CN101506194A - New pyridine analogues - Google Patents
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- CN101506194A CN101506194A CNA2007800316322A CN200780031632A CN101506194A CN 101506194 A CN101506194 A CN 101506194A CN A2007800316322 A CNA2007800316322 A CN A2007800316322A CN 200780031632 A CN200780031632 A CN 200780031632A CN 101506194 A CN101506194 A CN 101506194A
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- nikithan
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Abstract
The present invention relates to certain new pyridin analogues of Formula ( I ), to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-trombotic agents etc, their use as medicaments in cardiovascular diseases as well as pharmaceutical compositions containing them.
Description
Invention field
The invention provides new pyridine compounds, this pyridine compounds as the purposes of medicine, contain the composition and method of making the same of this pyridine compounds.
Background of invention
Platelet adhesion reaction and gathering are the initiation events of artery thrombosis.Although platelet adhesion reaction may play an important role in the damaged vessel walls reparation to the process of interior subcutaneous surface, but the platelet aggregation that platelet adhesion reaction starts may quicken the acute thrombotic obturation of important blood vessels bed, causes high incidence incidents such as myocardial infarction and unstable angina.The platelet-mediated inaccessible or inaccessible again success that also jeopardizes the intervention (for example thrombolysis and angioplasty) that is used to prevent or alleviate these diseases.
Hemostasis is controlled by appropriate balance between platelet aggregation, blood coagulation and the fibrinolysis.Because the thrombosis (for example arteriolosclerosis plaque rupture) that pathologic conditions causes is started by platelet adhesion reaction, activation and gathering at first.The formation that this has not only caused the thrombocyte bolt also causes electronegative phosphatide to be exposed on the thrombocyte adventitia that promotes blood coagulation.Can expect that the formation that suppresses initial thrombocyte bolt can reduce thrombosis and reduce the number of times of cardiovascular event, as the anti-thrombosis function of for example acetylsalicylic acid indicated (BMJ1994; 308:81-106 Antiplatelet Trialists ' Collaboration.Collaborativeoverview of randomised trials of antiplatelet therapy, I:Prevention ofdeath, myocardial infarction, and stroke by prolonged antiplatelet therapyin various categories of patients (the interoperability summary I of anti-platelet therapy randomized clinical trial: in different classes of patient, prevent death, myocardial infarction and apoplexy) by prolonging anti-platelet therapy).
Can pass through various agonist induction platelet activation/gathering.Yet the essential intracellular signal transduction approach of uniqueness that activates is to obtain by the G Protein G
q, G
12/
13And G
iThe thrombocyte of mediation is fully assembled (Platelets, AD Michelson chief editor, Elsevier Science 2002, ISBN0-12-493951-1; 197-213:D Woulfe etc., Signal transduction duringthe initiation, extension, and perpetuation of platelet plug formation (that the thrombocyte bolt forms is initial, the signal transduction of expansion and permanent duration of existence)).In the thrombocyte, g protein coupled receptor P2Y
12(also claimed thrombocyte P in the past
2T, P2T
AcOr P2Y
CycAcceptor) sends signal by Gi, cause cAMP and abundant (full aggregation) reduction (Nature2001 that assembles in the born of the same parents; 409:202-207G Hollopeter etc., Identification of the platelet ADPreceptortargeted by antithrombotic drugs (by the evaluation of the platelet ADP receptor of antithrombotic drug target).The inevitable positive regeeration of the ADP that discharges from dense granule is given the P2Y12 acceptor so that fully assemble.
Provide ADP-P2Y by clinical use clopidogrel (clopidogrel)
12The clinical evidence of Feedback mechanism keying action, clopidogrel are a kind of thienopyridine prodrugs, are and P2Y
12The active metabolite of receptor-selective irreversible fixation, some clinical trials show the risk that effectively reduces cardiovascular event in facing the patient of risk, and (Lancet 1996; 348:1329-39:CAPRIE Steering committee, A randomised, blinded, trial of clopidogrelversus aspirin in patients at risk of ischaemic events (the CAPRIE steering committee faces the blind trial at random (CAPRIE) of clopidogrel and acetylsalicylic acid among the patient of ischemic event risk); N Engl J Med 2001; 345, (7): 494-502): The Clopidogrelin Unstable Angina to prevent Recurrent Events Trial Investigators, (clopidogrel is prevention of recurrence sexual behavior part experimental study personnel in unstable angina) .Effects ofclopidogrel in addition to aspirin in patients with acute coronarysyndromes without ST-segment elevation, (effect of clopidogrel in the acute coronary syndrome patient that no ST section is raised except that acetylsalicylic acid).In these researchs, the clinical benefit of clopidogrel treatment with clinical hemorrhage speed up relevant.Disclosed data show, compare reversibility P2Y with thienopyridine
12Antagonist may provide more clinical benefit also to reduce hemorrhage risk (Sem Thromb Haemostas 2005 simultaneously; 31 (2): 195-204, van Giezen ﹠amp; RG Humphries, Preclinical and clinical studies withselective reversible direct P2Y
12Antagonists (the direct P2Y of reversible selectivity
12The clinical preceding and clinical study of antagonist)).
Therefore, an object of the present invention is to provide effective reversible selectivity P2Y as antithrombotic drug
12Antagonist.
Summary of the invention
We find that against expectation the pyridine compounds of some following formula (I) or its pharmacy acceptable salt are reversible selectivity P2Y
12Antagonist hereinafter also claims compound of the present invention.Compound of the present invention against expectation has beneficial property, makes it to be specially adapted to treat following disease/illness (referring to the 67-68 page or leaf).The example of this class beneficial property is efficient, highly selective and favourable treatment window.
Detailed Description Of The Invention
The invention provides new formula (I) compound or its pharmacy acceptable salt:
Wherein:
R
1Expression R
6OC (O), R
7C (O), R
16SC (O), R
17S, R
18C (S) or following gII group:
Preferred R
1Expression R
6OC (O);
R
2Expression is optional by the isolated (C of oxygen
1-C
12) alkyl, wherein alkyl is replaced by one or more halogens (F, Cl, Br, I) atom; In addition, R
2(the C that expression is replaced by one or more halogens (F, Cl, Br, I) atom
1-C
12) alkoxyl group.
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
3Optional (the C that is replaced by one or more halogens (F, Cl, Br, I) atom of expression
1-C
12) alkoxyl group; In addition, R
3Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkylthio C (O), (C
1-C
12) alkyl C (S), (C
1-C
12) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
12) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
12) alkyl C (O), (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (3)R
B (3)Group, wherein R
A (3)And R
B (3)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
A (3)And R
B (3)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R4 represents H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
12) alkyl: OH, COOH, (C
1-C
6) alkoxy carbonyl, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
4Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkyl-cycloalkyl, (C
1-C
12) alkoxyl group, wherein alkoxyl group can be chosen wantonly by following group and replace: one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or (C
1-C
6) alkoxy carbonyl; In addition, R4 represents (C
1-C
12) alkylthio C (O), (C
1-C
12) alkyl C (S), (C
1-C
12) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
12) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
12) alkyl C (O), (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (4)R
B (4)Group, wherein R
A (4)And R
B (4)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
A (4)And R
B (4)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
Z represents O or does not exist;
R
5Expression H or (C
1-C
12) alkyl;
R
6Expression is optional by the isolated (C of oxygen
1-C
12) (precondition is that any this class oxygen must be apart from connecting R to alkyl
6At least 2 carbon atoms of the ester-oxygen of group) and/or the optional (C that is replaced by following group
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
12) alkyl, aryl or heterocyclic radical;
R
7Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
7Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, aryl or heterocyclic radical;
R
8Expression H, the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
12) alkyl: aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
8Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl or (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl;
R
14Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
12) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
12) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
14Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl or (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl, formula NR
A (14)R
D (14)Group, wherein R
A (14)And R
D (14)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkoxy C (O), perhaps R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
12) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
12) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
15Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (15)R
B (15)Group, wherein R
A (15)And R
B (15)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkoxy C (O), perhaps R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
16Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
17Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
17Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
18Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
18Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
cDo not exist or represent and do not replace or single replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylidene group oxygen base or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately separately and be independently selected from (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
B (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms; In addition, R
cExpression imino-(NH-), the imino-(NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylideneimino or N-
1-C
4) alkylideneimino (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is unsubstituted or is replaced by any above-mentioned substituting group list or polysubstituted; Preferred R
cExpression imino-or (C
1-C
4) alkylideneimino or unsubstituted or replaced or polysubstituted (C by any above-mentioned substituting group list
1-C
4) alkylidene group or (C
1-C
4) the oxo alkylidene group;
R
19When existing, represent H or (C
1-C
4) alkyl;
R
dExpression (C
1-C
12) alkyl, (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom and/or one or more following group replacement: OH, CN, NO
2, (C
1-C
12) alkyl, (C
1-C
12) alkoxy C (O), (C
1-C
12) (the C that replaces of alkoxyl group, halogen
1-C
12) (the C that replaces of alkyl, halogen
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (Rd)R
B (Rd)Group, wherein R
A (Rd)And R
B (Rd)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
X represents singly-bound, imino-(NH-), methylene radical (CH
2-), the imino-methylene radical (CH that is connected with B ring/ring system of carbon wherein
2-NH-), the methylene radical imino-(NH-CH that is connected with B ring/ring system of nitrogen wherein
2-), and any carbon in these groups and/or nitrogen can be chosen wantonly by (C
1-C
6) the alkyl replacement; X also can represent (CH
2-)
nGroup, n=2-6 wherein, this group is optional to be undersaturated and/or to be selected from following substituting group and to replace by one or more: halogen, hydroxyl or (C
1-C
6) alkyl;
B contains one or more nitrogen and optional one or more heterocycle/ring systems that are selected from the monocycle or the dicyclo of oxygen or sulphur atom for 4-11 unit, this nitrogen is connected with pyridine ring (according to formula I), precondition is that B is not a piperazine, and in addition, B ring/ring system also is connected with other locational X in the ring.Substituent R
14And R
15Can (not be connected) the formation quaternary ammonium compound with B ring/ring system ways of connecting by these.
The preferred value and the embodiment of each variable group or its combination are as follows.For any value, definition, claim, aspect or the embodiment defined in this paper context, if suitably, just can use these values or embodiment.Particularly each value all can be as indivedual restrictions in any other embodiment of generalized definition and formula (I).
For fear of producing ambiguity, should be appreciated that, if group limited with " this paper above definition ", " herein as defined above " or " defined above " in the specification sheets, then described group comprises and occurring for the first time and each and all concrete definition of generalized definition and this group.
Should be appreciated that, when formula I compound contains chiral centre, compound of the present invention can optically active form or racemic modification exist and can be separated.The present invention includes as P2Y
12Any optically active form or the racemic modification of the formula I compound of receptor antagonist.The synthetic of optically active form can be undertaken by organic chemistry standard technique well-known in the art, for example fractionation by racemic mixture, by chiral chromatography, synthetic or by asymmetric synthesis by the optically active form raw material.
To be appreciated that also can there be tautomerism in formula I compound, the present invention includes as P2Y
12Any tautomer of the formula I compound of receptor antagonist.
To be appreciated that also relevant compound of the present invention exists as solvate, particularly hydrate, so these all are integral parts of the present invention.
To be appreciated that also generic term for example " alkyl " comprises straight chain and branched group, for example the butyl and the tertiary butyl.Yet, when using concrete term for example when " butyl ", refer in particular to straight chain butyl or " just " butyl, when the meaning is branched chain isomer, be to refer in particular to side chain for example " tertiary butyl ".
In one embodiment, alkyl is unsubstituted or replaces by one or more halogens (F, Cl, Br, I) atom and/or by one or more following groups: OH, CN, NO
2, (C
1-C
12) alkyl, (C
1-C
12) alkoxy C (O), (C
1-C
12) (the C that replaces of alkoxyl group, halogen
1-C
12) alkyl, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
aR
bGroup, wherein R
aAnd R
bIndependent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
aAnd R
bRepresent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
Term " alkyl " comprise the straight or branched group both, optional replaced by one or more halogens (F, Cl, Br, I) or blended halogen atom.
When being replaced by one or more halogen atoms (F, Cl, Br, I), the alkyl of an embodiment of alkyl for for example being replaced by one or more fluorine atoms.Another embodiment of the alkyl that is replaced by halogen comprises perfluoroalkyl, for example trifluoromethyl.
The general expression of term " cycloalkyl " replaces or unsubstituted (C
3-C
6), only stipulate the cyclic hydrocarbon radical of chain length in addition.
In one embodiment, cycloalkyl is replaced by one or more halogens (F, Cl, Br, I) atom and/or is replaced by one or more following groups: OH, CN, NO
2, (C
1-C
12) alkyl, (C
1-C
12) alkoxy C (O), (C
1-C
12) (the C that replaces of alkoxyl group, halogen
1-C
12) alkyl, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
aR
bGroup, wherein R
aAnd R
bIndependent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
aAnd R
bRepresent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
Term " alkoxyl group " comprise the straight or branched group both, optional replaced by one or more halogens (F, Cl, Br, I) or blended halogen atom.
Term aryl is meant and replaces or unsubstituted (C
6-C
14) aromatic hydrocarbon, include but not limited to phenyl, naphthyl, tetralyl, indenyl, indanyl, anthryl (antracenyl), phenanthryl (fenantrenyl) and fluorenyl.
In one embodiment, aryl is replaced by one or more halogens (F, Cl, Br, I) atom and/or is replaced by one or more following groups: OH, CN, NO
2, (C
1-C
12) alkyl, (C
1-C
12) alkoxy C (O), (C
1-C
12) (the C that replaces of alkoxyl group, halogen
1-C
12) alkyl, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
aR
bGroup, wherein R
aAnd R
bIndependent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
aAnd R
bRepresent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
Term " heterocyclic radical " is meant replacement of 4-10 unit or unsubstituted monocycle or encircles ring system more, one or more atoms in wherein one or more rings are the elements that are different from carbon, nitrogen for example, oxygen or sulphur, especially 4 yuan, 5 yuan or 6 yuan of aromatics or aliphatic heterocyclic radical, include but not limited to azetidinyl, furyl, thienyl, pyrryl, pyrrolinyl, pyrrolidyl, the dioxolane base, the oxathiolane base, oxazolidine base oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, isothiazolyl oxadiazole base, the furazan base, triazolyl, thiadiazolyl group, pyranyl, pyridyl and pyridine-N-oxide, piperidyl alkyl dioxin, morpholinyl, the dithiane base, the oxathiane base, thio-morpholinyl, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, triazinyl, the thiadiazine base, the dithiazine base, azaindolyl, azaindolinyl, indyl, indolinyl, naphthyridinyl Ben Bing oxadiazole base, dihydrobenzo dioxin base, benzothienyl, the diazosulfide base, the Imidazothiazole base, 2,3-dihydro benzo furyl isoxazolyl, 3-benzoisoxazole base, 1,2-benzoisoxazole base, the pyrazoline base, and should be understood to comprise all isomer of above-mentioned appointment group.For above-mentioned group azetidinyl etc. for example, term " azetidinyl " and " azetidine subunit (azetidinylene) " etc. should be understood to comprise all possible regional isomer.What it is also understood that is, the term heterocyclic radical can specifically represent by an option in the specified feasible variable embodiment, and can specifically represent by other (or identical) option of other variable, for example, and R
4When being chosen to be heterocyclic radical, can be furans, work as R
d(also when being chosen to be heterocyclic radical) can be the pyrroles.
In one embodiment, heterocyclic radical is replaced by one or more halogens (F, Cl, Br, I) atom and/or is replaced by one or more following groups: OH, CN, NO
2, (C
1-C
12) alkyl, (C
1-C
12) alkoxy C (O), (C
1-C
12) (the C that replaces of alkoxyl group, halogen
1-C
12) alkyl, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
aR
bGroup, wherein R
aAnd R
bIndependent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
aAnd R
bRepresent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
In another embodiment of the invention, heterocyclic radical comprise 5 yuan or 6 yuan contain 1,2 or 3 aromatic heterocycle that is selected from nitrogen, oxygen and sulfur heteroatom and 5 yuan or 6 yuan contain 1,2 or 3 be selected from nitrogen, oxygen and sulfur heteroatom and with phenyl ring condensed aromatic heterocycle;
In an alternate embodiment of the present invention, heterocyclic radical be 5 yuan or 6 yuan contain 1,2 or 3 be selected from nitrogen, oxygen and sulfur heteroatom and with phenyl ring condensed non-aromatic heterocyclic.
In yet another embodiment of the present invention, heterocyclic radical is to be selected from following group: furyl, pyrryl, thienyl, pyridyl, N-oxidation-pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, imidazolyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl oxadiazole base, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, benzofuryl, quinolyl, isoquinolyl, benzimidazolyl-, indyl, the coumaran base, benzodioxole base (for example 1,3-benzodioxole base) Ben Bing oxadiazole, the dihydrobenzo dioxin, thionaphthene, diazosulfide, Imidazothiazole, 2,3-Dihydrobenzofuranes isoxazole, pyrazoline and benzo dioxane base (for example 1,4-benzo dioxane base).More particularly value comprises for example furyl, pyrryl, thienyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, Ben Bing oxadiazole, dihydrobenzo dioxin, thionaphthene, diazosulfide, Imidazothiazole, 2,3-Dihydrobenzofuranes, isoxazole, 1,2-benzoisoxazole, pyrazoline and benzo dioxane base (for example 1,4-benzo dioxane base).
In other another embodiment of the present invention, heterocyclic radical is to be selected from following group: furyl, pyrryl, thienyl, pyridyl, N-oxidation-pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, Ben Bing oxadiazole, dihydrobenzo dioxin, thionaphthene, diazosulfide, Imidazothiazole, 2,3-Dihydrobenzofuranes, isoxazole, 1,2-benzoisoxazole or pyrazoline.
In one embodiment of the invention, R
1Expression R
6OC (O).
In yet another embodiment of the present invention, R
1Be R
6OC (O), wherein R
6Can be methyl, ethyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, sec.-propyl, cyclopropyl, isobutyl-, normal-butyl, cyclobutyl, n-propyl, the tertiary butyl, cyclopentyl, 2,2-dimethyl propyl, benzyl and 4-luorobenzyl.
R
1Also can specifically be expressed as following gII group:
R wherein
8Be selected from H, (C
1-C
6) alkyl, for example methyl or ethyl.
At R
8In another embodiment of group, this group can be selected from hydrogen, methyl, ethyl, n-propyl and normal-butyl.
R
2Embodiment for example comprise (the C that is replaced by one or more halogens (F, Cl, Br, I) atom or blended halogen atom
1-C
4) alkyl.
In another embodiment, R
2Be (the C that is replaced by one or more fluorine atoms
1-C
4) alkyl.
R
2Another embodiment be the (C that is replaced by one or more fluorine atoms and optional one or more chlorine atoms
1-C
4) alkyl.
In another embodiment, R
2Be (the C that is replaced by one or more fluorine atoms and one or more chlorine atom
1-C
4) alkyl.
In other another embodiment, R
2Be the methyl that is replaced by one or more fluorine atoms.
R
2Another alternate embodiment be the methyl that is replaced by two fluorine atoms.
R
2Another embodiment be the (C that is replaced by one or more fluorine atoms and optional one or more chlorine atoms
1-C
4) alkoxyl group.
R
2The oxyethyl group of a specific embodiments for being replaced by one or more fluorine atoms.
R
3Embodiment comprise for example H, methyl, methylsulfinyl, hydroxymethyl, methoxyl group or unsubstituted or optional by one or two methyl substituted amino.
R
3Other embodiment comprise H or unsubstituted or optional by one or two methyl substituted amino.
R
4Embodiment comprise H, halogen for example chlorine, methyl, cyano group, nitro, unsubstituted or optional by one or two methyl substituted amino, and also comprise 4-methoxyl group-4-oxo butoxy, 3-carboxyl-propoxy-and methyl carbonyl.
In one embodiment of the invention, Z does not exist.
In another embodiment of the invention, Z represents O.
In one embodiment of the invention, R
5Expression hydrogen or methyl.In another embodiment of the invention, R
5Be hydrogen.
R
8Other embodiment comprise hydrogen, methyl and ethyl.
R
14Other embodiment comprise for example hydrogen, methyl, amino, tert-butoxycarbonyl, tert-butoxycarbonyl-imino-, 2-propyloic and 3-tert.-butoxy-3-oxo-propyl group.
R
14Other embodiment in addition comprises for example hydrogen, methyl, tert-butoxycarbonyl-imino-and amino.
In one embodiment of the invention, R
15Expression H.
R
dEmbodiment comprise alkyl, cycloalkyl, aryl or heterocyclic radical, be more particularly aryl or aromatic heterocyclic radical.
In one embodiment of the invention, R
dBe (C
1-C
6) alkyl, the optional (C that is replaced by following group
3-C
6) cycloalkyl: alkyl, aryl or one or more halogen (F, Cl, Br, I) atom or blended halogen atom.
R
dAnother embodiment comprise aryl (for example phenyl) and aromatic heterocyclic radical (for example thienyl).
R
dOther embodiment comprise and can choose substituted phenyl wantonly.
In a specific embodiments, R
dExpression aryl, heterocyclic radical or (C
3-C
6) cycloalkyl, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom or blended halogen atom and/or one or more following group replacement: OH, CN, NO
2, (C
1-C
12) alkyl, (C
1-C
12) alkoxy C (O), (C
1-C
12) (the C that replaces of alkoxyl group, halogen
1-C
12) (the C that replaces of alkyl, halogen
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (Rd)R
B (Rd)Group, wherein R
A (Rd)And R
B (Rd)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
dOther embodiment in addition comprises chooses substituted phenyl on 2,3,4 or 5 and any combination bit wantonly.Substituent example is cyano group, tetrazolium-5-base, methoxyl group, trifluoromethoxy, methyl, trifluoromethyl, fluorine, chlorine, bromine, methyl sulphonyl, nitro, 3-methyl-5-oxo-4,5-dihydro-1 h-pyrazole-1-base.Two phase ortho positions (for example 2,3) also can be connected to form ring.This substituent example is the 2-naphthyl.Other of heteroaryl value more specifically is 2-chloro-5-thienyl; 3-bromo-5-chloro-2-thienyl; 2; 1; 3-Ben Bing oxadiazole-4-base; 2; 4-dimethyl-1; 3-thiazole-5-base; 2; 3-dihydro-1; 4-benzo dioxine-6-base; 5-chloro-3-methyl isophthalic acid-thionaphthene-2-base; 2; 1; 3-diazosulfide-4-base; 2; 5-dimethyl-3-furyl; 6-chlorine imidazo [2; 1-b] [1; 3] thiazole-5-base; 2; 3-dihydro-1-cumarone-5-base; 5-chloro-3-thienyl; 5-isoxazole-5-base-2-thienyl; 5-isoxazole-3-base-2-thienyl; 4-bromo-5-chloro-2-thienyl; 5-bromo-6-chloropyridine-3-base; 5-bromo-2-thienyl; 5-pyridine-2-base-2-thienyl; 2; 5-two chloro-3-thienyls; 4; 5-two chloro-2-thienyls; thionaphthene-3-base; 2; 5-dimethyl-3-thienyl; the 3-thienyl; the 2-thienyl; 5-methyl-isoxazole-4-base; pyridin-3-yl; [1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-2-thienyl; 5-chloro-1,3-dimethyl-1H-pyrazoles-4-base; the 4-[(4-chloro-phenyl-) alkylsulfonyl]-3-methyl-2-thienyl; 5-(methoxycarbonyl)-2-furyl and 4-(methoxycarbonyl)-5-methyl-2-furyl.
In one embodiment of the invention, R
cExpression does not replace or single the replacement or dibasic (C
1-C
4) alkylidene group, wherein any substituting group is separately separately and be independently selected from (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
D (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine, R with nitrogen-atoms
dExpression aryl, i.e. R
cR
dExpression has above-mentioned any substituent aryl-(C
1-C
4) alkylidene group.
In a preferred embodiment of the invention, R
cExpression does not replace or single the replacement or dibasic (C
1-C
3) alkylidene group, wherein any substituting group is separately separately and be independently selected from (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
B (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine, R with nitrogen-atoms
dExpression aryl, i.e. R
cR
dExpression has above-mentioned any substituent aryl-(C
1-C
3) alkylidene group.
In yet another embodiment of the present invention, R
cDo not exist or represent and do not replace or single replacement or dibasic (C
1-C
4) alkylidene group, wherein any substituting group is separately separately and be independently selected from (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
B (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine, R with nitrogen-atoms
dThe expression heterocyclic radical.
In another embodiment preferred of the present invention, R
cDo not exist or represent and do not replace or single replacement or dibasic (C
1-C
3) alkylidene group, wherein any substituting group is separately separately and be independently selected from (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
B (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine, R with nitrogen-atoms
dThe expression heterocyclic radical.
In specific embodiments of the present invention, R
cDo not exist or represent that wherein any substituting group separately separately and be independently selected from the C of following group
1-alkylidene group: (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
B (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine, R with nitrogen-atoms
dThe expression aryl.
In one embodiment of the invention, R
cDo not exist.
In one embodiment of the invention, R
19When existing, represent hydrogen.
In another embodiment of the invention, R
19When existing, represent methyl.
In an embodiment the most special of the present invention, R
cR
dExpression benzyl or according to described substituted benzyl when replacing about aryl.
In one embodiment of the invention, X represents singly-bound.
In another embodiment of the invention, X represents singly-bound or methylene radical (CH
2-).In another embodiment, X represents that imino-(NH-).In another embodiment, X represents methylene radical (CH
2-).
The suitable value of B ring/ring system comprises for example Diazesuberane subunit (diazepanylene), piperidines subunit (piperidinylene), pyrrolidylidene (pyrrolidinylene) and azetidine subunit, wherein, can their arbitrary isomer there be (for example piperazine-tetrahydro pyridazine-tetrahydropyrimidine) in any in them.
The another embodiment of B ring/ring system is when B is selected from piperidines subunit and azetidine subunit.
An alternate embodiment of B ring/ring system is when B is the piperidines subunit.
Another alternate embodiment of B ring/ring system is when B is the azetidine subunit.
The embodiment of B ring/ring system comprises for example Diazesuberane subunit, piperidines subunit, pyrrolidylidene and azetidine subunit.Other embodiment comprises being had (C
1-C
6) R of alkyl
14The group that replaces, wherein (C
1-C
6) alkyl is optional by OH, COOH or COOR
eGroup replaces (for example 2-propyloic), wherein R
eExpression H, aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
12) alkyl: halogen (F, Cl, Br, I) or blended halogen atom, OH, aryl, cycloalkyl and heterocyclic radical.
In an alternate embodiment of above-mentioned B ring/ring system, this embodiment comprises choosing wantonly to be had (C
1-C
6) R of alkyl
14The piperidines subunit, pyrrolidylidene or azetidine subunit, the wherein (C that replace
1-C
6) alkyl is optional by OH, COOH or COOR
eGroup replaces (for example 2-propyloic), wherein R
eExpression H, aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) or blended halogen atom, OH, aryl, cycloalkyl and heterocyclic radical.
