embodiment 18, reacted to obtain following intermediate F-1R with similar intermediate feed.
Embodiment 19: intermediate 6- ((tert-butoxycarbonyl) amino) -3- chloro-2-methyl pyridine -4- sodium mercaptides (F-1S) Preparation
Step 1: 3- ((6- ((tert-butoxycarbonyl) amino) -3- chloro-2-methyl pyridin-4-yl) is thio) methyl propionate
((6- ((tert-butoxycarbonyl) the amino) -2,3- dichloro pyrrole of intermediate 3- obtained in synthetic intermediate F-1A process Pyridine -4- base) it is thio) methyl propionate be used for following reaction.
3- ((6- ((tert-butoxycarbonyl) amino)-is sequentially added under nitrogen protection into dry 100mL round-bottomed flask 2,3- dichloropyridine -4- bases) thio) methyl propionate (600mg, 1.57mmol), [1,1'- bis- (tert-butyl phosphine) ferrocene dichloros Change palladium (103mg, 0.157mmol), three boroxane of front three basic ring (301mg, 2.4mmol), potassium carbonate (331mg, 2.4mmol), 1,4- dioxane (10mL) and water (1mL).This reaction mixture 100 DEG C heating stirring 6 hours under nitrogen protection.Filtering is simultaneously It is purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 40% gradient) in the residue being concentrated under reduced pressure to give, obtains 3- ((6- ((tert-butoxycarbonyl) amino) -3- chloro-2-methyl pyridin-4-yl) is thio) methyl propionate (420mg, yield: 74%).
1H NMR (400MHz, DMSO-d6) δ 9.90 (s, 1H), 7.64 (s, 1H), 3.64 (s, 3H), 3.21 (t, J= 6.9Hz, 2H), 2.80 (t, J=6.9Hz, 2H), 1.46 (s, 9H) ppm；LCMS:m/z 361.1[M+H]+.
Step 2: 6- ((tert-butoxycarbonyl) amino) -3- chloro-2-methyl pyridine -4- sodium mercaptides (F-1S)
3- ((6- ((tert-butoxycarbonyl) amino) -3- chloro-2-methyl is sequentially added into dry 100mL round-bottomed flask Pyridin-4-yl) thio) methyl propionate (420mg, 1.17mmol) and tetrahydrofuran (10mL), then it is slowly added dropwise at room temperature again The ethanol solution (21%, 2mL) of sodium ethoxide, the reaction solution are stirred at room temperature 1 hour.The lower concentration of decompression, is then added dichloromethane A large amount of brown solids are precipitated in alkane (10mL), filtering, and are washed with methylene chloride, obtain 6- ((tert-butoxycarbonyl) ammonia after dry Base) -3- chloro-2-methyl pyridine -4- sodium mercaptides F-1S (320mg, yield: 92%).
1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),7.63(s,1H),3.64(s,3H),1.46(s,9H)ppm； LCMS:m/z 275.0[M+H]+.
Embodiment 20: the preparation of intermediate 3- amino -2- chlorobenzenethiol hydrochloride (F-2A)
Step 1: the chloro- 3- amino benzenethiol tert-butyl ester of 2-
Sequentially added under nitrogen protection into dry 100mL round-bottomed flask the chloro- 3- fluoroaniline (5g, 34.3mmol) of 2- and 2- methylpropane -2- mercaptan (8.66g, 96.04mmol) and cesium carbonate is then added in N-Methyl pyrrolidone (50mL) (22.36g, 68.6mmol), reaction mixture 120 DEG C heating stirring 16 hours.After being cooled to room temperature, reaction solution 60mL second Acetoacetic ester dilution, and with successively with saturation water lithium chloride solution (30mL), water (30mL) and saturated sodium-chloride water solution (30mL) Washing, is then dried, filtered with anhydrous sodium sulfate, and being concentrated under reduced pressure to give the chloro- 3- amino benzenethiol tert-butyl ester of 2-, (6.04g is received Rate: 82%).
LCMS:m/z 216.1[M+H]+.
Step 2: 3- amino -2- chlorobenzenethiol hydrochloride (F-2A)
The chloro- 3- amino benzenethiol tert-butyl ester (6.04g, 28mmol) of 2- and dense is added into dry 100mL round-bottomed flask Hydrochloric acid (50mL), reaction mixture 45 DEG C heating stirring 8 hours.After naturally cooling to room temperature, reaction solution is continued to be cooled to 0 DEG C, a large amount of white solids are precipitated, filtering, then successively use concentrated hydrochloric acid, and petroleum ether obtains 3- amino -2- chlorobenzenethiol hydrochloric acid Salt F-2A (4.9g, yield: 90%).
LCMS:m/z 160.0[M+H]+.
Embodiment 21: compound 1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -4- first The preparation of phenylpiperidines -4- amine
Step 1: (1- (8- iodine imidazo [1,2-c] pyrimidine -5- base) -4- methyl piperidine -4- base) t-butyl carbamate
Under nitrogen protection, chloro- 8- iodine imidazo [1, the 2-c] pyrimidine of 5- is sequentially added into dry 50mL single-necked flask E1 (50mg, 0.18mmol), (4- methyl piperidine -4- base) t-butyl carbamate (77mg, 0.36mmol), DIEA (46mg, 0.36mmol) with NMP (5mL), then it is stirred to react at 90 DEG C 2 hours.After completion of the reaction, the residue of acquisition is poured into water (10mL) is stirred 5 minutes at room temperature.Then it is extracted with ethyl acetate (3x50mL), by combined organic phase MgSO4It is dry It is dry, it filters and is purified by silica gel chromatography (ethyl acetate/petroleum of 0 to 80% gradient in the residue being concentrated under reduced pressure to give Ether), obtain faint yellow solid (1- (8- iodine imidazo [1,2-c] pyrimidine -5- base) -4- methyl piperidine -4- base) carbamic acid uncle Butyl ester (70mg, yield: 43%)
1H NMR(400MHz,DMSO-d6) δ 8.02 (s, 1H), 7.89 (d, J=1.5Hz, 1H), 7.62 (d, J=1.4Hz, 1H), 3.49 (d, J=13.4Hz, 2H), 3.21 (ddd, J=13.3,10.8,2.6Hz, 2H), 2.18 (d, J=13.9Hz, 2H), 1.65 (ddd, J=14.1,10.7,3.8Hz, 2H), 1.40 (s, 9H), 1.28 (s, 3H) ppm；LCMS:m/z 458.1[M +H]+.
Step 2: (1- (8- ((2,3- dichlorophenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5-) -4- methyl piperidine -4- Base) t-butyl carbamate
(1- (8- iodine imidazo [1,2-c] pyrimidine -5- base) -4- first is sequentially added in dry 50mL three-necked flask bottle Phenylpiperidines -4- base) t-butyl carbamate (70mg, 0.15mmol), cuprous iodide (3mg, 0.015mmol), 1,10- phenanthroline The two of (6mg, 0.030mmol), 2,3- thiophenol dichlorobenzene (32mg, 0.18mmol), potassium phosphate (66mg, 0.30mmol) and 5mL Six ring of oxygen.The mixture heats reaction 3 hours under the protection of nitrogen.After reaction, saturation NH is added4Cl solution (10mL).Then it is extracted with ethyl acetate (3x50mL).Combined organic phase Na2SO4It dries, filters, filtrate decompression concentration, Obtained residue is purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 60% gradient), obtains faint yellow solid (1- (8- ((2,3- dichlorophenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5-) -4- methyl piperidine -4- base) tertiary fourth of carbamic acid Ester (30mg, yield: 39%).
LC-MS:m/z 508.1[M+H]+.
Step 3: 1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -4- methyl piperidine -4- Amine
(1- (8- ((2,3- dichlorophenyl) sulfenyl) imidazo [1,2-c] is sequentially added in dry 50mL round-bottomed flask Pyrimidine -5-) -4- methyl piperidine -4- base) t-butyl carbamate (30mg, 0.059mmol) and hydrochloric acid 1,4- dioxane it is molten Liquid (7M, 5mL) reacts at room temperature 1 hour.Reaction solution is concentrated under reduced pressure, and gained crude product obtains product with high-efficient liquid phase chromatogram purification 1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -4- methyl piperidine -4- amine (15mg, yield: 62%).
1H NMR (400MHz, DMSO-d6) δ 8.02 (s, 1H), 7.84 (d, J=1.3Hz, 1H), 7.55 (d, J= 1.2Hz, 1H), 7.41 (dd, J=8.0,1.2Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (dd, J=8.1,1.2Hz, 1H), 3.60 (t, J=4.2Hz, 4H), 1.73-1.60 (m, 4H), 1.19 (s, 3H) ppm；LC-MS:m/z 408.1[M+H]+.
Using the synthetic method of embodiment 21, following compound can be synthesized:
Embodiment 22:8- ((2,3- dichlorophenyl) is thio) -5- (1,8- diaza spiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 7.41 (d, J= 8.1Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.72 (d, J=8.1Hz, 1H), 3.79 (ddd, J=13.9,7.1,3.7Hz, 2H), 3.49 (ddd, J=12.8,8.0,3.4Hz, 2H), 3.19 (t, J=6.9Hz, 2H), 2.04 (ddd, J=12.3,8.1, 3.5Hz, 2H), 1.93 (dt, J=20.5,6.5Hz, 6H) ppm；LC-MS:m/z 434.1[M+H]+.
Embodiment 23: compound 8- ((2,3- dichlorophenyl) is thio) -5- (piperidin-1-yl) imidazo [1,2-c] pyrimidine Preparation
The chloro- 8- of 5- ((2,3- dichlorophenyl) is thio) imidazo [1,2- is sequentially added into dry 50mL single-necked flask C] pyrimidine B1 (50mg, 0.15mmol), piperidines (20mg, 0.23mmol), DIEA (39mg, 0.3mmol) and NMP (5mL), then It is stirred to react at 90 DEG C 2 hours.After completion of the reaction, the residue of acquisition is poured into water (100mL), stirs 5 points at room temperature Clock.Then it is extracted with ethyl acetate (3x 50mL), by combined organic phase MgSO4It dries, filters and is being concentrated under reduced pressure to give Residue be purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 80% gradient), high-efficient liquid phase chromatogram purification obtains Product ((1- (8- ((2,3- dichlorophenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) pyrrolidin-3-yl) methyl) amino first Tert-butyl acrylate (20mg, yield: 35%)
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.83 (d, J=1.4Hz, 1H), 7.55 (d, J= 1.4Hz, 1H), 7.41 (dd, J=8.0,1.3Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (dd, J=8.1,1.3Hz, 1H), 3.50 (d, J=5.6Hz, 4H), 1.79-1.63 (m, 6H) ppm；LC-MS:m/z 378.7[M+H]+.
Using the synthetic method of embodiment 23, following compound can be synthesized:
Embodiment 24:8- ((2,3- dichlorophenyl) is thio) -5- (3,5- lupetazin -1- base) imidazo [1,2-c] Pyrimidine
1H NMR (400MHz, DMSO-d6) δ 8.23 (s, 1H), 8.03 (s, 1H), 7.92 (d, J=1.2Hz, 1H), 7.55 (d, J=1.2Hz, 1H), 7.44-7.37 (m, 1H), 7.12 (t, J=8.1Hz, 1H), 6.69 (dd, J=8.1,1.1Hz, 1H), 3.89 (d, J=12.0Hz, 2H), 3.02 (d, J=6.6Hz, 2H), 2.72-2.59 (m, 2H), 1.05 (t, J=6.0Hz, 7H) ppm；LC-MS:m/z 407.7[M+H]+.
Embodiment 25:8- ((2,3- dichlorophenyl) is thio) -5- (4- methylpiperazine-1-yl) imidazo [1,2-c] pyrimidine
1H NMR (400MHz, DMSO-d6) δ 8.20 (s, 1H), 8.04 (s, 1H), 7.91 (d, J=1.4Hz, 1H), 7.57 (d, J=1.4Hz, 1H), 7.41 (dd, J=8.0,1.2Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.70 (dd, J=8.1, 1.2Hz,1H),3.59-3.50(m,4H),2.59-2.53(m,4H),2.27(s,3H)ppm；LC-MS:m/z 393.8[M+H ]+.
Embodiment 26:(1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -4- phenyl piperazine Pyridine -4- base) methylamine
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.88(s,1H),7.54(s,1H),7.50-7.33(m, 5H), 7.28 (t, J=6.8Hz, 1H), 7.10 (t, J=8.0Hz, 1H), 6.67 (d, J=8.1Hz, 1H), 3.77 (d, J= 12.5Hz, 2H), 3.31-3.22 (m, 2H), 3.09 (s, 1H), 2.82 (s, 1H), 2.32 (s, 2H), 2.06 (t, J=10.3Hz, 2H)；LC-MS:m/z484.7[M+H]+.
Embodiment 27:(R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -3,3- two Fluoro- 8- azaspiro [4.5] decane -1- amine
1H NMR(400MHz,DMSO-d6) δ 8.03 (s, 1H), 7.81 (d, J=1.5Hz, 1H), 7.57 (d, J=1.4Hz, 1H), 7.42 (dd, J=8.0,1.3Hz, 1H), 7.12 (t, J=8.1Hz, 1H), 6.69 (dd, J=8.1,1.4Hz, 1H), 3.93 (t, J=14.9Hz, 2H), 3.31 (d, J=19.3Hz, 2H), 3.28-3.16 (m, 3H), 2.252.06 (m, 2H), 1.90 (dd, J=32.1,11.8Hz, 2H), 1.61-1.45 (m, 2H) ppm；LC-MS:m/z 484.1[M+H]+.
Embodiment 28:(R) -3- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -3- azepine Spiral shell [5.5] hendecane -7- amine
1H NMR (400MHz, DMSO-d6) δ 8.02 (s, 1H), 7.82 (d, J=1.2Hz, 1H), 7.56 (d, J= 1.2Hz, 1H), 7.41 (dd, J=8.0,1.2Hz, 1H), 7.12 (t, J=8.1Hz, 1H), 6.68 (dd, J=8.1,1.2Hz, 1H), 3.80 (d, J=4.8Hz, 2H), 3.33 (dd, J=29.0,11.6Hz, 2H), 2.77 (d, J=5.2Hz, 1H), 2.04 (dd, J=30.0,14.7Hz, 2H), 1.85-1.12 (m, 10H) ppm；LC-MS:m/z 461.7[M+H]+.
Embodiment 29:1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -4- ethyl piperidine - 4- amine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.88 (d, J=1.5Hz, 1H), 7.58 (d, J= 1.4Hz, 1H), 7.42 (dd, J=8.0,1.3Hz, 1H), 7.12 (t, J=8.1Hz, 1H), 6.70 (dd, J=8.1,1.4Hz, 1H), 3.71-3.64 (m, 4H), 1.90-1.73 (m, 4H), 1.69 (q, J=7.3Hz, 2H), 0.93 (t, J=7.5Hz, 3H) ppm；LC-MS:m/z 422.1[M+H]+.
Embodiment 30:8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -1- methyl -8- nitrogen Miscellaneous-spiral shell [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.33 (s, 1H), 7.83 (s, 1H), 7.56 (s, 1H), 7.41 (d, J= 8.1Hz, 1H), 7.17-7.08 (m, 1H), 6.69 (d, J=8.2Hz, 1H), 4.08-3.93 (m, 2H), 3.18-3.04 (m, 2H), 3.04-2.94 (m, 1H), 2.45 (s, 1H), 1.90-1.29 (m, 8H), 0.95 (t, J=6.3Hz, 3H) ppm；LC-MS: m/z 462.1[M+H]+.