Second embodiment of formula I is defined as:
R
1Expression R
6OC (O), R
7C (O), R
16SC (O), R
17S, R
18C (S) or following gII group:
R
2Expression is optional by the isolated (C of oxygen
1-C
6) alkyl, wherein alkyl is replaced by one or more halogens (F, Cl, Br, I) atom; In addition, R
2(the C that expression is replaced by one or more halogens (F, Cl, Br, I) atom
1-C
6) alkoxyl group;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom; In addition, R
3Optional (the C that is replaced by one or more halogens (F, Cl, Br, I) atom of expression
1-C
6) alkoxyl group; In addition, R
3Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkylthio C (O), (C
1-C
6) alkyl C (S), (C
1-C
6) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
6) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
6) alkyl C (O), (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (3)R
B (3)Group, wherein R
A (3)And R
B (3)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (3)And R
B (3)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
4Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: OH, COOH, (C
1-C
6) alkoxy carbonyl, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom; In addition, R
4Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxyl group, wherein alkoxyl group can be chosen wantonly by following group and replace: one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or (C
1-C
3) alkoxy carbonyl; In addition, R
4Expression (C
1-C
6) alkylthio C (O), (C
1-C
6) alkyl C (S), (C
1-C
6) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
6) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
6) alkyl C (O), (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (4)R
B (4)Group, wherein R
A (4)And R
B (4)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (4)And R
B (4)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
Z represents O or does not exist;
R
5Expression H or (C
1-C
6) alkyl;
R
6Expression is optional by the isolated (C of oxygen
1-C
6) (precondition is that any this class oxygen must be apart from connecting R to alkyl
6At least 1 carbon atom of the ester-oxygen of group) and/or the optional (C that is replaced by following group
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
6) alkyl, aryl or heterocyclic radical;
R
7Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
7Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, aryl or heterocyclic radical;
R
8Expression H, the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
8Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl, heterocyclic radical, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl or (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl;
R
14Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
6) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
14Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (14)R
B (14)Group, wherein R
A (14)And R
B (14)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), perhaps R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
6) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
15Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (15)R
B (15)Group, wherein R
A (15)And R
B (15)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), perhaps R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
16Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
17Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
17Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
18Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
18Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
cDo not exist or represent and do not replace or single replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylidene group oxygen base or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately separately and be independently selected from (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
B (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms; In addition, R
cExpression imino-(NH-), the imino-(NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylideneimino or N-
1-C
4) alkylideneimino (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is unsubstituted or is replaced by any above-mentioned substituting group list or polysubstituted; Preferred R
cExpression imino-or (C
1-C
4) alkylideneimino or unsubstituted or replaced or polysubstituted (C by any above-mentioned substituting group list
1-C
4) alkylidene group or (C
1-C
4) the oxo alkylidene group;
R
19When existing, represent H or (C
1-C
4) alkyl;
R
dExpression (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom and/or one or more following group replacement: OH, CN, NO
2, (C
1-C
6) alkyl, (C
1-C
6) alkoxy C (O), (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) (the C that replaces of alkyl, halogen
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (Rd)R
B (Rd)Group, wherein R
A (Rd)And R
B (Rd)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
X represents singly-bound, imino-(NH-), methylene radical (CH
2-), the imino-methylene radical (CH that is connected with B ring/ring system of carbon wherein
2-NH-), the methylene radical imino-(NH-CH that is connected with B ring/ring system of nitrogen wherein
2-), any carbon and/or nitrogen in these groups can be chosen wantonly by (C
1-C
6) the alkyl replacement; X also can represent (CH
2-)
nGroup, n=2-6 wherein, this group is optional to be undersaturated and/or to be selected from following substituting group and to replace by one or more: halogen, hydroxyl or (C
1-C
6) alkyl;
B contains one or more nitrogen and optional one or more heterocycle/ring systems that are selected from the monocycle or the dicyclo of oxygen or sulphur atom for 4-11 unit, this nitrogen is connected with pyridine ring (according to formula I), precondition is that B is not a piperazine, and in addition, B ring/ring system is connected with X on other position in ring.Substituent R
14And R
15Can (not be connected) the formation quaternary ammonium compound with B ring/ring system ways of connecting by these.
The 3rd embodiment of formula I is defined as:
R
1Expression R
6OC (O), R
16SC (O) or following gII group:
R
2Expression is optional by the isolated (C of oxygen
1-C
6) alkyl, wherein alkyl is replaced by one or more halogens (F, Cl, Br, I) atom; In addition, R
2(the C that expression is replaced by one or more halogens (F, Cl, Br, I) atom
1-C
6) alkoxyl group;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom; In addition, R
3Optional (the C that is replaced by one or more halogens (F, Cl, Br, I) atom of expression
1-C
6) alkoxyl group; In addition, R
3Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkylthio C (O), (C
1-C
6) alkyl C (S), (C
1-C
6) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
6) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
6) alkyl C (O), (C
1-C
6) alkyl sulphinyl or formula NR
A (3)R
B (3)Group, wherein R
A (3)And R
B (3)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (3)And R
B (3)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
4Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: OH, COOH, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom; In addition, R
4Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxyl group, wherein alkoxyl group can be chosen wantonly by following group and replace: one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or methoxycarbonyl; In addition, R
4Expression (C
1-C
6) alkylthio C (O), (C
1-C
6) alkyl C (S), (C
1-C
6) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
6) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
6) alkyl C (O) or formula NR
A (4)R
B (4)Group group, wherein R
A (4)And R
B (4)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (4)And R
B (4)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
Z represents O or does not exist;
R
5Expression H or (C
1-C
6) alkyl;
R
6Expression is optional by the isolated (C of oxygen
1-C
6) (precondition is that any this class oxygen must distance and R to alkyl
6At least 1 carbon atom of ester-oxygen that group connects) and/or the optional (C that is replaced by following group
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
6) alkyl, aryl or heterocyclic radical;
R
8Expression H, the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
8Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
14Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
6) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
14Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy or formula NR
A (14)R
B (14)Group, wherein R
A (14)And R
B (14)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), perhaps R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
6) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
15Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy or formula NR
A (15)R
B (15) group, wherein R
A (15)And R
B (15)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), perhaps R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Be ethyl;
R
cDo not exist or represent and do not replace or single replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylidene group oxygen base or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately separately and be independently selected from (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
B (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms; In addition, R
cExpression imino-(NH-), the imino-(NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylideneimino or N-
1-C
4) alkylideneimino (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is unsubstituted or is replaced by any above-mentioned substituting group list or polysubstituted; Preferred R
cExpression imino-or (C
1-C
4) alkylideneimino or unsubstituted or replaced or polysubstituted (C by any above-mentioned substituting group list
1-C
4) alkylidene group or (C
1-C
4) the oxo alkylidene group;
R
19When existing, represent H or (C
1-C
4) alkyl;
R
dExpression (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom and/or one or more following group replacement: CN, NO
2, (C
1-C
6) alkyl, (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) (the C that replaces of alkyl, halogen
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl or (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl;
X represents singly-bound, imino-(NH-), methylene radical (CH
2-), the imino-methylene radical (CH that is connected with B ring/ring system of carbon wherein
2-NH-), the methylene radical imino-(NH-CH that is connected with B ring/ring system of nitrogen wherein
2-), any carbon and/or nitrogen in these groups can be chosen wantonly by (C
1-C
6) the alkyl replacement; X also can represent (CH
2-)
nGroup, n=2-6 wherein, this group is optional to be undersaturated and/or to be selected from following substituting group and to replace by one or more: halogen, hydroxyl or (C
1-C
6) alkyl;
B contains one or more nitrogen and optional one or more heterocycle/ring systems that are selected from the monocycle or the dicyclo of oxygen or sulphur atom for 4-11 unit, this nitrogen is connected with pyridine ring (according to formula I), precondition is that B is not a piperazine, and in addition, B ring/ring system other position in ring is connected with X.Substituent R
14And R
15Can (not be connected) the formation quaternary ammonium compound with B ring/ring system ways of connecting by these.
The 4th embodiment of formula I is defined as:
R
1Expression R
6OC (O);
R
2(the C that expression is replaced by one or more halogens (F, Cl, Br, I) atom
1-C
4) alkyl;
R
3Expression H;
R
4Expression CN or halogen (F, Cl, Br, I);
Z does not exist;
R
5Expression H;
R
6Expression is optional by the isolated (C of oxygen
1-C
6) (precondition is that any this class oxygen must be apart from connecting R to alkyl
6At least 2 carbon atoms of the ester-oxygen of group) and/or the optional (C that is replaced by following group
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom;
R
14Expression H;
R
15Expression H;
R
cThere is not or represents unsubstituted (C
1-C
4) alkylidene group;
R
dExpression (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom and/or one or more following group replacement: CN, (C
1-C
6) alkyl, (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) (the C that replaces of alkyl, halogen
1-C
6) alkoxyl group;
X represents singly-bound or methylene radical (CH
2-); With
B contains one or more nitrogen and optional one or more monocyclic heterocycles/ring systems that are selected from oxygen or sulphur atom for 4-7 unit, and this nitrogen is connected with pyridine ring (according to formula I), and precondition is that B is not a piperazine, and in addition, B ring/ring system is connected with other locational X in the ring.Substituent R
14And R
15Can (not be connected) the formation quaternary ammonium compound with B ring/ring system ways of connecting by these.
The 5th embodiment of formula I is defined as:
R
1Be ethoxy carbonyl or isopropoxy carbonyl;
R
2Be selected from methyl fluoride, chloromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 1-fluoro ethyl, 2-fluorine oxyethyl group, 2,2,2-trifluoro ethoxy, difluoro-methoxy and 2,2-difluoroethoxy;
R
3Be H;
R
4Be selected from chlorine or cyano group;
Z does not exist;
R
5Be H;
R
6Be ethyl or sec.-propyl;
R
14Be H;
R
15Be H;
R
cDo not exist or be selected from methylene radical (CH
2-) or ethylidene (CH
2CH
2-);
R
dBe selected from normal-butyl, the 4-methylcyclohexyl, phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, 2-(trifluoromethoxy) phenyl, 4-(trifluoromethoxy) phenyl, the 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, the 2-chloro-phenyl-, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 2, the 4-dichlorophenyl, the 2-cyano-phenyl, the 3-cyano-phenyl, the 4-cyano-phenyl, the 3-p-methoxy-phenyl, the 2-naphthyl, 2, the 6-difluorophenyl, 4-fluoro-3-aminomethyl phenyl, 2-chloro-4-fluorophenyl, 2,3, the 6-trifluorophenyl, 2, the 4-difluorophenyl, 4-chloro-2-fluorophenyl, 5-fluoro-2-aminomethyl phenyl, 2-fluoro-5-aminomethyl phenyl, the 3-p-methoxy-phenyl, 3, the 4-difluorophenyl, 4-hydroxymethyl phenyl and 5-chloro-2-thienyl;
X represents singly-bound or methylene radical (CH
2-);
B is selected from 4-piperidines-1-subunit, 3-tetramethyleneimine-1-subunit and 3-azetidine-1-subunit, substituent R
14And R
15Can (not be connected) the formation quaternary ammonium compound with the mode of B ring/ring system by these.
In the 6th embodiment of formula (I), formula (I) is defined as any compound of following formula (Ia)-(Id):
In following formula Ia-Id, Z and R (remove R
5For H outer) different values as above define, and comprise previous embodiments.
In the 7th embodiment of formula (I), formula (I) is defined as any compound of following formula (Iaa)-(Idd);
In above-mentioned formula Iaa-Idd, Z and R (remove R
5, R
14And R
15All be that H is outer) different values as above define, and comprise previous embodiments.
The example of particular compound of the present invention can be selected from:
(1) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) Nikithan
(2) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(3) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(4) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(5) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(6) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(7) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(8) methyl 5-cyano group-2-(difluoromethyl)-6-{4-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(9) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(10) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(11) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(12) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(13) 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(14) 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(15) 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(16) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(17) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(18) 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
(19) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(20) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(21) 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(22) 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(23) 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(24) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(25) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(26) 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
(27) methyl 5-cyano group-2-(difluoromethyl)-6-{3-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
(28) 5-cyano group-6-[3-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
(29) 5-cyano group-6-[3-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
(30) 5-cyano group-2-(difluoromethyl)-6-{3-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
(31) 5-cyano group-2-(difluoromethyl)-6-{3-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
(32) 5-cyano group-6-[3-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
(33) 5-cyano group-2-(difluoromethyl)-6-(3-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl) Nikithan
(34) 6-(3-{[(butyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(35) 5-cyano group-6-[4-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
(36) 5-cyano group-6-[4-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
(37) 5-cyano group-2-(difluoromethyl)-6-{4-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(38) 5-cyano group-2-(difluoromethyl)-6-{4-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(39) 5-cyano group-6-[4-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
(40) 5-cyano group-2-(difluoromethyl)-6-(4-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl) Nikithan
(41) 6-(4-{[(butyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(42) 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(43) 5-cyano group-6-[3-(2-oxo-2-{[(2-phenylethyl) alkylsulfonyl] amino } ethyl) tetramethyleneimine-1-yl]-2-(trifluoromethyl) Nikithan
(44) 6-[3-(2-{[(5-chloro-2-thienyl) alkylsulfonyl] amino }-the 2-oxoethyl) tetramethyleneimine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(45) 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(46) 5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(47) 5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(48) 5-cyano group-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(49) 5-cyano group-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(50) 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(51) 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(52) 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(53) 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(54) 6-[3-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(55) 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(56) 5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(57) 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(58) 5-cyano group-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(59) 5-cyano group-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(60) 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(61) 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(62) 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(63) 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(64) 6-[4-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(65) 5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(66) 5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(67) 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(68) 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(69) 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(70) 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(71) 5-cyano group-2-(methyl fluoride)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(72) 5-cyano group-2-(methyl fluoride)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(73) 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(74) methyl 5-cyano group-2-(methyl fluoride)-6-{3-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
(75) 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(76) 5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(77) 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(78) 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(79) 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(80) 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(81) 5-cyano group-2-(methyl fluoride)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(82) 5-cyano group-2-(methyl fluoride)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(83) 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(84) methyl 5-cyano group-2-(methyl fluoride)-6-{4-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(85) 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(86) 5-cyano group-6-(3-{[(2-cyano group benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(87) 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(methyl fluoride) Nikithan
(88) 5-cyano group-2-(methyl fluoride)-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(89) 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(90) 5-cyano group-2-(methyl fluoride)-6-(3-{[(2,3,6-trifluoro-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(91) 5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(methyl fluoride) Nikithan
(92) 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(93) 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
(94) 5-cyano group-2-(difluoromethyl)-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(95) 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(96) 5-cyano group-2-(difluoromethyl)-6-(3-{[(5-fluoro-2-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(97) 5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
(98) 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(99) 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(100) 5-cyano group-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(101) 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(102) 5-cyano group-6-(3-{[(5-fluoro-2-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(103) 5-cyano group-6-(3-{[(2,3,6-trifluoro-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(104) 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(105) 5-cyano group-6-(4-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
(106) 5-cyano group-2-(difluoromethyl)-6-(4-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl) Nikithan
(107) 5-cyano group-2-(methyl fluoride)-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(108) 5-cyano group-6-(4-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(trifluoromethyl) Nikithan
(109) 5-cyano group-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(110) 5-cyano group-2-(difluoromethyl)-6-(4-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl) Nikithan
(111) 5-cyano group-2-(difluoromethyl)-6-(3-{[(3-methoxy-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(112) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan
(113) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan
(114) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan
(115) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan
(116) 6-(4-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(117) 5-cyano group-6-(4-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(methyl fluoride) Nikithan
(118) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-2-(chloromethyl)-5-cyano group Nikithan
(119) 5-cyano group-2-(difluoromethyl)-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(120) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-2-(chloromethyl)-5-cyano group Nikithan
(121) 5-cyano group-6-(3-{[(3,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
(122) 5-cyano group-6-(4-{[(3,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
(123) 5-cyano group-6-(4-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
(124) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2-fluorine oxyethyl group) Nikithan
(125) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-[(2,2, the 2-trifluoro ethoxy) methyl] Nikithan
(126) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-[(2,2, the 2-trifluoro ethoxy) methyl] Nikithan
(127) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(difluoro-methoxy) Nikithan
(128) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
(129) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) Nikithan
(130) 5-cyano group-2-(difluoromethyl)-6-[3-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) azetidine-1-yl] Nikithan
(131) 5-cyano group-2-(difluoromethyl)-6-[4-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) piperidines-1-yl] Nikithan
(132) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
(133) 5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(134) 5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(135) 5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(2, the 2-difluoroethoxy) Nikithan
(136) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(difluoromethyl) isopropyl nicotinate
(137) 5-cyano group-6-[3-({ [(4-methylcyclohexyl) methyl] alkylsulfonyl } formamyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan;
And pharmacy acceptable salt.
Method
Provide following method together with intermediate product as another feature of the present invention.
A1-a9 preparation formula (I) compound by the following method;
A1) formula (I) compound, wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z, R
cAnd R
dAs definition in the following formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6), can pass through following formula (II) compound and the reaction of formula (III) compound are formed:
In the formula (II), R
1, R
2, R
3, R
4, B, Z, R
14And R
15As definition in the following formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6);
R
5-NHS?O
2-R
c-R
d (III)
R in the formula (III)
5, R
cAnd R
dAs definition in the following formula (I).
Generally at ambient temperature, in inert organic solvents such as methylene dichloride, carry out this reaction.Reaction can adopt standard conditions to carry out, and perhaps carries out in the presence of the combination of PyBrop, TBTU, EDCI or EDCI and HOBT.Optional reaction can be carried out in the presence of organic basess such as triethylamine or DIPEA.
A2) formula (I) compound, wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z, R
cAnd R
dAs definition in the following formula (I), X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members, can form by making following formula (IV) compound and general formula (III) compound reaction as defined above:
In the formula (IV), R
1, R
2, R
3, R
4, B, R
14And R
15As definition in the following formula (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.
Generally in inert solvents such as DCM, carry out this reaction.This reaction can be carried out in the presence of CDI.Optional reaction can be carried out in the presence of organic basess such as triethylamine, DBU or DIPEA.
A3) formula (I) compound, wherein R
1, R
2, R
3, R
4, B, R
14, R
15, Z, Rc and R
dAs definition in the following formula (I), R
5Be hydrogen, X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members, can be by making above-mentioned a2) in formula (IV) compound and following formula V compound reaction formation of definition:
O＝C＝N—SO
2-R
cR
d (V)
R wherein
cAnd R
dAs definition in the following formula (I).
Generally in inert solvents such as THF, carry out this reaction.Optional reaction can be carried out in the presence of organic basess such as triethylamine or DIPEA.
A4) formula (I) compound, wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z, R
cAnd R
dAs definition in the following formula (I), X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members, can form by making the reaction of formula defined above (IV) compound and following formula (VI) compound:
R
dR
c-SO
2NR
5-COOCH
2CCl
3 (VI)
R wherein
5, R
cAnd R
dAs definition in the following formula (I).Generally in the DMA equal solvent, carry out this reaction.Optional reaction can be carried out in the presence of organic basess such as triethylamine or DIPEA.
A5) formula (I) compound also can prepare by following formula (VII) compound and general formula (VIII) compound are reacted:
In the formula (VII), R
1, R
2, R
3, R
4With definition in Z such as the following formula (I), L is suitable leavings group, for example chlorine, bromine, iodine, fluorine, trifluoromethanesulfonic acid base (OTf) or toluenesulphonic acids base (OTs),
In the general formula (VIII), B, X, R
5, R
14, R
15, R
cAnd R
dAs definition in the following formula (I).
Generally in inert solvents such as DMA, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
Generally at high temperature, adopt standard equipment or in single node microwave oven (single-nodemicrowave oven), carry out this reaction.
For some compound, it is favourable carrying out this reaction in the presence of organic basess such as triethylamine or DIPEA.
A6) formula (I) compound, wherein R
1Expression R
6OC (O), R
2, R
3, R
4, B, R
5, R
6, R
14, R
15, X, Z, R
cAnd R
dAs definition in the above-mentioned formula (I), can adopt standard method to carry out transesterify, perhaps by with R
6'-O-Li
+Reagent react is to form other compound of general formula (I), wherein R
1Become R
6OC (O).
A7) formula (I) compound, wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z and R
dAs definition in the above-mentioned formula (I), Rc represents that imino-(NH-) or (C
1-C
4) alkyl imino, wherein imino-can be chosen wantonly in the presence of highly basic such as NaH, adopts standard conditions or uses alkylating agent such as L-R
19Replace, obtain formula (I) compound, alkylating agent L-R
19In, R
19As definition in the above-mentioned formula (I), L is for example chlorine, bromine, iodine, trifluoromethanesulfonic acid base (OTf) or a toluenesulphonic acids base (OTs) of leavings group, in the gained formula (I), and R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z and R
dAs definition in the above-mentioned formula (I), R
cImino-(the NR that expression N-replaces
19-) or (C that replaces of N-
1-C
4) alkyl imino (N (R
19)-((C
1-C
4) alkyl).
A8) formula (I) compound, wherein R
1, R
3, R
4, B, R
5, R
14, R
15, X, Z, R
cWith definition in Ru such as the above-mentioned formula (I), R
2(C for definition in the above-mentioned formula (I)
1-C
12) alkoxyl group, can prepare by following formula (IX) compound and following formula (X) compound are reacted:
In the formula (IX), R
1, R
3, R
4, B, R
5, R
14, R
15, X, Z, R
cAnd R
dAs definition in the above-mentioned formula (I),
L-R
2’ (X)
In the formula (X), (C of R2 ' for being replaced by one or more halogen atoms
1-C
12) alkyl, L is a leavings group, for example chlorine, bromine, iodine, trifluoromethanesulfonic acid base (OTf) or toluenesulphonic acids base (OTs).
This is reflected at DMA, THF or CH
3Carry out in the inert organic solvents such as CN.Can adopt standard conditions or in the presence of suitable alkali such as sodium hydride, DIPEA, silver carbonate or salt of wormwood, carry out this reaction.
Can be at ambient temperature or at high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
A9) formula (I) compound, wherein R
1, R
3, R
4, B, R
5, R
6, R
14, R
15, X, R
cAnd R
dAs definition in the above-mentioned formula (I), R
2(C for the replacement of definition in the above-mentioned formula (I)
1-C
12) alkoxyl group, can be by making (the C of following formula (IXA) compound and corresponding replacement
1-C
12) alcohol reaction prepares:
In the formula (IXA), R
1, R
3, R
4, Z, B, R
5, R
6, R
14, R
15, X, R
cAnd R
dAs definition in the above-mentioned formula (I), L is suitable leavings group, for example Cl, Br, I, toluenesulphonic acids base (OTs) or trifluoromethanesulfonic acid base (OTf).
Can adopt standard conditions or (for example or Pd (PPh at palladium catalyst
3)
4Or Pd
2(dba)
3) exist down and suitable phosphine part (phosphine ligand) (PPh for example
3Or 9,9-dimethyl-4, two (diphenyl phosphine) xanthenes (XANTPHOS) of 5-) make up and carry out this reaction.Can be in inert solvents such as DCM, THF Huo diox, choose wantonly in the presence of alkali such as DIPEA and carry out this reaction.
Can be at ambient temperature or at high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
Above-mentioned intermediate product can prepare by for example following method/step.
B1) formula (II) compound, wherein R
1, R
2, R
3, R
4, B, Z, R
14And R
15As definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6), can prepare by formula defined above (VII) compound and following general formula (XII) compound are reacted:
In the formula (XII), B, R
14, R
15As definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6).
Generally at high temperature, adopt standard equipment or in single node microwave oven, carry out this reaction.Can for example carry out this reaction in ethanol, DMA or the solvent mixture (for example alcohol-water) at inert solvent.Choose wantonly in the presence of organic basess such as TEA or DIPEA and carry out this reaction.
B2) formula (II) compound, wherein R
1, R
3, R
4, B, Z, R
14And R
15As definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6), R
2(C for definition in the above-mentioned formula (I)
1-C
12) alkoxyl group, can prepare by following formula (IIB) compound and formula (X) compound are as defined above reacted, in the formula (IIB), R
1, R
3, R
4, B, Z, R
14And R
15As definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6).
At DMA, THF or CH
3Carry out this reaction in the inert organic solvents such as CN.Can adopt standard conditions or in the presence of suitable alkali such as sodium hydride, DIPEA, silver carbonate or salt of wormwood, carry out this reaction.
Can be at ambient temperature or at high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
B3) formula (II) compound, wherein R
1, R
3, R
4, B, Z, R
14And R
15As definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6), R
2(C for definition in the above-mentioned formula (I)
1-C
12) alkoxyl group, can be by making (the C of following formula (IIA) compound and corresponding replacement
1-C
12) alcohol reaction prepares:
In the formula (IIA), R
1, R
3, R
4, B, Z, R
14And R
15As definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6), L is suitable leavings group, for example Cl, Br, I, toluenesulphonic acids base (OTs) or trifluoromethanesulfonic acid base (OTf).
Can adopt standard conditions (for example or Pd (PPh at palladium catalyst
3)
4Or Pd
2(dba)
3) exist down and suitable phosphine part (PPh for example
3Or 9,9-dimethyl-4, two (diphenyl phosphine) xanthenes of 5-) make up and carry out this reaction.
Can be in inert solvents such as DCM, THF Huo diox, choose wantonly in the presence of alkali such as DIPEA and carry out this reaction.
Can be at ambient temperature or at high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
C1) formula (IV) compound can prepare by formula (VII) compound and following formula (XIII) compound are reacted as defined above, in the formula (XIII), and B, R
14, R
15As definition in the above-mentioned formula (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.
Generally at high temperature, adopt standard equipment or in single node microwave oven, carry out this reaction.Can for example carry out this reaction in ethanol, DMA or the solvent mixture (for example alcohol-water) at inert solvent.Choose wantonly in the presence of organic basess such as TEA or DIPEA and carry out this reaction.
C2) above-mentioned general formula (IV) compound, wherein R
1, R
3, R
4, B, Z, R
14, R
15Suc as formula definition in (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members, R
2(C for definition in the above-mentioned formula (I)
1-C
12) alkoxyl group, can prepare by following formula (IVB) compound and formula (X) compound are as defined above reacted, in the formula (IVB), R
1, R
3, R
4, B, Z, R
14, R
15Suc as formula definition in (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.
At DMA, THF or CH
3Carry out this reaction in the inert organic solvents such as CN.Can adopt standard conditions or in the presence of suitable alkali such as sodium hydride, DIPEA, silver carbonate or salt of wormwood, carry out this reaction.
Can be at ambient temperature or at high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
C3) above-mentioned general formula (IV) compound, wherein R
1, R
3, R
4, B, Z, R
14, R
15Suc as formula definition in (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members, R
2(C for definition in the above-mentioned formula (I)
1-C
12) alkoxyl group, can be by making (the C of following formula (IVA) compound and corresponding replacement
1-C
12) alcohol reaction prepares:
In the formula (IVA), R
1, R
3, R
4, B, Z, R
14, R
15Suc as formula definition in (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members, L is suitable leavings group, for example Cl, Br, I, toluenesulphonic acids base (OTs) or trifluoromethanesulfonic acid base (OTf).
Can adopt standard conditions (for example or Pd (PPh at palladium catalyst
3)
4Or Pd
2(dba)
3) exist down and suitable phosphine part (PPh for example
3Or 9,9-dimethyl-4, two (diphenyl phosphine) xanthenes of 5-) make up and carry out this reaction.
Can be in inert solvents such as DCM, THF Huo diox, choose wantonly in the presence of alkali such as DIPEA and carry out this reaction.
Can be at ambient temperature or at high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
D) synthetic the comprising the following steps (d1-d5) of general formula (XXX) compound,
In the formula (XXX), R
2, R
3, R
4, B, R
8, R
14And R
15As definition in the above-mentioned formula (I), X
Be carbon, singly-bound or (CH
2-)
n(n=2-6).
D1) make accordingly general formula (XII) compound and the reaction of following general formula (XXI) compound as defined above, obtain formula (XXII) compound:
In the general formula (XXI), R
2, R
3And R
4As definition in the above-mentioned formula (I), L is suitable leavings group, for example chlorine, bromine, iodine, trifluoromethanesulfonic acid base (OTf) or toluenesulphonic acids base (OTs).
At high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.Choose wantonly in the presence of organic basess such as TEA or DIPEA and carry out this reaction.
D2) then with following formula (XXII) compound and the reaction of following general formula (XXIII) compound, obtain general formula (XXIV) compound:
In the formula (XXIII), R
8As definition in the above-mentioned formula (I).Adopt standard conditions or in the presence of the combination of EDCI or EDCI and HOBT, carry out this reaction.Choose wantonly in the presence of organic basess such as TEA or DIPEA and carry out this reaction.
D3) can will should change into general formula (XX) compound by (XXIV) compound then.
D4) adopt for example methylsulfonyl chloride of currently known methods or known agent, prepare following general formula (XX) compound:
R wherein
2, R
3, R
4, B, R
8, R
14And R
15As definition in the above-mentioned formula (I), X is carbon, singly-bound or (CH
2-)
n(n=2-6).Choose wantonly and can in the presence of organic basess such as TEA, carry out this reaction.
D5) adopt for example DDQ of known oxygenant, prepare general formula (XXX) compound as defined above by the corresponding general formula of oxidation (XX) compound.
E) preparation of general formula (XXX) compound also comprises the following steps (e1-e4):
E1) adopt standard conditions or in the presence of the combination of EDCI or EDCI and HOBT, following general formula (XXXI) compound and general formula (XXXII) compound reacted:
In the general formula (XXXI), R
2, R
3And R
4As definition in the above-mentioned formula (I), in the general formula (XXXII), R
8As definition in the above-mentioned formula (I).
Choose wantonly and can in the presence of organic basess such as TEA, carry out this reaction.This reaction obtains general formula (XXXIII) compound.
E2) adopt for example POCl of known technology or use known agent
3, resulting following general formula (XXXIII) compound can be changed into following general formula (XXXIV) compound then:
In the formula (XXXIV), R
2, R
3, R
4And R
8As definition in the above-mentioned formula (I).
E3) can adopt known technology or reagent such as oxalyl chloride or thionyl chloride then, make general formula (XXXIV) compound be converted into following general formula (XXXV) compound:
R wherein
2, R
3, R
4, R
8As definition in the above-mentioned formula (I), L is abundant leavings group, for example chlorine, bromine, iodine, trifluoromethanesulfonic acid base (OTf) or toluenesulphonic acids base (OTs).
E4) can make formula (XXXV) compound and general formula (XII) compound reaction as defined above then, obtain general formula (XXX) compound.At high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.Choose wantonly in the presence of organic basess such as TEA or DIPEA and carry out this reaction.
F) following general formula (XXXVI) compound comprises the following steps (f1-f4), in the formula (XXXVI), and R
2, R
3, R
4, B, R
8, R
14And R
15As definition in the above-mentioned formula (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.
F1) make general formula (XIII) compound and general formula (XXI) compound reaction as defined above as defined above, obtain following general formula (XXVIII) compound.
At high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.Choose wantonly in the presence of organic basess such as TEA or DIPEA and carry out this reaction.
F2) formula (XXVIII) compound can with the reaction of formula (XXIII) compound as defined above, obtain following general formula (XXIX) compound.Adopt standard conditions or in the presence of the combination of EDCI or EDCI and HOBT, carry out this reaction.Choose wantonly and can in the presence of organic basess such as TEA or DIPEA, carry out this reaction.
F3) adopt for example methylsulfonyl chloride of currently known methods or enough reagent, this compound can be changed into following general formula (XXVI) compound then:
R wherein
2, R
3, R
4, B, R
8, R
14And R
15As definition in the above-mentioned formula (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.Choose wantonly and can in the presence of organic basess such as TEA, carry out this reaction.
F4) then can by oxidation as defined above general formula (XXVI) compound prepare (XXXVI) compound.Can adopt reagent such as standard conditions or DDQ to carry out this reaction.
G) preparation of general formula (II) compound comprises the following steps (g1-g2), R in the formula (II)
1Be R
7C (O), R
2, R
3, R
4, R
7, B, R
14And R
15As definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6).
G1) make above-mentioned general formula (XXII) compound and N, the reaction of O-dimethyl hydroxylamine.Adopt known agent (as the combination of CDI, EDCI or EDCI and HOBT) to carry out this reaction, obtain following general formula (XXXVIII) compound.
G2) make general formula (XXXVIII) compound and general formula R as defined above
7-MgX ' reagent or formula R
7-M reagent react, R
7Among-the MgX ', R
7As definition in the above-mentioned formula (I), X ' is a halogen, and among the formula R7-M, M is a metal, for example Zn and Li.
H) preparation of general formula (IV) compound comprises the following steps (h1-h2), in the formula (IV), and R
1Be R
7C (O), R
2, R
3, R
4, R
7, B, R
14And R
15As definition in the above-mentioned formula (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.
H1) make general formula (XXVIII) compound and N as defined above, the reaction of O-dimethyl hydroxylamine.Can adopt known agent (as the combination of CDI, EDCI or EDCI and HOBT) to carry out this reaction, obtain following general formula (XLI) compound.
H2) as defined above general formula (XLI) compound can with general formula R
7-MgX ' reagent or formula R
7-M reagent react, formula R
7Among-the MgX ', R
7As definition in the above-mentioned formula (I), X ' is a halogen, formula R
7Among-the M, M is a metal, for example Zn and Li.
I) one of (i1-i4) forms general formula (VIII) compound set by step.R wherein
5For formula (VIII) compound of hydrogen preferably is separated into zwitter-ion.Being used for formula (XII) compound of the following step and the ring nitrogen of formula (XIII) compound can be protected by protecting group (for example tert-butoxycarbonyl).
I1) can form general formula (VIII) compound by making the reaction of formula (XII) compound and formula (III) compound, in the formula (VIII), B, R
5, R
14, R
15, R
cAnd R
dAs definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6).Generally at ambient temperature, in inert organic solvents such as methylene dichloride, carry out this reaction.Can adopt standard conditions or in the presence of the combination of EDCI or EDCI and HOBT, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
I2) can form general formula (VIII) compound by making as defined above formula (XIII) compound and formula V compound reaction as defined above, in the formula (VIII), R
5Be hydrogen, B, R
14, R
15, R
cAnd R
dAs definition in the above-mentioned formula (I), X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members.Generally in inert solvents such as THF, carry out this reaction.Also can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
I3) also can form general formula (VIII) compound, B, R in the formula (VIII) by making formula (XIII) compound and the reaction of formula (VI) compound as defined above
5, R
14, R
15, R
cAnd R
dAs definition in the above-mentioned formula (I), X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members.Generally in the DMA equal solvent, carry out this reaction.Also can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
I4) can adopt reagent such as standard method or HCl or TFA, formula (VIII) compound of tert-butoxycarbonyl protection is converted into the compound of unprotect base.
J) can adopt standard conditions or with halide reagent (for example oxalyl chloride, thionyl chloride, POCl
3Or POBr
3), make formula (XLVI) compound reaction formation general formula (VII) compound as defined above.Best available dimethyl formamide is as catalysts.Can in the presence of inert solvents such as methylene dichloride or toluene, carry out this reaction.Inert solvent is preferably toluene.Perhaps, can adopt (Tf)
2O or TsCl, preferably in the presence of alkali such as DIPEA or triethylamine, carry out this reaction.Can in inert solvents such as methylene dichloride or THF, carry out this reaction.
K) preparation of general formula (XLVII) compound comprises the following steps (k1-k3) as defined above:
K1) make following general formula (XLVIII) compound and general formula (XXIII) compound reaction as defined above, obtain formula (IL) compound.
This reaction generally at ambient temperature, carry out in DCM.Can adopt standard conditions or in the presence of the combination of EDCI or EDCI and HOBT, carry out this reaction.Choose wantonly in the presence of organic basess such as TEA or DIPEA and carry out this reaction.
K2) can adopt standard conditions or oxygenant (for example mixture of oxalyl chloride and DMSO), make formula (IL) compound be converted into formula (L) compound:
K3) can adopt standard conditions or in the presence of (methoxycarbonyl amino-sulfonyl) triethyl ammonium hydroxide (Burgess reagent) then, make formula (L) compound be converted into general formula (XLVII) compound.This reaction is generally carried out in inert solvents such as THF.At high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
L) remove R
3For beyond the hydrogen as defined above the preparation of general formula (XLVIII) compound comprise the following steps (l1-l3);
L1) make wherein R
2And R
6As following formula (LI) compound and the dimethoxy-N of definition in the above-mentioned formula (I), the reaction of N-dimethyl methylamine obtains formula (LII) compound.
L2) can make then formula (LII) compound further with R4 such as above-mentioned formula (I) in the general formula R of definition
4CH
2C (O) NH
2Compound reaction obtains general formula (LIII) compound, generally in inert solvents such as ethanol, choose wantonly in the presence of highly basic such as sodium ethylate and carry out this reaction.
L3) general formula (LIII) compound can be converted into general formula (XLVIII) compound then.Generally in protonic solvent (for example water) and solubility promoter (for example THF or methyl alcohol), carry out this reaction.Can adopt standard reagent or in the presence of LiOH, NaOH or KOH, carry out this reaction.
M) general formula (XXX) compound can prepare by following synthesis step as defined above:
M1) can adopt standard conditions or employing Cu (II) O and quinoline, wherein R
8Following general formula (LIV) compound as definition in the above-mentioned formula (I):
Be converted into following formula (LV) compound:
M2) can make the reaction of general formula (LV) compound and following general formula (LVI) compound, obtain general formula (XXX) compound:
In the formula (LVI), R
2, R
3, R
4, B, R
14And R
15Suc as formula definition in (I), X is carbon, singly-bound or (CH
2-)
n(n=2-6).Generally under inert atmosphere, in inert solvents such as THF, carry out this reaction.Can adopt standard conditions or in the presence of lithium alkylide (for example butyllithium (BuLi)), carry out this reaction, use ZnCl subsequently
2And Pd (PPh
3)
4(preferred catalytic amount) handled.
N) general formula (XXXVI) compound also can prepare according to the following step:
N1) make general formula (LV) compound and the reaction of general formula (LVII) compound as defined above, in the formula (LVII), R
2, R
3, R
4, B, R
14And R
15As definition in the above-mentioned formula (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.Also can adopt standard conditions or in the presence of lithium alkylide (for example BuLi), carry out this reaction, use ZnCl subsequently
2And Pd (PPh
3)
4(preferred catalytic amount) handled.
O) general formula (IX) compound can prepare according to the following step o1-o2, in the formula (IX), and X, B, R
14, R
15, R
5, R
cAnd R
dSuc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist.
O1) make the reaction of following general formula (LVIII) compound and formula (LIX) compound, in the formula (LVIII), R
5, B, R
14, R
15, X, R
cAnd R
dAs defining in the above-mentioned formula (I):
Generally in inert organic solvents such as EtOH or DMSO, carry out this reaction.
At ambient temperature or at high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
O2) can adopt and Macconi, the described essentially identical method [Macconi of people such as A, A etc., J.Heterocyclic chemistry, 26, the 1859th page (1989)], by being reacted, general formula (VIII) compound and following formula (LX) compound prepare general formula defined above (LVIII) compound.
O3) can prepare above-mentioned general formula (IX) compound by following formula (IIB) compound and formula (III) compound are as defined above reacted, in the formula (IX), B, R
14, R
15, R
5, R
cAnd R
dSuc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist, and X is singly-bound, carbon atom or (CH
2-)
n(n=2-6), in the formula (IIB), B, R
14, R
15Suc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist, and X is singly-bound, carbon atom or (CH
2)
n(n=2-6).
Generally at ambient temperature, in inert organic solvents such as methylene dichloride, carry out this reaction.Can adopt standard conditions or in the presence of the combination of TBTU, EDCI, PyBrop or EDCI and HOBT, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
O4) following general formula (IIC) compound and formula (LIX) compound are as defined above reacted and prepare general formula (IIB) compound, in the formula (IIB), B, R
14And R
15Suc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist, and X is singly-bound, carbon atom or (CH
2-)
n(n=2-6), in the general formula (IIC), R
14, R
15Define suc as formula (I) is middle with B, X is singly-bound, carbon atom or (CH
2-)
n(n=2-6).
Generally in inert organic solvents such as EtOH or DMSO, carry out this reaction.
At ambient temperature or at high temperature, adopt standard equipment or single node microwave oven to carry out this reaction.
O5) can adopt and Macconi, the described essentially identical method [Macconi of people such as A, A etc., J.Heterocyclic chemistry, 26, the 1859th page (1989)], by being reacted, general formula defined above (XII) compound and formula (LX) compound prepare general formula defined above (IIC) compound.
O6) can prepare above-mentioned general formula (IX) compound by following formula (IVB) compound and formula (III) compound are as defined above reacted, in the formula (IX), B, R
14, R
15, R
5, R
cAnd R
dSuc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist, and X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members, and in the formula (IVB), B, R
14, R
15Suc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist, and X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.
Generally in inert solvents such as DCM, carry out this reaction.Can in the presence of CDI, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine, DBU or DIPEA, carry out this reaction.
O7) can be by making as above-mentioned o6) in formula (IVB) compound of definition and logical formula V compound defined above react and prepare above-mentioned general formula (IX) compound, in the formula (IX), B, R
14, R
15, R
cAnd R
dSuc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist, R
5Be hydrogen, X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members.
Generally in inert solvents such as THF, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
O8) can be by making as above-mentioned o6) in formula (IVB) compound of definition react with general formula (VI) compound as defined above and prepare above-mentioned general formula (IX) compound, in the formula (IX), B, R
14, R
15, R
5, R
cAnd R
dSuc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist, and X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members.
Generally in inert solvents such as DMA, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
O9) can according to above-mentioned steps o4)-o5) described in essentially identical method, by formula (XIII) compound general formula (IVB) compound, in the formula (IVB), B, R
14, R
15Suc as formula definition in (I), R
1Be R
6OC (O), R
3Be H, R
4Be CN, Z does not exist, and X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.
P1) can adopt standard conditions or with halide reagent (for example oxalyl chloride, thionyl chloride, POCl
3Or POBr
3), above-mentioned formula (IIB) compound is reacted prepare general formula (IIA) compound as defined above, in the formula (IIB), R
1, R
3, R
4, B, Z, R
14And R
15As definition in the above-mentioned formula (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6).DMF preferably can be used as catalysts.Can in the presence of inert solvents such as methylene dichloride or toluene, carry out this reaction.
Perhaps, can adopt (Tf)
2O or TsCl, preferably in the presence of alkali such as DIPEA or triethylamine, carry out this reaction.Can in inert solvents such as methylene dichloride or THF, carry out this reaction.
P2) can adopt standard conditions or with halide reagent (for example oxalyl chloride, thionyl chloride, POCl
3Or POBr
3), formula (IVB) compound is reacted prepare general formula (IVA) compound as defined above, in the formula (IVB), R
1, R
3, R
4, B, Z, R
14, R
15Suc as formula definition in (I), X is nitrogen, (CH
2-NH
2) or the hydrogen that is connected with the nitrogen that is the B ring members.DMF preferably can be used as catalysts.Can in the presence of inert solvents such as methylene dichloride or toluene, carry out this reaction.
Perhaps, can adopt (Tf)
2O or TsCl, preferably in the presence of alkali such as DIPEA or triethylamine, carry out this reaction.Can in inert solvents such as methylene dichloride or THF, carry out this reaction.
Q) can be by following method q1-q4 preparation formula (IXA) compound.
Q1) can adopt standard conditions or with halide reagent (for example oxalyl chloride, thionyl chloride, POCl
3Or POBr
3), formula (IX) compound is reacted prepare general formula (IXA) compound as defined above.DMF preferably can be used as catalysts.Can in the presence of inert solvents such as methylene dichloride or toluene, carry out this reaction.
Perhaps, can adopt (Tf)
2O or TsCl, preferably in the presence of alkali such as DIPEA or triethylamine, carry out this reaction.Can in inert solvents such as methylene dichloride or THF, carry out this reaction.
Q2) above-mentioned formula (IIA) compound and formula (III) compound are reacted and prepare general formula (IXA) compound, in the formula (IXA), R
1, R
3, R
4, B, Z, R
5, R
6, R
14, R
15, R
cAnd R
dSuc as formula definition in (I), X is singly-bound, carbon or (CH
2-)
n(n=2-6).
Generally at ambient temperature, in inert organic solvents such as methylene dichloride, carry out this reaction.Can adopt standard conditions or in the presence of the combination of PyBrop, TBTU, EDCI or EDCI and HOBT, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
Q3) can make formula (IVA) compound and the reaction of formula V compound as defined above forming general formula (IXA) compound, in the formula (IXA), R
1, R
3, R
4, B, Z, R6, R
14, R
15, R
cAnd R
dSuc as formula definition in (I), X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members.
Generally in inert solvents such as THF, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
Q4) can make formula (IV) compound and the reaction of formula (VI) compound as defined above forming general formula (IXA) compound, in the formula (IXA), R
1, R
3, R
4, B, Z, R
5, R
6, R
14, R
15, R
cAnd R
dSuc as formula definition in (I), X is nitrogen, (CH
2-NH-) or the singly-bound that is connected with the nitrogen that is the B ring members.
Generally in the DMA equal solvent, carry out this reaction.Choose wantonly and can in the presence of organic basess such as triethylamine or DIPEA, carry out this reaction.
R) preparation of following general formula (LXI) compound comprises the following steps, in the formula (LXI), and R
14And R
15Suc as formula definition in (I), just R
14Be connected on the same atom that is connected with X, X is defined as singly-bound:
R1) adopt standard conditions or in the presence of the mixture (to form LDA) of BuLi and Diisopropylamine, make (LXII) and R accordingly
14-L reaction is to form general formula (LXI) compound, R
14Among-the L, L is suitable leavings group, for example chlorine, bromine, iodine, trifluoromethanesulfonic acid base (OTf) or toluenesulphonic acids base (OTs).
S) preparation of formula (III) compound comprises the following steps (s1-s3).
S1) adopt a SMOPS
*Series reaction (
*Baskin and Wang, Tetrahedron Letters, 2002,43,8479-83. is especially referring to the 8480th page of left hand column), with formula LR
cR
dCompound is converted into corresponding compounds (III), at room temperature with alkali (as the NaOMe) hydrolysis that is dissolved in inert solvent (as DMSO), uses NH more subsequently
2OSO
3H and NaOAc handle, and obtain formula (III) compound.Formula LR
cR
dIn, L is suitable leavings group, for example chlorine, bromine, iodine.
S2) formula LSO
2R
cR
dCompound can with the ammonium hydroxide or the H that are dissolved in inert solvent (for example DCM)
2NR
5Reaction obtains formula (III) compound.Formula LSO
2R
cR
dIn, L is suitable leavings group, for example chlorine, bromine, iodine.
S3) an available NaSO
3Series reaction, make formula LR
cR
dCompound is converted into corresponding compounds (III), uses PCl subsequently
5, POCl
3Or SOCl
2Deng reagent, re-use ammonium hydroxide or H
2NR
5, obtain formula (III) compound.Formula LR
cR
dIn, L is suitable leavings group, for example chlorine, bromine, iodine.
In substituted any stage of pyridine synthetic of amine, all can adopt known technology, the halogenic substituent on 2,4 or 6 of pyridines is replaced by trinitride.Trinitride is reducible to be corresponding amine.Adopt currently known methods subsequently or, make these amino-alkylations or acidylate respectively with alkyl halide or etheride.
Those skilled in the art will appreciate that acid can be converted into corresponding active ester (for example acyl chlorides), subsequently with mercaptan R
16The SH reaction obtains thioesters R
16SC (O).
Those skilled in the art will appreciate that acid can be converted into corresponding active ester (for example acyl chlorides), subsequently with pure R
6The OH reaction obtains ester R
6OC (O).
Those skilled in the art will appreciate that and to use alkyl halide, on the carbon atom of sulphonamide α position, make formula (III) alkylation.Preferably under alkaline alkaline conditions such as use sodium hydride.
Those skilled in the art will appreciate that and adopt known technology or R
17SSR
17And nitrite tert-butyl, the nitrogen substituting group on 3 of the pyridines can be by thioether chain R
17The S-displacement.
Those skilled in the art will appreciate that and adopt known technology or use Lawessons reagent, can prepare thioketones by corresponding ketone.
Those skilled in the art will appreciate that when trifluoroacetic anhydride exists or do not exist, adopt oxygenant for example Urea Peroxide or hydrogen peroxide, can form pyridine N-oxides by pyridine.
Adopt routine techniques, compound of the present invention can be separated from its reaction mixture.
Those skilled in the art should be appreciated that, for with alternative and obtain compound of the present invention in more convenient in some cases mode, above-mentioned each treatment step all can be undertaken by different orders, and/or each reaction all can be carried out (being that different intermediate products all can be chemically converted into and the relevant intermediate product of above-mentioned concrete reaction) in the different steps of whole piece synthetic route.
The functional group that those skilled in the art will appreciate that the described method intermediate compound of this paper context base protection that may need protection.
The functional group that needs protection comprises hydroxyl, amino and carboxylic acid.The protecting group that hydroxyl is suitable comprises optional the replacement and/or undersaturated alkyl (for example methyl, allyl group, benzyl or the tertiary butyl), trialkylsilkl or alkyl diaryl silyl (for example t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl) and THP trtrahydropyranyl.The protecting group that carboxylic acid is suitable comprises (C
1-C
6) alkyl or benzyl ester.Amino suitable protecting group comprises allyl group, tert-butoxycarbonyl, benzyloxycarbonyl, 2-(trimethyl silyl) ethoxyl methyl or 2-trimethylsilylethoxy) carbonyl (Teoc).
In aforesaid method, the protection of functional group and deprotection can take place before or after any reaction.
Those skilled in the art should be appreciated that, for with alternative and obtain compound of the present invention in mode more easily in some cases, above-mentioned each treatment step all can be undertaken by different orders, and/or each reaction all can be carried out (be substituting group can be added on the different intermediate products in the above-mentioned stage relevant with concrete reaction and/or carry out chemical conversion on the different intermediate products in the above-mentioned stage relevant with concrete reaction) in the different steps of whole piece synthetic route.This may cancel the needs of protecting group, and the necessary needs to protecting group perhaps are provided.
The raw material that those skilled in the art will appreciate that any aforesaid method can be commercially available in some cases.
Those skilled in the art will appreciate that for some above-mentioned raw materials, can just can obtain by common sense.
The type of related chemical method can be stipulated the needs of protecting group and finish the synthetic order.
Protecting group use details can be referring to " Protective groups in Organic Chemistry (protecting group in the organic chemistry) ", J W F McOmie chief editor, Plenum Press (1973) and " Protective Groups in Organic Synthesis (protecting group in the organic synthesis) ", the third edition, T.W.Greene ﹠amp; P.G.M Wutz, Wiley-Interscince (1999).
But application standard deprotection technology (for example under alkalescence or acidic conditions) changes into compound of the present invention with the protected derivative of the present invention by chemical method.The technology of the present invention personnel will be appreciated that also some compound of formula (II)-(LXII) also can be described as " protected derivative ".
Compound of the present invention also can contain one or more unsymmetrical carbons, therefore can have optically-active and/or diastereomer phenomenon.Diastereomer can adopt routine techniques (for example chromatography or crystallization process) to separate.Also can use routine techniques such as HPLC separates various steric isomers by racemic mixture or other mixture that splits compound.Perhaps, by under the condition that does not cause racemization or epimerization, reaction by suitable optically-active raw material, perhaps by for example with homochiral acid derivatize, split non-enantiomer derivative by ordinary method (for example HPLC, silica gel chromatography or crystallization process) subsequently, prepare required optically active isomer.Also can introduce three-dimensional center by asymmetric synthesis (for example adopting the metal organic reaction of chiral ligand).All steric isomers all comprise within the scope of the invention.
All new intermediate products all constitute another aspect of the present invention.
Can be (for example optional by C by making free acid or its salt or free alkali or its salt or derivative and the appropriate base more than 1 equivalent
1-C
6Ammonium hydroxide or alkali metal hydroxide or alkaline earth metal hydroxides that-alkyl replaces) or acid (for example haloid acid (especially HCl), sulfuric acid, oxalic acid or phosphoric acid) reaction, thereby the salt of the formula of formation (I) compound.Salt is in undissolved solvent or the medium therein, perhaps therein salt be soluble solvent (for example water, ethanol, tetrahydrofuran (THF) or ether, but these vacuum are removed or by lyophilize) in react.Also can on ion exchange resin, react.Be preferably physiologically acceptable non-toxic salt, although can use other salt, for example when the isolated or purified product.
Pharmacology data
Can use P2Y
12The cytolemma of the Chinese hamster ovary celI of transfection is measured P2Y by the external test method
12The functional inhibition of acceptor, the method brief description is as follows.
2-Me-S-ADP inductive P2Y
12The functional inhibition of signal transduction: 5 μ g films are diluted in 200 μ l 200mM NaCl, 1mM MgCl
2, among 50mM HEPES (pH7.4), 0.01%BSA, 30 μ g/ml saponin(es and the 10 μ M GDP.To wherein adding EC
80The test compound of the agonist of concentration (2-methyl-sulfenyl-adenosine diphosphate (ADP)), desired concn and 0.1 μ Ci
35S-GTP γ S.Reaction was carried out 45 minutes.Use then cell harvester with sample transfer to GF/B filter paper, with lavation buffer solution (50mM Tris (pH7.4), 5mMMgCl
2, 50mM NaCl) washing.Filter paper covers with scintillator then, keeps on the statistics filter paper
35The amount of S-GTP γ S.Maximum activity is that agonist exists the amount of measuring down, and minimum activity is the non-existent amount of agonist, deducts the non-specific active value of being surveyed subsequently.According to following formula the effect of compound under the different concns is mapped:
y＝A+((B-A)/(1+((C/x)^D)))
Estimate IC
50, wherein
A is the bottom platform of curve, promptly final minimum y value
B is the top platform of curve, promptly final maximum y value
C is a curve intermediary x value.The log EC of this expression when A+B=100
50Value
D is a slope factor.
X is known initial x value.
Y is known initial y value.
When the about 4 μ M of concentration are following, at above-mentioned 2-Me-S-ADP inductive P2Y
12When measuring during the functional inhibition of signal transduction is measured, most of compounds of the present invention have activity.
Compound described in the embodiment 41 and 74 for example is at described 2-Me-S-ADP inductive P2Y
12In the functional inhibition assay method of signal transduction, obtain following test-results.
IC
50(μM)
Embodiment 41 0.49
Embodiment 74 0.27
The compounds of this invention can be used as P2Y
12Therefore receptor antagonist can be used for treatment.Therefore, according to another aspect of the invention, the formula that is provided for treating (I) compound or its pharmacy acceptable salt.
Aspect another, provide formula (I) compound or its pharmacy acceptable salt to be used for the treatment of purposes in the medicine of platelet aggregation obstacle in preparation.In the present invention on the other hand, provide formula (I) compound or its pharmacy acceptable salt to be used to suppress P2Y in preparation
12Purposes in the medicine of acceptor.