Embodiment 31: compound 1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) pyrroles The preparation of alkane -3- amine
Step 1: (1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) pyrrolidin-3-yl) T-butyl carbamate
Using the identical method of embodiment 23, B1 obtains (1- (8- ((2,3- dichlorophenyl) sulphur after being replaced by corresponding amine Generation) imidazo [1,2-c] pyrimidine -5- base) pyrrolidin-3-yl) t-butyl carbamate.
LC-MS:m/z 424.1[M+H]+.
Step 2: compound 1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) pyrrolidines - 3- amine
Use the identical method of 21 step 3 of embodiment, (1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] Pyrimidine -5- base) pyrrolidin-3-yl) t-butyl carbamate take off Boc protecting group after obtain compound 1- (8- ((2,3- dichloro-benzenes Base) thio) imidazo [1,2-c] pyrimidine -5- base) pyrrolidines -3- amine.
1H NMR (400MHz, DMSO-d6) δ 8.18 (s, 1H), 7.93 (d, J=1.1Hz, 1H), 7.46 (s, 1H), 7.40 (d, J=8.0Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 6.63 (d, J=8.1Hz, 1H), 4.14 (d, J=9.3Hz, 1H), 4.05 (d, J=5.9Hz, 1H), 3.82 (d, J=11.2Hz, 3H), 2.24 (d, J=7.3Hz, 1H), 2.02 (s, 1H) ppm； LC-MS:m/z379.9[M+H]+.
Using the synthetic method of embodiment 31, following compound can be synthesized:
Embodiment 32:1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) piperidines -4- amine
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.03(s,1H),7.86(s,1H),7.57(s,1H), 7.42 (d, J=7.6Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (d, J=8.1Hz, 1H), 4.00 (d, J=13.0Hz, 2H), 3.13 (d, J=11.5Hz, 2H), 2.02-1.86 (m, 3H), 1.62 (dd, J=21.0,9.8Hz, 2H), 1.23 (s, 1H)；LC-MS:m/z394.7[M+H]+.
Embodiment 33:(1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) pyrrolidines -3- Base) methylamine
1H NMR (400MHz, DMSO-d6) δ 8.17 (d, J=1.6Hz, 1H), 7.91 (s, 1H), 7.45 (d, J= 1.5Hz, 1H), 7.39 (d, J=7.7Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.63 (d, J=8.1Hz, 1H), 4.04 (ddd, J=11.5,8.9,5.5Hz, 2H), 3.94-3.86 (m, 1H), 3.72 (dd, J=10.8,7.6Hz, 2H), 2.93 (d, J =7.2Hz, 2H), 2.16 (dq, J=11.9,6.2Hz, 1H), 1.79 (dq, J=12.3,8.3Hz, 1H) ppm；LC-MS:m/z 394.1[M+H]+.
Embodiment 34:(1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -4- methyl piperazine Pyridine -4- base) methylamine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.83 (d, J=1.5Hz, 1H), 7.57 (d, J= 1.4Hz, 1H), 7.42 (dd, J=8.0,1.3Hz, 1H), 7.12 (t, J=8.1Hz, 1H), 6.69 (dd, J=8.1,1.3Hz, 1H), 3.68 (dt, J=13.7,4.6Hz, 2H), 3.44 (td, J=9.6,4.8Hz, 2H), 2.76 (s, 2H), 1.70 (ddd, J =13.3,9.2,3.7Hz, 2H), 1.62-1.49 (m, 2H), 1.08 (s, 3H) ppm；LC-MS:m/z 422.1[M+H]+.
Embodiment 35:(1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) piperidin-4-yl) Methylamine
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.03(s,1H),7.83(s,1H),7.57(s,1H), 7.42 (d, J=7.7Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (d, J=8.0Hz, 1H), 4.05 (d, J=13.2Hz, 2H), 3.07 (t, J=12.3Hz, 2H), 2.75 (d, J=5.9Hz, 2H), 1.88 (d, J=11.8Hz, 3H), 1.53-1.35 (m,2H)ppm；LC-MS:m/z 409.8[M+H]+.
Embodiment 36:2- (1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) piperidines -4- Base) second -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.85 (d, J=1.2Hz, 1H), 7.56 (d, J= 1.2Hz, 1H), 7.41 (dd, J=8.0,1.2Hz, 1H), 7.12 (t, J=8.1Hz, 1H), 6.69 (dd, J=8.1,1.2Hz, 1H), 4.02 (d, J=12.9Hz, 2H), 3.03 (t, J=12.0Hz, 2H), 2.87-2.78 (m, 2H), 1.82 (d, J= 12.5Hz, 2H), 1.70 (s, 1H), 1.55 (dd, J=14.7,6.9Hz, 2H), 1.40 (dd, J=21.6,11.5Hz, 2H) ppm；LC-MS:m/z 422.7[M+H]+.
Embodiment 37: compound (S) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) - The synthesis of 2- oxa- -8- azaspiro [4.5] decane -4- amine
Step 1: (R)-N- ((S) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -2- Oxa- -8- azaspiro [4.5] decane -4- base) -2- methylpropane -2- sulfenamide
Using the identical method of embodiment 23, B1 obtains (R)-N- ((S) -8- (8- ((2,3- bis- after being replaced by corresponding amine Chlorphenyl) thio) imidazo [1,2-c] pyrimidine -5- base) -2- oxa- -8- azaspiro [4.5] decane -4- base) -2- methyl-prop Alkane -2- sulfenamide.
LC-MS:m/z 554.1[M+H]+.
Step 2: (S) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -2- oxa- -8- Azaspiro [4.5] decane -4- amine
(R)-N- ((S) -8- (8- ((2,3- dichlorophenyl) sulphur is sequentially added in single-necked flask under from nitrogen guarantor to 50mL Generation) imidazo [1,2-c] pyrimidine -5- base) -2- oxa- -8- azaspiro [4.5] decane -4- base) -2- methylpropane -2- sulfenyl Hydrochloric acid Isosorbide-5-Nitrae-dioxane solution (0.05mL, 4M) is added dropwise in amine (70mg, 0.13mmol) and methanol (0.5mL) at room temperature, should Reaction 1 hour is stirred at room temperature in mixture.After completion of the reaction, it is cooled to room temperature, filters and in the residual being concentrated under reduced pressure to give Object purifies to obtain (S) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine-by high performance liquid preparative chromatography 5- yl) -2- oxa- -8- azaspiro [4.5] decane -4- amine (10mg, yield: 17%).
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.83 (d, J=1.5Hz, 1H), 7.57 (d, J= 1.4Hz, 1H), 7.42 (dd, J=8.0,1.4Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (dd, J=8.1,1.4Hz, 1H), 4.00 (dd, J=8.8,6.4Hz, 1H), 3.87-3.71 (m, 2H), 3.66 (d, J=8.5Hz, 1H), 3.29-3.27 (m, 1H), 3.17 (t, J=5.8Hz, 2H), 1.92-1.76 (m, 2H), 1.57 (dd, J=12.5,5.8Hz, 2H), 1.24 (d, J= 3.2Hz,1H)ppm；LC-MS:m/z 450.1[M+H]+.
According to the synthetic method of embodiment 37, following compound can be synthesized:
Embodiment 38:(R) -1- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) azepine cycloheptyl Alkane -4- amine
1H NMR (400MHz, DMSO-d6) δ 8.39 (s, 1H), 7.95 (s, 2H), 7.48 (s, 1H), 7.40 (d, J= 7.9Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.66 (d, J=8.0Hz, 1H), 4.03-3.89 (m, 2H), 3.81-3.61 (m, 2H), 3.20 (s, 1H), 2.15 (s, 1H), 1.95 (d, J=14.1Hz, 4H), 1.56 (d, J=10.7Hz, 1H) ppm；LC- MS:m/z 409.8[M+H]+.
Embodiment 39:(R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -3,3- two Methyl-1-oxa--8- azaspiro [4.5] decane-4- amine
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.03(s,1H),7.84(s,1H),7.56(s,1H), 7.41 (d, J=7.9Hz, 1H), 7.12 (t, J=8.1Hz, 1H), 6.70 (d, J=8.1Hz, 1H), 3.94 (t, J=13.7Hz, 2H), 3.54 (d, J=8.7Hz, 1H), 3.45 (d, J=8.7Hz, 1H), 3.32 (d, J=12.2Hz, 2H), 2.68 (s, 1H), 1.98-1.88(m,2H),1.65(s,2H),1.02(s,3H),0.95(s,3H)；LC-MS:m/z 479.7[M+H]+.
Embodiment 40:(S) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -3,3- two Methyl-1-oxa--8- azaspiro [4.5] decane-4- amine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.84 (s, 1H), 7.56 (s, 1H), 7.41 (d, J= 7.9Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (d, J=8.1Hz, 1H), 3.94 (t, J=14.1Hz, 2H), 3.54 (d, J=8.7Hz, 1H), 3.45 (d, J=8.7Hz, 1H), 3.35-3.25 (m, 2H), 2.69 (s, 1H), 1.98-1.85 (m, 2H),1.71-1.59(m,2H),1.03(s,3H),0.95(s,3H)；LC-MS:m/z 479.7[M+H]+.
Embodiment 41:(1R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -2- first Base -8- aza-spiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.81 (dd, J=7.4,1.6Hz, 1H), 7.56 (d, J= 1.6Hz, 1H), 7.41 (dd, J=8.0,1.4Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.68 (dd, J=8.1,1.4Hz, 1H), 3.95 (d, J=11.9Hz, 2H), 3.12 (t, J=12.0Hz, 2H), 2.89 (d, J=5.8Hz, 1H), 2.08-1.44 (m, 9H), 1.00 (dd, J=31.0,6.6Hz, 3H) ppm；LC-MS:m/z 462.1[M+H]+.
Embodiment 42:(1R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -3- first Base -8- aza-spiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.41 (d, J= 8.0Hz, 1H), 7.12 (t, J=8.1Hz, 1H), 6.69 (d, J=8.1Hz, 1H), 3.99-3.80 (m, 2H), 3.24-2.98 (m,3H),2.27-1.14(m,9H),1.04-0.95(m,3H)ppm；LC-MS:m/z 462.1[M+H]+.
Embodiment 43:(4R) -4- amino -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -2- alcohol
1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),8.04(s,1H),7.81(s,1H),7.57(s,1H), 7.42 (d, J=7.9Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.68 (d, J=8.0Hz, 1H), 4.15 (d, J=6.5Hz, 1H), 3.91 (d, J=14.3Hz, 2H), 3.22 (s, 2H), 2.93 (t, J=7.3Hz, 1H), 2.27-2.20 (m, 1H), 1.89- 1.66 (m, 5H), 1.54 (dt, J=13.4,6.7Hz, 1H), 1.35 (d, J=12.9Hz, 1H) ppm；LC-MS:m/z 465.7 [M+H]+.
Embodiment 44:(3S, 4S) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -3- Methyl -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.84 (s, 1H), 7.56 (s, 1H), 7.41 (d, J= 7.9Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (d, J=8.0Hz, 1H), 4.15-4.06 (m, 1H), 3.73 (s, 2H), 3.56 (d, J=8.5Hz, 1H), 3.42-3.27 (m, 3H), 3.05 (d, J=4.8Hz, 1H), 1.91 (dt, J=39.6, 9.8Hz, 2H), 1.67 (dd, J=25.7,13.7Hz, 2H), 1.12 (d, J=6.4Hz, 3H) ppm；LC-MS:m/z 463.7[M +H]+.
Embodiment 45:(R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -1- oxa- - 8- aza-spiro [4.5] decane -4- amine
1H NMR (400MHz, DMSO-d6) δ 7.95 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.20 (d, J= 6.4Hz, 1H), 6.95 (t, J=6.4Hz, 1H), 6.70 (d, J=6.4Hz, 1H), 4.00-3.85 (m, 4H), 3.46 (t, J= 8.8Hz, 2H), 3.20 (t, J=5.2Hz, 1H), 2.39-2.35 (m, 1H), 1.94-1.89 (m, 2H), 1.80-1.74 (m, 2H),1.68-1.65(m,1H)ppm；LCMS:m/z 450.1[M+H]+.
Embodiment 46: compound (R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) - The synthesis of N- methyl -8- aza-spiro [4.5] decane -1- amine
Step 1: (R)-N- ((R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- Azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide
Using the identical method of embodiment 23, (R)-N- ((R) -8- (8- ((2,3- dichloro-benzenes are obtained after B1 and amine substitution Base) thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide (70mg, yield: 80%)
LC-MS:m/z 552.1[M+H]+.
Step 2: (R)-N- ((R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- Azaspiro [4.5] decane -1- base)-N, 2- dimethylpropane -2- sulfenamide
Into dry 50mL round-bottomed flask, (R)-N- ((R) -8- (8- ((2,3- dichlorophenyl) is thio) miaow is sequentially added Azoles simultaneously [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide (70mg, 0.13mmol) and DMF (5mL).Then at 0 DEG C, it is slowly added to NaH (10.4mg, 0.26mmol), mixed liquor is at this temperature Then stirring 10 minutes is kept for 0 DEG C and is slowly added to CH3I (28mg, 0.20mmol) is then stirred at room temperature 2 hours.Reaction After, water (10mL) quenching reaction is added, is then extracted with ethyl acetate (3x 10mL), by combined organic phase MgSO4 It dries, filters and is purified by silica gel chromatography (ethyl acetate/stone of 0 to 80% gradient in the residue being concentrated under reduced pressure to give Oily ether), obtain faint yellow solid (R)-N- ((R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1-
Base)-N, 2- dimethylpropane -2- sulfenamide (50mg, yield: 49%)
LC-MS:m/z 566.1[M+H]+.
Step 3: (R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base)-N- methyl -8- Aza-spiro [4.5] decane -1- amine
Use the identical method of 37 step 2 of embodiment, (R)-N- ((R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazoles And [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base)-N, the sub- sulphur of 2- dimethylpropane -2- sulfenamide removing Acyl group obtains (R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base)-N- methyl -8- aza-spiro [4.5] decane -1- amine.
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.03(s,1H),7.82(s,1H),7.55(s,1H), 7.41 (d, J=8.0Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (d, J=8.1Hz, 1H), 3.87 (d, J=13.2Hz, 2H), 3.22 (dd, J=22.1,10.8Hz, 2H), 2.56 (t, J=7.3Hz, 1H), 2.35 (s, 3H), 1.89 (ddd, J= 33.1,16.7,7.8Hz,4H),1.72-1.33(m,6H)ppm；LC-MS:m/z 461.7[M+H]+.
Embodiment 47:(R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
Step 1: (R)-N- ((R) -8- (8- iodine imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- Base) -2- methylpropane -2- sulfonamide
Sequentially added into dry 50mL single-necked flask chloro- 8- iodine imidazo [1,2-c] the pyrimidine E1 of 5- (50mg, 0.18mmol), (R) -2- methyl-N- ((R) -8- azaspiro [4.5] decane -1- base) propane -2- sulfenamide (C-1A) (93mg, 0.36mmol), DIEA (46mg, 0.36mmol) and NMP (5mL), are then stirred to react at 90 DEG C 2 hours.Reaction After, the residue of acquisition is poured into water (10mL), is stirred 5 minutes at room temperature.Then extracted with ethyl acetate (3x 20mL) It takes, by combined organic phase MgSO4It dries, filters and is purified by silica gel chromatography (0 in the residue being concentrated under reduced pressure to give To the ethyl acetate/petroleum ether of 80% gradient), obtaining faint yellow solid (R)-N-, ((8- iodine imidazo [1,2-c] is phonetic by (R) -8- Pyridine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfonamide (80mg, yield: 88%)
1H NMR (400MHz, DMSO-d6) δ 8.02 (s, 1H), 7.79 (d, J=1.4Hz, 1H), 7.64 (d, J= 1.4Hz, 1H), 4.97 (d, J=8.0Hz, 1H), 3.77-3.65 (m, 2H), 3.23-3.13 (m, 1H), 3.04 (dd, J= 30.0,11.5Hz,2H),2.03-1.78(m,4H),1.67-1.31(m,6H),1.13(s,9H)ppm；LC-MS:m/z 502.1 [M+H]+.
Step 2: (R)-N- ((R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- Azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide
(R)-N- ((R) -8- (8- iodine imidazo [1,2-c] pyrimidine-is sequentially added in dry 50mL three-necked flask bottle 5- yl) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfonamide (80mg, 0.16mmol), cuprous iodide (3mg, 0.016mmol), 1,10- phenanthroline (6mg, 0.032mmol), 2,3- thiophenol dichlorobenzene (34mg, 0.192mmol), phosphorus The dioxane solution of sour potassium (68mg, 0.32mmol) and 10mL.The mixture heats reaction 3 hours under the protection of nitrogen. After reaction, saturation NH is added4Cl solution (50mL).It is extracted with ethyl acetate (3x 20mL).Combined organic phase is used Na2SO4It dries, filters, obtained residue is purified by silica gel chromatography the (first of 0 to 10% gradient by filtrate decompression concentration Alcohol/ethyl acetate), obtain faint yellow solid (R)-N- ((R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] Pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide (60mg, yield: 68%).
1H NMR (400MHz, DMSO-d6) δ 8.02 (s, 1H), 7.76 (d, J=1.4Hz, 1H), 7.56 (d, J= 1.4Hz, 1H), 7.40 (dd, J=8.0,1.3Hz, 1H), 7.11 (t, J=8.0Hz, 1H), 6.68 (dd, J=8.1,1.3Hz, 1H), 5.00 (d, J=8.1Hz, 1H), 3.94 (dd, J=12.8,3.4Hz, 2H), 3.26-3.14 (m, 3H), 2.08-1.84 (m,4H),1.69-1.36(m,6H),1.14-1.11(m,9H)ppm；LC-MS:m/z 552.1[M+H]+.
Step 3: (R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
(R)-N- ((R) -8- (8- ((2,3- dichlorophenyl) is thio) miaow is sequentially added in dry 50mL round-bottomed flask Azoles simultaneously [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide (embodiment 17- 2) Isosorbide-5-Nitrae-dioxane solution (7M, 5mL) of (60mg, 0.11mmol) and hydrochloric acid reacts at room temperature 1 hour.Reaction solution decompression is steamed It evaporates, gained crude product is purified to obtain product (R) -8- (8- ((2,3- dichlorophenyl) is thio) imidazoles with reversed-phase high performance liquid chromatography And [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine (25mg, yield: 51%).
1H NMR(400MHz,CD3OD-d4)δ8.54(s,2H),8.04(s,1H),7.81(s,1H),7.58(s,1H), 7.33 (dd, J=8.0,1.3Hz, 1H), 7.05 (t, J=8.0Hz, 1H), 6.68 (dd, J=8.1,1.3Hz, 1H), 4.03 (t, J=14.7Hz, 2H), 3.38 (s, 2H), 2.27 (d, J=5.4Hz, 1H), 1.97-1.63 (m, 9H) ppm；LC-MS:m/z 448.1[M+H]+.
According to the synthetic method of embodiment 47, following compound can be synthesized:
Embodiment 48:(R) -7- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -7- azepine - Spiral shell [3.5] nonane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.34 (s, 1H), 8.02 (s, 1H), 7.82 (d, J=1.6Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=7.8Hz, 1H), 7.12 (t, J=8.1Hz, 1H), 6.69 (d, J=7.9Hz, 1H), 3.91 (d, J= 13.2Hz, 1H), 3.84-3.73 (m, 1H), 3.18-3.08 (m, 3H), 2.13 (q, J=8.0Hz, 1H), 1.83 (td, J= 10.7,8.5,4.2Hz,2H),1.80-1.69(m,3H)ppm；LC-MS:m/z 434.1[M+H]+.
Embodiment 49:7- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -7- aza-spiro [3.5] nonane -2- amine
1H NMR (400MHz, DMSO-d6) δ 8.01 (s, 1H), 7.83 (d, J=1.6Hz, 1H), 7.56 (d, J= 1.5Hz, 1H), 7.41 (dd, J=8.0,1.4Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.69 (dd, J=8.1,1.4Hz, 1H), 3.50 (d, J=10.2Hz, 2H), 3.41 (s, 2H), 2.71-2.64 (m, 1H), 2.36-2.30 (m, 1H), 2.21 (s, 2H), 1.81 (d, J=26.6Hz, 5H) ppm；LC-MS:m/z 434.1[M+H]+.
Embodiment 50:(7R) -2- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -2- nitrogen Miscellaneous-spiral shell [4.4] nonane -7- base amine
1H NMR(400MHz,DMSO-d6) δ 8.36 (brs, 1H), 8.18 (s, 1H), 7.89 (d, J=2.4Hz, 1H), 7.43 (s, 1H), 7.38 (d, J=6.0Hz, 1H), 7.11 (t, J=6.4Hz, 1H), 6.64 (d, J=6.0Hz, 1H), 3.96- 3.74(m,4H),3.53-3.51(m,1H),2.00-1.60(m,8H)ppm；LCMS:m/z 434.2[M+H]+.
Embodiment 51:(R) (8- ((6- amino -3- chloro-2-methyl-pyridin-4-yl) is thio) imidazo [1,2-c] is phonetic by -8- Pyridine -5- base) -3,3- dimethyl 1- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.17(s,2H),8.08(s,1H),7.90(s,1H),7.65(s,1H), 5.67 (s, 1H), 4.09-3.93 (m, 2H), 3.61 (dd, J=14.2,9.1Hz, 4H), 3.10 (d, J=5.4Hz, 1H), 2.35 (d, J=15.8Hz, 3H), 2.03-1.71 (m, 4H), 1.16 (s, 3H), 1.07 (s, 3H) ppm；LCMS:m/z 474.1[M+H ]+.
Embodiment 52:(S) -8- (8- ((2,3- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
1H NMR(DMSO-d6)δ8.43(s,1H),8.02(s,1H),7.79-7.80(d,1H),7.56-7.57(d, 1H),7.40-7.42(d,1H),7.11-7.15(t,1H),6.68-6.71(d,1H),3.88(t,2H),3.24(t,2H), 3.01(t,1H),1.60-1.90(m,5H),1.30-1.59(m,5H)ppm；LC-MS:m/z 448.1[M+H]+.
Embodiment 53:(R) -8- (8- ((2- chlorphenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 7.97 (s, 1H), 7.80 (d, J=1.5Hz, 1H), 7.57 (d, J= 1.4Hz, 1H), 7.49 (dd, J=7.7,1.6Hz, 1H), 7.15 (dtd, J=19.6,7.4,1.6Hz, 2H), 6.76 (dd, J= 7.7,1.7Hz, 1H), 3.93-3.80 (m, 2H), 3.21 (td, J=11.2,2.7Hz, 2H), 3.00 (s, 1H), 2.05-1.75 (m,4H),1.75-1.35(m,6H)ppm；LCMS:m/z 414.1[M+H]+.
Embodiment 54:(R) -8- (8- ((3- chlorphenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR(CD3OD-d4)δ7.96(s,1H),7.78(s,1H),7.58(s,1H),7.23-7.27(m,3H), 7.14-7.16(m,1H),3.83(m,2H),3.24(m,2H),2.89(m,1H),1.77-1.83(m,4H),1.51-1.62(m, 2H),1.354-1.46(m,4H)ppm；LCMS:m/z 414.1[M+H]+.
Embodiment 55:(R) -8- (8- ((4- chlorphenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 7.91 (s, 1H), 7.79-7.75 (m, 1H), 7.58 (d, J=1.2Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 7.23 (d, J=8.5Hz, 2H), 3.91-3.71 (m, 2H), 3.18 (t, J=12.3Hz, 2H),3.00(s,1H),2.05-1.66(m,5H),1.64-1.34(m,5H)ppm；LCMS:m/z 414.1[M+H]+.
Embodiment 56:(R) -8- (8- ((2,6- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.66(s,1H),7.64(s,1H),7.60(s,1H), 7.51 (t, J=8.1Hz, 1H), 7.09 (s, 1H), 3.64 (s, 2H), 3.04 (q, J=12.4Hz, 2H), 2.74 (t, J= 7.2Hz,1H),1.89-1.74(m,4H),1.52(s,2H),1.42-1.24(m,4H)ppm；LCMS:m/z 450.0[M+H]+.
Embodiment 57:(R) -8- (8- ((2,4 dichloro benzene base) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.00 (s, 1H), 7.81 (d, J=1.6Hz, 1H), 7.69 (d, J= 2.3Hz, 1H), 7.56 (d, J=1.4Hz, 1H), 7.20 (dd, J=8.6,2.3Hz, 1H), 6.75 (d, J=8.6Hz, 1H), 3.94-3.79 (m, 2H), 3.20 (q, J=11.9Hz, 2H), 2.77 (t, J=7.3Hz, 1H), 1.90-1.77 (m, 4H), 1.67-1.52 (m, 2H), 1.37 (td, J=27.0,26.1,12.9Hz, 4H) ppm；LCMS:m/z 450.0[M+H]+.
Embodiment 58:(R) -8- (8- ((2,5- dichlorophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
1H NMR(CD3OD-d4)δ8.02(s,1H),7.82(s,1H),7.52-7.58(m,2H),7.22-7.25(m, 1H),6.71(s,1H),3.88-3.89(m,2H),3.22-3.24(m,2H),2.81-2.83(m,1H),1.77-1.83(m, 4H),1.51-1.62(m,2H),1.354-1.46(m,4H)ppm；LCMS:m/z 450.0[M+H]+.
Embodiment 59:(R) -8- (8- ((2- isopropyl phenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 7.76 (s, 1H), 7.58 (s, 2H), 7.37 (d, J=7.7Hz, 1H), 7.24 (s, 1H), 7.06 (d, J=6.1Hz, 2H), 3.73 (s, 2H), 3.52 (s, 1H), 3.11 (d, J=12.8Hz, 2H), 2.76 (s, 1H), 1.83 (d, J=31.7Hz, 4H), 1.58 (d, J=42.0Hz, 2H), 1.36 (s, 4H), 1.24 (d, J=7.0Hz, 6H) ppm；LCMS:m/z 423.2[M+H]+.
Embodiment 60:(R) -8- (8- ((2- methoxyphenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.19 (t, J= 7.9Hz, 1H), 7.05 (d, J=8.2Hz, 1H), 6.82-6.69 (m, 2H), 3.87 (s, 3H), 3.77 (d, J=12.4Hz, 2H),3.17(s,2H),2.97(s,2H),1.97(s,1H),1.77-1.30(m,9H)ppm；LCMS:m/z 410.1[M+H]+.
Embodiment 61:(R) ((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] is phonetic by-methyl 2- Pyridine -8- base) thio) benzoic ether
1H NMR (400MHz, DMSO-d6) δ 8.38 (s, 1H), 7.95 (dd, J=7.8,1.6Hz, 1H), 7.78 (d, J= 1.5Hz, 1H), 7.53 (d, J=1.4Hz, 1H), 7.30 (td, J=7.7,1.6Hz, 1H), 7.21 (t, J=7.5Hz, 1H), 6.77 (d, J=8.1Hz, 1H), 3.91 (s, 3H), 3.85 (d, J=13.4Hz, 2H), 3.23 (d, J=12.8Hz, 2H), 2.97 (t, J=7.0Hz, 1H), 1.97 (d, J=7.0Hz, 2H), 1.82-1.40 (m, 8H) ppm；LC-MS:m/z 438.1[M+H]+.
Embodiment 62:(R) -8- (8- ((4- aminophenyl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 7.71 (s, 1H), 7.61 (s, 1H), 7.24 (d, J=7.5Hz, 2H), 7.13 (s, 1H), 6.58 (d, J=7.5Hz, 2H), 5.48 (s, 2H), 3.60 (s, 2H), 3.17 (s, 2H), 3.04-3.01 (m, 1H), 1.40(s,10H)ppm；LC-MS:m/z 396.2[M+H]+.
Embodiment 63:(R) -8- (8- ((3- amino -2- chlorphenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- nitrogen Miscellaneous spiral shell [4.5] decane -1- amine
1H NMR(400MHz,DMSO-d6)δ8.31(s,2H),7.85(s,1H),7.78(s,1H),7.58(s,1H), 6.80 (t, J=7.9Hz, 1H), 6.59 (d, J=8.0Hz, 1H), 5.94 (d, J=7.8Hz, 1H), 5.50 (s, 2H), 3.84 (t, J=13.1Hz, 2H), 3.17 (s, 2H), 3.04 (s, 1H), 2.00 (q, J=7.2Hz, 2H), 1.83-1.37 (m, 10H) ppm；LC-MS:m/z429.1[M+H]+.
Embodiment 64:(R) -8- (8- ((3- (trifluoromethyl) phenyl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- Azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.31 (s, 2H), 8.00 (s, 1H), 7.79 (d, J=1.6Hz, 1H), 7.59-7.52 (m, 1H), 7.47 (dd, J=16.9,9.2Hz, 5H), 3.84 (t, J=13.0Hz, 2H), 3.22 (d, J= 13.1Hz, 2H), 2.98 (s, 1H), 1.79 (d, J=13.8Hz, 5H), 1.60-1.36 (m, 5H) ppm；LC-MS:m/z 448.1 [M+H]+.
Embodiment 65:(R) (((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] is phonetic by 4- by-N- Pyridine -8- base) sulfenyl) phenyl) acetamide
1H NMR (400MHz, DMSO-d6) δ 10.04 (d, J=5.3Hz, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.61 (d, J=13.9Hz, 2H), 7.54 (d, J=8.5Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 3.73 (t, J= 12.0Hz, 2H), 3.12 (s, 2H), 2.97 (s, 1H), 2.02 (s, 3H), 1.96 (s, 1H), 1.74 (dt, J=53.1, 26.6Hz, 5H), 1.50 (d, J=35.3Hz, 4H) ppm；LC-MS:m/z 396.2[M+H]+.
Embodiment 66:(R) -5- ((5- (1- amino -8- aza-spiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine - 8- yl) sulfenyl) -1,3,4- thiadiazoles -2- amine
1H NMR (400MHz, DMSO-d6) δ 8.33 (s, 1H), 7.96 (s, 1H), 7.81 (d, J=1.5Hz, 1H), 7.66 (d, J=1.4Hz, 1H), 7.33 (s, 2H), 3.83 (td, J=11.2,9.7,4.9Hz, 2H), 3.20 (s, 2H), 3.05 (d, J =6.9Hz, 1H), 1.99 (t, J=6.5Hz, 1H), 1.86-1.69 (m, 4H), 1.62-1.38 (m, 5H) ppm；LC-MS:m/z 403.1[M+H]+.