Described compound can be used for treatment, especially assisting therapy, they are needed in particular as following aspect: platelet activation, the inhibitor of gathering and threshing, thrombocyte depolymerization promotor, antithrombotic drug or be used for the treatment of or prevent following disease: unstable angina, coronary angioplasty (PTCA), myocardial infarction, periphery thrombolysis (perithrombolysis), atherosclerotic aorta thrombus forms complication for example thrombotic apoplexy or embolic stroke, transient ischemic attack, peripheral vascular disease, with or do not have a thromboclastic myocardial infarction, by angioplasty, endarterectomy, support is placed, atherosclerosis such as coronary vasodilator and other blood vessel grafting are got involved caused artery complication, operation or physical abuse (are for example organized behind accident or the operation wound and are remedied, the reconstruction operations that comprises skin and muscle flap) thrombosis complication, with the disease of dispersivity thrombus formation/platelet consumption composition disseminated inravascular coagulation for example, thrombocytopenic purpura,thrombotic, hemolytic uremic syndrome, septicemia thrombosis complication, adult respiratory distress syndrome, antiphospholipid syndrome, heparin-induced thrombocytopenia and preeclampsia/eclampsia or venous thrombosis be venous thrombosis for example, venous occlusive disease, hematologic diseases such as myeloproliferative diseases comprise thrombocythemia, drepanocytosis; Perhaps be used for prevention mechanicalness inductive platelet activation (for example cardiopulmonary bypass and extracorporeal membrane oxygenation (extracorporeal membraneoxygenation) (preventing small thromboembolism)) in the body, external mechanicalness inductive platelet activation (for example be used for the preservation of blood productss such as PC or in the shunting obturation (shunt occlusion) of kidney dialysis and plasmapheresis etc.), vasculitis for example, arteritis, glomerulonephritis, blood vessel injury such as inflammatory bowel and organ graft repulsion/inflammation secondary thrombus forms, disease such as migraine for example, Raynaud's phenomenon (Raynaud ' s phenomenon), thrombocyte may promote the illness of potential diseases associated with inflammation process in the vessel wall, for example atheromatous plaque formation/development, narrow/restenosis and other inflammatory conditions, asthma for example, wherein the Immunological diseases process relates to thrombocyte and platelet derived growth factor.
The present invention also provides The compounds of this invention to be used for the treatment of purposes in the medicine of above-mentioned disease in preparation.Compound of the present invention is used in particular for treating myocardial infarction, thrombotic apoplexy, transient ischemic attack, peripheral vascular disease and stenocardia, especially unstable angina.The present invention also provides the method for the above-mentioned disease of treatment, and this method comprises the The compounds of this invention of the patient treatment significant quantity of suffering from this class disease.
Aspect another, provide the pharmaceutical composition that comprises formula (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable thinner, auxiliary and/or carrier of the present invention.
Compound can topical administration, and for example the form with solution, suspensoid, HFA aerosol and dry powder formulations gives lung and/or air flue; Perhaps can give by whole body, for example with the form oral administration of tablet, pill, capsule, syrup, powder or granule, perhaps with the form parenteral admin of aseptic parenteral solution or suspensoid, by subcutaneous administration or with the form rectal administration or the percutaneous dosing of suppository.
Compound of the present invention can be individually dosed, perhaps as the pharmaceutical composition administration that comprises The compounds of this invention and pharmaceutically acceptable thinner, auxiliary or carrier.Particularly preferably be composition and do not contain the material that can cause untoward reaction (for example atopic reaction).
But administration is gone in the dry powder formulations of The compounds of this invention and compressed suction of HFA aerosol through port or snuffing.As for the fine degree that sucks compound is gratifying.Compound of the present invention also can give by Diskus.Sucker can be single dose or multi-dose inhaler, and can be manual Diskus.
A kind of feasible way is with miniaturization compound and for example carrier substance mixings such as monose, disaccharide, polysaccharide, sugar alcohol or other polyvalent alcohol.Suitable carriers comprises sugar and starch.Perhaps, the miniaturization compound can be with other material dressing.Powdered mixture also can divide and installs in the hard gelatin capsule, and each contains the active compound of required dosage.
Another feasible way is that fines is processed at suction process dispersive spheroid.The nodularization powder filling can be gone into multi-dose inhaler (for example is called
Sucker) drug reservoir in, wherein dosing unit measures required dosage, this dosage is sucked by the patient then.The active compound that will contain or not contain carrier substance with this system is delivered to the patient.
For oral administration, the pharmaceutical composition that comprises The compounds of this invention can be tablet, pill, capsule, syrup, powder or granule easily; For parenteral admin is aseptic parenteral or subcutaneous solution, suspensoid; Be suppository perhaps for rectal administration.
For oral administration, active compound can be pressed into tablet after following composition mixes again: auxiliary or carrier, for example starch, derivatived celluloses such as lactose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, yam starch, W-Gum or amylopectin, tackiness agent are for example Magnesium Stearate, calcium stearate, polyoxyethylene glycol, wax, paraffin etc. of gelatin or polyvinylpyrrolidone and lubricant for example.Coated tablet if desired, as above Zhi Bei label can be with containing for example concentrated sugar solution dressing of Sudan Gum-arabic, gelatin, talcum powder, titanium dioxide etc.Perhaps, tablet can be with the suitable polymers dressing that is dissolved in volatile organic solvent or the water-containing solvent.
For the preparation of Gelseal, compound can mix mutually with for example vegetables oil or polyoxyethylene glycol.Can use above-mentioned tablet excipient (for example lactose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch, derivatived cellulose) or gelatin, with the granule of the compound hard gelatin capsule of packing into.Also the liquid preparation or the semi-solid preparation of medicine can be filled in the hard gelatin capsule.
Liquid preparation for oral use can be the form of syrup or suspensoid, for example contains the solution of compound, so that the mixture equilibrium of sugar and ethanol, water, glycerine and propylene glycol.Optional this class I liquid I preparation can contain tinting material, correctives (for example asccharin) and thickening material (for example carboxymethyl cellulose) or other vehicle well known by persons skilled in the art.
Further specify the present invention with following non-limiting example below:
Embodiment
General experimental program
Mass spectrum Finnigan LCQ Duo ion trap mass spectrometer record, the LC-ms system that this mass spectrograph has been equipped with electron spray(ES) interface (LC-ms) or has been made up of the Waters ZQ that adopts the LC-Agilent1100LC system.
1H NMR measures and to carry out with Varian Mercury VX 400 spectrometers, respectively by 400 and Varian UNITY add the 1H frequency of 400,500 and 600 spectrometers, under 400,500 and 600 1H frequency, operate.The chemical shift solvent is marked with ppm in being and provides.Only be reported in proton on the heteroatoms that detects among the NMR (N for example
HAnd O
HProton), thus the proton on the heteroatoms may omit.Chromatography is carried out with Biotage silica gel 40S, 40M, 12i or Merck silica gel 60 (0.063-0.200mm).Flash chromatography is with normal glass post or plastic column or carry out in Biotage Horizon system.HPLC separates available WatersYMC-ODS AQS-3 120 Angstrom, 3 x 500mm or use Kromasil C8 in Waters Delta preparation system, and 10 μ m posts carry out.
The purification system and the LC-MS system that are used for following method A-E are Waters FractionLynx II purification system: post: Sunfire Prep C18,5 μ m OBD, 19 x 100mm posts.Gradient is 5-95%CH
3The 0.1mM HCOOH solution (pH=3) of CN.The fraction collector that adopts MS to trigger.Mass spectrum single four utmost points of ZQ or the Micromass quattro micro mass spectrograph record that has been equipped with pneumatic auxiliary electrical spraying interface.
Being reflected among Personal Chemistry Smith Creator, Smith synthesizer or the Emrys Optimizer of carrying out in microwave reactor carried out.
Used abbreviation table look-up:
Abbreviation
Explanation
AcOH acetate
The aq aqueous solution
The br broad peak
The salt solution saturated aqueous sodium chloride
The BSA bovine serum albumin
(Boc)
2The O tert-Butyl dicarbonate
The BuLi butyllithium
The CDI carbonyl dimidazoles
D is bimodal
DBU 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
The DCM methylene dichloride
DDQ 2,3-two chloro-5,6-dicyano-1,4-benzoquinones
DIPEA N, the N-diisopropylethylamine
The DMA N,N-dimethylacetamide
DMAP N, N-lutidine-4-amine
DMF N, dinethylformamide
The DMSO methyl-sulphoxide
EDCI N-[3-(dimethylamino) propyl group]-N '-ethyl carbodiimide
Hydrochloride
The EtOAc ethyl acetate
EtOH ethanol
H hour
HATU phosphofluoric acid O-(7-azepine benzotriazole-1-
Base)-1,1,3, the 3-tetramethyl-urea
HEPES 4-(2-hydroxyethyl)-1-piperazine ethyl sulfonic acid
The HFA hydro fluoroalkanes
HOAc acetate
The HOBT I-hydroxybenzotriazole
The HPLC high performance liquid chromatography
The Hz hertz
The IPA Virahol
The J coupling constant
The LDA lithium diisopropylamine
The m multiplet
The Me methyl
The MHz megahertz
Min minute
The ml milliliter
The MS mass spectrum
NCS N-neoprene imide
OAc acetate (salt/ester)
The iPrOAc isopropyl acetate
PyBrop phosphofluoric acid bromine (tripyrrole alkane-1-base) Phosphonium
The q quartet
The r.t room temperature
S is unimodal
The t triplet
TB Tyrodes damping fluid
The TBDMSCl tertiary butyl (chlorine) dimethylsilane
The TBME t-butyl methyl ether
TBTU Tetrafluoroboric acid N-[(1H-1,2,3-benzotriazole-1-base oxygen
Base) (dimethylamino) methylene radical]-N-methyl first ammonium
The TEA triethylamine
The Tf trifyl
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
TMEDA N, N, N ', N '-tetramethylethylened
The Ts p-toluenesulfonyl
Synthesizing of sulphonamide (sulfone amide)
One of the following three kinds of methods of synthetic usefulness that are used for the sulphonamide of following examples are carried out:
I) make the THF or the MeOH solution reaction of corresponding SULPHURYL CHLORIDE and ammonia, perhaps handle with the dichloromethane solution of ammonium hydroxide.The gained sulphonamide need not to be further purified just and can use.
Ii) substantially according to Seto, the described method of people such as T. (Seto, T. etc., J.OrganicChemistry, the 68th volume, the 10th phase (2003), 4123-4125 page or leaf) is carried out.
Perhaps
Iii) substantially according to Wang, the described method of people such as Z (Wang, Z etc., TetrahedronLetters, the 43rd volume (2002), 8479-8483 page or leaf) is carried out.
Embodiment's is synthetic
Following universal method (being method A-E) is used for preparing some compound of following examples and relates to each specific embodiment.
The example of method A: embodiment 10 methods
With DIPEA (64mg, 0.5mmol) be added to 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid (35.3mg, 0.1mmol) and TBTU (38.5mg, 0.12mmol) DCM (5ml) solution in, with mixture at room temperature stir add after 30 minutes 1-(2-fluorophenyl) Toluidrin that is dissolved in DCM (1ml) (23mg, 0.12mmol).The reactant stirring is spent the night.LC-MS shows and to still have residual raw material, again with TBTU (19mg, 0.06mmol) and DIPEA (26mg 0.2mmol) is added in the mixture, continues stirring 2 hours again.Reaction mixture 1%KHSO
4Washing, water extracts with DCM (1ml), and the organic phase of merging is evaporated in vacuum centrifuge by behind the phase splitter.The gained crude product obtains 5-cyano group-2-(difluoromethyl)-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl with HPLC purifying (referring to general experimental technique)] Nikithan.Output: 41mg (78%).
The example of method B: embodiment 42 methods
With DIPEA (128mg, 1.0mmol) be added to 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] tetramethyleneimine-3-yl acetate (74.2mg, 0.2mmol) and TBTU (77mg, 0.24mmol) DCM (7ml) solution in, after mixture at room temperature stirred 30 minutes, (41mg 0.24mmol), makes the reactant standing over night to add the 1-phenyl methanesulfonamide acid amides that is dissolved in DCM (1ml).Reaction mixture 1%KHSO
4Washing, water extracts with DCM, and the organic phase of merging is evaporated in vacuum centrifuge by behind the phase splitter.The gained crude product obtains 6-(3-{2-[(benzyl alkylsulfonyl) amino with HPLC purifying (referring to general experimental technique)]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 88mg (84%).
The example of method C: embodiment 55 methods
With DIPEA (43mg, 0.3mmol) and TBTU (64mg, 0.20mmol) be added to 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid (74.2mg, 0.2mmol) DMF solution in, after mixture at room temperature stirred 2 hours, be added to 1-(4-fluorophenyl) Toluidrin that is dissolved in DMF (38mg, 0.22mmol) in.With reaction mixture stir spend the night after, by the SCX-2 ion exchange column.The gained crude product obtains 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl with HPLC purifying (referring to general experimental technique)]-2-(trifluoromethyl) Nikithan.Output: 4.3mg (4%).
The example of method D: embodiment 45 methods
With CDI (26mg 0.16mmol) is added to 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid (51mg, CH 0.15mmol)
3(emit gas) in the CN solution, mixture heating up to 50 ℃ is reached 2 hours.In said mixture, add then 1-(4-fluorophenyl) Toluidrin (28mg, 0.15mmol) and DBU (23mg, CH 0.15mmol)
3CN solution at room temperature stirs reactant and to spend the night.With HPLC purifying (referring to general experimental technique), obtain 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan.Output: 2.9mg (4%).
The example of method E: embodiment 75 methods
With DIPEA (38mg, 0.3mmol) be added to 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid (35.3mg, 0.1mmol) and TBTU (38.5mg, 0.12mmol) DCM (2ml) solution in, after at room temperature stirring mixture in 10 minutes, adding 1-(2-fluorophenyl) Toluidrin (19mg, 0.10mmol).The reactant stirring is spent the night.Reaction mixture 1M KHSO
4The washing, make organic phase pass through phase splitter after, in vacuum centrifuge, evaporate.The gained crude product obtains 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl with HPLC purifying (referring to general experimental technique)]-2-(methyl fluoride) Nikithan.Output: 13mg (25%).
Embodiment 1
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) Nikithan (a) 2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-ethyl formate
Under nitrogen atmosphere, with 2-methyl-6-oxo-1,6-dihydropyridine-3-ethyl formate (2.0g, 11.04mmol) (Sobczak, A etc., Synth.Commun, the 35th volume, the 23rd phase, 2005, the 2993-3001 pages or leaves) be added to 2-methoxyl group-N-(2-methoxy ethyl)-N-(three fluoro-λ
4-sulfenyl) ethamine (7.82g, CH 22.08mmol)
3In the CN solution.Reactant is refluxed spend the night, add 2-methoxyl group-N-(2-methoxy ethyl)-N-(three fluoro-λ afterwards again
4-sulfenyl) (2.73g 7.7mmol), continues stirring and consumes up to all raw materials ethamine.Reactant dilutes with ether, removes by filter black solid, water and NaHCO
3(saturated aqueous solution) washing.Two-phase is filtered once more to remove more black solid.Water is with extracted with diethyl ether (2 times), with the organic phase drying (MgSO that merges
4), after filtering and concentrating, the furnishing pulpous state is to remove yellow impurities in ether.With residual white solid drying, obtain 2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-ethyl formate.Output: 370mg (14%).
1HNMR(400MHz，CDCl
3)δ1.38(3H，t，J＝7.2Hz)，4.36(2H，q，J＝7.2Hz)，6.69(1H，d，J＝10Hz)，7.56(1H，t，J＝54Hz)，7.99(1H，d，J＝10Hz)。
(b) 5-chloro-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-ethyl formate
(270mg 2.02mmol) is added to 2-(difluoromethyl)-6-oxo-1, and (365mg 1.44mmol) in the solution, is heated to 100 ℃ with reactant and spends the night 6-dihydropyridine-3-ethyl formate will to be dissolved in the NCS of DMF (2ml).Owing to still have residual raw material, (270mg after 5 hours 2.02mmol), continues heating and disappears up to raw material for 135mg, 1.01mmol so add the NCS of aliquot once more.After reactant dilutes with DCM, water and salt water washing.Water DCM extracting twice, the organic phase of merging are evaporated after by phase splitter.With purified by flash chromatography (Horizon Flash40+M, elutriant: adopt gradient be the EtOAc/ heptane from 50% to 100%EtOAc), obtain 5-chloro-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-ethyl formate, be yellow oil, need not further analysis or purifying and just can be used for next step.Output: 88mg (15%).
(c) 5,6-two chloro-2-(difluoromethyl) Nikithans
(0.1ml 1.18mmol) is added to 5-chloro-2-(difluoromethyl)-6-oxo-1 with DMF (0.1ml), and (85.5mg in DCM solution 0.217mmol), ℃ reaches mixture heating up to 42 at 3 hours to 6-dihydropyridine-3-ethyl formate with oxalyl chloride.As not detecting product, then add 0.1ml (1.18mmol) oxalyl chloride once more, and continue down to stir to spend the night at 42 ℃.Reactant makes it to pour into quencher in ice/water mixture after diluting with DCM.Separate each mutually after, organic phase NaHCO
3(saturated aqueous solution) and salt water washing.The water that merges extracts with DCM, and the organic phase of merging is filtered the back evaporation by phase splitter.Resistates concentrates twice altogether with DCM, obtains 5, and 6-two chloro-2-(difluoromethyl) Nikithans are yellow oil, need not to be further purified just to can be used for next step.Output: 113mg (51%).
(d) formamyl 4-[(benzyl alkylsulfonyl)] piperidines-1-t-butyl formate
Under nitrogen atmosphere, room temperature, with triethylamine (591g, 5840mmol) be added to 1-(tert-butoxycarbonyl) piperidines-4-formic acid (448g, 1954mmol), LiCl (23.1g, 545mmol) and TBTU (657g, 2046mmol) with the stirred suspension of THF (3000ml) in.1.5 (the 1300ml THF solution of 352g, 2056mmol) solution and continuation are stirred and are spent the night to add 1-phenyl methanesulfonamide acid amides after hour.Solvent removed in vacuo obtains thick griege soup compound (the about 2500ml of volume).Add the EtOAc (3500ml) and the HCl aqueous solution (1960ml3.6M HCl and 1960ml water) successively.After removing water, organic phase is washed with 2 x 1500ml 1M HCl.Make organic phase be cooled to 0 ℃, obtain the HOBT throw out through leaching.Vacuum is removed most of solvents, obtains thick canescence soup compound.Adding EtOH (50%, 4000ml), soup compound was stirred 1.5 hours.Leach precipitated product, dry under 25 ℃ in vacuum oven after 50%EtOH (500ml+2 x 1500ml) washing, obtain 4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-t-butyl formate, be white solid.Output: 584g (78%).
(e) N-(benzyl alkylsulfonyl) piperidines-4-methane amide
Under nitrogen atmosphere, with 4-[(benzyl alkylsulfonyl) formamyl] (583g 1524mmol) is suspended in the formic acid (3000ml) piperidines-1-t-butyl formate, and reactant was stirred 20 minutes.Reactant bubbles owing to emitting gas, and (500ml) gets off foam from the reactor vessel wall upper punch with formic acid.After 2 hours, foaming stops, and reactant becomes transparent, stays a little solid.With reactant stir spend the night after, vacuum is removed 2500ml formic acid.After adding entry (1000ml), reactant is filtered.Add entry (3000ml) after making transparent solution evaporation.With saturated ammonium hydroxide aqueous solution (add 390ml altogether, pH is by 3.10 to 6.10) with in and acidic solution, (pH=6.10) forms a large amount of precipitated products at terminal point.Mixture stirred spends the night, leach throw out after, water (1000ml) washing.Dry under 25 ℃ in vacuum oven, obtain N-(benzyl alkylsulfonyl) piperidines-4-methane amide, be white powder.Output: 372.4g (87%).
(f) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) Nikithan
With TEA (149 μ l 1.07mmol) are added to 5,6-two chloro-2-(difluoromethyl) Nikithans (113mg, 0.214mmol)) and N-(benzyl alkylsulfonyl) piperidines-4-methane amide (66mg, 0.24mmol) and CH
3In the solution of CN (3ml) and water (2ml).Reactant was heated 20 minutes in 120 ℃ in single node microwave oven.Solvent removed in vacuo, crude mixture are used 1%KHSO after diluting with DCM
4(aqueous solution) washed twice.The water that merges passes through phase splitter, solvent removed in vacuo subsequently with the organic phase that merges after extracting with DCM.Crude product preparation HPLC purifying (KromasilC
8, 10 μ m, 50.8 x 300mm), with 5% acetonitrile/moisture NH
4After OAc damping fluid (pH7) was added to compound on the post, adopting gradient was 30-100% acetonitrile/moisture NH
4OAc damping fluid (pH3) wash-out.
The product flow point is merged, and solvent removed in vacuo is ground after-filtration with DCM.Solvent removed in vacuo obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) Nikithan, be white solid.Output: 13mg (11%).
1H?NMR(400MHz，CDCl
3)δ?1.38(3H，t，J＝7.1Hz)，1.73-1.91(4H，m)，2.27-2.42(1H，m)，2.87-3.05(2H，m)，4.19-4.30(2H，m)，4.30-4.41(2H，m)，4.67(2H，s)，7.29-7.43(5H，m)，7.48-7.54(1H，m)，8.16(1H，s)。
Embodiment 2
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(a) 5-cyano group-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-ethyl formate
With 1,1-dimethoxy-N, N-dimethyl methylamine (4.8ml 36.1mmol) is added to 4,4-two fluoro-ethyl 3-oxobutanoates (5.0g, 30.1mmol) in (thermopositive reaction).Orange solution at room temperature stirred spend the night, concentrate back and toluene coevaporation.With resistates be dissolved in EtOH (99.5%, 10ml), obtain red solution.With the NaOEt of prepared fresh (1M, 30ml) be added to the 2-malonamide nitrile (2.53g, EtOH 30.1mmol) (99.5%, 30m1) in the solution, reactant was at room temperature stirred 1 hour, drip above-mentioned red solution.Formed red suspension stirring is spent the night, and behind the adding AcOH (6ml), solution becomes is transparent.This solution concentrated in water (50ml) and the furnishing pulpous state after stirred 1 hour, leach behind the throw out air-dryly afterwards, obtain 5-cyano group-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-ethyl formate is brown solid.Output: 3.03g (41%).
1H-NMR (400MHz, DMSO-d
6) δ 1.30 (3H, t, J=7.2Hz), 4.28 (2H, q, J=7.2Hz), 7.48 (1H, t, J=52.5Hz, F-couplings), 8.58 (1H, s).
(b) 6-chloro-5-cyano group-2-(difluoromethyl) Nikithan
Successively with oxalyl chloride (5.3ml, 62.6mmol) and DMF (0.097ml) be added to 5-cyano group-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-ethyl formate (3.0g, 12.5mmol) DCM (45ml) soup compound in, reactant is heated to 50 ℃ reaches a few hours, add again oxalyl chloride (1ml, 11.8mmol), twice adding DMF (0.2ml) refluxes and continues heated overnight down between a few hours.After making the reaction mixture evaporation, resistates is dissolved in DCM, water and NaHCO
3(saturated aqueous solution) washing.Water extracts (twice) with DCM, after the organic phase of merging is concentrated, with purified by flash chromatography (Horizon, adopting gradient is the elutriant of heptane/EtOAc7/1 to 100%EtOAc), obtain 6-chloro-5-cyano group-2-(difluoromethyl) Nikithan, be yellow oil.Output: 2.0g (60%).
1H-NMR(400MHz，DMSO-d
6)δ1.34(3H，t，J＝7.0)，4.37(2H，q，J＝7.0Hz)，7.46(1H，t，J＝53.2Hz)，8.99(1H，s)。
(c) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
With TEA (0.4ml, 2.89mmol) be added to 6-chloro-5-cyano group-2-(difluoromethyl) Nikithan (200mg, 0.721mmol) and N-(benzyl alkylsulfonyl) piperidines-4-methane amide (224mg, 0.793mmol) with the solution of water (2.5ml) and EtOH (2ml) in.With mixture in single node microwave oven in 120 ℃ the heating 20 minutes, make solvent evaporation after, resistates is dissolved in DCM, use 1%KHSO
4Washing (twice).After the water that merges extracts (twice) with DCM, the organic phase that merges is filtered and concentrated by phase splitter.With HPLC purifying (Kromasil C
8, 10 μ m, elutriant: gradient 40%CH
3CN to 100%CH
3CN/ (50mM HCOOH and 50mMNH
4OOCH pH=3), obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan, be white solid.Output: 250mg (68%).
1H?NMR(400MHz，DMSO-d
6)δ?1.31(3H，t，J＝7.4Hz)，1.73-1.59(2H，m)，1.91-1.81(2H，m)，2.61(1H，m)，3.27-3.15(2H，m)，4.28(2H，q，J＝7.4Hz)，4.61-4.51(2H，m)，4.69(2H，s)，7.33-7.22(2H，m)，7.44-7.34(3H，m)，7.53(1H，s)，8.50(1H，s)，11.61(1H，s)。
Embodiment 3
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(a) 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan
With oxalyl chloride (12.20g, 96.1mmol) and DMF (0.744ml) be added to 5-cyano group-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-ethyl formate (5g, solution 19.22mmol) is (substantially according to following literature method preparation: Mosti, L etc., Farmaco, the 47th volume, the 4th phase, 1992, the 427-437 page or leaf) in, reactant is heated to 50 ℃ spends the night.After making the reactant evaporation, crude product is dissolved in EtOAc and water.Separate each mutually after, organic phase is with salt solution and NaHCO
3(saturated aqueous solution) washing.Water is with EtOAc extraction (3 times), with the organic phase drying (Na that merges
2CO
3), filter the back and concentrate, obtain 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan, be brown solid, need not to be further purified just and can use.Output: 5.21g (95%).
1H?NMR(400MHz，DMSO-d
6)δ?1.31(3H，t，J＝7.2Hz)，4.38(2H，q，J＝6.9Hz)，9.07(1H，s)。
(b) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
With TEA (142mg, 1.41mmol) be added to 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan (140mg, 0.352mmol) and N-(benzyl alkylsulfonyl) piperidines-4-methane amide (109mg, 0.387mmol) with the solution of water (2ml) and EtOH (2.5ml) in.With mixture in single node microwave oven in 120 ℃ the heating 20 minutes, make solvent evaporation after, resistates is dissolved in DCM, use 1%KHSO
4Washing (twice).The water that merges filters the back with the organic phase that merges by phase splitter and concentrates with DCM extraction (twice).With HPLC purifying (Kromasil C
8, 10 μ m, elutriant: gradient 30%CH
3CN to 100%CH
3CN/ (50mM HCOOH and 50mMNH
4OOCH pH=3), obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan, be white solid.Output: 107mg (58%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.5Hz)，1.74-1.58(2H，m)，1.91-1.79(2H，m)，2.65-2.54(1H，m)，3.27-3.15(2H，m)，4.28(2H，q，J＝7.5Hz)，4.55-4.46(2H，m)，4.68(2H，s)，7.33-7.23(2H，m)，7.47-7.35(3H，m)，8.54(1H，s)，11.61(1H，s)。
Embodiment 4
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(a) 1-(tert-butoxycarbonyl) azetidine-3-formic acid
At room temperature, in 20 minutes, will be dissolved in MeOH (70ml) (Boc)
2O (25.535g, 117mmol) be added drop-wise to azetidine-3-formic acid (10.11g, 100mmol) and Et
3N (27.8ml, 200mmol) with the stirring slurries of MeOH (105ml) in (faint thermopositive reaction), mixture is stirred spend the night (18 hours).It is dried that reactant is evaporated to, and adds the evaporation of THF (120ml) back, obtains crude product 1-(tert-butoxycarbonyl) azetidine-3-formic acid, need not to be further purified just to can be used for next step.Output: 25.89g (128%).
1H?NMR(400MHz，CDCl
3)δ?1.43(9H，s)，3.21-3.34(1H，m)，4.00-4.13(4H，m)。
(b) formamyl 3-[(benzyl alkylsulfonyl)] azetidine-1-t-butyl formate
With TBTU (33.71g, 105mmol) and TEA (30.3g, 300mmol) be added in THF (200ml) solution of 1-(tert-butoxycarbonyl) azetidine-3-formic acid (25.89g supposes and contains 100mmol) that derives from above-mentioned reaction, reactant was at room temperature stirred 30 minutes.Add 1-phenyl methanesulfonamide acid amides (17.97g, 105mmol) and LiCl (1.844g 43.5mmol), at room temperature continues stirring spend the night (23 hours).Leave standstill after reactant is concentrated into about 1/3, add EtOAc (500ml), organic phase with 2M HCl (1 x 150ml, 2x50ml), water (2 x 50ml) washing.Dry (MgSO
4), filter the back evaporating solvent, obtain brown powder (48.6g).With powder furnishing pulpous state in 150ml TBME, stirred 3 hours.After leaching solid, with TBME (40ml) washing.This process repeats twice (washing with 25ml) with 100ml TBME, is still contained the brown powder (33g) of a little HOBT.Powder is dissolved among the EtOH of about 100ml heat, adds entry (130ml) so that the product crystallization.Leach the crystallization after drying, obtain pure 3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-t-butyl formate, pale powder.Output: 25.4g (71%).
1H NMR (400MHz, DMSO-d
6) δ 1.39 (9H, s), 3.30 (1H, m is with water signal overlap among the DMSO), 3.78-3.95 (4H, m), 4.73 (2H, s), 7.28-7.34 (2H, m), 7.36-7.41 (3H, m), 11.71 (1H, br s).
MS?m/Z：353(M-1)。
(c) N-(benzyl alkylsulfonyl) azetidine-3-methane amide
At room temperature, with 3-[(benzyl alkylsulfonyl) formamyl] (25.4g 71.7mmol) is added among the HCOOH (300ml) azetidine-1-t-butyl formate, and reactant is stirred spend the night (22 hours).Vacuum is removed formic acid removal, adds entry (40ml) and vacuum and removes.(130ml) is added in the resistates with water, adds NH then
4OH (aqueous solution), pH reaches 7.4 up to when the beginning crystallization time.Leach the crystallization after drying, obtain pure N-(benzyl alkylsulfonyl) azetidine-3-methane amide, be white solid.Output: 15.73g (86%).
1H?NMR(400MHz，DMSO-d
6)δ?3.22(1H，m)，3.87-3.96(4H，m)，4.28(2H，s)，7.20-7.32(5H，m)。
MS?m/Z：255(M+1)。
(d) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
With TEA (291mg; 2.88mmol) be added to 6-chloro-5-cyano group-2-(difluoromethyl) Nikithan (200mg; 0.721mmol) and N-(benzyl alkylsulfonyl) azetidine-3-methane amide (201mg, 0.793mmol) with the solution of water (2ml) and EtOH (2.5ml) in.With mixture in single node microwave oven in 120 ℃ the heating 20 minutes, make solvent evaporation, resistates is dissolved in DCM after, use 1%KHSO
4Washing (twice).The water that merges filters the back with the organic phase that merges by phase splitter and concentrates with DCM extraction (twice).With HPLC purifying (Kromasil C
8, 10 μ m, elutriant: gradient 40%CH
3CN to 100%CH
3CN/ (50mM HCOOH and 50mM NH
4OOCH pH=3), obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan, be white solid.Output: 264mg (72%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.3Hz)，3.64-3.53(1H，m)，4.27(2H，q，J＝6.9Hz)，4.53-4.31(4H，m)，4.75(2H，s)，7.40-7.30(5H，m)，7.40(1H，t，J＝53.6Hz)，8.47(1H，s)，11.81(1H，s)。
MS?m/Z：478(M+1)。
Embodiment 5
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(a) 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan
With oxalyl chloride (8.13ml, 96.1mmol) and DMF (0.744ml 9.61mmol) is added to 5-cyano group-6-oxo-2-(trifluoromethyl)-1, solution (the 5.0g of 6-dihydropyridine-3-ethyl formate, 19.22mmol, substantially according to following literature method preparation: Mosti L, etc., Farmaco, the 47th volume, the 4th phase, 1992, the 427-437 page or leaf) in, reactant is heated to backflow spends the night.After making solvent evaporation, resistates is dissolved in EtOAc/ water.Separate each mutually after, organic phase is with salt solution and NaHCO
3(aqueous solution) washing (twice).Water is with EtOAc extraction (3 times), with the organic phase drying (Na that merges
2CO
3), filter the back and concentrate, obtain 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan, need not to be further purified just and can use.Output: 5.21g (95%).
1H?NMR(400MHz，DMSO-d
6)δ?1.31(3H，t，J＝7Hz)，4.38(2H，q，J＝7Hz)，9.07(1H，s)。
(b) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
With TEA (142mg; 1.41mmol) be added to 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan (140mg; 0.352mmol) and N-(benzyl alkylsulfonyl) azetidine-3-methane amide (98.4mg, 0.387mmol) with the solution of water (2ml) and EtOH (2.5ml) in.Mixture was heated 20 minutes in 120 ℃ in single node microwave oven.Reactant is filtered with behind the disgorging, make solvent evaporation.Resistates is dissolved in DCM, uses 1%KHSO
4Washing (twice).After the water that merges extracts (twice) with DCM, the organic phase that merges is filtered the back by phase splitter concentrate.With HPLC purifying (Kromasil C
8, 10 μ m, elutriant: gradient 30%CH
3CN to 100%CH
3CN/ (0.1%HCOOH (aqueous solution)) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan, be white solid.Output: 102mg (58%).
1H?NMR(400MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.3Hz)，3.63-3.52(1H，m)，4.27(2H，q，J＝7.3Hz)，4.52-4.31(4H，m)，4.74(2H，s)，8.50(1H，s)，11.80(1H，s)。
MS?m/Z：496(M+1)。
Embodiment 6
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(a) 5-cyano group-2-(methyl fluoride)-6-oxo-1,6-dihydropyridine-3-ethyl formate
At room temperature, with 1,1-dimethoxy-N, N-dimethyl methylamine (4.83g, 40.5mmol) be added to 4-fluoro-ethyl 3-oxobutanoate (5.0g, 33.75mmol) in (thermopositive reaction), mixture stirred spends the night, concentrate back and toluene coevaporation.Adding EtOH (99.5%, 10ml), obtain red solution.(34.5ml, 2.35g 34.5mmol) are added to 2-malonamide nitrile (3.12g with the sodium ethylate 1M solution of prepared fresh, 37.13mmol) EtOH (99.5%, 30ml) in the solution, at room temperature stir 35 minutes after, dropping derives from the red solution of above-mentioned reaction, continues to stir and spends the night.Add AcOH (6ml) (thermopositive reaction) carefully, after formed throw out is filtered, wash with ether.Obtain 5-cyano group-2-(methyl fluoride)-6-oxo-1 after the drying, 6-dihydropyridine-3-ethyl formate is light brown solid.Output: 4.42g (56%).
1H?NMR(400MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.2Hz)，4.12(2H，q，J＝6.9Hz)，5.42(2H，d，J＝47.5Hz)，7.96(1H，s)。
MS?m/Z：225(M+1)。
(b) 6-chloro-5-cyano group-2-(methyl fluoride) Nikithan
With oxalyl chloride (5.49ml, 64.9mmol) and DMF (0.5ml 6.5mmol) is added to 5-cyano group-2-(methyl fluoride)-6-oxo-1,6-dihydropyridine-3-ethyl formate (3.0g, 12.98mmol) DCM (120ml) solution in, mixture heating up was refluxed 6 hours.After making solvent evaporation, resistates is dissolved in EtOAc/ water.Separate each mutually after, organic phase is with salt solution and NaHCO
3(aqueous solution) washing.After water extracts (twice) with EtOAc, the organic phase of merging is concentrated, obtain 6-chloro-5-cyano group-2-(methyl fluoride) Nikithan, be light brown solid, need not to be further purified just and can use.Output: 2.92g (90%).
1H?NMR(400MHz，DMSO-d
6)δ?1.33(t，J＝7.1Hz，3H)，4.34(q，J＝7.1Hz，2H)，5.88(s，1H)，5.77(s，1H)，8.89(s，1H)。
MS?m/Z：243(M+1)。
(c) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
With TEA (326mg, 3.23mmol) be added to 6-chloro-5-cyano group-2-(methyl fluoride) Nikithan (200mg, 0.81mmol) and N-(benzyl alkylsulfonyl) piperidines-4-methane amide (251mg, 0.89mmol) and CH
3In the solution of CN (1.5ml) and 95%EtOH (2.5ml).Mixture was heated 20 minutes in 120 ℃ in single node microwave oven.After making solvent evaporation, resistates is dissolved in DCM, uses 1%KHSO
4Washing (twice).The water that merges extracts with DCM, the organic phase that merges is filtered the back by phase splitter concentrate.With HPLC purifying (KromasilC
8, 10 μ m, elutriant: gradient 40%CH
3CN to 100%CH
3CN/ (0.1%HCOOH (aqueous solution)) obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan, be light brown solid.Output: 257mg (65%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，1.71-1.56(2H，m)，1.89-1.79(2H，m)，2.65-2.54(1H，m)，3.24-3.12(2H，m)，4.25(2H，q，J＝7.2Hz)，4.64-4.53(2H，m)，4.68(2H，s)，5.63(1H，s)，5.75(1H，s)，7.33-7.23(2H，m)，7.44-7.34(3H，m)，8.40(1H，s)，11.60(1H，s)。
MS?m/Z：489(M+1)。
Embodiment 7
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
With TEA (326mg, 3.23mmol) be added to 6-chloro-5-cyano group-2-(methyl fluoride) Nikithan (200mg, 0.81mmol) and N-(benzyl alkylsulfonyl) azetidine-3-methane amide (225mg, 0.89mmol) and CH
3In the solution of CN (1.5ml) and 95%EtOH (2.5ml).Mixture was heated 20 minutes in 120 ℃ in single node microwave oven.After making solvent evaporation, resistates is dissolved in DCM, uses 1%KHSO
4Washing.The water that merges extracts with DCM, the organic phase that merges is filtered the back by phase splitter concentrate.With HPLC purifying (Kromasil C
8, 10 μ m, elutriant: gradient 40%CH
3CN to 100%CH
3CN/ (0.1%HCOOH (aqueous solution)) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan, be light brown solid.Output: 221mg (59%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.2Hz)，3.62-3.51(1H，m)，4.24(2H，q，J＝7.2Hz)，4.39-4.29(2H，m)，4.51-4.39(2H，m)，4.74(2H，s)，5.61(1H，s)，5.73(1H，s)，7.42-7.29(5H，m)，8.38(1H，s)，11.81(1H，s)。
MS?m/Z：461(M+1)。
Embodiment 8
5-cyano group-2-(difluoromethyl)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(a) 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid
TEA (423mg, 4.18mmol) be added to 6-chloro-5-cyano group-2-(difluoromethyl) Nikithan (290mg, 1.05mmol) and piperidines-4-formic acid (148mg is in water/EtOH 1.15mmol) (4.5ml) solution.Mixture was heated 10 minutes in 120 ℃ in single node microwave oven.After making solvent evaporation, resistates is dissolved in DCM, uses 1%KHSO
4Washing.The water that merges extracts (twice) with DCM, the organic phase that merges is filtered the back by phase splitter to be concentrated, obtain 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid, be white solid, need not to be further purified just and can use.Output: 356mg (94%).
1H-NMR(400MHz，CDCl
3)δ?1.39(3H，t，J＝7.2Hz)，1.84-1.97(2H，m)，2.08-2.17(2H，m)，2.69-2.79(1H，m)，3.37-3.47(2H，m)，4.37(2H，q，J＝7.2Hz)，4.61-4.70(2H，m)，7.39(1H，t，C
HF
2)，8.43(1H，s)。
MS?m/z：354(M+1)。
(b) methyl 5-cyano group-2-(difluoromethyl)-6-{4-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
With DIPEA (64mg, 0.5mmol) be added to 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid (35.3mg, 0.1mmol) and TBTU (38.5mg, 0.12mmol) DCM (5ml) solution in, after mixture at room temperature stirred 30 minutes, add 1-(4-methylcyclohexyl) Toluidrin be dissolved in DCM (1ml) (23mg, 0.12mmol) in.The reactant stirring is spent the night.LC-MS shows and to still have residual raw material, therefore in mixture, add again TBTU (19mg, 0.06mmol) and DIPEA (26mg 0.2mmol), continues stirring 2 hours again.Reaction mixture 1%KHSO
4Washing, water extracts with DCM (1ml), and the organic phase of merging is evaporated in vacuum centrifuge by behind the phase splitter.Gained crude product HPLC purifying (Kromasil C
8, 10 μ m, adopting gradient is 20% to 100%CH
3CN/0.2%AcOH (aqueous solution)), obtain 5-cyano group-2-(difluoromethyl)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan, be white solid.Output: 22mg (40%).
1H?NMR(400MHz，CDCl
3)δ8.61(1H，s)，8.42(1H，s)，7.36(1H，t，J＝54.3Hz)，4.75(2H，m)，4.35(2H，q，J＝7.3Hz)，3.46(1H，m)，3.38-3.22(3H，m)，2.59(1H，m)，2.30-2.18(1H，m)，2.10-1.97(2H，m)，1.96-1.79(3H，m)，1.75-1.47(6H，m)，1.37(3H，t，J＝7.2Hz)，1.22-1.04(2H，m)，0.92-0.83(3H，m)。
MS?m/Z：527(M+1)。
Embodiment 9
5-cyano group-2-(difluoromethyl)-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(a) 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid
With TEA (423mg, 4.18mmol) be added to 6-chloro-5-cyano group-2-(difluoromethyl) Nikithan (290mg, 1.05mmol) and azetidine-3-formic acid (116mg is in 95%EtOH 1.15mmol) (4.5ml) solution.Mixture was heated 10 minutes in 120 ℃ in single node microwave oven.After making solvent evaporation, resistates is dissolved in DCM, uses 1%KHSO
4Washing.The water that merges extracts (twice) with DCM, the organic phase that merges is filtered the back by phase splitter to be concentrated, obtain 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid, be white solid, need not to be further purified just and can use.Output: 359mg (101%).
1H-NMR(400MHz，CDCl
3)δ?1.39(3H，t，J＝7.1Hz)，3.62-3.72(1H，m)，4.36(2H，q，J＝7.1Hz)，4.63-4.75(4H，m)，7.34(1H，t，J＝54.2Hz，C
HF
2)，8.36(1H，s)。
MS?m/Z：326(M+1)。
(b) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
With DIPEA (64mg, 0.5mmol) be added to 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid (32.5mg, 0.1mmol) and TBTU (38.5mg, 0.12mmol) DCM (5ml) solution in, after mixture at room temperature stirred 30 minutes, add 1-(2-fluorophenyl) Toluidrin be dissolved in DCM (1ml) (23mg, 0.12mmol).The reactant stirring is spent the night.LC-MS shows and to still have residual raw material, therefore in mixture, add again TBTU (19mg, 0.06mmol) and DIPEA (26mg 0.2mmol), continues stirring 2 hours again.Reaction mixture 1%KHSO
4Washing, water extracts with DCM (1ml), and the organic phase of merging is evaporated in vacuum centrifuge by behind the phase splitter.Gained crude product HPLC purifying (Kromasil C
8, 10 μ m, adopting gradient is 20% to 100%CH
3CN/0.2%AcOH (aqueous solution)), obtain 5-cyano group-2-(difluoromethyl)-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan, be white solid.Output: 42mg (83%).
1H?NMR(400MHz，CDCl
3)δ?1.38(3H，t，J＝7.1Hz)，3.50-3.40(1H，m)，4.35(2H，q，J＝7.2Hz)，4.67-4.51(4H，m)，4.72(2H，s)，7.22-7.08(2H，m)，7.46-7.34(2H，m)，7.44(1H，t，C
HF
2)，8.35(1H，s)。
MS?m/Z：497(M+1)。
Embodiment 10
5-cyano group-2-(difluoromethyl)-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(2-fluorophenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan.Output: 41mg (78%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝6.8Hz)，1.60-1.68(2H，m)，1.85-1.90(2H，m)，2.57-2.64(1H，m)，3.17-3.24(2H，m)，4.25(2H，q，J＝7.0Hz)，4.53-4.58(2H，m)，4.72(2H，s)，7.20-7.26(2H，m)，7.35-7.45(2H，m)，7.37(1H，t，J＝54.1Hz)，8.47(1H，s)。
MS?m/z：525(M+1)。
Embodiment 11
5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-fluorophenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan.Output: 21mg (40%).
1H?NMR(600MHz，DMSO-d
6)δ?8.45(1H，s)，7.35(1H，t，J＝53.5Hz)，7.38-7.43(1H，m)，7.16-7.22(1H，m)，7.05-7.11(2H，m)，4.69(2H，s)，4.48-4.55(2H，m)，4.24(2H，q，J＝7.1Hz)，3.14-3.21(2H，m)，2.53-2.58(1H，m)，1.78-1.84(2H，m)，1.56-1.65(2H，m)，1.27(3H，t，J＝7.1Hz)。
MS?m/Z：525(M+1)。
Embodiment 12
5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-fluorophenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan.Output: 19mg (36%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.2Hz)，1.58-1.67(2H，m)，1.81-1.87(2H，m)，3.15-3.22(2H，m)，4.26(2H，q，J＝7.1Hz)，4.51-4.58(2H，m)，4.66(2H，s)，7.19-7.23(2H，m)，7.28-7.32(2H，m)，7.37(1H，t，J＝54.1Hz)，8.47(1H，s)。
Note! A H is hidden in the DMSO signal.
MS?m/Z：525(M+1)。
Embodiment 13
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(2-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan.Output: 36mg (67%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.2Hz)，1.60-1.69(2H，m)，1.86-1.92(2H，m)，3.18-3.24(2H，m)，4.25(2H，q，J＝7.0Hz)，4.51-4.59(2H，m)，4.81(2H，s)，7.26-7.53(5H，m)，8.47(1H，s)。Note! A H is hidden in the DMSO signal.
MS?m/Z：541(M+1)。
Embodiment 14
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan.Output: 42mg (78%).
1H?NMR(600MHz，DMSO-d
6)δ?1.27(3H，t，J＝6.8Hz)，1.57-1.65(2H，m)，1.78-1.84(2H，m)，2.53-2.59(1H，m)，3.14-3.21(2H，m)，4.24(2H，q，J＝6.9Hz)，4.49-4.56(2H，m)，4.68(2H，s)，7.18-7.46(5H，m)，8.46(1H，s)。
MS?m/Z：541(M+1)。
Embodiment 15
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan.Output: 33mg (61%).
1H?NMR(400MHz，DMSO-d
6)δ?1.31(3H，t，J＝7.2Hz)，1.58-1.72(2H，m)，1.82-1.92(2H，m)，2.56-2.68(1H，m)，3.16-3.26(2H，m)，4.28(2H，q，J＝7.2Hz)，4.52-4.61(2H，m)，4.70(2H，s)，7.28-7.35(2H，m)，7.39(1H，t，J＝54.1Hz)，7.44-7.51(2H，m)，8.50(1H，s)，11.64(1H，s)。
MS?m/Z：541(M+1)。
Embodiment 16
5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan.Output: 17mg (32%).
1H?NMR(400MHz，DMSO-d
6)δ?1.31(3H，t，J＝7.3Hz)，1.59-1.73(2H，m)，1.79-1.89(2H，m)，2.29(3H，s)，2.54-2.64(1H，m)，3.16-3.26(2H，m)，4.28(2H，q，J＝7.4Hz)，4.53-4.61(2H，m)，4.63(2H，s)，7.04-7.10(2H，m)，7.16-7.22(1H，m)，7.24-7.31(1H，m)，7.39(1H，t，J＝53.9Hz)，8.49(1H，s)，11.59(1H，s)。
MS?m/Z：521(M+1)。
Embodiment 17
5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan.Output: 19mg (36%).
1H?NMR(600MHz，DMSO-d
6)δ?1.27(3H，t，J＝7.2Hz)，1.57-1.65(2H，m)，1.79-1.85(2H，m)，2.26(3H，s)，3.14-3.21(2H，m)，4.24(2H，q，J＝7.3Hz)，4.50-4.56(2H，m)，4.58(2H，s)，7.10-7.18(4H，m)，7.36(1H，t，J＝53.4Hz)，8.46(1H，s)。Note! A H is hidden in the DMSO signal.
MS?m/Z：521(M+1)。
Embodiment 18
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid and 1-(2; the 4-dichlorophenyl) Toluidrin preparation; obtain 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan.Output: 27mg (47%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.0Hz)，1.59-1.68(2H，m)，1.87-1.93(2H，m)，2.54-2.60(1H，m)，3.18-3.24(2H，m)，4.26(2H，q，J＝6.8Hz)，4.52-4.58(2H，m)，4.81(2H，s)，7.26-7.52(3H，m)，7.69(1H，s)，8.47(1H，s)。
MS?m/Z：575(M+1)。
Embodiment 19
5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-fluorophenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan.Output: 47mg (95%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.3Hz)，3.51-3.59(1H，m)，4.25(2H，q，J＝7.4Hz)，4.26-4.51(4H，m)，4.75(2H，s)，7.12-7.22(3H，m)，7.35-7.42(1H，m)，7.37(1H，t，J＝53.2Hz)，8.44(1H，s)。
MS?m/Z：497(M+1)。
Embodiment 20
5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-fluorophenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan.Output: 41mg (83%).
1H?NMR(600MHz，DMSO-d
6)δ?1.26(3H，t，J＝7.1Hz)，3.49-3.57(1H，m)，4.23(2H，q，J＝7.1Hz)，4.26-4.50(4H，m)，4.69(2H，s)，7.12-7.19(2H，m)，7.32-7.37(2H，m)，7.36(1H，t，J＝54.2Hz)，8.43(1H，s)。
MS?m/Z：497(M+1)。
Embodiment 21
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan.Output: 42mg (82%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，3.58-3.68(1H，m)，4.27(2H，q，J＝7.5Hz)，4.36-4.57(4H，m)，4.90(2H，s)，7.35-7.46(2H，m)，7.40(1H，t，J＝54.2Hz)，7.47-7.56(2H，m)，8.47(1H，s)，12.03(1H，s)。
MS?m/Z：513(M+1)。
Embodiment 22
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan.Output: 46mg (90%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.1Hz)，3.51-3.59(1H，m)，4.24(2H，q，J＝7.2Hz)，4.25-4.54(4H，m)，4.76(2H，s)，7.26-7.30(1H，m)，7.35-7.47(4H，m)，8.44(1H，s)。
MS?m/Z：513(M+1)。
Embodiment 23
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan.Output: 45mg (88%).
1H?NMR(600MHz，DMSO-d
6)δ?1.26(3H，t，J＝7.0Hz)，3.50-3.57(1H，m)，4.23(2H，q，J＝7.0Hz)，4.27-4.50(4H，m)，4.70(2H，s)，7.30-7.34(2H，m)，7.36(1H，t，J＝53.8Hz)，7.38-7.43(2H，m)，8.43(1H，s)。
MS?m/Z：513(M+1)。
Embodiment 24
5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan.Output: 36mg (73%).
1H?NMR(600MHz，DMSO-d
6)δ?1.26(3H，t，J＝7.6Hz)，2.22(3H，s)，3.48-3.56(1H，m)，4.23(2H，q，J＝7.0Hz)，4.24-4.49(4H，m)，4.64(2H，s)，7.06-7.10(2H，m)，7.12-7.16(1H，m)，7.19-7.23(1H，m)，7.36(1H，t，J＝54.9Hz)，8.43(1H，s)。
MS?m/Z：493(M+1)。
Embodiment 25
5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan.Output: 31mg (63%).
1H?NMR(600MHz，DMSO-d
6)δ?1.26(3H，t，J＝6.9Hz)，2.24(3H，s)，3.47-3.55(1H，m)，4.23(2H，q，J＝6.9Hz)，4.26-4.49(4H，m)，4.63(2H，s)，7.11-7.19(4H，m)，7.36(1H，t，J＝53.8Hz)，8.43(1H，s)。
MS?m/Z：493(M+1)。
Embodiment 26
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid and 1-(2; the 4-dichlorophenyl) Toluidrin preparation; obtain 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan.Output: 7mg (12%).
1H?NMR(600MHz，DMSO-d
6)δ?1.26(3H，t，J＝7.3Hz)，3.44-3.55(1H，m)，4.23(2H，q，J＝7.3Hz)，4.29-4.52(4H，m)，4.67-4.83(2H，m)，7.35(1H，t，J＝54.3Hz)，7.38-7.50(2H，m)，7.57-7.64(1H，m)，8.42(1H，s)。
MS?m/Z：547(M+1)。
Embodiment 27
5-cyano group-2-(difluoromethyl)-6-{3-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-methylcyclohexyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-{3-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl amino) carbonyl] azetidine-1-yl Nikithan.Output: 27mg (55%).
1H?NMR(400MHz，DMSO-d
6)δ?0.80-0.95(3H，m)，1.01-1.20(2H，m)，1.30(3H，t，J＝7.0Hz)，1.40-1.58(5H，m)，1.60-1.88(2H，m)，2.04-2.15(1H，m)，3.40-3.45(2H，m)，3.59-3.69(1H，m)，4.26(2H，q，J＝7.4Hz)，4.33-4.58(4H，m)，7.38(1H，t，J＝54.3Hz)，8.46(1H，s)，11.93(1H，s)。
MS?m/Z：499(M+1)。
Embodiment 28
5-cyano group-6-[3-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 3-cyano group benzsulfamide, obtain 5-cyano group-6-[3-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan.Output: 47mg (64%).
1H?NMR(600MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.2Hz)，3.51-3.59(1H，m)，4.15-4.30(4H，m)，4.32-4.46(2H，m)，7.32(1H，t，J＝53.6Hz)，7.76-7.81(1H，m)，8.09-8.29(3H，m)，8.38(1H，s)。
MS?m/z：490(M+1)。
Embodiment 29
5-cyano group-6-[3-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 4-cyano group benzsulfamide, obtain 5-cyano group-6-[3-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan.Output: 42mg (57%).
1H?NMR(400MHz，DMSO-d
6)δ?1.28(3H，t，J＝8.0Hz)，3.54-3.65(1H，m)，4.18-4.33(2H，m)，4.25(2H，q，J＝7.2Hz)，4.34-4.63(2H，m)，7.36(1H，t，J＝53.1Hz)，7.75-7.89(1H，m)，8.03-8.12(3H，m)，8.42(1H，s)。
MS?m/Z：490(M+1)。
Embodiment 30
5-cyano group-2-(difluoromethyl)-6-{3-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 4-(trifluoromethoxy) benzsulfamide, obtain 5-cyano group-2-(difluoromethyl)-6-{3-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl amino) carbonyl] azetidine-1-yl Nikithan.Output: 37mg (45%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝7.2Hz)，3.51-3.58(1H，m)，4.15-4.26(2H，m)，4.21(2H，q，J＝7.0Hz)，4.33-4.46(2H，m)，7.32(1H，t，J＝54.1Hz)，7.53-7.59(2H，m)，7.99-8.05(2H，m)，8.39(1H，s)。
MS?m/Z：549(M+1)。
Embodiment 31
5-cyano group-2-(difluoromethyl)-6-{3-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 2-(trifluoromethoxy) benzsulfamide, obtain 5-cyano group-2-(difluoromethyl)-6-{3-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl amino) carbonyl] azetidine-1-yl Nikithan.Output: 44mg (53%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝6.8Hz)，3.50-3.61(1H，m)，4.14-4.27(2H，m)，4.21(2H，q，J＝7.0Hz)，4.30-4.51(2H，m)，7.32(1H，t，J＝54.0Hz)，7.48-7.60(2H，m)，7.71-7.83(1H，m)，8.01-8.08(1H，m)，8.39(1H，s)。
MS?m/z：549(M+1)。
Embodiment 32
5-cyano group-6-[3-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-cyano-phenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan.Output: 52mg (69%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.2Hz)，3.57-3.65(1H，m)，4.24(2H，q，J＝7.2Hz)，4.31-4.56(4H，m)，4.89(2H，s)，7.37(1H，t，J＝54.2Hz)，7.54-7.63(2H，m)，7.70-7.75(1H，m)，7.84-7.89(1H，m)，8.44(1H，s)。
MS?m/z：504(M+1)。
Embodiment 33
5-cyano group-2-(difluoromethyl)-6-(3-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid and naphthalene-2-sulphonamide preparation, obtain 5-cyano group-2-(difluoromethyl)-6-(3-{[(2-naphthyl alkylsulfonyl) amino] carbonyl azetidine-1-yl) Nikithan.Output: 48mg (62%).