Embodiment 67:(R) -8- (8- ((1- methyl-1 H- imidazoles -2- base) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) - 8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 7.76 (d, J=1.5Hz, 1H), 7.60 (dd, J=6.8,1.4Hz, 1H), 7.39 (d, J=1.1Hz, 1H), 7.35 (d, J=7.0Hz, 1H), 7.00 (d, J=1.1Hz, 1H), 3.80 (d, J=2.6Hz, 3H), 3.63 (d, J=10.4Hz, 2H), 3.08 (t, J=12.2Hz, 2H), 2.73 (t, J=7.3Hz, 1H), 1.90-1.67 (m,4H),1.65-1.51(m,2H),1.50-1.29(m,4H)ppm；LC-MS:m/z 384.1[M+H]+.
Embodiment 68:(R) -8- (8- (naphthalene -1- base sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] Decane -1- amine
1H NMR(CD3OD-d4)δ8.35-8.40(m,2H),7.99-8.02(m,1H),7.89-7.91(m,1H),7.76 (m,1H),7.57-7.64(m,4H),7.43-7.47(m,2H),3.73(m,2H),3.11(m,2H),2.95(m,1H),1.71- 2.05(m,4H),1.35-1.68(m,6H)ppm；LC-MS:m/z 430.2[M+H]+.
Embodiment 69:(R) -8- (8- (thiazol-2-yl is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.35 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.69 (d, J= 3.3Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=3.3Hz, 1H), 3.89 (d, J=4.1Hz, 2H), 3.25 (t, J= 12.2Hz,2H),3.07(s,1H),2.32-2.25(m,2H),2.06-1.69(m,5H),1.65-1.40(m,5H)ppm；LC- MS:m/z 387.1[M+H]+.
Embodiment 70:(R) -8- (8- (oxazole -2- base is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR(CD3OD-d4)δ8.12(s,1H),8.04(s,1H),7.80(s,1H),7.60(s,1H),7.22(s, 1H),3.86(m,2H),3.22(m,2H),2.98(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LC- MS:m/z 371.1[M+H]+.
Embodiment 71: compound (R)-N- (3- ((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1, 2-c] pyrimidine -8- base) sulfenyl) -2- chlorphenyl) acrylamide synthesis
Step 1: N- (the chloro- 3- of 2- ((5- ((R) -1- ((R) -1,1- dimethyl ethyl is sub-) -8- azaspiro [4.5] decane - 8- yl) imidazo [1,2d] pyrimidine -8- base) sulfenyl) phenyl) acrylamide
During synthetic example 63, obtained intermediate (R)-N- ((R) -8- (8- ((3- amino -2- chlorphenyl) sulphur Base) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems cyclobutane -1- base) -2- methylpropane -2- sulfenamide For following reaction.
(R)-N- ((R) -8- (8- ((3- amino -2- chlorphenyl) is sequentially added into the round-bottomed flask of 100mL at 0 DEG C Sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems cyclobutane -1- base) -2- methylpropane -2- sulfenyl Amine (60mg, 0.11mmol), triethylamine (22mg, 0.22mmol) and methylene chloride (5mL), it is then slow to reaction solution at 0 DEG C It is added dropwise acryloyl chloride (23mg, 0.22mmol), rear reaction solution is added dropwise and reacts at room temperature 2 hours.After completion of the reaction, it is added The water quenching reaction of 10mL, is then extracted with ethyl acetate (3 × 20mL), organic phase washed with water (20mL × 1), saturated common salt Water (20mL × 1) washing.Organic phase is collected, anhydrous sodium sulfate dries, filters, filtrate decompression concentration.With chromatographic column method (petroleum Ether: ethyl acetate=1:1) obtain crude product N- (the chloro- 3- of 2- ((5- ((R) -1- ((R) -1,1- dimethyl ethyl is sub-) -8- azepine Spiral shell [4.5] decane -8- base) imidazo [1,2d] pyrimidine -8- base) sulfenyl) phenyl) acrylamide (30mg, yield: 46%).
LC-MS:m/z 587.2[M+H]+.
Step 2: (R)-N- (3- ((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine - 8- yl) sulfenyl) -2- chlorphenyl) acrylamide
According to the identical method of 37 step 2 of embodiment, (R)-N- (3- ((5- (1- amino-is obtained after removing sulfinyl 8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine -8- base) sulfenyl) -2- chlorphenyl) acrylamide.
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.99(s,1H),7.80(s,1H),7.57(s,1H), 7.49 (s, 1H), 7.10 (t, J=8.0Hz, 1H), 6.72-6.51 (m, 2H), 6.29 (d, J=16.9Hz, 1H), 5.81 (d, J =10.3Hz, 1H), 3.87 (dd, J=14.9,10.9Hz, 2H), 3.20 (s, 2H), 3.01 (t, J=6.8Hz, 1H), 2.05- 1.34(m,10H)ppm；LC-MS:m/z 482.8[M+H]+.
According to the synthetic method of embodiment 71, following compound can be synthesized:
Embodiment 72:(R) (((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] is phonetic by 3- by-N1- Pyridine -8- base) thio) -2- chlorphenyl)-N2, N2- dimethyl oxygen aldehyde amide
1H NMR(400MHz,DMSO-d6) δ 8.00 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.41 (d, J= 8.0Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 6.62 (d, J=8.2Hz, 1H), 5.49 (s, 1H), 3.86 (d, J= 12.7Hz, 2H), 3.81 (s, 3H), 3.23 (t, J=12.7Hz, 2H), 3.11 (s, 3H), 3.02 (d, J=6.8Hz, 1H), 2.05-1.75 (m, 5H), 1.54 (dd, J=41.2,13.2Hz, 5H) ppm；LC-MS:m/z 528.2[M+H]+.
Embodiment 73: compound (R)-N- (3- ((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1, 2-c] pyrimidine -8- base) sulfenyl) -2- chlorphenyl) -2- hydroxyl -4- carbonyl -4H- pyrido [1,2-a] pyrimidine -3- formamide conjunction At
Step 1: 2- hydroxyl -4- carbonyl -4H- pyrido [1,2-a] pyrimidine -3- carboxylic acid, ethyl ester
Under nitrogen protection, methane three is added into dimethylbenzene (10mL) solution of pyridine -2- amine (940mg, 10mmol) Carboxylic acid triethyl (4.64g, 20mmol).Mixture is futher stirred 4 hours at 140 DEG C, TLC monitoring reaction is anti-to raw material It should finish, reaction mixture is filtered and wash to obtain 2- hydroxyl -4- carbonyl -4H- pyrido [1,2-a] with ethyl acetate phonetic Pyridine -3- carboxylic acid, ethyl ester (1.95g, yield: 83%)
1H NMR(400MHz,DMSO-d6) δ 12.47 (s, 1H), 8.93 (dd, J=7.4,1.5Hz, 1H), 8.19 (ddd, J =8.6,7.1,1.6Hz, 1H), 7.43-7.34 (m, 2H), 4.15 (q, J=7.1Hz, 2H), 1.23 (t, J=7.1Hz, 3H) ppm；LCMS:m/z 235[M+H]+.
Step 2: N- (the chloro- 3- of 2- ((5- ((R) -1- ((R) -1,1- dimethyl ethyl is sub-) -8- azaspiro [4.5] decane - 8- yl) imidazo [1,2d] pyrimidine -8- base) sulfenyl) phenyl) -2- hydroxyl -4- carbonyl -4H- pyrido [1,2-a] pyrimidine -3- first Amide
During synthetic example 63, obtained intermediate (R)-N- ((R) -8- (8- ((3- amino -2- chlorphenyl) sulphur Base) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems cyclobutane -1- base) -2- methylpropane -2- sulfenamide For following reaction.
Under a nitrogen atmosphere, to 2- hydroxyl -4- carbonyl -4H- pyrido [1,2-a] pyrimidine -3- carboxylic acid, ethyl ester (40mg, (R)-N- ((R) -8- (8- ((3- amino -2- chlorphenyl) sulfenyl) imidazo is added in DMF (2mL) solution 0.169mmol) [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems cyclobutane -1- base) -2- methylpropane -2- sulfenamide (60mg, 0.113mmol).Mixture is reacted 1 hour under the conditions of 160 DEG C of microwave.After mixture is cooled to room temperature, by mixture mistake Filter is extracted after being diluted with water using ethyl acetate (20mL × 3), and saturated common salt water washing simultaneously mixes organic layer, through anhydrous slufuric acid Sodium is dried, filtered and concentrated, and obtains N- (the chloro- 3- of 2- ((5- ((R) -1- ((R) -1,1- dimethyl ethyl is sub-) -8- azaspiro [4.5] decane -8- base) imidazo [1,2d] pyrimidine -8- base) sulfenyl) phenyl) -2- hydroxyl -4- carbonyl -4H- pyrido [1,2- A] pyrimidine -3- formamide (20mg, yield 21.7%).
LCMS:m/z 721[M+H]+.
Step 3: (R)-N- (3- ((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine - 8- yl) sulfenyl) -2- chlorphenyl) -2- hydroxyl -4- carbonyl -4H- pyrido [1,2-a] pyrimidine -3- formamide
According to the identical method of 37 step 2 of embodiment, (R)-N- (3- ((5- (1- amino-is obtained after removing sulfinyl 8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine -8- base) sulfenyl) -2- chlorphenyl) -2- hydroxyl -4- carbonyl - 4H- pyrido [1,2-a] pyrimidine -3- formamide.
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.43(s,1H),7.94(s,1H),7.79(s,1H), 7.63 (d, J=34.6Hz, 2H), 7.03 (d, J=8.2Hz, 1H), 6.61-6.51 (m, 1H), 6.40 (d, J=8.2Hz, 1H), 6.00 (d, J=6.9Hz, 1H), 5.45 (s, 1H), 3.94-3.80 (m, 2H), 3.23 (s, 2H), 3.05 (s, 1H), 2.09- 1.34(m,10H)ppm；LC-MS:m/z 617.1[M+H]+.
Embodiment 74: compound (R)-N- (3- ((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1, 2-c] pyrimidine -8- base) sulfenyl) -2- chlorphenyl) -2- hydroxyl -4- carbonyl -6,7,8,9- tetrahydro -4H- pyrido [1,2-a] is phonetic The synthesis of pyridine -3- formamide
Step 1: 2- hydroxyl -4- carbonyl -6,7,8,9- tetrahydro -4H- pyrido [1,2-a] pyrimidine -3- Ethyl formate
2- hydroxyl -4- carbonyl -4H- pyrido [1,2-a] pyrimidine -3- carboxylic acid is sequentially added into the round-bottomed flask of 100mL Ethyl ester (obtained by 69 step 1 of embodiment) (1g, 4.12mmol), methanol (25mL) and 10%Pd/C (862mg).Mixture is existed Room temperature futher stirs 2.5 hours under conditions of hydrogen (hydrogen balloon), TLC monitoring reaction to raw material end of reaction, and reaction is mixed It closes object to filter by diatomite, vacuum concentration obtains 2- hydroxyl -4- carbonyl -6,7, and 8,9- tetrahydro -4H- pyridos [1,2-a] are phonetic Pyridine -3- Ethyl formate (700mg, yield: 69.4%).
1H NMR(400MHz,DMSO-d6) δ 12.39 (s, 1H), 4.09 (q, J=7.1Hz, 2H), 3.66 (t, J= 6.0Hz, 2H), 2.77 (t, J=6.4Hz, 2H), 1.88-1.80 (m, 2H), 1.78-1.71 (m, 2H), 1.19 (t, J= 7.1Hz,3H)ppm；LCMS:m/z[M+H]+.
(R)-N- (3- ((5- (1- amino -8- azaspiro is obtained according to 73 step 2 of embodiment and the identical method of step 3 [4.5] decane -8- base) imidazo [1,2-c] pyrimidine -8- base) sulfenyl) -2- chlorphenyl) -2- hydroxyl -4- carbonyl -6,7,8,9- Tetrahydro -4H- pyrido [1,2-a] pyrimidine -3- formamide.
1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.24(s,1H),7.96(s,1H),7.85(s,1H), 7.81-7.72 (m, 2H), 7.58 (s, 1H), 3.86 (dd, J=30.5,16.1Hz, 4H), 3.29-3.15 (m, 4H), 2.85- 2.78(m,1H),2.11-1.61(m,14H)；LC-MS:m/z 621.1[M+H]+.
Embodiment 75:(R) -8- (8- (2,3- dichlorophenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] The synthesis of decane -1- amine
Step 1: (R)-N- ((R) -8- (8- (2,3- dichlorophenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide
Sequentially add (R)-N- ((R) -8- (8- iodine imidazo [1,2-c] pyrimidine -5- at room temperature in the tube sealing of 20mL Base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfonamide (60mg, 0.12mmol), Isosorbide-5-Nitrae-dioxane (2mL), pure water (0.5mL), (2,3- dichlorophenyl) boric acid (50mg, 0.24mmol), [1,1'- bis- (diphenylphosphinos) two Luxuriant iron] palladium chloride (9mg, 0.012mmol) and potassium carbonate (50mg, 0.36mmol).Nitrogen is bubbled one minute, and tube sealing is heated to It 80 degrees Celsius, reacts 6 hours.20mL water is added into reaction solution and is extracted with ethyl acetate (50mL × 3) for end of reaction.Have Machine mutually successively uses water (20mL × 1), saturated salt solution (20mL × 1) washing.Organic phase is collected, anhydrous sodium sulfate dries, filters, Filtrate decompression concentration.Crude product (R)-N- ((R) -8- (8- (2,3- is obtained with chromatographic column method (petroleum ether: ethyl acetate=1:1) Dichlorophenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenyl Amine.(30mg, yield: 48%), being faint yellow solid.
LC-MS:m/z 520.1[M+H]+.
Step 2: (R) -8- (8- (2,3- dichlorophenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems Alkane -1- amine
According to the identical method of 37 step 2 of embodiment, (R)-N- ((R) -8- (8- (2,3- dichlorophenyl) imidazo [1, 2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) and -2- methylpropane -2- sulfenamide removing sulfinyl after To (R) -8- (8- (2,3- dichlorophenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine.
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.75(s,3H),7.60(s,1H),7.49(s,1H), 3.79(s,2H),3.21-3.12(m,2H),2.93(s,1H),1.82(s,5H),1.46(s,7H)ppm；LCMS:m/z 416.1 [M+H]+.
Embodiment 76: (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine-of compound (R) -8 5- yl) -8- azaspiro [4.5] decane -1- amine synthesis
Step 1: (R)-N- ((R) -8- (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide
Sequentially added in single-necked flask to 100mL under nitrogen guarantor crude product (R)-N- ((R) -8- (8- iodine imidazo [1, 2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfonamide (100mg, 0.20mmol), 2- Amino -3- chloropyridine -4- sodium mercaptides (43mg, 0.26mmol), Pd2(dba)3(20mg,0.02mmol)、Xantphos(23mg, 0.040mmol), DIPEA (52mg, 0.40mmol) and 1,4- dioxane solution (10mL), the mixture is under nitrogen protection 100 DEG C of heating is stirred to react 6 hours.After completion of the reaction, it is cooled to room temperature, filters and passes through in the residue being concentrated under reduced pressure to give Silica gel chromatography (ethyl acetate/methanol of 0 to 30% gradient) obtains (R)-N- ((R) -8- (8- ((2- amino -3- chlorine Pyridin-4-yl) thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- Sulfenamide (40mg, yield: 37%).