1H?NMR(600MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.1Hz)，3.51-3.59(1H，m)，4.13-4.25(2H，m)，4.20(2H，q，J＝7.0Hz)，4.33-4.45(2H，m)，7.30(1H，t，J＝54.4Hz)，7.62-7.71(2H，m)，7.84-7.88(1H，m)，7.99-8.03(1H，m)，8.07-8.13(1H，m)，8.15-8.20(1H，m)，8.36(1H，s)，8.54-8.59(1H，m)。
MS?m/z：515(M+1)。
Embodiment 34
6-(3-{[(butyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid and butane-1-sulphonamide preparation, obtain 6-(3-{[(butyl alkylsulfonyl) amino] carbonyl azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan.Output: 44mg (65%).
1H NMR (600MHz, DMSO-d
6) δ 0.85 (3H, t, J=7.1Hz), 1.27 (3H, t, J=7.1Hz), 1.36 (2H, sextet, J=7.2Hz), 1.62 (2H, quintet, J=7.7Hz), 3.36 (2H, t, J=7.8Hz), 3.58-3.66 (1H, m), 4.23 (2H, q, J=6.6Hz), and 4.29-4.56 (4H, m), 7.36 (1H, t, J=54.8Hz), 8.43 (1H, s).
MS?m/Z：445(M+1)。
Embodiment 35
5-cyano group-6-[4-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 3-cyano group benzsulfamide, obtain 5-cyano group-6-[4-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan.Output: 9mg (12%).
1H?NMR(600MHz，DMSO-d
6)δ?1.27(3H，t，J＝6.9Hz)，1.43-1.51(2H，m)，1.79-1.85(2H，m)，3.15-3.22(2H，m)，4.24(2H，q，J＝7.3Hz)，4.43-4.49(2H，m)，7.34(1H，t，J＝54.2Hz)，7.71-7.76(1H，m)，8.02-8.08(1H，m)，8.09-8.13(1H，m)，8.17-8.21(1H，m)，8.43(1H，s)。Note! H signal and DMSO signal overlap.
MS?m/Z：518(M+1)。
Embodiment 36
5-cyano group-6-[4-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 4-cyano group benzsulfamide, obtain 5-cyano group-6-[4-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan.Output: 9mg (12%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝7.3Hz)，1.41-1.49(2H，m)，1.78-1.83(2H，m)，3.15-3.21(2H，m)，4.23(2H，q，J＝7.0Hz)，4.41-4.46(2H，m)，7.32(1H，t，J＝53.8Hz)，7.92-8.01(4H，m)，8.41(1H，s)。Note! H signal and DMSO signal overlap.
MS?m/Z：518(M+1)。
Embodiment 37
5-cyano group-2-(difluoromethyl)-6-{4-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 4-(trifluoromethoxy) benzsulfamide, obtain 5-cyano group-2-(difluoromethyl)-6-{4-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl amino) carbonyl] piperidines-1-yl Nikithan.Output: 17mg (19%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝7.6Hz)，1.41-1.50(2H，m)，1.79-1.84(2H，m)，3.14-3.20(2H，m)，4.23(2H，q，J＝7.2Hz)，4.42-4.48(2H，m)，7.32(1H，t，J＝54.6Hz)，7.52-7.56(2H，m)，7.95-8.00(2H，m)，8.42(1H，s)。Note! H signal and DMSO signal overlap.
MS?m/Z：577(M+1)。
Embodiment 38
5-cyano group-2-(difluoromethyl)-6-{4-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 2-(trifluoromethoxy) benzsulfamide, obtain 5-cyano group-2-(difluoromethyl)-6-{4-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl amino) carbonyl] piperidines-1-yl Nikithan.Output: 50mg (58%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝6.9Hz)，1.43-1.56(2H，m)，1.81-1.90(2H，m)，2.61-2.71(1H，m)，3.16-3.28(2H，m)，4.26(2H，q，J＝7.3Hz)，4.46-4.54(2H，m)，7.36(1H，t，J＝53.1Hz)，7.53-7.61(2H，m)，7.77-7.84(1H，m)，8.00-8.06(1H，m)，8.46(1H，s)。
MS?m/Z：577(M+1)。
Embodiment 39
5-cyano group-6-[4-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 2-(trifluoromethoxy) benzsulfamide, obtain 5-cyano group-2-(difluoromethyl)-6-{4-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl amino) carbonyl] piperidines-1-yl Nikithan.Output: 14mg (17%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝6.9Hz)，1.60-1.68(2H，m)，1.87-1.93(2H，m)，3.19-3.24(2H，m)，4.25(2H，q，J＝6.8Hz)，4.51-4.57(2H，m)，4.81(2H，s)，7.36(1H，t，J＝53.6Hz)，7.49-7.52(1H，m)，7.53-7.59(1H，m)，7.70-7.75(1H，m)，7.85-7.89(1H，m)，8.47(1H，s)。Note! H signal and DMSO signal overlap.
MS?m/Z：532(M+1)。
Embodiment 40
5-cyano group-2-(difluoromethyl)-6-(4-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid and naphthalene-2-sulphonamide preparation, obtain 5-cyano group-2-(difluoromethyl)-6-(4-{[(2-naphthyl alkylsulfonyl) amino] carbonyl piperidines-1-yl) Nikithan.Output: 31mg (38%).
1H?NMR(600MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.1Hz)，1.39-1.47(2H，m)，1.78-1.83(2H，m)，3.12-3.19(2H，m)，4.22(2H，q，J＝7.1Hz)，4.42-4.47(2H，m)，7.31(1H，t，J＝53.5Hz)，7.61-7.71(2H，m)，7.79-7.84(1H，m)，7.98-8.02(1H，m)，8.07-8.10(1H，m)，8.14-8.18(1H，m)，8.40(1H，s)，8.50-8.56(1H，m)。Note! H signal and DMSO signal overlap.
MS?m/z：543(M+1)。
Embodiment 41
6-(4-{[(butyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid and butane-1-sulphonamide preparation, obtain 6-(4-{[(butyl alkylsulfonyl) amino] carbonyl piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan.Output: 36mg (51%).
1H?NMR(400MHz，DMSO-d
6)δ?0.86(3H，t，J＝7.2Hz)，1.30(3H，t，J＝7.4Hz)，1.33-1.43(2H，m)，1.56-1.70(4H，m)，1.90-1.98(2H，m)，2.64-2.74(1H，m)，3.20-3.29(2H，m)，3.32-3.38(2H，m)，4.28(2H，q，J＝7.3Hz)，4.53-4.62(2H，m)，7.38(1H，t，J＝53.8Hz)，8.49(1H，s)，11.71(1H，s)。
MS?m/Z：473(M+1)。
Embodiment 42
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] and tetramethyleneimine-3-yl } acetate
With TEA (606mg, 5.99mmol) be added to 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan (341mg, 1.2mmol) and tetramethyleneimine-3-guanidine-acetic acid (209mg is in water/EtOH 1.62mmol) (4.5ml) solution.Mixture was heated 20 minutes in 120 ℃ in single node microwave oven.After making solvent evaporation, resistates is dissolved in DCM, uses 1%KHSO
4Washing.The water that merges extracts with DCM, the organic phase that merges is filtered the back by phase splitter concentrate.With HPLC purifying (Kromasil C
8, 10 μ m, elutriant: gradient 5%CH
3CN to 100%CH
3CN/ (0.2%AcOH (aqueous solution)), obtain 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] tetramethyleneimine-3-yl acetate, be white solid.Output: 219mg (49%).
1H?NMR(400MHz，CDCl
3)δ?1.35(3H，t，J＝7.2Hz)，1.85-1.68(1H，m)，2.38-2.23(1H，m)，2.64-2.47(2H，m)，2.81-2.66(1H，m)，3.57-3.40(1H，m)，3.91-3.77(1H，m)，4.08-3.97(1H，m)，4.21-4.10(1H，m)，4.33(2H，q，J＝7.3Hz)，8.31(1H，s)。
MS?m/Z：371(M+1)。
(b) 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
By { 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] tetramethyleneimine-3-yl } acetate and the preparation of 1-phenyl methanesulfonamide acid amides, obtain 6-(3-{2-[(benzyl alkylsulfonyl) amino according to method B]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 88mg (84%).
1H?NMR(600MHz，DMSO-d
6)δ1.26(3H，t，J＝7.3Hz)，1.59-1.68(1H，m)，2.09-2.17(1H，m)，2.40-2.44(2H，m)，3.64-3.77(1H，m)，3.81-3.91(1H，m)，3.94-4.06(1H，m)，4.24(2H，q，J＝7.0Hz)，4.68(2H，s)，7.24-7.39(5H，m)，8.45(1H，s)。Note! A H is hidden in the DMSO peak, and a H is hidden in H
2In the O peak.
MS?m/Z：525(M+1)。
Embodiment 43
5-cyano group-6-[3-(2-oxo-2-{[(2-phenylethyl) alkylsulfonyl] amino } ethyl) tetramethyleneimine-1-yl]-2-(trifluoromethyl) Nikithan
By { 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] tetramethyleneimine-3-yl } acetate and the preparation of 2-diphenylphosphino ethane sulphonamide, obtain 5-cyano group-6-[3-(2-oxo-2-{[(2-phenylethyl) alkylsulfonyl according to method B] amino } ethyl) tetramethyleneimine-1-yl]-2-(trifluoromethyl) Nikithan.Output: 73mg (68%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝7.0Hz)，1.58-1.66(1H，m)，2.05-2.13(1H，m)，2.37-2.40(2H，m)，2.92-2.98(2H，m)，3.62-3.67(2H，m)，3.67-3.75(1H，m)，3.80-3.99(2H，m)，4.23(2H，q，J＝7.3Hz)，7.15-7.31(5H，m)，8.43(1H，s)。Note! A H is hidden in the DMSO peak, and a H is hidden in H
2In the O peak.
MS?m/Z：537(M-1)。
Embodiment 44
6-[3-(2-{[(5-chloro-2-thienyl) alkylsulfonyl] amino }-the 2-oxoethyl) tetramethyleneimine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
By { 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] tetramethyleneimine-3-yl } acetate and 5-chlorothiophene-2-sulphonamide preparation, obtain 6-[3-(2-{[(5-chloro-2-thienyl) alkylsulfonyl according to method B] amino }-the 2-oxoethyl) tetramethyleneimine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 86mg (78%).
1H?NMR(500MHz，DMSO-d
6)δ?1.29(3H，t，J＝6.9Hz)，1.60-1.69(1H，m)，2.06-2.14(1H，m)，2.44-2.48(1H，m)，2.55-2.60(1H，m)，3.33-3.39(1H，m)，3.68-3.76(1H，m)，3.84-3.96(2H，m)，4.28(2H，q，J＝7.2Hz)，7.22(1H，d，J＝4.2Hz)，7.63(1H，d，J＝4.2Hz)，8.41(1H，s)。
MS?m/z：549(M-1)。
Embodiment 45
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid
With TEA (0.908g, 8.97mmol) be added to 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan (1.0g, 3.59mmol) and azetidine-3-formic acid (0.399g in EtOH 3.95mmol) (10ml) suspension, heats mixture 20 minutes in single node microwave oven.After making solvent evaporation, resistates is at iPrOAc (10ml)/water and Na
2CO
3Between distribute.After the water phase separated, add dense HCl and make it acidifying.Acid water extracts with iPrOAc (2 x 10ml).With the extract drying (MgSO that merges
4) the back evaporation, obtain 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid, be brown solid, need not to be further purified just and can use.Output: 1.04g (84%).
1H-NMR(500MHz，DMSO-d
6)δ?1.27(3H，t，J＝7.1Hz)，3.55-3.62(1H，m)，4.28(2H，q，J＝7.1Hz)，4.38-4.58(4H，m)，8.46(1H，s)。
(b) 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan.Output: 2.9mg (4%).
MS?m/Z：515(M+1)。
Embodiment 46
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan.Output: 46.2mg (90%).
1H NMR (500MHz, CDCl
3) δ 1.30 (3H, t, J=7.1Hz), 3.46 (1H, quintet, J=7.4Hz), 4.29 (2H, q, J=7.2Hz), 4.44 (4H, br s), 4.58 (2H, s), 7.02-7.09 (3H, m), 7.29 (1H, td, J=8.0,5.9Hz), 8.18 (1H, s), 10.83 (1H, s).
MS?m/Z：515(M+1)。
Embodiment 47
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan.Output: 45.1mg (88%).
1H?NMR(500MHz，CDCl
3)δ?1.39(3H，t，J＝7.1Hz)，3.60(1H，tt，J＝8.7，6.0Hz)，4.37(2H，q，J＝7.2Hz)，4.52-4.67(4H，m)，4.73(2H，s)，7.15(1H，t，J＝9.0Hz)，7.21(1H，t，J＝7.6Hz)，7.42(2H，dd，J＝13.5，7.1Hz)，8.26(1H，s)，10.65(1H，s)。
MS?m/Z：515(M+1)。
Embodiment 48
5-cyano group-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan.Output: 42.4mg (55%).
1H?NMR(500MHz，CDCl
3)δ?1.39(3H，t，J＝7.1Hz)，2.37(3H，s)，3.54(1H，tt，J＝8.3，6.2Hz)，4.37(2H，q，J＝7.1Hz)，4.39-4.49(4H，br?s)，4.63(2H，s)，7.20(2H，d，J＝7.8Hz)，7.26(2H，d，J＝7.9Hz)，8.27(1H，s)。
MS?m/z：511(M+1)。
Embodiment 49
5-cyano group-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan.
MS?m/Z：511(M+1)。
Embodiment 50
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 0.96mg (1%).
MS?m/z：531(M+1)。
Embodiment 51
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 49.9mg (63%).
1H NMR (500MHz, CDCl
3) δ 1.38 (3H, t, J=7.1Hz), 3.62 (1H, tt, J=8.8,6.2Hz), 4.37 (2H, q, J=7.2Hz), 4.87 (2H, s), 7.35 (2H, quintet, J=7.6,1.7Hz), 7.48 (2H, ddd, J=13.5,7.5,1.7Hz), 8.26 (1H, s), 10.98 (1H, s).
MS?m/Z：531(M+1)。
Embodiment 52
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 21.6mg (27%).
1H NMR (500MHz, CDCl
3) δ 1.39 (3H, t, J=7.1Hz), 3.55 (1H, quintets, J=7.4Hz), 4.37 (2H, q, J=7.1Hz), 4.49-4.57 (4H, m), 4.65 (2H, s), 7.26 (1H, d, J=7.7Hz), 7.35 (1H, t, J=7.9Hz), 7.41 (1H, d, J=8.0Hz), 7.41 (1H, s), 8.27 (1H, s), 10.78 (1H, s).
MS?m/Z：531(M+1)。
Embodiment 53
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid and 1-(2; the 4-dichlorophenyl) Toluidrin preparation; obtain 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan.Output: 14.1mg (16%).
1H?NMR(500MHz，CDCl
3)δ?1.39(3H，t，J＝7.1Hz)，3.64(1H，tt，J＝8.7，6.0Hz)，4.37(2H，q，J＝7.1Hz)，4.52-4.70(4H，br?s)，4.84(2H，s)，7.33(1H，dd，J＝8.4，2.0Hz)，7.45(1H，d，J＝8.3Hz)，7.50(1H，d，J＝2.0Hz)，8.27(1H，s)，11.41(1H，s)。
MS?m/z：565(M+1)。
Embodiment 54
6-(3-{[(5-chloro-2-thienyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid and 5-chlorothiophene-2-sulphonamide preparation, obtain 6-(3-{[(5-chloro-2-thienyl) alkylsulfonyl] formamyl azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 43.9mg (56%).
1H NMR (500MHz, CDCl
3) δ 1.38 (3H, t, J=7.1Hz), 3.63 (1H, quintet, J=7.4Hz), 4.36 (2H, q, J=7.2Hz), 4.50-4.64 (4H, br s), 6.97 (1H, d, J=4.0Hz), 7.70 (1H, d, J=4.2Hz), 8.24 (1H, s), 11.48 (1H, s).
MS?m/Z：523(M+1)。
Embodiment 55
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid
With TEA (0.908g, 8.97mmol) be added to 6-chloro-5-cyano group-2-(trifluoromethyl) Nikithan (1.0g, 3.59mmol) and piperidines-4-formic acid (0.510g in EtOH 3.95mmol) (10ml) suspension, heats mixture 15 minutes in single node microwave oven.After making solvent evaporation, resistates is at iPrOAc (10ml)/water and 20%Na
2CO
3Distribute (1ml).Water phase separated behind the adding 1ml EtOH, makes aqueous phase as acidified by adding dense HCl.Acid water extracts with iPrOAc (2 x 10ml).With organic phase drying (MgSO
4), filter the back and concentrate, obtain 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid, be brown solid, need not to be further purified just and can use.Output: 1.06g (79%).
1H?NMR(500MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.1Hz)，1.6l-1.71(2H，m)，1.95-2.02(2H，m)，2.60-2.68(1H，m)，3.31-3.38(2H，m)，4.28(2H，q，J＝7.1Hz)，4.41-4.48(2H，m)，8.51(1H，s)。
(b) 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan.Output: 4.3mg (4%).
1H?NMR(600MHz，CDCl
3)δ?1.36(3H，t，J＝7Hz)，1.78-1.94(4H，m)，2.49-2.55(1H，m)，3.23(2H，t，J＝12.5Hz)，4.35(2H，q，J＝7Hz)，4.60(2H，s)，4.67(2H，br?d，J＝12.5Hz)，7.06(2H，t，J＝8.5Hz)，7.31(2H，dd，J＝5，8.5Hz)，8.34(1H，s)，9.50(1H，s)。
MS?m/Z：543(M+1)。
Embodiment 56
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan.Output: 5.7mg (5%).
1H?NMR(500MHz，CDCl
3)δ?1.40(3H，t，J＝7.5Hz)，1.81-1.97(4H，m)，2.53-2.61(1H，m)，3.28(2H，t，J＝12.5Hz)，4.39(2H，q，J＝7.5Hz)，4.67(2H，s)，4.71(2H，br?d，J＝12.5Hz)，7.12-7.15(3H，m)，7.36-7.41(1H，m)，8.38(1H，s)，9.68(1H，s)。
MS?m/Z：543(M+1)。
Embodiment 57
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(2-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan.Output: 5.1mg (5%).
1H?NMR(400MHz，CDCl
3)δ?1.35(3H，t，J＝6.5Hz)，1.80-1.99(4H，m)，2.53-2.61(1H，m)，3.27(2H，t，J＝13Hz)，4.34(2H，q，J＝6.5Hz)，4.67(2H，br?d，J＝13Hz)，4.69(2H，s)，7.11(1H，t，J＝9Hz)，7.17(1H，t，J＝7.5Hz)，7.34-7.39(2H，m)，8.33(1H，s)，9.63(1H，s)。
MS?m/Z：543(M+1)。
Embodiment 58
5-cyano group-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan.Output: 3.4mg (3%).
1H?NMR(400MHz，CDCl
3)δ?1.36(3H，t，J＝7.5Hz)，1.75-1.93(4H，m)，2.34(3H，s)，2.44-2.52(1H，m)，3.23(2H，t，J＝12.5Hz)，4.35(2H，q，J＝7.5Hz)，4.58(2H，s)，4.66(2H，br?d，J＝12.5Hz)，7.15-7.21(4H，m)，8.33(1H，s)，8.88(1H，s)。
MS?m/Z：539(M+1)。
Embodiment 59
5-cyano group-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan.Output: 2.8mg (3%).
1H?NMR(400MHz，CDCl
3)δ?1.31(3H，t，J＝7.5Hz)，1.71-1.88(4H，m)，2.28(3H，s)，2.39-2.47(1H，m)，3.18(2H，t，J＝13Hz)，4.30(2H，q，J＝7.5Hz)，4.54(2H，s)，4.61(2H，br?d，J＝13Hz)，7.05-7.23(4H，m)，8.29(1H，s)，8.72(1H，s)。
MS?m/Z：539(M+1)。
Embodiment 60
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 6.6mg (6%).
1H?NMR(600MHz，CDCl
3)δ?1.20(3H，t，J＝7.5Hz)，1.63-1.70(2H，m)，1.74-1.79(2H，m)，2.39-2.41(1H，m)，3.09(2H，t，J＝12.5Hz)，4.18(2H，q，J＝7.5Hz)，4.42(2H，s)，4.52(2H，br?d，J＝12.5Hz)，7.12(2H，d，J＝8.5Hz)，7.19(2H，d，J＝8.5Hz)，8.18(1H，s)，11.32(1H，s)。
MS?m/Z：559(M+1)。
Embodiment 61
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(2-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 7.8mg (7%).
1H?NMR(600MHz，CDCl
3)δ?1.35(3H，t，J＝7Hz)，1.81-1.90(2H，m)，1.96-2.00(2H，m)，2.56-2.64(1H，m)，3.26(2H，t，J＝12Hz)，4.34(2H，q，J＝7Hz)，4.68(2H，br?d，J＝12Hz)，4.84(2H，s)，7.27-7.34(2H，m)，7.42(2H，t，J＝7Hz)，8.34(1H，s)，10.03(1H，s)。
MS?m/Z：559(M+1)。
Embodiment 62
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 7.3mg (6%).
1H?NMR(500MHz，CDCl
3)δ?1.40(3H，t，J＝7.5Hz)，1.81-1.90(2H，m)，1.91-1.97(2H，m)，2.54-2.62(1H，m)，3.28(2H，t，J＝12.5Hz)，4.39(2H，q，J＝7.5Hz)，4.64(2H，s)，4.72(2H，br?d，J＝12.5Hz)，7.25(1H，d，J＝7.5Hz)，7.34-7.42(3H，m)，8.38(1H，s)，10.02(1H，s)。
MS?m/Z：559(M+1)。
Embodiment 63
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid and 1-(2; the 4-dichlorophenyl) Toluidrin preparation; obtain 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan.Output: 5.5mg (5%).
1H?NMR(600MHz，CDCl
3)δ?1.35(3H，t，J＝7.5Hz)，1.83-1.90(2H，m)，1.97-2.01(2H，m)，2.56-2.64(1H，m)，3.29(2H，t，J＝12.5Hz)，4.34(2H，q，J＝7.5Hz)，4.68(2H，br?d，J＝12.5Hz)，4.80(2H，s)，7.28(1H，dd，J＝2，8.5Hz)，7.37(1H，d，J＝8.5Hz)，7.45(1H，d，J＝2Hz)，8.33(1H，s)，10.04(1H，s)。
MS?m/Z：593(M+1)。
Embodiment 64
6-[4-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
According to method C by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid and 5-chlorothiophene-2-sulphonamide preparation, obtain 6-[4-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 19.1mg (17%).
1H?NMR(400MHz，CDCl
3)δ?1.34(3H，t，J＝7Hz)，1.72-1.84(2H，m)，1.91-1.97(2H，m)，2.55-2.65(1H，m)，3.27(2H，t，J＝12.5Hz)，4.33(2H，q，J＝7.5Hz)，4.61(2H，br?d，J＝12.5Hz)，6.91(1H，d，J＝4Hz)，7.62(1H，d，J＝4Hz)，8.30(1H，s)，10.99(1H，s)。
MS?m/Z：551(M+1)。
Embodiment 65
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid
With TEA (653mg, 6.46mmol) be added to 6-chloro-5-cyano group-2-(methyl fluoride) Nikithan (400mg, 1.61mmol) and azetidine-3-formic acid (179mg is in water/EtOH 1.78mmol) (4.5ml) solution.Mixture was heated 20 minutes in 120 ℃ in single node microwave oven.After making solvent evaporation, resistates is dissolved in DCM, uses 1%KHSO
4Washing.Water extracts with DCM, the organic phase that merges is filtered the back by phase splitter concentrate.With HPLC purifying (Kromasil C
8, 10 μ m, elutriant: gradient 5%CH
3CN to 100%CH
3CN/ (0.2%AcOH (aqueous solution)) obtains 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid, be white solid.Output: 302mg (60%).
1H?NMR(400MHz，CDCl
3)δ?1.31(3H，t，J＝7.3Hz)，3.59-3.69(1H，m)，4.31(2H，q，J＝7.3Hz)，4.60-4.70(4H，m)，5.69(2H，d，J＝47.3Hz)，8.30(1H，br?s)。
(b) 5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan.Output: 21mg (44%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，3.55-3.66(1H，m)，4.25(2H，q，J＝7.2Hz)，4.34-4.44(2H，m)，4.43-4.56(2H，m)，4.80(2H，s)，5.68(2H，d，J＝47.1Hz)，7.18-7.32(2H，m)，7.37-7.52(2H，m)，8.39(1H，s)，11.80-12.19(1H，m)。
MS?m/Z：479(M+1)。
Embodiment 66
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan.Output: 25mg (53%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.1Hz)，3.54-3.64(1H，m)，4.24(2H，q，J＝7.1Hz)，4.28-4.36(2H，m)，4.39-4.53(2H，m)，4.79(2H，s)，5.67(2H，d，J＝47.1Hz)，7.13-7.27(3H，m)，7.37-7.47(1H，m)，8.38(1H，s)，11.55-12.36(1H，m)。
MS?m/Z：479(M+1)。
Embodiment 67
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan.Output: 27mg (56%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.2Hz)，3.55-3.77(1H，m)，4.24(2H，q，J＝7.1Hz)，4.29-4.37(2H，m)，4.41-4.51(2H，m)，4.73(2H，s)，5.66(2H，d，J＝47.1Hz)，7.15-7.23(2H，m)，7.34-7.42(2H，m)，8.37(1H，s)。
MS?m/Z：479(M+1)。
Embodiment 68
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan.Output: 13mg (27%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，3.59-3.69(1H，m)，4.25(2H，q，J＝7.2Hz)，4.36-4.56(4H，m)，4.90(2H，s)，5.67(2H，d，J＝47.3Hz)，7.34-7.56(4H，m)，8.38(1H，s)，11.73-12.28(1H，m)。
MS?m/Z：495(M+1)。
Embodiment 69
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan.Output: 28mg (58%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，3.51-3.65(1H，m)，4.25(2H，q，J＝7.2Hz)，4.27-4.37(2H，m)，4.40-4.53(2H，m)，4.79(2H，s)，5.67(2H，d，J＝47.1Hz)，7.27-7.50(4H，m)，8.36-8.40(1H，m)，11.71-12.13(1H，m)。
MS?m/Z：495(M+1)。
Embodiment 70
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-chloro-phenyl-) Toluidrin, obtain 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan.Output: 33mg (68%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.2Hz)，3.45-3.58(1H，m)，4.24(2H，q，J＝7.2Hz)，4.29-4.38(2H，m)，4.38-4.50(2H，m)，4.60(2H，s)，5.66(2H，d，J＝47.1Hz)，7.29-7.41(4H，m)，8.36(1H，s)。
MS?m/Z：495(M+1)。
Embodiment 71
5-cyano group-2-(methyl fluoride)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(methyl fluoride)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan.Output: 41mg (86%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，2.27(3H，s)，3.51-3.60(1H，m)，4.25(2H，q，J＝7.2Hz)，4.29-4.37(2H，m)，4.39-4.51(2H，m)，4.69(2H，s)，5.67(2H，d，J＝50.0Hz)，7.07-7.32(4H，m)，8.38(1H，s)，11.59-12.03(1H，m)。
MS?m/Z：475(M+1)。
Embodiment 72
5-cyano group-2-(methyl fluoride)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(methyl fluoride)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan.Output: 12mg (25%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.2Hz)，2.28(3H，s)，3.53-3.60(1H，m)，4.24(2H，q，J＝7.2Hz)，4.29-4.36(2H，m)，4.39-4.50(2H，m)，4.67(2H，s)，5.67(2H，d，J＝47.1Hz)，7.15-7.23(4H，m)，8.37-8.40(1H，m)，11.48-12.04(1H，m)。
MS?m/Z：475(M+1)。
Embodiment 73
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid and 1-(2; the 4-dichlorophenyl) Toluidrin preparation; obtain 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan.Output: 27mg (51%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.2Hz)，3.56-3.65(1H，m)，4.24(2H，q，J＝7.2Hz)，4.35-4.58(4H，m)，4.86(2H，s)，5.67(2H，d，J＝47.1Hz)，7.41-7.70(3H，m)，8.36-8.39(1H，m)。
MS?m/Z：529(M+1)。
Embodiment 745-cyano group-2-(methyl fluoride)-6-{3-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-methylcyclohexyl) Toluidrin; obtain 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan.Output: 28mg (57%).