LC-MS:m/z 534.2[M+H]+.
Step 2: (R) -8 (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- Azaspiro [4.5] decane -1- amine
According to the identical method of 37 step 2 of embodiment, (R)-N- ((R) -8- (8- ((2- amino -3- chloropyridine -4- base) It is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide is de- Except obtaining (R) -8 (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- base)-after sulfinyl 8- azaspiro [4.5] decane -1- amine.
1H NMR (400MHz, DMSO-d6) δ 8.32 (d, J=6.9Hz, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.58 (d, J=1.4Hz, 1H), 7.54 (d, J=5.4Hz, 1H), 6.35 (s, 1H), 5.78 (d, J=5.4Hz, 1H), 3.89 (t, J= 12.5Hz,2H),3.29-3.17(m,3H),3.00(s,1H),1.97(s,1H),1.89-1.33(m,6H)ppm；LCMS:m/z 430.1[M+H]+.
According to the synthetic method of embodiment 76, following compound can be synthesized:
Embodiment 77:(R) -8- (8- ((3- chloropyridine -4- base) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
1H NMR(CD3OD-d4)δ8.54(s,1H),8.35(s,1H),8.15-8.16(m,1H),8.09(s,1H), 7.83-7.84(m,1H),7.57-7.58(m,1H),6.67-6.68(m,1H),3.92(m,2H),3.26(m,2H),3.00(m, 1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LCMS:m/z 415.1[M+H]+.
Embodiment 78:(R) -8- (8- ((3- (fluoroform) pyridin-4-yl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) - 8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.82 (s, 1H), 8.41 (d, J=5.5Hz, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 6.90 (d, J=5.4Hz, 1H), 3.93 (s, 2H), 3.28-3.20 (m, 2H), 2.94(s,1H),1.90-1.32(m,10H)；LCMS:m/z 449.1[M+H]+.
Embodiment 79:(3S, 4S) -8- (8- ((2- amino -5- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.62 (d, J= 1.3Hz, 1H), 5.91 (s, 2H), 5.65 (s, 1H), 4.13 (d, J=5.2Hz, 1H), 3.77 (d, J=8.5Hz, 3H), 3.60 (d, J=8.6Hz, 1H), 3.40 (s, 1H), 3.14 (s, 1H), 1.81 (dd, J=82.1,33.6Hz, 5H), 1.14 (d, J= 6.3Hz,3H)ppm；LC-MS:m/z 462.1[M+H]+.
Embodiment 80:(3S, 4S) -8- (8- ((6- amino -3- chloro-2-methyl-pyridin-4-yl) is thio) imidazo [1,2- C] pyrimidine -5- base) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.04(s,1H),7.85(s,1H),7.63(s,1H), 5.82 (s, 2H), 5.51 (s, 1H), 4.26-4.18 (m, 1H), 3.88 (t, J=13.0Hz, 3H), 3.70 (d, J=8.9Hz, 1H), 3.42 (d, J=4.3Hz, 1H), 3.27 (s, 2H), 2.31 (s, 3H), 1.99 (d, J=10.0Hz, 2H), 1.80 (d, J= 13.5Hz, 1H), 1.69 (d, J=12.8Hz, 1H), 1.23 (d, J=6.4Hz, 3H) ppm；LC-MS:m/z 459.8[M+H]+.
Embodiment 81:(R) -8- (8- ((the chloro- 2- cyclopropyl-pyrimidine -4- base of 3-) sulfenyl) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.06 (s, 1H), 7.97 (d, J=5.3Hz, 1H), 7.82 (d, J= 1.5Hz, 1H), 7.57 (d, J=1.4Hz, 1H), 6.40 (d, J=5.3Hz, 1H), 3.91 (t, J=13.1Hz, 2H), 3.25 (t, J=11.7Hz, 2H), 3.02 (t, J=6.6Hz, 1H), 2.03-1.65 (m, 5H), 1.67-1.37 (m, 5H), 1.04 (ddt, J=8.0,5.6,2.4Hz, 2H), 0.97 (dq, J=6.9,4.2,3.4Hz, 2H) ppm；LCMS:m/z 455.1[M+H ]+.
Embodiment 82:(R) -8- (8- ((3- chloro-2-methyl-pyridin-4-yl) is thio) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.35-8.29 (m, 1H), 8.07 (s, 1H), 8.02 (d, J=5.4Hz, 1H), 7.83 (s, 1H), 7.57 (d, J=1.4Hz, 1H), 6.50 (d, J=5.3Hz, 1H), 3.91 (t, J=12.9Hz, 2H), 3.26 (t, J=12.3Hz, 2H), 3.01 (s, 1H), 2.55 (s, 3H), 2.02-1.77 (m, 4H), 1.75-1.38 (m, 6H) ppm；LCMS:m/z429.1[M+H]+.
Embodiment 83:(R) -8- (8- ((2- amino -5- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine
1H NMR(CD3OD-d4)δ8.38(s,1H),8.04(s,1H),7.82-7.84(m,2H),7.61(m,1H),5.93 (s,2H),5.66(m,1H),3.87-3.93(m,2H),3.21-3.28(m,2H),2.98(m,1H),1.71-2.05(m,4H), 1.35-1.68(m,6H)ppm；LCMS:m/z 430.1[M+H]+.
Embodiment 84:(R) -8- (8- ((2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- Azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.10 (s, 1H), 8.00 (d, J=5.3Hz, 1H), 7.83 (d, J= 1.5Hz, 1H), 7.59 (d, J=1.4Hz, 1H), 6.72 (d, J=5.3Hz, 1H), 4.03-3.87 (m, 2H), 3.27 (d, J= 13.6Hz, 2H), 3.14 (t, J=6.3Hz, 1H), 2.05 (q, J=6.4Hz, 1H), 1.87-1.42 (m, 9H) ppm；LCMS:m/ z 449.1[M+H]+.
Embodiment 85:(R) -8- (8- ((2- picoline -3- base) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- nitrogen Miscellaneous spiral shell [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.25 (dd, J=4.7,1.5Hz, 1H), 7.89 (s, 1H), 7.79 (d, J= 1.4Hz, 1H), 7.56 (d, J=1.4Hz, 1H), 7.23 (dd, J=7.9,1.5Hz, 1H), 7.06 (dd, J=7.9,4.7Hz, 1H), 3.89-3.70 (m, 2H), 3.17 (dd, J=22.2,10.5Hz, 2H), 2.80 (t, J=7.2Hz, 1H), 2.60 (s, 3H),1.88-1.20(m,10H)ppm；LCMS:m/z 395.2[M+H]+.
Embodiment 86:(R) -8- (8- ((2- (trifluoromethyl) pyridin-3-yl) sulfenyl) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.52 (s, 1H), 8.35 (s, 1H), 7.75 (s, 1H), 7.21 (d, J= 8.2Hz, 2H), 6.52 (d, J=8.4Hz, 2H), 5.39 (s, 2H), 4.69 (s, 2H), 2.87 (s, 1H), 1.93-1.30 (m, 10H)ppm；LCMS:m/z 449.1[M+H]+.
Embodiment 87:(R) -8- (8- ((2- chloropyridine -3- base) sulfenyl) imidazo [1,2-c] pyrimidine -5- base) -8- azepine Spiral shell [4.5] decane -1- amine
1H NMR(CD3OD-d4)δ8.38(s,1H),8.16-8.18(m,1H),8.06(s,1H),7.81(m,2H),7.23 (m,1H),7.14-7.22(m,2H),3.88(m,2H),3.23(m,2H),2.97(m,1H),1.71-2.05(m,4H),1.35- 1.68(m,6H)ppm；LCMS:m/z 415.1[M+H]+.
Embodiment 88:(R) -8- (8- ((6- Amino-2-Chloropyridine -3- base) sulfenyl) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.33 (s, 1H), 7.74 (d, J=1.4Hz, 1H), 7.61 (d, J= 1.4Hz, 1H), 7.51 (d, J=8.5Hz, 1H), 7.40 (s, 1H), 6.73 (s, 2H), 6.38 (d, J=8.4Hz, 1H), 3.68 (d, J=12.5Hz, 3H), 3.10 (s, 2H), 2.97 (t, J=6.8Hz, 1H), 2.01-1.31 (m, 10H) ppm.LC-MS:m/z 431.1[M+H]+.
Embodiment 89:(R) -8- (8- (benzo [d] thiazole -7- base is thio) imidazo [1,2-c] pyrimidine -5- base) -8- nitrogen Miscellaneous spiral shell [4.5] decane -1- amine
1HNMR(CD3OD-d4)δ9.43(m,1H),8.35(s,3H),8.00-8.02(m,1H),7.88(s,1H),7.76 (m,1H),7.56-7.58(m,1H),7.47-7.51(m,1H),7.38-7.40(m,1H),3.80(m,2H),3.17(m,2H), 2.98(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LC-MS:m/z 437.1[M+H]+.
Embodiment 90:(R) -8- (8- (phenylsulfartyl) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems Alkane -1- amine
1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.83(s,1H),7.76(s,1H),7.59(s,1H), 7.25 (tq, J=14.0,7.4Hz, 5H), 3.84-3.70 (m, 2H), 3.16 (d, J=12.4Hz, 2H), 3.01 (t, J= 6.8Hz, 1H), 1.97 (dd, J=13.2,7.2Hz, 1H), 1.86-1.26 (m, 9H) ppm；LCMS:m/z 380.1[M+H]+.
Embodiment 91:(R) -8- (8- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-4-yl) sulfenyl) imidazo [1,2- C] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.97 (d, J=5.1Hz, 1H), 7.80 (s, 1H), 7.61-7.49 (m, 2H), 6.56-6.39 (m, 2H), 3.84 (d, J=22.6Hz, 5H), 3.22 (t, J=12.5Hz, 2H), 2.98 (t, J=6.9Hz, 1H), 2.03-1.33 (m, 10H) ppm；LC-MS:m/z 433.9[M+H]+.
Embodiment 92:(R) -8- (8- ((2,3- Dihydrobenzofuranes -5- base) sulfenyl) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine
1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.62(s,1H),7.46(s,1H),7.39(s,1H), 7.27 (d, J=8.2Hz, 1H), 6.77 (d, J=8.3Hz, 1H), 4.54 (t, J=8.7Hz, 2H), 3.69 (t, J=11.9Hz, 2H), 3.11 (dt, J=29.5,12.5Hz, 6H), 1.99 (s, 1H), 1.87-1.36 (m, 9H) ppm；LC-MS:m/z 422.1 [M+H]+.
Embodiment 93:(R) -8- (8- (quinolyl-4 is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.52 (d, J=4.8Hz, 1H), 8.26 (dd, J=8.4,1.3Hz, 1H), 8.12 (s, 1H), 8.04 (dd, J=8.5,1.2Hz, 1H), 7.89-7.79 (m, 2H), 7.73 (ddd, J=8.2,6.8, 1.3Hz, 1H), 7.56 (d, J=1.4Hz, 1H), 6.82 (d, J=4.8Hz, 1H), 3.91 (dd, J=15.3,11.3Hz, 2H), 3.37-3.16 (m, 2H), 3.05 (t, J=6.5Hz, 1H), 2.10-1.65 (m, 5H), 1.67-1.38 (m, 5H) ppm；LC-MS: m/z 431.2[M+H]+.
Embodiment 94:(1R) -8- (8- ((2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- base) - 3- methyl -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.32 (s, 1H), 8.09 (d, J=6.5Hz, 1H), 8.00 (d, J= 5.3Hz, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 6.71 (d, J=5.3Hz, 1H), 4.03-3.85 (m, 2H), 3.26-3.15 (m, 2H), 2.98 (d, J=21.9Hz, 1H), 2.14 (dd, J=25.3,11.9Hz, 2H), 1.87 (dd, J=41.5, 14.7Hz, 3H), 1.43 (dd, J=32.2,18.7Hz, 2H), 1.28 (dd, J=18.2,8.7Hz, 1H), 1.12 (d, J= 12.5Hz,1H),1.05-0.93(m,3H)ppm；LC-MS:m/z 462.8[M+H]+.
Embodiment 95:(1R) -8- (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- Base) -3- methyl -8- azaspiro [4.5] decane -1- amine
1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.02(s,1H),7.80(s,1H),7.63-7.49(m, 2H), 6.34 (s, 2H), 5.78 (d, J=5.4Hz, 1H), 3.98-3.83 (m, 2H), 3.18 (dd, J=27.6,14.3Hz, 2H),3.06-2.94(m,1H),2.23-2.07(m,2H),1.96-1.89(m,1H),1.86-1.67(m,2H),1.51-1.33 (m,2H),1.33-1.20(m,1H),1.21-1.09(m,1H),1.08-0.94(m,3H)ppm；LC-MS:m/z 443.8[M+ H]+.
Embodiment 96:(1R) -8- (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -3- methyl -8- aza-spiro [4.5] decane -1- amine
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.06(s,1H),7.84(s,1H),7.61(s,1H), 6.33 (s, 2H), 5.62 (s, 1H), 4.00-3.86 (m, 2H), 3.17 (d, J=13.0Hz, 1H), 3.07-2.95 (m, 1H), 2.25-2.07 (m, 2H), 1.94 (dd, J=12.0,8.2Hz, 2H), 1.79 (dd, J=28.2,13.0Hz, 2H), 1.45 (dd, J=33.4,19.7Hz, 2H), 1.34-1.11 (m, 2H), 1.01 (dd, J=18.3,10.3Hz, 3H)；LCMS:m/z 447.8 [M+H]+.
Embodiment 97:(S) -8- (8- ((2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- base) -2- Oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR (400MHz, DMSO-d6) δ 8.19 (s, 1H), 8.10 (s, 1H), 8.00 (d, J=5.3Hz, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 6.72 (d, J=5.3Hz, 1H), 4.02 (dd, J=8.8,6.4Hz, 1H), 3.85 (dd, J= 17.4,13.7Hz, 2H), 3.72 (dd, J=21.2,8.6Hz, 2H), 3.43 (dd, J=9.0,4.8Hz, 2H), 3.25 (dd, J =15.2,9.6Hz, 2H), 1.98-1.86 (m, 1H), 1.85-1.73 (m, 1H), 1.61 (s, 2H)；LC-MS:m/z 451.7[M +H]+.
Embodiment 98:(S) -8- (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- Base) -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.04(s,1H),7.83(s,1H),7.60(s,1H), 7.55 (d, J=5.4Hz, 1H), 6.35 (s, 2H), 5.78 (d, J=5.4Hz, 1H), 4.10 (dd, J=9.9,6.0Hz, 1H), 3.92-3.76 (m, 4H), 3.69 (dd, J=10.1,3.1Hz, 1H), 3.53 (s, 1H), 3.24 (d, J=10.8Hz, 1H), 1.99-1.83 (m, 2H), 1.73 (d, J=12.0Hz, 2H), 1.24 (d, J=6.4Hz, 1H) ppm；LC-MS:m/z 431.8[M +H]+.