1H?NMR(400MHz，DMSO-d
6)δ?0.75-0.92(4H，m)，0.95-1.17(3H，m)，1.25(3H，t，J＝7.1Hz)，1.35-1.54(4H，m)，1.55-1.64(1H，m)，1.74-1.84(1H，m)，2.00-2.10(1H，m)，3.22-3.28(1H，m)，3.51-3.63(1H，m)，4.20(2H，q，J＝7.1Hz)，4.29-4.39(2H，m)，4.40-4.51(2H，m)，5.61(2H，d，J＝47.3Hz)，8.32(1H，s)。
MS?m/Z：481(M+1)。
Embodiment 75
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] piperidines-4-formic acid
With TEA (653mg, 6.46mmol) be added to 6-chloro-5-cyano group-2-(methyl fluoride) Nikithan (400mg, 1.61mmol) and piperidines-4-formic acid (229mg is in water/EtOH 1.78mmol) (4.5ml) solution.Mixture was heated 20 minutes in 120 ℃ in single node microwave oven.After making solvent evaporation, resistates is dissolved in DCM, uses 1%KHSO
4Washing.Water extracts with DCM, the organic phase that merges is filtered the back by phase splitter concentrate.With HPLC purifying (KromasilC
8, elutriant: gradient 5%CH
3CN to 100%CH
3CN/ (0.2%HOAc (aqueous solution)) obtains 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid, be white solid.Output: 76mg (14%).
1H?NMR(400MHz，CDCl
3)δ?1.36(3H，t，J＝7.2Hz)，1.82-1.94(2H，m)，2.05-2.14(2H，m)，2.66-2.76(1H，m)，3.32-3.42(2H，m)，4.31(2H，t，J＝7.2Hz)，4.61-4.69(2H，m)，5.70(2H，d，J＝47.3Hz)，8.36(1H，br?s)。
(b) 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(2-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan.Output: 13mg (25%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.1Hz)，1.56-1.75(2H，m)，1.82-1.93(2H，m)，2.56-2.64(1H，m)，3.14-3.26(2H，m)，4.25(2H，q，J＝7.1Hz)，4.55-4.64(2H，m)，4.68(2H，s)，5.68(2H，d，J＝47.1Hz)，7.18-7.30(2H，m)，7.32-7.48(2H，m)，8.39(1H，s)。
MS?m/Z：507(M+1)。
Embodiment 76
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan.Output: 16mg (31%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.1Hz)，1.56-1.71(2H，m)，1.79-1.89(2H，m)，2.55-2.61(1H，m)，3.15-3.26(2H，m)，4.25(2H，q，J＝7.1Hz)，4.53-4.64(2H，m)，4.70(2H，s)，5.69(2H，d，J＝47.1Hz)，7.07-7.17(2H，m)，7.20-7.28(1H，m)，7.39-7.49(1H，m)，8.39-8.42(1H，m)，11.47-12.06(1H，m)。
MS?m/Z：507(M+1)。
Embodiment 77
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-fluorophenyl) Toluidrin, obtain 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan.Output: 23mg (45%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.1Hz)，1.56-1.70(2H，m)，1.78-1.89(2H，m)，2.52-2.56(1H，m)，3.14-3.24(2H，m)，4.25(2H，q，J＝7.1Hz)，4.51-4.63(4H，m)，5.68(2H，d，J＝47.1Hz)，7.16-7.24(2H，m)，7.27-7.34(2H，m)，8.39(1H，s)。
MS?m/Z：507(M+1)。
Embodiment 78
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(2-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan.Output: 24mg (45%).
1H?NMR(400MHz，DMSO-d
6)δ?1.29(3H，t，J＝7.2Hz)，1.56-1.74(2H，m)，1.84-1.95(2H，m)，2.56-2.66(1H，m)，3.16-3.27(2H，m)，4.25(2H，q，J＝7.2Hz)，4.54-4.65(2H，m)，4.80(2H，s)，5.68(2H，d，J＝47.3Hz)，7.35-7.46(3H，m)，7.48-7.55(1H，m)，8.39(1H，s)。
MS?m/Z：523(M+1)。
Embodiment 79
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan.
Output: 24mg (46%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.1Hz)，1.57-1.70(2H，m)，1.76-1.88(2H，m)，2.53-2.61(1H，m)，3.15-3.27(2H，m)，4.25(2H，q，J＝7.1Hz)，4.55-4.63(2H，m)，4.68(2H，s)，5.68(2H，d，J＝47.3Hz)，7.18-7.52(4H，m)，8.40(1H，s)。
MS?m/Z：523(M+1)。
Embodiment 80
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-chloro-phenyl-) Toluidrin, obtain 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan.
Output: 24mg (46%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，1.56-1.71(2H，m)，1.80-1.90(2H，m)，2.54-2.60(1H，m)，3.13-3.26(2H，m)，4.25(2H，q，J＝7.1Hz)，4.55-4.63(2H，m)，4.66(2H，s)，5.68(2H，d，J＝47.1Hz)，7.30(2H，d，J＝8.5Hz)，7.46(2H，d，J＝8.5Hz)，8.38-8.41(1H，m)。
MS?m/Z：523(M+1)。
Embodiment 81
5-cyano group-2-(methyl fluoride)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(methyl fluoride)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan.
Output: 6mg (12%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.1Hz)，1.58-1.71(2H，m)，1.79-1.88(2H，m)，2.28(3H，s)，2.52-2.58(1H，m)，3.17-3.23(2H，m)，4.25(2H，q，J＝7.1Hz)，4.48-4.68(4H，m)，5.68(2H，d，J＝47.1Hz)，7.00-7.32(4H，m)，8.40(1H，s)，11.27-11.80(1H，m)。
MS?m/z：503(M+1)。
Embodiment 82
5-cyano group-2-(methyl fluoride)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(methyl fluoride)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan.
Output: 20mg (40%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，1.57-1.72(2H，m)，1.80-1.92(2H，m)，2.30(3H，s)，2.54-2.64(1H，m)，3.11-3.25(2H，m)，4.26(2H，q，J＝7.2Hz)，4.52-4.68(4H，m)，5.69(2H，d，J＝47.3Hz)，7.11-7.28(4H，m)，8.41(1H，s)，11.33-11.86(1H，m)。
MS?m/Z：503(M+1)。
Embodiment 83
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] piperidines-4-formic acid and 1-(2; the 4-dichlorophenyl) Toluidrin preparation; obtain 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan.
Output: 21mg (38%).
1H?NMR(400MHz，DMSO-d
6)δ?1.30(3H，t，J＝7.2Hz)，1.56-1.72(2H，m)，1.83-1.94(2H，m)，2.54-2.59(1H，m)，3.15-3.27(2H，m)，4.25(2H，q，J＝7.2Hz)，4.53-4.63(2H，m)，4.73(2H，s)，5.68(2H，d，J＝47.3Hz)，7.39-7.53(2H，m)，7.62-7.70(1H，m)，8.35-8.43(1H，m)。
MS?m/Z：557(M+1)。
Embodiment 84
5-cyano group-2-(methyl fluoride)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
According to method E by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-methylcyclohexyl) Toluidrin, obtain 5-cyano group-2-(methyl fluoride)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl amino) carbonyl] piperidines-1-yl Nikithan.
Output: 18mg (36%).
1H?NMR(400MHz，DMSO-d
6)δ?0.80-0.90(4H，m)，0.96-1.20(3H，m)，1.29(3H，t，J＝7.2Hz)，1.38-1.69(7H，m)，1.77-1.97(3H，m)，1.99-2.09(1H，m)，2.59-2.71(2H，m)，3.16-3.29(2H，m)，4.25(2H，q，J＝7.2Hz)，4.51-4.66(2H，m)，5.67(2H，d，J＝47.3Hz)，8.39(1H，s)。
MS?m/Z：509(M+1)。
Embodiment 85
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(a) amino 3-{2-[(benzyl alkylsulfonyl)]-the 2-oxoethyl } azetidine-1-t-butyl formate
With DIPEA (0.3ml, 1.72mmol) be added to [1-(tert-butoxycarbonyl) azetidine-3-yl] acetate (193mg, 0.90mmol) and TBTU (326mg, 1.02mmol) with the mixture of anhydrous DCM (4ml) in.After reaction mixture at room temperature stirred 1 hour, (169mg 0.99mmol), at room temperature continued to stir 19 hours to add 1-phenyl methanesulfonamide acid amides.Add NaHCO
3After (aqueous solution), mixture extracts (3 times) with EtOAc.The organic layer that merges filters the back evaporation through anhydrous MgSO4 drying, obtains 3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-t-butyl formate, need not to be further purified and just can be used for next step.Output: 383mg (116%).
MS?m/Z：367(M-1)。
(b) 2-azetidine-3-base-N-(benzyl alkylsulfonyl) ethanamide
To derive from the crude product 3-{2-[(benzyl alkylsulfonyl of above-mentioned steps) amino]-the 2-oxoethyl } (383mg 0.90mmol) is dissolved in DCM (5ml) back and adds TFA (4ml) azetidine-1-t-butyl formate.Reaction mixture was at room temperature stirred 1.5 hours.After making solvent evaporation, obtain 2-azetidine-3-base-N-(benzyl alkylsulfonyl) ethanamide, need not to be further purified and just can be used for next step.Output: 240mg (100%).
MS?m/Z：269(M+1)，267(M-1)。
(c) 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
DIPEA (1ml) is added to crude product 2-azetidine-3-base-N-(benzyl alkylsulfonyl) ethanamide of deriving from above-mentioned steps and 6-chloro-5-cyano group-2-(difluoromethyl) Nikithan, and (180mg is in EtOH 0.69mmol) (9ml) solution.With the heating of microwave single-unit reaction mixture is heated to 120 ℃ and reaches 5 minutes.Add NaHCO
3(aqueous solution), mixture extracts (3 times) with DCM.The organic layer that makes merging evaporates after by phase splitter.Crude product HPLC purifying (Kromasil C
810 μ m, 21.5 x 250mm, the employing gradient is CH
3CN/0.1M NH
4OAc20% to 50%, flow velocity 25ml/ minute), obtain 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan.Output: 156mg (after 3 steps 46%).
1H NMR (500MHz, DMSO-d
6) δ 1.31 (3H, t, J=7.1Hz), 2.71 (2H, d, J=7.6Hz), and 3.04-3.11 (1H, m), 4.08 (2H, apparent br s), 4.28 (2H, q, J=7.1Hz), (4.52 2H, apparent br s), 4.70 (2H, s), 7.29-7.32 (2H, m), 7.37-7.44 (3H, m), 7.40 (1H, t, J=53Hz ,-CHF
2), 8.44 (1H, s), 11.68 (1H, s).
MS?m/Z：493(M+1)，491(M-1)。
Embodiment 86
5-cyano group-6-(3-{[(2-cyano group benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-cyano-phenyl) Toluidrin, obtain 5-cyano group-6-(3-{[(2-cyano group benzyl) alkylsulfonyl] formamyl azetidine-1-yl)-2-(trifluoromethyl) Nikithan.
Output: 45mg (58%).
1H?NMR(500MHz，CDCl
3)δ?1.38(3H，t，J＝7.1Hz)，3.70(1H，tt，J＝8.7，6.1Hz)，4.37(2H，q，J＝7.2Hz)，4.55-4.70(4H，m)，4.91(2H，s)，7.55(1H，t，J＝7.5Hz)，7.64(1H，d，J＝7.1Hz)，7.69(1H，t，J＝7.6Hz)，7.75(1H，d，J＝7.6Hz)，8.26(1H，s)，11.20(1H，br?s)。
MS?m/Z：522(M+1)。
Embodiment 87
5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(methyl fluoride) Nikithan
According to method A by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid and 1-(2; the 6-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(methyl fluoride) Nikithan.Output: 6.2mg (12%).
1H?NMR(600MHz，DMSO-d
6)δ?1.27(3H，t，J＝7.2Hz)，3.55-3.62(1H，m)，4.22(2H，q，J＝7.3Hz)，4.31-4.42(2H，m)，4.42-4.54(2H，m)，4.77(2H，s)，5.64(2H，d，J＝47.8Hz)，7.11-7.19(2H，m)，7.46-7.53(1H，m)，8.36(1H，s)。
MS?m/Z：497(M+1)。
Embodiment 88
5-cyano group-2-(methyl fluoride)-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
According to method A by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-fluoro-3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(methyl fluoride)-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl azetidine-1-yl) Nikithan.Output: 17.1mg (35%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝6.9Hz)，2.15(3H，s)，3.50-3.57(1H，m)，4.20(2H，q，J＝7.4Hz)，4.23-4.33(2H，m)，4.32-4.47(2H，m)，4.65(2H，s)，5.63(2H，d，J＝46.8Hz)，7.05-7.21(3H，m)，8.34(1H，s)。
MS?m/Z：493(M+1)。
Embodiment 89
6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
According to method A by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-chloro-4-fluorophenyl) Toluidrin, obtain 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan.Output: 18.7mg (36%).
1H?NMR(600MHz，DMSO-d
6)δ?1.27(3H，t，J＝7.1Hz)，3.56-3.63(1H，m)，4.22(2H，q，J＝7.0Hz)，4.32-4.51(4H，m)，4.86(2H，s)，5.64(2H，d，J＝46.5Hz)，7.24-7.30(1H，m)，7.47-7.57(2H，m)，8.35(1H，s)。
MS?m/Z：513(M+1)。
Embodiment 90
5-cyano group-2-(methyl fluoride)-6-(3-{[(2,3,6-trifluoro-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
According to method A by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid and 1-(2; 3; the 6-trifluorophenyl) Toluidrin preparation; obtain 5-cyano group-2-(methyl fluoride)-6-(3-{[(2; 3, the 6-trifluoro-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan.Output: 24.4mg (47%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝7.2Hz)，3.55-3.62(1H，m)，4.20(2H，q，J＝7.1Hz)，4.30-4.52(4H，m)，4.82(2H，s)，5.63(2H，d，J＝46.1Hz)，7.16-7.23(1H，m)，7.53-7.61(1H，m)，8.35(1H，s)。
MS?m/Z：515(M+1)。
Embodiment 91
5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(methyl fluoride) Nikithan
According to method A by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid and 1-(2; the 4-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(methyl fluoride) Nikithan.Output: 17.7mg (36%).
1H?NMR(600MHz，DMSO-d
6)δ?1.26(39H，t，J＝7.1Hz)，3.54-3.60(1H，m)，4.21(2H，q，J＝7.1Hz)，4.29-4.52(4H，m)，4.75(2H，s)，5.64(2H，d，J＝47.8Hz)，7.10-7.15(1H，m)，7.24-7.30(1H，m)，7.46-7.52(1H，m)，8.36(3H，s)。
MS?m/Z：497(M+1)。
Embodiment 92
6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
According to method A by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-chloro-2-fluorophenyl) Toluidrin, obtain 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan.Output: 19.9mg (39%).
1H?NMR(600MHz，DMSO-d
6)δ?1.27(3H，t，J＝6.9Hz)，3.54-3.61(1H，m)，4.21(2H，q，J＝6.8Hz)，4.29-4.52(4H，m)，4.77(2H，s)，5.64(2H，d，J＝47.4Hz)，7.32-7.35(1H，m)，7.44-7.50(2H，m)，8.36(1H，s)。
MS?m/Z：513(M+1)。
Embodiment 93
5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid and 1-(2; the 6-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan.Output: 14.5mg (28%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.1Hz)，3.53-3.61(1H，m)，4.24(2H，q，J＝7.1Hz)，4.30-4.56(4H，m)，4.75(1H，s)，7.10-7.17(2H，m)，7.37(1H，t，J＝54.2Hz)，7.44-7.53(1H，m)，8.44(1H，s)。
MS?m/Z：515(M+1)。
Embodiment 94
5-cyano group-2-(difluoromethyl)-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-fluoro-3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl azetidine-1-yl) Nikithan.Output: 24.7mg (48%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.1Hz)，2.17(3H，s)，3.52-3.59(1H，m)，4.25(2H，q，J＝7.1Hz)，4.27-4.50(4H，m)，4.67(2H，s)，7.08-7.13(1H，m)，7.16-7.22(2H，m)，7.37(1H，t，J＝54.8Hz)，8.45(1H，s)。
MS?m/Z：511(M+1)。
Embodiment 95
6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-chloro-4-fluorophenyl) Toluidrin, obtain 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan.Output: 24.6mg (46%).
1H?NMR(600MHz，DMSO-d
6)δ?1.26(3H，t，J＝7.2Hz)，3.56-3.62(1H，m)，4.23(2H，q，J＝7.2Hz)，4.29-4.54(4H，m)，4.85(2H，s)，7.23-7.29(1H，m)，7.36(1H，t，J＝52.7Hz)，7.43-7.56(2H，m)，8.43(1H，s)。
MS?m/Z：531(M+1)。
Embodiment 96
5-cyano group-2-(difluoromethyl)-6-(3-{[(5-fluoro-2-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(5-fluoro-2-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-(3-{[(5-fluoro-2-methyl-benzyl) alkylsulfonyl] formamyl azetidine-1-yl) Nikithan.Output: 30.8mg (60%).
1H?NMR(600MHz，DMSO-d
6)δ?1.26(3H，t，J＝6.9Hz)，2.30(3H，s)，3.57-3.63(1H，m)，4.23(2H，q，J＝7.4Hz)，4.29-4.54(4H，m)，4.75(2H，s)，7.02-7.12(2H，m)，7.22-7.27(1H，m)，7.35(1H，t，J＝53.9Hz)，8.43(1H，s)。
MS?m/Z：511(M+1)。
Embodiment 97
5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid and 1-(2; the 4-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan.Output: 24.2mg (47%).
1H?NMR(600MHz，DMSO-d6)δ1.26(3H，t，J＝7.0Hz)，3.54-3.61(1H，m)，4.23(2H，q，J＝7.1Hz)，4.30-4.53(4H，m)，4.75(2H，s)，7.09-7.13(1H，m)，7.22-7.27(1H，m)，7.36(1H，t，J＝54.0Hz)，7.46-7.51(1H，m)，8.43(1H，s)。
MS?m/Z：515(M+1)。
Embodiment 98
6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-chloro-2-fluorophenyl) Toluidrin, obtain 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan.Output: 27mg (51%).
1H?NMR(600MHz，DMSO-d
6)δ?1.28(3H，t，J＝7.0Hz)，3.55-3.62(1H，m)，4.25(2H，q，J＝7.4Hz)，4.29-4.56(4H，m)，4.77(2H，s)，7.31-7.35(1H，m)，7.39(1H，t，J＝59.6Hz)，7.45-7.49(2H，m)，8.45(1H，s)。
MS?m/Z：531(M+1)。
Embodiment 99
5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(trifluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid and 1-(2; the 6-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan.Output: 14.4mg (27%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝7.1Hz)，3.54-3.61(1H，m)，4.24(2H，q，J＝7.3Hz)，4.30-4.54(4H，m)，4.75(2H，s)，7.11-7.17(2H，m)，7.46-7.53(1H，m)，8.47(1H，s)。
MS?m/Z：533(M+1)。
Embodiment 100
5-cyano group-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(trifluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-fluoro-3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl azetidine-1-yl)-2-(trifluoromethyl) Nikithan.Output: 26.2mg (49%).
1H?NMR(600MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.5Hz)，2.15(3H，s)，3.50-3.57(1H，m)，4.21-4.47(4H，m)，4.23(2H，q，J＝7.4Hz)，4.64(2H，s)，7.04-7.23(3H，m)，8.46(1H，s)。
MS?m/Z：529(M+1)。
Embodiment 101
6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(trifluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(2-chloro-4-fluorophenyl) Toluidrin, obtain 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 34.5mg (63%).
1H?NMR(600MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.3Hz)，3.54-3.62(1H，m)，4.23(2H，q，J＝7.3Hz)，4.28-4.53(4H，m)，4.83(2H，s)，7.23-7.28(1H，m)，7.45-7.56(2H，m)，8.46(1H，s)。
MS?m/Z：549(M+1)。
Embodiment 102
5-cyano group-6-(3-{[(5-fluoro-2-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(trifluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(5-fluoro-2-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-6-(3-{[(5-fluoro-2-methyl-benzyl) alkylsulfonyl] formamyl azetidine-1-yl)-2-(trifluoromethyl) Nikithan.Output: 36.6mg (69%).
1H?NMR(600MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.4Hz)，2.30(3H，s)，3.57-3.63(1H，m)，4.23(2H，q，J＝7.4Hz)，4.27-4.53(4H，m)，4.75(2H，s)，7.02-7.12(2H，m)，7.22-7.27(1H，m)，8.46(1H，s)。
MS?m/Z：529(M+1)。
Embodiment 103
5-cyano group-6-(3-{[(2,3,6-trifluoro-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(trifluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid and 1-(2; 3; the 6-trifluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(3-{[(2; 3, the 6-trifluoro-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan.Output: 31.3mg (57%).
1H?NMR(600MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.0Hz)，3.56-3.62(1H，m)，4.23(2H，q，J＝7.2Hz)，4.28-4.54(4H，m)，4.80(2H，s)，7.17-7.22(1H，m)，7.54-7.60(1H，m)，8.46(1H，s)。
MS?m/Z：551(M+1)。
Embodiment 104
6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(trifluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-chloro-2-fluorophenyl) Toluidrin, obtain 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan.Output: 27.2mg (49%).
1H?NMR(600MHz，DMSO-d
6)δ?1.24(3H，t，J＝7.4Hz)，3.53-3.60(1H，m)，4.23(2H，q，J＝7.2Hz)，4.27-4.54(4H，m)，4.75(2H，s)，7.28-7.33(1H，m)，7.41-7.48(2H，m)，8.46(1H，s)。
MS?m/Z：549(M+1)。
Embodiment 105
5-cyano group-6-(4-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid and 1-(2; the 6-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(4-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan.Output: 7.8mg (14%).
1H?NMR(600MHz，DMSO-d
6)δ?1.25(3H，t，J＝18.3Hz)，1.59-1.66(2H，m)，1.86-1.90(2H，m)，3.17-3.23(2H，m)，4.24(2H，q，J＝7.4Hz)，4.52-4.57(4H，m)，4.70(2H，s)，7.12-7.18(2H，m)，7.35(1H，t，J＝54.2Hz)，7.44-7.51(1H，m)，8.45(1H，s)。Attention: H signal and DMSO signal overlap.
MS?m/Z：543(M+1)。
Embodiment 106
5-cyano group-2-(difluoromethyl)-6-(4-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl) Nikithan
According to method A by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] preparation of piperidines-4-formic acid and 1-(4-fluoro-3-aminomethyl phenyl) Toluidrin, obtain 5-cyano group-2-(difluoromethyl)-6-(4-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl piperidines-1-yl) Nikithan.Output: 29.1mg (54%).
1H?NMR(600MHz，DMSO-d
6)δ?1.27(3H，t，J＝7.0Hz)，1.57-1.66(3H，m)，1.78-1.83(2H，m)，2.17(3H，s)，3.14-3.21(2H，m)，4.24(2H，q，J＝7.0Hz)，4.50-4.55(2H，m)，4.60(2H，s)，7.08-7.15(3H，m)，7.35(1H，t，J＝53.9Hz)，8.46(1H，s)。
Attention: H signal and DMSO signal overlap.
MS?m/Z：539(M+1)。
Embodiment 107
5-cyano group-2-(methyl fluoride)-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
To be dissolved in DCM/DMF (1ml, 1/1) DIPEA (452mg, 0.5mmol) and TBTU (339mg, 0.15mmol) be added to 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] (31.1mg is in DCM/DMF 0.1mmol) (2ml, the 1/1) solution for azetidine-3-formic acid, after mixture at room temperature stirred 20 minutes, add 1-(the 2-fluoro-5-aminomethyl phenyl) Toluidrin be dissolved in DCM/DMF (1ml, 1/1) (149.2mg, 0.1mmol).Mixture at room temperature stirred spend the night.LC-MS shows residual a little raw material, therefore add in addition DIPEA (452mg, 0.5mmol) and DMAP (2.44mg, 0.02mmol).Continue to stir 2 days, but LC-MS still shows a little unreacted raw material.(46.6mg, 0.1mmol) the feasible product that changes into fully that spends the night is stirred in the back to add PyBrop.After making solvent evaporation, the described same procedure of crude product employing method A (referring to general experimental technique) is used the preparation HPLC purifying.Output: 21.6mg (44%).
1H?NMR(400MHz，DMSO-d
6)：δ1.29(3H，t，J＝7.0Hz)，2.27(3H，s)，3.54-3.64(1H，m)，4.24(2H，q，J＝7.0Hz)，4.33-4.54(4H，m)，4.72(2H，s)，5.67(2H，d，J＝47.3Hz)，7.08-7.15(1H，m)，7.18-7.26(2H，m)，8.38(1H，s)，11.93(1H，br?s)。
MS?m/Z：493(M+1)，491(M-1)。
Embodiment 108
5-cyano group-6-(4-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(trifluoromethyl) Nikithan
According to method described in the embodiment 107, by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid and the preparation of 1-(2-fluoro-5-aminomethyl phenyl) Toluidrin.Output: 3.9mg (7%).
1H?NMR(400MHz，DMSO-d
6)：δ?1.28(3H，t，J＝7.0Hz)，1.61-1.74(2H，m)，1.84-1.92(2H，m)，2.26(3H，s)，2.54-2.62(1H，m)，3.20-3.29(2H，m)，4.28(2H，q，J＝7.0Hz)，4.46-4.54(2H，m)，4.59(2H，s)，7.06-7.23(3H，m)，8.53(1H，s)，11.73(1H，br?s)。
MS?m/Z：557(M+1)，555(M-1)。
Embodiment 109
5-cyano group-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
According to method described in the embodiment 107, by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid and the preparation of 1-(2-fluoro-5-aminomethyl phenyl) Toluidrin.Output: 16.1mg (30%).
1H?NMR(400MHz，DMSO-d
6)：δ?1.27(3H，t，J＝7.0Hz)，2.23(3H，s)，3.38-3.50(1H，m)，4.26(2H，q，J＝7.0Hz)，4.30-4.49(4H，m)，4.52(2H，s)，7.00-7.09(1H，m)，7.11-7.21(2H，m)，8.47(1H，s)，11.93(1H，brs)。
MS?m/Z：529(M+1)，527(M-1)。
Embodiment 110
5-cyano group-2-(difluoromethyl)-6-(4-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl) Nikithan
According to method described in the embodiment 107, by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid and the preparation of 1-(2-fluoro-5-aminomethyl phenyl) Toluidrin.Output: 9.9mg (18%).