Embodiment 99:(3S, 4S) -8- (8- ((2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- Base) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR (400MHz, DMSO-d6) δ 8.17 (s, 1H), 8.10 (s, 1H), 8.00 (d, J=5.3Hz, 1H), 7.87 (s, 1H), 7.57 (d, J=1.0Hz, 1H), 6.72 (d, J=5.3Hz, 1H), 4.12 (dt, J=12.1,6.1Hz, 1H), 3.85-3.67 (m, 3H), 3.57 (d, J=8.5Hz, 1H), 3.41 (dd, J=26.4,9.0Hz, 2H), 3.06 (d, J= 4.9Hz, 1H), 1.99-1.81 (m, 2H), 1.68 (dd, J=27.9,14.6Hz, 2H), 1.13 (d, J=6.4Hz, 3H) ppm； LC-MS:m/z 464.8[M+H]+.
Embodiment 100:(3S, 4S) -8- (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.02(s,1H),7.84(s,1H),7.61-7.50(m, 2H), 6.34 (s, 2H), 5.79 (d, J=5.4Hz, 1H), 4.11 (dt, J=12.3,6.3Hz, 1H), 3.73 (d, J=8.5Hz, 3H), 3.56 (d, J=8.5Hz, 1H), 3.38-3.26 (m, 2H), 3.05 (d, J=4.9Hz, 1H), 1.99-1.81 (m, 2H), 1.67 (dd, J=26.4,15.3Hz, 2H), 1.18-1.02 (m, 3H) ppm；LC-MS:m/z 445.8[M+H]+.
Embodiment 101:4- ((5- (4- amino -4- methyl piperidine -1- base) imidazo [1,2-c] pyrimidine -8- base) sulfenyl) - 3- chloropyridine -2- amine
1H NMR (400MHz, DMSO-d6) δ 8.00 (s, 1H), 7.83 (s, 1H), 7.54 (d, J=5.8Hz, 2H), 6.29 (s, 2H), 5.79 (d, J=5.4Hz, 1H), 3.60 (d, J=4.3Hz, 4H), 1.77-1.53 (m, 4H), 1.19 (s, 3H) ppm； LC-MS:m/z 390.1[M+H]+.
Embodiment 102:(R) -8- (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 7.85 (d, J=1.5Hz, 1H), 7.60 (d, J= 1.4Hz, 1H), 6.32 (s, 2H), 5.62 (s, 1H), 3.90 (dd, J=13.2,8.5Hz, 2H), 3.23 (q, J=11.9, 11.0Hz, 2H), 2.77 (t, J=7.3Hz, 1H), 1.90-1.77 (m, 4H), 1.67-1.53 (m, 2H), 1.45-1.28 (m, 4H)ppm；LCMS:m/z466.1[M+H]+.
Embodiment 103:(R) -8- (8- ((6- amino -3- chloro-2-methyl-pyridin-4-yl) is thio) imidazo [1,2-c] Pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 7.88 (s, 4H), 7.66 (d, J=11.1Hz, 1H), 5.81 (s, 1H), 3.96 (t, J=13.9Hz, 2H), 3.37-3.23 (m, 3H), 2.42 (s, 3H), 2.14-2.05 (m, 1H), 1.88-1.46 (m, 9H)；LC-MS:m/z 443.8[M+H]+.
Embodiment 104:(S) (8- ((6- amino -3- chloro-2-methyl pyridin-4-yl) is thio) imidazo [1,2-c] is phonetic by -8- Pyridine -5- base) -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR (400MHz, DMSO-d6) δ 8.17 (d, J=4.9Hz, 3H), 7.91 (s, 1H), 7.68 (s, 1H), 5.81 (s, 1H), 4.13 (dd, J=10.4,5.8Hz, 1H), 3.90 (d, J=9.0Hz, 3H), 3.80 (d, J=9.0Hz, 1H), 3.74 (dd, J=10.3,2.6Hz, 1H), 3.63 (s, 1H), 3.40 (dd, J=12.6,8.6Hz, 1H), 3.30 (dd, J=12.6, 9.4Hz, 1H), 2.42 (s, 3H), 1.95-1.81 (m, 2H), 1.75 (d, J=10.3Hz, 2H)；LC-MS:m/z 445.8[M+ H]+.
Embodiment 105:(S) -8- (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.07(s,1H),7.87(s,1H),7.63(s,1H), 6.33 (s, 2H), 5.62 (s, 1H), 4.06 (dd, J=9.6,6.2Hz, 1H), 3.93-3.74 (m, 4H), 3.56 (dd, J= 9.5,4.0Hz,1H),3.26(s,3H),1.98-1.80(m,2H),1.67(s,2H)ppm；LC-MS:m/z 466.6[M+H]+.
Embodiment 106:(3S, 4S) -8- (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] Pyrimidine -5- base) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.18(s,3H),8.08(s,1H),7.87(s,1H),7.65(s,1H), 6.35 (s, 2H), 5.64 (s, 1H), 4.31-4.16 (m, 1H), 4.03-3.83 (m, 3H), 3.71 (d, J=9.0Hz, 1H), 3.46 (s, 1H), 3.24 (d, J=11.2Hz, 2H), 2.03 (t, J=12.3Hz, 2H), 1.75 (dd, J=41.2,13.7Hz, 2H), 1.24 (d, J=6.5Hz, 3H)；LCMS:m/z 479.7[M+H]+.
Embodiment 107:(3S, 4S) -8- (8- ((3- chloro-2-methyl pyridin-4-yl) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -3- methyl -2- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR (400MHz, DMSO-d6) δ 8.06 (s, 1H), 8.01 (d, J=5.3Hz, 1H), 7.85 (d, J= 1.5Hz, 1H), 7.56 (d, J=1.4Hz, 1H), 6.50 (d, J=5.3Hz, 1H), 4.15-4.05 (m, 1H), 3.74-3.66 (m, 5H), 3.45-3.42 (m, 1H), 3.03 (d, J=4.9Hz, 1H), 2.55 (s, 3H), 2.00-1.60 (m, 4H), 1.12 (d, J=6.4Hz, 3H) ppm；LC-MS:m/z 445.2[M+H]+.
Embodiment 108:(S) -8- (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.06(s,1H),7.88(s,1H),7.61(s,1H), 6.34 (s, 2H), 5.64 (s, 1H), 3.95 (d, J=14.3Hz, 2H), 3.55 (s, 1H), 3.44 (s, 1H), 3.31 (d, J= 11.5Hz, 2H), 2.69 (s, 1H), 1.94 (d, J=12.4Hz, 2H), 1.66 (t, J=11.9Hz, 2H), 1.06-0.99 (m, 3H), 0.94 (d, J=14.9Hz, 3H)；LC-MS:m/z 493.7[M+H]+.
Embodiment 109:(S) -8- (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine - 5- yl) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.15(s,2H),7.89(s,1H),7.64(s,1H),6.33(s,1H), 5.63 (s, 1H), 4.03 (s, 2H), 3.59 (d, J=14.4Hz, 2H), 3.38 (s, 2H), 3.09 (s, 1H), 1.83 (s, 4H), 1.16(s,3H),1.07(s,3H)；LC-MS:m/z 493.7[M+H]+.
Embodiment 110:(S) -8- (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- Base) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.02(s,1H),7.84(s,1H),7.61-7.51(m, 2H), 6.33 (s, 2H), 5.80 (d, J=5.4Hz, 1H), 4.00-3.88 (m, 2H), 3.55 (d, J=8.7Hz, 1H), 3.46 (d, J=8.8Hz, 1H), 3.32-3.27 (m, 2H), 2.73 (s, 1H), 1.98-1.86 (m, 2H), 1.68 (s, 2H), 1.00 (d, J=29.6Hz, 6H)；LC-MS:m/z 459.8[M+H]+.
Embodiment 111:(R) -8- (8- ((2- amino -3- chloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- Base) -3,3- dimethyl -1- oxa- -8- azaspiro [4.5] decane -4- amine
1H NMR (400MHz, DMSO-d6) δ 8.15 (s, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 7.55 (d, J= 5.4Hz, 1H), 6.33 (s, 2H), 5.80 (d, J=5.3Hz, 1H), 4.01-3.91 (m, 2H), 3.56 (d, J=8.8Hz, 1H), 3.48 (d, J=8.9Hz, 1H), 3.32-3.26 (m, 2H), 2.80 (s, 1H), 1.97-1.88 (m, 2H), 1.70 (d, J= 12.3Hz,2H),1.06(s,3H),0.99(s,3H)；LC-MS:m/z 459.8[M+H]+.
Embodiment 112:(R) -8- (8- ((the chloro- 2- methoxypyridine -4- base of 3-) is thio) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine synthesis
Step 1: ((R) -1- ((R)-terf-butylsulfinyl) amino) -8- azaspiro [4.5] decane -8- base) imidazo - 8 base of [1,2-c] pyrimidine) sulfenyl) methyl propionate
(R)-N- ((R) -8- (8- iodine imidazo [1,2-c] is sequentially added in single-necked flask under from nitrogen guarantor to 100mL Pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfonamide (500mg, 1.0mmol), sulfydryl third Sour methyl esters (132mg, 1.1mmol), Pd2(dba)3(46mg,0.05mmol)、Xantphos(58mg,0.10mmol)、DIPEA (258mg, 2.0mmol) and Isosorbide-5-Nitrae-dioxane solution (30mL), the mixture heat 100 DEG C under nitrogen protection and are stirred to react 4 hours.After completion of the reaction, it is cooled to room temperature, filters and is purified by silica gel chromatography (0 in the residue being concentrated under reduced pressure to give To the ethyl acetate/petroleum ether of 30% gradient), obtain ((R) -1- ((R)-terf-butylsulfinyl) amino) -8- azaspiro [4.5] decane -8- base) -8 base of imidazo [1,2-c] pyrimidine) sulfenyl) methyl propionate (380mg, yield: 77%).
LCMS:m/z 494.2[M+H]+.
Step 2: ((R) -1- ((R) -1,1- dimethyl ethyl sulfonamido) -8- azaspiro [4.5] decane -8- base) Imidazo [1,2-c] pyrimidine -8- mercaptides
((R) -1- ((R)-terf-butylsulfinyl) amino) -8- nitrogen is sequentially added into dry 100mL round-bottomed flask Miscellaneous spiral shell [4.5] decane -8- base) -8 base of imidazo [1,2-c] pyrimidine) sulfenyl) methyl propionate (380mg, 0.77mmol) and tetrahydro Furans (20mL), is then slowly added dropwise the ethanol solution (21%, 3mL) of sodium ethoxide at room temperature again, which is stirred at room temperature 1 Hour.The lower concentration of decompression, obtains crude product ((R) -1- ((R) -1,1- dimethyl ethyl sulfonamido) -8- azaspiro [4.5] last of the ten Heavenly stems Alkane -8- base) imidazo [1,2-c] pyrimidine -8- mercaptides (400mg) without purifying.
LC-MS:m/z 408.2[M+H]+.
Step 3: ((8- ((the chloro- 2- methoxypyridine -4- base of 3-) is thio) imidazo [1,2-c] is phonetic by (R) -8- by (R)-N- Pyridine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfenamide)
Crude product is sequentially added in single-necked flask under from nitrogen guarantor to 100mL, and (((R) -1,1- dimethyl ethyl is sub- by (R) -1- Sulfonamido) -8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine -8- mercaptides (100mg, 0.23mmol), 3- chlorine-4-iodine -2- methoxypyridine (71mg, 0.26mmol), Pd2(dba)3(22mg,0.024mmol)、Xantphos(28mg, 0.048mmol), DIPEA (62mg, 0.48mmol) and 1,4- dioxane solution (10mL), the mixture is under nitrogen protection 100 DEG C of heating is stirred to react 4 hours.After completion of the reaction, it is cooled to room temperature, filters and passes through in the residue being concentrated under reduced pressure to give Silica gel chromatography (ethyl acetate/methanol of 0 to 30% gradient) obtains (R)-N- ((R) -8- (8- ((chloro- 2- methoxy of 3- Yl pyridines -4- base) thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane - 2- sulfenamide (51mg, yield: 40%).
LCMS:m/z 549.2[M+H]+.
Step 4: (R) -8- (8- ((the chloro- 2- methoxypyridine -4- base of 3-) is thio) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine
(R)-N- ((R) -8- (8- ((chloro- 2- methoxyl group of 3- is sequentially added in single-necked flask under from nitrogen guarantor to 100mL Pyridin-4-yl) thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- Sulfenamide (40mg, 0.09mmol) and methanol (2.3mL), at room temperature be added dropwise hydrochloric acid Isosorbide-5-Nitrae-dioxane solution (0.23mL, 4M), which is stirred at room temperature reaction 1 hour.After completion of the reaction, it is cooled to room temperature, filters and is being concentrated under reduced pressure to give Residue purify to obtain (R) -8- (8- ((the chloro- 2- methoxypyridine -4- base of 3-) is thio) miaow by high performance liquid preparative chromatography Azoles simultaneously [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine (15mg, yield: 37%).
1H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 7.83 (d, J=1.6Hz, 1H), 7.77 (d, J= 5.5Hz, 1H), 7.56 (d, J=1.5Hz, 1H), 6.28 (d, J=5.5Hz, 1H), 3.93 (s, 3H), 3.88 (d, J=9.4Hz, 2H), 3.23 (d, J=11.6Hz, 2H), 2.76 (t, J=7.2Hz, 1H), 1.80 (d, J=11.4Hz, 4H), 1.66-1.52 (m,2H),1.44-1.29(m,4H).LCMS:m/z 445.1[M+H]+.
According to the synthetic method of embodiment 112, following compound can be synthesized:
Embodiment 113:(R) -3- ((5- (1- amino -8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine - 8- yl) thio) methyl propionate
1H NMR (400MHz, DMSO-d6) δ 7.73 (d, J=2.7Hz, 2H), 7.64 (d, J=1.3Hz, 1H), 3.70 (d, J=4.0Hz, 2H), 3.56 (s, 3H), 3.26 (t, J=7.0Hz, 2H), 3.15-3.04 (m, 3H), 2.61 (t, J= 7.0Hz,2H),2.05-1.68(m,5H),1.66-1.37(m,5H)ppm；LC-MS:m/z 390.1[M+H]+.
Embodiment 114:(R) -8- (8- ((the chloro- 2- fluorine pyridin-4-yl of 3-) is thio) imidazo [1,2-c] pyrimidine -5- base) - 8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.10 (s, 1H), 7.86-7.80 (m, 2H), 7.58 (d, J=1.4Hz, 1H), 6.66 (d, J=5.4Hz, 1H), 3.95 (d, J=12.7Hz, 2H), 3.28 (s, 2H), 2.95 (s, 1H), 1.97-1.80 (m, 4H), 1.66 (d, J=32.2Hz, 2H), 1.56-1.41 (m, 4H) ppm；LCMS:m/z 434.1[M+H]+.
Embodiment 115:(R) -8- (8- ((3- chloro- 2- (dimethylamino) pyridin-4-yl) sulfenyl) imidazo [1,2-c] Pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.03 (s, 1H), 7.83 (d, J=1.6Hz, 1H), 7.79 (d, J= 5.3Hz, 1H), 7.56 (d, J=1.4Hz, 1H), 6.15 (d, J=5.3Hz, 1H), 3.98-3.79 (m, 2H), 3.23 (d, J= 11.6Hz, 3H), 2.90 (s, 6H), 2.77 (t, J=7.3Hz, 1H), 1.83-1.74 (m, 7H), 1.69-1.51 (m, 3H), 1.49-1.27(m,5H)ppm；LCMS:m/z 458.2[M+H]+.
Embodiment 116:(R) ((5- (1- amino -8- aza-spiro [4.5] decane -8- base) imidazo [1,2-c] is phonetic by -4- Pyridine -8- base) sulfenyl) indoline -2,3- diketone
1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),8.02(s,1H),7.81(s,1H),7.58(s,1H), 7.24 (t, J=8.0Hz, 1H), 6.58 (d, J=7.7Hz, 2H), 6.21 (d, J=8.3Hz, 1H), 3.90 (s, 3H), 3.24 (s, 3H), 2.97 (s, 1H), 1.69 (d, J=93.3Hz, 9H) ppm；LC-MS:m/z 449.1[M+H]+.
Embodiment 117: compound (R) -8- (8- ((3- chlorine pyridazine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- Base) -8- azaspiro [4.5] decane -1- amine synthesis
Step 1: (R)-N- ((R) -8- (8- ((3- chlorine pyridazine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- base) - 8- azaspiro [4.5] last of the ten Heavenly stems cyclobutane -1- base) -2- methylpropane -2- sulfenamide
Crude product is sequentially added in single-necked flask under from nitrogen guarantor to 100mL, and (((R) -1,1- dimethyl ethyl is sub- by (R) -1- Sulfonamido) -8- azaspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine -8- mercaptides (50mg, 0.12mmol), 3, Then DIPEA (31mg, 0.24mmol) is added in 4- dichloro-pyridazine (19mg, 0.13mmol) and acetonitrile (3mL), and reaction solution is 80 Heating stirring 16 hours at DEG C.After reaction solution is cooling, the residue that decompression contracting obtains is purified by silica gel chromatography (0 to 30% The ethyl acetate/methanol of gradient), obtaining (R)-N-, ((8- ((3- chlorine pyridazine -4- base) is thio) imidazo [1,2-c] is phonetic by (R) -8- Pyridine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems cyclobutane -1- base) -2- methylpropane -2- sulfenamide (10mg, yield: 16%).
LCMS:m/z 520.2[M+H]+.
Step 2: (R) -8- (8- ((3- chlorine pyridazine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
(R)-N- ((R) -8- (8- ((3- chlorine pyridazine -4- base) is sequentially added in single-necked flask under from nitrogen guarantor to 50mL It is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems cyclobutane -1- base) -2- methylpropane -2- sulfenyl Hydrochloric acid Isosorbide-5-Nitrae-dioxane solution (0.05mL, 4M) is added dropwise in amine (10mg, 0.02mmol) and methanol (0.5mL) at room temperature, should Reaction 1 hour is stirred at room temperature in mixture.After completion of the reaction, it is cooled to room temperature, filters and in the residual being concentrated under reduced pressure to give Object purifies to obtain (R) -8- that (8- ((3- chlorine pyridazine -4- base) is thio) imidazo [1,2-c] is phonetic by high performance liquid preparative chromatography Pyridine -5- base) -8- azaspiro [4.5] decane -1- amine (2mg, yield: 24%).
1H NMR (400MHz, DMSO-d6) δ 8.79 (d, J=5.4Hz, 1H), 8.36 (s, 2H), 8.12 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.01 (d, J=5.4Hz, 1H), 3.88 (d, J=9.4Hz, 2H), 3.23 (d, J=11.6Hz, 2H), 2.76 (t, J=7.2Hz, 1H), 1.70-1.32 (m, 9H)；LCMS:m/z 416.1[M+H]+.
According to the synthetic method of embodiment 117, following compound can be synthesized:
Embodiment 118:(R) -8- (8- ((2- chlorine pyrimidine-4-yl) is thio) imidazo [1,2-c] pyrimidine -5- base) -8- nitrogen Miscellaneous spiral shell [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.37 (d, J=5.5Hz, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.61 (d, J=1.2Hz, 1H), 7.06 (d, J=5.5Hz, 1H), 3.93 (t, J=12.9Hz, 2H), 3.25 (s, 2H), 3.09 (s, 1H), 2.03 (s, 1H), 1.81 (dd, J=19.3,13.3Hz, 4H), 1.65-1.46 (m, 5H) ppm；LCMS: m/z 416.1[M+H]+.
Embodiment 119: compound (R) -8- (8- (pyridine -2- base is thio) imidazo [1,2-c] pyrimidine -5- base) -8- nitrogen The preparation of miscellaneous spiral shell [4.5] decane -1- amine
Step 1: (R) -2- methyl-N- (R) -8- (8- (pyridine -2- base is thio) imidazo [1,2-c] pyrimidine -5- base) - 8- azaspiro [4.5] last of the ten Heavenly stems piperazine -1- base) propane -2- sulfenamide
(R)-N- ((R) -8- (8- iodine imidazo [1,2-c] is sequentially added in single-necked flask under from nitrogen guarantor to 100mL Pyrimidine -5- base) -8- azaspiro [4.5] decane -1- base) -2- methylpropane -2- sulfonamide (50mg, 0.10mmol), pyridine -2- Mercaptan (13mg, 0.12mmol), Cu (OTf)2(4mg, 0.01mmol), BINAM (3mg, 0.01mmol) and 1,4- dioxane Cesium carbonate (65mg, 0.2mmol) then is added, reaction solution heating stirring 16h at 100 DEG C in (3mL).After reaction solution is cooling, subtract It compresses obtained residue and is purified by silica gel chromatography (ethyl acetate/methanol of 0 to 50% gradient), obtain (R) -2- first Base-N- (R) -8- (8- (pyridine -2- base is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] last of the ten Heavenly stems piperazine -1- Base) propane -2- sulfenamide (20mg, yield: 41%).
LCMS:m/z 485.2[M+H]+.
Step 2: (R) -8- (8- (pyridine -2- base is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] Decane -1- amine
Use the identical method of 37 step 2 of embodiment, (R) -2- methyl-N- (R) -8- (8- (pyridine -2- base is thio) miaow Azoles simultaneously [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane piperazine -1- base) propane -2- sulfenamide removes sulfinyl After obtain (R) -8- (8- (pyridine -2- base is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- Amine..
1H NMR (400MHz, DMSO-d6) δ 8.34 (d, J=3.1Hz, 2H), 8.02 (s, 1H), 7.78 (s, 1H), 7.63-7.48 (m, 2H), 7.11 (dd, J=7.3,4.9Hz, 1H), 6.93 (d, J=8.1Hz, 1H), 3.86 (t, J= 13.0Hz, 2H), 3.22 (t, J=12.4Hz, 2H), 3.03 (t, J=6.5Hz, 1H), 2.04-1.35 (m, 10H) ppm；LCMS: m/z 381.2[M+H]+.
According to the synthetic method of embodiment 119, following compound can be synthesized:
Embodiment 120:(R) -8- (8- (pyridazine -3- base is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR (400MHz, DMSO-d6) δ 8.97 (d, J=4.8Hz, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 7.48 (dd, J=8.9,4.9Hz, 1H), 7.33 (d, J=8.8Hz, 1H), 3.90 (s, 2H), 3.25 (d, J= 12.2Hz,3H),3.18(s,1H),1.86-1.46(m,9H)；LCMS:m/z 382.1[M+H]+.
Embodiment 121:(R) -8- (8- (pyrazine -2- base is thio) imidazo [1,2-c] pyrimidine -5- base) -8- azaspiro [4.5] decane -1- amine
1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.36(s,1H),8.31(s,1H),8.07(s,1H), 7.79 (s, 1H), 7.58 (s, 1H), 3.89 (t, J=12.8Hz, 2H), 3.24 (d, J=12.2Hz, 2H), 2.06-1.46 (m, 9H)；LCMS:m/z 382.1[M+H]+.
Embodiment 122: (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] is phonetic by compound 8- Pyridine -5- base) -1- methyl -8- azaspiro [4.5] decane -1- amine preparation
Step 1: 8- (8- iodine imidazo [1,2-c] pyrimidine -5- base) -1- methylspiro [4.5] decane -1- amine
At 0 DEG C, to the anhydrous DMF solution (10mL) of chloro- 8- iodine imidazo [1, the 2-c] pyrimidine (56mg, 0.2mmol) of 5- Middle addition 1- methyl -8- azaspiro [4.5] decane -1- amine (40mg, 0.24mmol), is then added diisopropylethylamine (51.6mg, 0.4mmol), reaction solution stir 1 hour at 0 DEG C.After completion of the reaction, this reaction solution is directly used in reacts in next step.
LCMS:m/z 412.0[M+H]+.
Step 2: (8- (8- iodine imidazo [1,2-c] pyrimidine -5- base) -1- methylspiro [4.5] decane -1- base) amino first Tert-butyl acrylate
By in the solution in previous step, it is added (Boc)2Diisopropylethylamine is then added in O (87mg, 0.4mmol) (51.6mg, 0.4mmol), reaction solution are stirred at room temperature 4 hours.After completion of the reaction, water quenching reaction is added, then uses acetic acid second Ester (3 × 10mL) extraction.Combined organic phase is dry with anhydrous sodium sulfate.It filters and depressurizes lower concentration.The residue that will be obtained It is purified by silica gel chromatography (ethyl acetate/petroleum ether of 0 to 30% gradient) and obtains that ((8- iodine imidazo [1,2-c] is phonetic by 8- Pyridine -5- base) -1- methylspiro [4.5] decane -1- base) t-butyl carbamate (15mg, the above two steps yield: 7%)
LC-MS:m/z=512.0 [M+H]+.
Step 3: (8- (8- ((6- ((tert-butoxycarbonyl) amino) -2,3- dichloropyridine -4- base) sulfenyl) imidazo [1,2-c] pyrimidine -5- base)-methyl loop coil [4.5] decane -1- base) t-butyl carbamate.
According to the synthetic method of step 1 in embodiment 76, (8- (8- iodine imidazo [1,2-c] pyrimidine -5- base) -1- methyl Spiral shell [4.5] decane -1- base) t-butyl carbamate and 6- ((tert-butoxycarbonyl) amino) -2,3- dichloropyridine -4- sodium mercaptides (8- (8- ((6- ((tert-butoxycarbonyl) amino) -2,3- dichloropyridine -4- base) sulfenyl) imidazo [1,2-c] is obtained after coupling Pyrimidine -5- base)-methyl loop coil [4.5] decane -1- base) t-butyl carbamate (4mg, yield: 15%).LC-MS:m/z 678.2[M+H]+.
Step 4: 4- ((5- (1- amino -1- methylspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine -8- base) sulphur Base) -5,6- dichloropyridine -2- amine.
According to the synthetic method of 21 step 3 of embodiment, (8- (8- ((6- ((tert-butoxycarbonyl) amino) -2,3- dichloro Pyridin-4-yl) sulfenyl) imidazo [1,2-c] pyrimidine -5- base)-methyl loop coil [4.5] decane -1- base) t-butyl carbamate 4- ((5- (1- amino -1- methylspiro [4.5] decane -8- base) imidazo [1,2-c] pyrimidine -8- base) sulphur is obtained after de- Boc protection Base) -5,6- dichloropyridine -2- amine (2mg, yield: 60%)
1HNMR(400MHz,DMSO-d6)δ8.10(s,1H),7.87(s,1H),7.64(s,1H),6.42(s,2H), 5.63 (s, 1H), 4.06 (s, 2H), 3.18 (t, J=12.4Hz, 2H), 1.96-1.37 (m, 9H), 1.26 (s, 3H), 0.98- 0.84(m,1H)ppm；LC-MS:m/z=478.2 [M+H]+。
According to the synthetic method of embodiment 122, following compound can be synthesized:
Embodiment 123:(R) -8- (8- ((6- amino -3- chloro-2-methyl-pyridin-4-yl) is thio) imidazo [1,2-c] Pyrimidine -5- base) two fluoro- 8- azaspiro [4.5] decane -1- amine of -3,3-
1H NMR(400MHz,DMSO-d6)δ8.19(s,2H),8.07(s,1H),7.84(s,1H),7.65(s,1H), 5.65 (s, 1H), 3.99 (t, J=15.1Hz, 2H), 3.62-3.55 (m, 3H), 2.74-2.63 (m, 2H), 2.44-2.33 (m, 5H), 2.01 (t, J=11.8Hz, 1H), 1.85-1.60 (m, 3H) ppm；LC-MS:m/z=480.2 [M+H]+.
Embodiment 124: compound (R) -8- (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2- C] pyrimidine -5- base) -3,3- two fluoro- 8- azaspiro [4.5] decane -1- amine preparation
Step 1 and step 2: the chloro- 4- of 5,6- bis- ((5- chlorine imidazo [1,2-c] pyrimidine -8- base) sulfenyl) pyridine -2- amine
According to the synthetic method of step 3 and step 4 in embodiment 1,8- iodine imidazo [1,2-c] pyrimidine -5- phenol and 6- Chloro- the 4- ((5- of 5,6- bis- is obtained after the coupling of ((t-butoxy carbonyl) amino) -2,3- dichloropyridine -4- thiolic acid sodium and halogenation Chlorine imidazo [1,2-c] pyrimidine -8- base) sulfenyl) pyridine -2- amine.
LC-MS:m/z 347.9[M+H]+
Step 3: (R) -8- (8- ((6- amino -2,3- dichloropyridine -4- base) is thio) imidazo [1,2-c] pyrimidine -5- Base) two fluoro- 8- azaspiro [4.5] decane -1- amine of -3,3-
According to the synthetic method of embodiment 23,5,6- bis- chloro- 4- ((5- chlorine imidazo [1,2-c] pyrimidine -8- base) sulfenyl) Pyridine -2- amine obtained after being replaced by fluoro- 8- azaspiro [4.5] decane -1- amine of (R) -3,3- two (R) -8- (8- ((amino -2 6-, 3- dichloropyridine -4- base) thio) imidazo [1,2-c] pyrimidine -5- base) two fluoro- 8- azaspiro [4.5] decane -1- amine of -3,3-.
1H NMR(400MHz,DMSO-d6)δ8.35(s,2H),8.06(s,1H),7.86(s,1H),7.61(s,1H), 6.31 (s, 2H), 5.62 (s, 1H), 3.92 (d, J=14.9Hz, 2H), 3.21 (d, J=12.8Hz, 3H), 3.07 (t, J= 8.1Hz, 2H), 2.12-1.98 (m, 3H), 1.91 (d, J=12.4Hz, 2H), 1.47 (t, J=16.6Hz, 3H) ppm；LC-MS: m/z 501.7[M+H]+.
Embodiment 125-127 pharmacology related embodiment
The experiment of embodiment 125:SHP2 inhibition of enzyme activity
Compound powder, which is dissolved in DMSO, is made mother liquor.When experiment, it is dilute that compound storage solution with DMSO carries out 3- times of gradient It releases, 10 different test concentrations are arranged in same compound.Take the compound of 1 each concentration point of μ L to detection plate (Corning, Costar 3915) in hole, each concentration point is arranged 2 and parallel repeats.Albumen used is the active egg of the 76th amino acids mutation White SHP2E76A, substrate used is DiFMUP (Invitrogen, E12020).SHP2E76AAlbumen and substrate use buffer respectively (0.1M NaAc (pH 7.2), 0.02%Tween 20,0.1%BSA, 1mM EDTA, 5mM DTT) is diluted to 1.2nM and 20 μ M.50 μ L enzyme solutions are added into detection hole, add 50 μ L substrates therewith.In Spectra max i3 (Molecular Devices) on instrument, every 1 minute record (Ex 358nm/Em 455nm) first order fluorescence signal, the product of product is calculated with this Rate is tired out to characterize enzymatic activity.Nonlinear regression analysis is carried out with GraphPad Prism 5, passes through Y=Bottom+ (Top- Bottom)/(1+10^ ((LogIC50-X) * HillSlope)) equation model goes out the curve that enzymatic activity changes with compound concentration. Acquire the IC of each compound50Value.
As a result
Following table shows the IC of part of compounds of the present invention50Value.
Alphabetical A represents IC50Less than 100nM；
Letter b represents IC50For 100nM to 1000nM；
Embodiment 126: phosphorylated protein kinase (p-ERK) cell experiment
Inhibit the phosphorylation level of intracellular protein kinase (ERK) by AlphaLISA method detection compound.
First step compound handles cell.Untested compound first carries out 3- times with 100%DMSO and dilutes, and 9 are arranged altogether not Same concentration gradient；Then MOLM13 cell is inoculated with to 96 orifice plates, every 100 μ L of pore volume with 30000, every hole cell density；With Every hole is separately added into the DMSO of 0.5 μ L or the untested compound of various concentration afterwards, and 2 repetitions are arranged in each concentration, DMSO's Final concentration is controlled 0.5%.
Second step lytic cell.After cell is handled 2 hours, culture medium is removed, phosphate buffered saline solution washs cell 3 Secondary, the lysis buffer of the 50 fresh configurations of μ l is added in every hole, shakes and is placed at room temperature for 10 minutes.
Third stepUltraTMP-ERK 1/2 (Thr202/Tyr204) kit (Perkin Elmer, ALSU-PERK-A10K)) detection phosphorilated extracellular signal-regulated kinase (p-ERK).Take 10 μ l's Above-mentioned lysate is to 384 orifice plates (Perkin Elmer, 6005350), according to the extracellular signal of product description test sample Adjust the phosphorylation level of kinases.It is detected using the AlphaScreen on Spectra max i3 (Molecular Devices) Device reads signal.Percentage (%) is inhibited to be calculated by the following formula acquisition:
Inhibit percentage (%)=(the p-ERK signal of 1- compound processing cell/DMSO processing cell p-ERK letter Number) * 100 results
Following table shows the IC of part of compounds of the present invention50Value.
Alphabetical A represents IC50Less than 100nM；
Letter b represents IC50For 100nM to 1000nM；
Embodiment 127:MOLM-13 cell proliferation experiment
It is suspended in culture medium (RPMI-1640 contains 10%FBS and 1%Penicillin-Streptomycin, Gibco) MOLM-13 cell be inoculated on 384 orifice plates with 800 cells (40 hole μ L/).Cell is immediately at untested compound Reason, compound concentration is respectively 50,16.67,5.56,1.85,0.617,0.206,0.069,0.023,0.0076 μ Μ.3 days Afterwards, the CellTiter-Glo reagent (Promega, ZG7572) of 5 μ L of every hole addition, room temperature avoid light place 10 minutes.Pass through Spectra max i3 (Molecular Devices) detects fluorescence signal.The relative growth rate of processing cell is compareed with DMSO It is compared.
As a result
Following table shows the IC of part of compounds of the present invention50Value.
Alphabetical A represents IC50Less than 100nM；
Letter b represents IC50For 100nM to 1000nM；
According to phosphorylated protein kinase described in the experiment of SHP2 inhibition of enzyme activity described in embodiment 125, embodiment 126 (p-ERK) the identical test method of MOLM-13 cell proliferation experiment described in cell experiment and embodiment 127, applicant are directed to 2015/107493 A1 of WO or document (Nature 2016,535,148-152) disclosed compound SHP099 (6- (4- amino- 4- methyl piperidine -1- base) -3- (2,3- dichlorophenyl) pyrazine -2- amine) corresponding experiment has been carried out, this hair is listed in following table The comparative experimental data of compound and SHP099 obtained by bright section Example, by being found after comparison, pyrimidine of the present invention And cycle compound has more superior activity.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention, It should be equivalent substitute mode, be included within the scope of the present invention.

Claims (28)

1. pyrimido cycle compound shown in formula (I), its pharmaceutically acceptable salt or its solvate,
Wherein
Z1、Z2Simultaneously be C or in which one of be N；
X independently is S or is not present；
Y independently is C or N；
N independently is 0,1 or 2；
R1Independently 0 to 4 R1aSubstituted phenyl, 0 to 4 R1aWhat is replaced contains 1-4 azepine aryl, 0 to 4 R1aReplace Naphthalene, 0 to 4 R1aWhat is replaced contains 1-4 azanaphthalene aryl, 0 to 4 R1aSubstituted or unsubstituted benzheterocycle, 0 to 4 A R1aIt is substituted or unsubstituted to contain 1-4 azepine virtue and ring, 0 to 4 R1aWhat is replaced contains 1-4 N, NR1b, O or S (O) m Etc. heteroatomic hetero-aromatic ring, R1cSubstituted or unsubstituted C1-8Alkyl, R1cSubstituted or unsubstituted C1-8Halogenated alkyl；Wherein m is selected From 0,1 and 2；
R1aIt independently is halogen, R1a1Substituted or unsubstituted C1-4Alkoxy, R1a1Substituted or unsubstituted C1-4Alkyl, fluoroform Base, C (=O) OR1a2、NR1a2R1a3, NHC (=O) R1a4、R1a1Substituted or unsubstituted C3-8Naphthenic base；R1a1It independently is halogen Or C1-4Alkyl；R1a2、R1a3It independently is hydrogen, C1-4Alkyl；R1a4It independently is C1-4Alkyl, substituted or unsubstituted alkenyl, acyl Amine, C3-12Single or multiple heterocycle；
R1bIt independently is hydrogen, R1a1Substituted or unsubstituted C1-4Alkyl；
R1cIt independently is hydrogen ,-C (=O) OR1a2、R1a1Substituted or unsubstituted C1-4Alkyl；
R2a、R2b、R3aAnd R3bIt independently is hydrogen, R1a1Substituted or unsubstituted C1-4Alkyl；
As Y=N, R4It independently is hydrogen, R1a1Substituted or unsubstituted C1-4Alkyl；R5It is not present；
As Y=C, R4、R5It independently is hydrogen, aryl, C1-4Alkyl, C1-4Alkoxy ,-O-C1-4Alkyl, amino, C1-4Alkyl takes For amino ,-O-C1-4Alkyl-substituted amino or R4And R50 to 3 R is formed together with Y4a3 to the 7 yuan of saturations replaced or part Unsaturated loop coil, the ring can be optionally containing 1 to 3 independently selected from hetero atoms or the groups such as N, C (=O) and/or O；
R4aIt independently is hydrogen, halogen, R1a1Substituted or unsubstituted C1-4Alkoxy, R1a1Substituted or unsubstituted C1-4Alkyl, hydroxyl Base, amino, C1-4Alkyl amino.
2. pyrimido cycle compound as described in claim 1, its pharmaceutically acceptable salt or its solvate, wherein R1Choosing From with flowering structure:
Wherein, 0,1,2,3 or 4 o；Ring A is the heteroaryl containing 1 to 4 N atom；Ring B is miscellaneous containing 1 to 4 N, S, O etc. The heteroaryl of atom；G independently is hetero atoms or the groups such as C, C (=O), N, S or O；R1aa、R1abIt independently is such as claim The R of 1 definition1a；R1acIt independently is R1cSubstituted or unsubstituted C1-8Alkyl, R1cSubstituted or unsubstituted C1-8Alkyl halide.
3. pyrimido cycle compound as described in claim 1, its pharmaceutically acceptable salt or its solvate, wherein R2a、 R2b、R3aAnd R3bIt independently is hydrogen or methyl.
4. pyrimido cycle compound as described in claim 1, its pharmaceutically acceptable salt or its solvate, wherein working as Y When=N, R4It independently is hydrogen, methyl；R5It is not present.
5. pyrimido cycle compound as described in claim 1, its pharmaceutically acceptable salt or its solvate, wherein working as Y When=C, R4、R5It independently is hydrogen, methyl, ethyl, phenyl, amino, methylamino or ethylamino.
6. pyrimido cycle compound as described in claim 1, its pharmaceutically acceptable salt or its solvate, wherein working as Y When=C, R4And R5It is selected from the ring that Y is formed together with flowering structure:
Wherein, 0,1,2 or 3 p；R4aAs claim 1 defines.
7. pyrimido cycle compound as described in claim 1, its pharmaceutically acceptable salt or its solvate, wherein working as Y When=C, R4And R5It is following configuration with the Y ring being formed together:
Wherein, 0,1,2 or 3 p；R4aAs claim 1 defines.
8. pyrimido cycle compound as described in claim 1, its pharmaceutically acceptable salt or its solvate, structural formula are Formula (II)
9. pyrimido cycle compound as claimed in claim 8, its pharmaceutically acceptable salt or its solvate are selected from following Any compound:
10. a kind of such as the described in any item pyrimido cycle compounds of claim 1-9, its pharmaceutically acceptable salt or its solvent The compound isotopically labelled of compound, the isotope are selected from2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl and125I。
11. pyrimido cycle compound preparation method shown in a kind of formula (II), includes the following steps:
Halogenated intermediates compound A and boric acid, mercaptan or sulphur sodium (F) obtain formula (II), reaction equation after carrying out coupling reaction It is as follows:
Wherein, W1Represent halogen, preferably Br, I；X,Y,n,R1、R2a、R2b、R3a、R3b、R4And R5Definition such as claim 1 institute It states.
12. a kind of preparation method of midbody compound A comprising the steps of:
Halogenated intermediates E is replaced to obtain halogenated intermediates compound A under alkaline condition by intermediate amine C, and reaction equation is such as Under:
Wherein, Y, n, R2a、R2b、R3a、R3b、R4And R5Definition it is as described in claim 1；W1Represent halogen, preferably Br, I.
13. pyrimido cycle compound preparation method shown in a kind of formula (II), includes the following steps:
Halogenated intermediates compound B and amine C obtains formula (II) after replacing, and reaction equation is as follows:
Wherein, W2Represent halogen, preferably Cl, Br, I；X,Y,n,R1、R2a、R2b、R3a、R3b、R4And R5Definition such as claim 1 It is described.
14. a kind of preparation method of midbody compound B comprising the steps of:
Dichloro pyrimidine compound B-1 is replaced to obtain intermediate B -2 by amine；Intermediate B -2 condensation and cyclization and water under strongly acidic conditions Solution obtains halogenated intermediates B-3；Halogenated intermediates B-3 obtains intermediate B -4 under conditions of catalytic coupling, is then converted into halogen For intermediate B, reaction equation is as follows:
Wherein, X, R1Definition it is as described in claim 1；W1Represent halogen, preferably Br, I；W2Represent halogen, preferably Cl, Br, I.
15. pyrimido cycle compound preparation method shown in a kind of formula (II-A), includes the following steps:
Sulphur sodium midbody compound D and halides are coupled to obtain formula (II-A), and reaction equation is as follows:
Wherein, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5Definition it is as described in claim 1.
16. a kind of preparation method of midbody compound D comprising the steps of:
Midbody compound A and mercapto-propionate obtain intermediate D-1 under the conditions of catalytic coupling, then under alkaline condition Corresponding sulphur sodium compound D is obtained, reaction equation is as follows:
Wherein, Y, n, R2a、R2b、R3a、R3b、R4And R5Definition it is as described in claim 1；W1Represent halogen, preferably Br, I.
17. pyrimido cycle compound preparation method shown in a kind of formula (II-B), includes the following steps:
The protecting group for removing intermediate II-B1 under acid or alkaline conditions obtains compound II-B, and reaction equation is as follows:
Wherein, Pg is selected from protecting group Boc, Ac, S (=O)tBu；R4Pg、R5PgTogether with the carbon of connection, selected from flowering structure:
R4、R5Together with the carbon of connection, selected from flowering structure:
X、n、R1、R2a、R2b、R3a、R3b、R4、R5As claim 1 defines；R4aAs claim 1 defines；P is 0,1,2 or 3.
18. pyrimido cycle compound preparation method shown in a kind of formula (II-C), includes the following steps:
Compound II-C is obtained after the amino group of intermediate II-C1, reaction equation is as follows:
Wherein, X, Y, n, R1、R2a、R2b、R3a、R3b、R4、R5、R1aAnd R1a4Definition it is as described in claim 1.
19. a kind of intermediate for being used to prepare pyrimido cycle compound according to any one of claims 8, the midbody compound choosing From:
Wherein X, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5Definition it is as described in claim 1；W1Represent halogen, preferably Br, I； W2Represent halogen, preferably Cl, Br, I.
20. pyrimido cycle compound preparation method shown in a kind of formula (I), includes the following steps:
Halogenated intermediates compoundIt is obtained after carrying out coupling reaction with boric acid, mercaptan or sulphur sodium (F) Formula (I), reaction equation is as follows:
Wherein, W1Represent halogen, preferably Br, I；Z1、Z2、X、Y、n、R1、R2a、R2b、R3a、R3b、R4And R5Definition such as claim Described in 1.
21. pyrimido cycle compound preparation method shown in a kind of formula (I), includes the following steps:
IntermediateFormula (I) is obtained after replacing with amine C, reaction equation is as follows:
Wherein, W2Represent halogen, preferably Cl, Br, I；Z1、Z2、X、Y、n、R1、R2a、R2b、R3a、R3b、R4And R5Definition such as right It is required that described in 1.
22. a kind of such as the described in any item pyrimido cycle compounds of claim 1-9, its pharmaceutically acceptable salt, its solvent Compound or compound isotopically labelled described in any one of claim 10 are in preparation treatment and the abnormal related disease of SHP2 activity or illness Drug in terms of purposes.
23. a kind of disease as claimed in claim 22 or illness are thin selected from southern syndrome, leopard syndrome, teenager's marrow monokaryon is exerted Born of the same parents' leukaemia, neuroblastoma, melanoma, acute myeloid leukaemia, breast cancer, cancer of the esophagus, lung cancer, colon cancer, head cancer, Neuroblastoma, the squamous cell carcinoma of neck, gastric cancer, primary cutaneous type or spongioblastoma.
24. a kind of pharmaceutical composition, comprising according to claim 1 any one of -9 pyrimido cycle compound, its pharmaceutically Acceptable salt or its solvate or compound isotopically labelled described in any one of claim 10 and pharmaceutically acceptable auxiliary Material.
25. a kind of pharmaceutical preparation, the pyrimido cycle compound comprising any one of claim 1-9, its is pharmaceutically acceptable Salt or its solvate or compound isotopically labelled described in any one of claim 10, the pharmaceutical preparation be selected from tablet, capsule, Pill, powder, particle, elixir, tincture, suspended matter, syrup, lotion, solution.
26. the mode of giving of a kind of pharmaceutical preparation as claimed in claim 25, the pharmaceutical preparation is selected from: oral, sublingual to contain Clothes, subcutaneous injection, intravenous injection, intramuscular injection, breastbone inner injection, nose is taken, local surfaces are administered or rectally.
27. a kind of pharmaceutical preparation as claimed in claim 25, the daily single of pharmaceutical preparation is taken or is repeatedly taken.
28. a kind of pyrimido cycle compound, its pharmaceutically acceptable salt or its solvent of any one of such as claim 1-9 Compound or compound isotopically labelled described in any one of claim 10 are used in combination with other drugs, and the other drugs are selected from: anti- Cancer medicine, tumour immunity drug, antiallergic, antiemetic, antalgesic, cell-protecting medicines.
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