1H?NMR(400MHz，DMSO-d
6)：δ?1.31(3H，t，J＝7.0Hz)，1.60-1.73(2H，m)，1.84-1.92(2H，m)，2.27(3H，s)，2.54-2.63(1H，m)，3.20-3.29(2H，m)，4.28(2H，q，J＝7.0Hz)，4.52-4.61(2H，m)，4.63(2H，s)，7.08-7.25(3H，m)，7.39(1H，t，J＝54.0Hz)，8.49(1H，s)，11.73(1H，brs)。
MS?m/z：539(M+1)，537(M-1)。
Embodiment 111
5-cyano group-2-(difluoromethyl)-6-(3-{[(3-methoxy-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
With 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid (135mg, 0.41mmol) and TBTU (176mg, 0.55mmol) in anhydrous DCM (4ml), mix after, add DIPEA (0.3ml, 1.72mmol).Reaction mixture was at room temperature stirred 1.5 hours, and adding 1-(3-p-methoxy-phenyl) Toluidrin (113mg, 0.56mmol).Reaction mixture was at room temperature stirred 18 hours.Add NaHCO
3(aqueous solution), mixture extracts (3 times) with DCM.The organic layer that makes merging evaporates after by phase splitter.Crude product preparation HPLC purifying (Kromasil C
8, 10 μ m, 21.5 x 250mm posts, elutriant A:100% acetonitrile, elutriant B:0.1M NH
4The aqueous solution of OAc (containing 5% acetonitrile); flow velocity 25ml/ minute; adopting gradient is the elutriant A of 20-40%; in 35 minutes); obtain 5-cyano group-2-(difluoromethyl)-6-(3-{[(3-methoxy-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan, be white solid.Output: 111mg (53%).
MS?m/Z：509(M+1)，507(M-1)。
Embodiment 112
6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan
(a) methylene radical 2-[(dimethylamino)]-4,4,5,5,5-five fluoro-3-oxopentanoic acid ethyl esters
Substantially according to method described in the embodiment 2 (a), by 1,1-dimethoxy-N, N-dimethyl methylamine and 4,4,5,5, the preparation of 5-five fluoro-3-oxopentanoic acid ethyl esters obtains product.
(b) 5-cyano group-6-oxo-2-(pentafluoroethyl group)-1,6-dihydropyridine-3-ethyl formate
(345mg 4.10mmol) is suspended among the EtOH (10ml), and (1.55ml, 21% EtOH solution 4.15mmol), at room temperature stirred mixture 30 minutes to drip NaOEt with malonamide nitrile.Add the 2-[(dimethylamino be dissolved in EtOH (5ml)) methylene radical]-4,4,5,5, (1.08g 3.73mmol), at room temperature stirs reaction mixture and to spend the night 5-five fluoro-3-oxopentanoic acid ethyl esters.After adding AcOH (0.5ml), make solvent evaporation.Add entry, mixture extracts (3 times) with DCM.The organic layer that makes merging evaporates after by phase splitter.Crude product preparation HPLC purifying (Kromasil C
8, 10 μ m, 50.8 x 300mm posts, elutriant A:100% acetonitrile, elutriant B:0.1M NH
4The aqueous solution of OAc (containing 5% acetonitrile), flow velocity 50ml/ minute, adopting gradient was the elutriant A of 10-40%, in 60 minutes), obtaining 5-cyano group-6-oxo-2-(pentafluoroethyl group)-1,6-dihydropyridine-3-ethyl formate is solid.Output: 243mg (21%).
MS?m/z：309(M-1)。
(c) 6-chloro-5-cyano group-2-(pentafluoroethyl group) Nikithan
With 5-cyano group-6-oxo-2-(pentafluoroethyl group)-1, (240mg 0.77mmol) is suspended in toluene (30ml) to 6-dihydropyridine-3-ethyl formate, drips SOCl
2(0.5ml, 6.9mmol) and DMF (0.1ml, 1.3mmol).Reaction mixture is heated to 80 ℃ reaches 20 hours.After making solvent evaporation, crude product (440mg) need not to be further purified and just can be used for next step.(d) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan
With crude product 6-chloro-5-cyano group-2-(pentafluoroethyl group) Nikithan (100mg; 0.30mmol), N-(benzyl alkylsulfonyl) piperidines-4-methane amide (96mg; 0.34mmol) and DIPEA (0.3ml; 1.72mmol) in EtOH (4ml), mix, reaction mixture is heated to 120 ℃ reaches 5 minutes in microwave oven.Add NaHCO
3(aqueous solution), mixture extracts (3 times) with DCM.The organic layer that makes merging evaporates after by phase splitter.Crude product preparation HPLC purifying (Kromasil C
810 μ m, 21.5 x 250mm posts, elutriant A:100% acetonitrile, elutriant B:0.1M NH
4The aqueous solution of OAc (containing 5% acetonitrile); flow velocity 25ml/ minute, adopting gradient was the elutriant A of 30-60%, in 35 minutes); obtain 6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan, be solid.Output: 108mg (62%).
1H?NMR(500MHz，DMSO-d
6)：δ?1.29(3H，t，J＝7.1Hz)，1.61-1.71(2H，m)，1.82-1.88(2H，m)，2.58-2.65(1H，m)，3.20-3.27(2H，m)，4.30(2H，q，J＝7.1Hz)，4.42-4.48(2H，m)，4.70(2H，s)，7.27-7.32(2H，m)，7.37-7.42(3H，m)，8.56(1H，s)，11.61(1H，br?s)。
MS?m/Z：575(M+1)，573(M-1)。
Embodiment 113
6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan
According to method described in the embodiment 112 (d); by 6-chloro-5-cyano group-2-(pentafluoroethyl group) Nikithan and N-(benzyl alkylsulfonyl) azetidine-3-methane amide preparation; obtain 6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan, be solid.Output: 35mg (21%).
1H?NMR(500MHz，DMSO-d
6)：δ?1.29(3H，t，J＝7.1Hz)，3.53(1H，m)，4.28(2H，q，J＝7.1Hz)，4.28-4.36(2H，m)，4.36-4.46(2H，m)，4.68(2H，s)，7.32-7.37(5H，m)，8.50(1H，s)，11.80(1H，br?s)。
MS?m/Z：547(M+1)，545(M-1)。
Embodiment 114
6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan
(a) methylene radical 2-[(dimethylamino)]-4-fluoro-3-oxopentanoic acid ethyl ester
(2.28g, (2.0ml 15.1mmol), at room temperature stirred mixture 18 hours 14.1mmol) to be dissolved in dimethoxy-methyl-dimethyl-amine with 4-fluoro-3-oxopentanoic acid ethyl ester.LCMS shows conversion fully.Concentrating under reduced pressure mixture, crude product need not to be further purified and just can be used for next step.Output is assumed to quantitatively.
MS?m/z：218(M+1)。
(b) 5-cyano group-2-(1-fluoro ethyl)-6-oxo-1,6-dihydropyridine-3-ethyl formate
With malonamide nitrile (1.176g 14.0mmol) is suspended among the EtOH (40ml), add NaOEt (5.5ml, the EtOH solution of 21% (weight), 14.7mmol).Reaction mixture was at room temperature stirred 2 hours.Add the crude product 2-[(dimethylamino that is dissolved in EtOH (10ml)) methylene radical]-(3.04g 14.0mmol), at room temperature stirred reaction mixture 21 hours 4-fluoro-3-oxopentanoic acid ethyl ester.After adding AcOH (1.5ml), make solvent evaporation.Add entry, after leaching solid and washing with water, drying under reduced pressure obtains 5-cyano group-2-(1-fluoro ethyl)-6-oxo-1, and 6-dihydropyridine-3-ethyl formate is solid.Output: 2.78g (84%).
MS?m/Z：239(M+1)，237(M-1)。
(c) 6-chloro-5-cyano group-2-(1-fluoro ethyl) Nikithan
With 5-cyano group-2-(1-fluoro ethyl)-6-oxo-1, (1.026g 4.31mmol) is suspended in toluene (45ml) to 6-dihydropyridine-3-ethyl formate, adds SOCl
2(2.5ml, 34.4mmol) and dry DMF (0.3ml, 3.87mmol).Reaction mixture is heated to 80 ℃ reaches 3 hours.LCMS shows residual 28% raw material.Add SOCl
2(2ml, 27.5mmol) and DMF (0.3ml 3.87mmol), is heated to 80 ℃ with reaction mixture and reaches 17 hours.LCMS shows the noresidue raw material.Make solvent evaporation, crude product need not to be further purified and just can be used for next step.Output is assumed to quantitatively.
MS?m/Z：257(M+1)，255(M-1)。
(d) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan
With crude product 6-chloro-5-cyano group-2-(1-fluoro ethyl) Nikithan (87mg, 0.34mmol) and N-(benzyl alkylsulfonyl) azetidine-3-methane amide (87mg 0.34mmol) is dissolved among the EtOH (3ml), add DIPEA (1ml, 5.7mmol).Reaction mixture is heated to 120 ℃ reaches 5 minutes in microwave oven.Add NaHCO
3(aqueous solution), mixture extracts (3 times) with DCM.The organic layer that makes merging evaporates after by phase splitter.Crude product preparation HPLC purifying (Kromasil C
810 μ m, 21.5 x 250mm posts, elutriant A:100% acetonitrile, elutriant B:0.1M NH
4The aqueous solution of OAc (containing 5% acetonitrile); flow velocity 25ml/ minute, adopting gradient was the elutriant A of 20-40%, in 35 minutes); obtain 6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan, be white solid.Output: 63mg (39%).
MS?m/Z：475(M+1)，MS?m/Z?473(M+1)。
Embodiment 115
6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan
According to method described in the embodiment 114 (d); by 6-chloro-5-cyano group-2-(1-fluoro ethyl) Nikithan and N-(benzyl alkylsulfonyl) azetidine-3-methane amide preparation; obtain 6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan, be white solid.Output: 40mg (26%).
MS?m/Z：503(M+1)，501(M-1)。
Embodiment 116
6-(4-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
With DIPEA (64mg, 0.5mmol) be added to 1-[3-cyano group-6-(methyl fluoride)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid (33.5mg, 0.1mmol) and TBTU (160mg, 0.5mmol) DCM solution in, after mixture at room temperature stirred 10 minutes, adding 1-(4-fluoro-2-chloro-phenyl-) Toluidrin (22mg, 0.10mmol).The reactant stirring is spent the night.Reaction mixture 0.1M KHSO
4Washing, organic phase is evaporated in vacuum centrifuge by behind the phase splitter.The gained crude product obtains 6-(4-{[(2-chloro-4-luorobenzyl) alkylsulfonyl with HPLC purifying (referring to general experimental technique)] formamyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan, output: 19mg (34%).
1H?NMR(500MHz，DMSO-d
6)：δ?1.31(3H，t，J＝7.1Hz)，1.61-1.71(2H，m)，1.88-1.95(2H，m)，2.60-2.67(1H，m)，3.18-3.26(2H，m)，4.26(2H，q，J＝7.1Hz)，4.58-4.64(2H，m)，4.83(2H，s)，5.69(2H，d，J＝47Hz)，7.29-7.35(1H，m)，7.48-7.52(1H，m)，7.53-7.57(1H，m)，8.41(1H，s)，11.82(1H，br?s)。
MS?m/Z：541(M+1)。
Embodiment 117
5-cyano group-6-(4-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(methyl fluoride) Nikithan
According to method described in the embodiment 116; by 1-[3-cyano group-6-(methyl fluoride)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid and 1-(2; the 4-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(4-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(methyl fluoride) Nikithan.Output: 8.7mg (17%).
1H?NMR(400MHz，DMSO-d
6)：δ?1.31(3H，t，J＝7.1Hz)，1.61-1.70(2H，m)，1.87-1.93(2H，m)，2.58-2.60(1H，m)，3.18-3.26(2H，m)，4.26(2H，q，J＝7.1Hz)，4.58-4.64(2H，m)，4.72(2H，s)，5.69(2H，d，J＝47Hz)，7.14-7.20(1H，m)，7.30-7.36(1H，m)，7.43-7.49(1H，m)，8.41(1H，s)，11.77(1H，br?s)。
MS?m/Z：525(M+1)。
Embodiment 118
6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-2-(chloromethyl)-5-cyano group Nikithan
(a) 2-(chloromethyl)-5-cyano group-6-oxo-1,6-dihydropyridine-3-ethyl formate
With 4-chloro-ethyl 3-oxobutanoate (10g, 60.75mmol), diacetyl oxide (27.3g, 267.3mmol) and the heating 3 hours of under 120 ℃, (bathing temperature) of the mixture of triethyl orthoformate.Dark-coloured mixture behind vacuum concentration, with toluene (50ml) coevaporation once.Add heptane (50ml) with precipitated product, vacuum is removed heptane then.Crude product is dissolved in EtOH (50ml).In independent flask, with sodium ethylate (50ml, 60.75mmol, prepare by sodium and EtOH (50ml) reaction) be added drop-wise to 2-malonamide nitrile (5.11g, 60.75mmol) with cold (＜5 ℃) solution of EtOH (50ml) in, after mixture stirring 30 minutes, in 10 minutes, add the solution of above-mentioned crude product, at room temperature continue to stir and spend the night.After formed solid separates after filtration, with MTBE (50ml) washing.Behind this solid drying, obtain 2-(chloromethyl)-5-cyano group-6-oxo-1,6-dihydropyridine-3-ethyl formate is light brown solid.Output: 8.15g (56%).
1H?NMR(500MHz，DMSO-d
6)δ1.27(3H，t，J＝7.0Hz)，4.16(2H，q，J＝7.0Hz)，4.75(2H，s)，8.02(1H，s)。
(b) 6-chloro-2-(chloromethyl)-5-cyano group Nikithan
At room temperature, (0.076g 1.04mmol) is added to 2-(chloromethyl)-5-cyano group-6-oxo-1,6-dihydropyridine-3-ethyl formate (1.00g with DMF, 4.16mmol) and oxalyl chloride (10.55g (observes and emits gas immediately) in stirring slurries 83.11mmol).After mixture heating up to 70 ℃ reached 4 hours, under 50 ℃, spend the night.Mixture evaporates (twice of 20ml) to remove excessive oxalyl chloride with butyronitrile dilution back.Resistates is distributed between butyronitrile (50ml) and water (50ml), water with dense HCl (0.5ml) acidifying after, add MgCl
2(aqueous solution) is separated to help.After organic phase is separated, water (25ml), 20%Na
2CO
3(aqueous solution) (0.5ml), MgCl
2(aqueous solution) (10ml) washs and dry (MgSO
4).Crude product obtains required product with silica gel chromatography purifying (elutriant: heptane/EtOAc, the employing gradient is 90:10 to 40:60%), is colorless solid.Output: 2.56g (61%).
1H?NMR(500MHz，DMSO-d
6)δ?1.36(3H，t，J＝7.1Hz)，4.38(2H，q，J＝7.1Hz)，5.09(2H，s)，8.90(1H，s)。
MS?m/Z：258(M-1)。
(c) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-2-(chloromethyl)-5-cyano group Nikithan
6-chloro-2-(chloromethyl)-5-cyano group Nikithan (540mg packs in the microwave bottle; 2.08mmol), N-(benzyl alkylsulfonyl) piperidines-4-methane amide (618mg; 2.19mmol) and TEA (527mg 5.21mmol), is heated to 100 ℃ and reaches 10 minutes in microwave oven.Solvent removed in vacuo is distributed resistates between the iPrOAc (20ml) and the HCl aqueous solution (the 15ml aqueous solution of 40 μ l37%HCl).Water extracts with iPrOAc (10ml) after separating again.The organic phase MgCl that merges
2The aqueous solution (10ml) washing, dry (MgSO
4) the back evaporation, obtain product, need not to be further purified just and can use.Output: 929mg (88%).
1H?NMR(500MHz，CDCl
3)δ?1.41(3H，t，J＝7.1Hz)，1.75-1.94(4H，m)，2.50(1H，ddd，J＝15.0，10.8，4.1Hz)，3.19(2H，dd，J＝25.1，2.3Hz)，4.37(2H，q，J＝7.2Hz)，4.63(2H，s)，4.71(2H，d，J＝13.7Hz)，4.98(2H，s)，7.27-7.45(5H，m)，8.41(1H，s)。
Embodiment 119
5-cyano group-2-(difluoromethyl)-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
According to method described in the embodiment 107, by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid and the preparation of 1-(2-fluoro-5-aminomethyl phenyl) Toluidrin.Output: 15.9mg (31%).
1H?NMR(400MHz，DMSO-d
6)：δ?1.30(3H，t，J＝7.0Hz)，2.27(3H，s)，3.55-3.65(1H，m)，4.27(2H，q，J＝7.0Hz)，4.33-4.55(4H，m)，4.72(2H，s)，7.07-7.14(1H，m)，7.18-7.26(2H，m)，7.40(1H，t，J＝53.9Hz)，8.47(1H，s)，11.93(1H，br?s)。
MS?m/z：511(M+1)，509(M-1)。
Embodiment 120
6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-2-(chloromethyl)-5-cyano group Nikithan
6-chloro-2-(chloromethyl)-5-cyano group Nikithan (417mg packs in the microwave bottle; 1.61mmol), N-(benzyl alkylsulfonyl) azetidine-3-methane amide (429mg; 1.69mmol), (407mg 4.02mmol) and EtOH (5ml), is heated to 100 ℃ and reaches 10 minutes TEA.Mixture dilutes with DCM (25ml), water (10ml) and dense HCl (226 μ l).Separate each mutually after, organic phase drying (MgSO
4) the back evaporation, obtain required product, be light yellow solid.Output: 590mg (77%).
1H?NMR(500MHz，DMSO-d
6)δ?1.32(3H，t，J＝7.1Hz)，3.55-3.63(1H，m)，4.28(2H，q，J＝7.1Hz)，4.31-4.53(4H，m)，4.76(2H，s)，4.95(2H，s)，7.31-7.43(5H，m)，8.42(1H，s)，11.83(1H，s)。
Embodiment 121
5-cyano group-6-(3-{[(3,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
With 1-(3, the 4-difluorophenyl) Toluidrin (25mg, 0.12mmol) be added to 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid (28.9mg, 0.1mmol), PyBrop (70mg, 0.15mmol) and DIPEA (129mg, 1mmol) with the mixture of DCM in, mixture at room temperature stirred spends the night.Add 0.5M KHSO
4(2ml), collect organic phase, obtain crude product, be added to again in the Waters Oasis MAX cylinder (2x500mg, tetra-allkylammonium phase) with phase splitter.When about 10 (with 0.1M NaOH titration) of pH, product mixtures is added in the post, uses extra 0.1M NaOH (2ml) washing subsequently, through 1/1CH
3CN/H
2O (4.5ml) and 100%CH
3CN wash-out from PyBrop reagent goes out phosphonic acids triamide by product.Product 90%CH then
3CN and 2% formic acid wash-out.After making solvent evaporation, obtain product, be white solid; according to method described in the general experimental technique; be further purified with preparation HPLC, obtain 5-cyano group-6-(3-{[(3,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan.Output: 29mg (56%).
1H?NMR(400MHz，DMSO-d
6)：δ?1.31(3H，t，J＝7.1Hz)，3.55-3.64(1H，m)，4.28(2H，q，J＝7.1Hz)，4.32-4.39(2H，m)，4.43-4.52(2H，m)，4.77(2H，s)，7.19-7.24(1H，m)，7.40(1H，t，J＝54Hz)，7.41-7.48(2H，m)，8.48(1H，s)，11.90(1H，br?s)。
MS?m/Z：515(M+1)。
Embodiment 122
5-cyano group-6-(4-{[(3,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
According to embodiment 121 by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid and 1-(3; the 4-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(4-{[(3,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan.Output: 7mg (13%).
1HNMR(400MHz，DMSO-d
6)：δ?1.32(3H，t，J＝7.1Hz)，1.60-1.71(2H，m)，1.84-1.91(2H，m)，2.57-2.66(1H，m)，3.19-3.28(2H，m)，3.29(2H，q，J＝7.1Hz)，4.54-4.61(2H，m)，4.73(2H，s)，7.12-7.16(1H，m)，7.34-7.40(1H，m)，7.40(1H，t，J＝54Hz)，7.45-7.53(1H，m)，8.51(1H，s)，11.69(1H，br?s)。
MS?m/Z：543(M+1)。
Embodiment 123
5-cyano group-6-(4-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
According to embodiment 121 by 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid and 1-(2; the 4-difluorophenyl) Toluidrin preparation; obtain 5-cyano group-6-(4-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan.Output: 15mg (27%).
1H?NMR(400MHz，DMSO-d
6)：δ?1.32(3H，t，J＝7.1Hz)，1.62-1.73(2H，m)，1.88-1.95(2H，m)，2.59-2.65(1H，m)，3.19-3.28(2H，m)，4.29(2H，q，J＝7.1Hz)，4.55-4.62(2H，m)，4.74(2H，s)，7.14-7.21(1H，m)，7.30-7.37(1H，m)，7.40(1H，t，J＝54Hz)，7.43-7.50(1H，m)，8.51(1H，s)，11.77(1H，br?s)。
MS?m/Z：543(M+1)。
Embodiment 124
6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2-fluorine oxyethyl group) Nikithan
(a) 4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-t-butyl formate
With 4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-t-butyl formate (11.47g; 30mmol; referring to embodiment 1 (d)), 3-bromine third-1-alkene (10.89g, 90mmol) and DIPEA (7.76g 60mmol) at room temperature stirred 21 hours with the mixture of DMF (30ml).After adding entry (75ml), water extracts with heptane/DCM 4/1 (3 x 75ml).With the organic phase drying (MgSO that merges
4), filter the back evaporation, obtain product, need not to be further purified just and can use.
(b) N-allyl group-N-(benzyl alkylsulfonyl) piperidines-4-methane amide trifluoroacetate
Under 0 ℃ (ice/water-bath); TFA/DCM 2/1 (30ml) is added to 4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-t-butyl formate (12.68g; 30mmol) with the stirred solution of DCM (10ml) in, continue to stir after 5 minutes, at room temperature stirred 4 hours.After making solvent evaporation, mixture and DCM coevaporation twice obtain product, are tfa salt, need not to be further purified just to can be used for next step.
(c) N-allyl group-N-(benzyl alkylsulfonyl)-1-(2-cyanoimino ethyl) piperidines-4-methane amide
With N-allyl group-N-(benzyl alkylsulfonyl) piperidines-4-methane amide trifluoroacetate (30mmol) be added to 2-cyano group ethanimidic acid ethyl ester (ethyl 2-cyanoethanimidoate) (referring to McElvain, S.M.; Schroeder, J.P.; J.Am.Chem.Soc.71, the 40th page (1949)) (15.14g, 101.25mmol, purity 75%) and DIPEA (23.26g, 180mmol) with cold (ice/water-bath temperature) solution of EtOH (200ml) in, the mixture restir after 10 minutes, was at room temperature stirred 16 hours.LC-MS shows that raw material transforms fully.This solution itself can be used for next step.
(d) 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-oxo-1,2-dihydropyridine-3-ethyl formate
(8.43g 39mmol) is added in the solution of above-mentioned steps (d), and reaction mixture was at room temperature stirred 18 hours with (oxyethyl group methylene radical) diethyl malonate.Evaporating solvent obtains the 32g crude product.Take out 8g (1/4), with preparation HPLC purifying (Kromasil C
8, 10 μ m, elutriant: A:CH
3CN; The aqueous solution/CH of B:0.2%AcOH
3CN95/5; C:0.1MNH
4OAc/CH
3CN 95/5.Adopt A/B/C 5/0/95 in injection period, use gradient elution then from A/B/C5/95/0 to 100/0/0), obtain two flow points that contain product.Flow point 1:308mg (chemical yield 8% is 100% according to LC-MS purity), flow point 2:853mg (according to LC-MS purity 76%).
1H-NMR(400MHz，CDCl
3)：δ?1.40(3H，t，J＝7.2Hz)，1.57-1.80(4H，m)，2.60-2.70(1H，m)，2.92-3.03(2H，m)，4.11-4.16(2H，m)，4.39/2H，q，J＝7.2Hz)，4.61(2H，s)，4.64-4.72(2H，m)，5.19-5.30(2H，m)，6.62-5.75(1H，m)，7.31-7.45(5H，m)，8.24(1H，s)，11.90(1H，br?s，NH)。
(e) 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2-fluorine oxyethyl group) Nikithan
Under nitrogen atmosphere, with 1-fluoro-2-iodoethane (142mg 0.82mmol) is added to 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-oxo-1,2-dihydropyridine-3-ethyl formate (100mg, 0.164mmol) and Ag
2CO
3(136mg, 0.492mmol) with the mixture of acetonitrile (20ml) in, mixture heating up was refluxed 1.5 hours.Other adds 1-fluoro-2-iodoethane, and (142mg 0.82mmol), continues to reflux 1.5 hours again.LC-MS shows still residual a little raw material, but other add 1-fluoro-2-iodoethane (142mg, 0.82mmol), and reflux spend the night after, reaction is finished.Solvent removed in vacuo, crude product need not to be further purified and just can be used for next step, are assumed to quantitative output.
(f) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2-fluorine oxyethyl group) Nikithan
Under nitrogen atmosphere; with 4-toluenesulfinic acid sodium (79mg; 0.445mmol) and four (triphenylphosphines) close palladium (190mg; 0.165mmol) be added to 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl-5-cyano group-2-(2-fluorine oxyethyl group) Nikithan (107mg; 0.165mmol, derive from the crude product of above-mentioned steps) DCM (10ml) solution in.After mixture at room temperature stirred 1 hour, solvent removed in vacuo.Resistates preparation HPLC purifying (Kromasil C
8, 10 μ m, 21.2 x 250mm posts, the employing gradient is 30%-95%CH
3CN/0.1M NH
4OAc), obtain 6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2-fluorine oxyethyl group) Nikithan, after the lyophilize yellow solid.Output: 33mg (being 38% after two steps).
1H?NMR(400MHz，DMSO-d
6)δ?1.26(3H，t，J＝7.1Hz)，1.55-1.70(2H，m)，1.75-1.88(2H，m)，2.25-2.39(1H，m)，3.10-3.22(2H，m)，4.19(2H，q，J＝7.3Hz)，4.44-4.53(2H，m)，4.53-4.57(1H，m)，4.58-4.65(3H，m)，4.66-4.71(1H，m)，4.78-4.82(1H，m)，7.24-7.30(2H，m)，7.32-7.40(3H，m)，8.28(1H，s)。
MS?m/Z：519(M+1)。
Embodiment 125
6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-[(2,2, the 2-trifluoro ethoxy) methyl] Nikithan
The 6-{3-[(benzyl alkylsulfonyl of in the microwave bottle, packing into) formamyl] azetidine-1-yl }-2-(chloromethyl)-5-cyano group Nikithan (25mg; 0.052mmol; referring to embodiment 120), cesium carbonate (34mg; 0.10mmol), sodium iodide (8mg; 0.052mmol), 2,2,2 tfifluoroethyl alcohol (0.36ml; 5.0mmol), reaction mixture is heated to 100 ℃ reaches 15 minutes in microwave oven.The LCMS demonstration thoroughly changes into required product.After the removal of solvent under reduced pressure, resistates is distributed between DCM and water.Organic phase after separating, concentrating under reduced pressure.The gained crude product obtains 6-{3-[(benzyl alkylsulfonyl with HPLC purifying (referring to general experimental technique)) formamyl] azetidine-1-yl }-5-cyano group-2-[(2,2, the 2-trifluoro ethoxy) methyl] Nikithan.Output: 5.6mg (18%).
1H?NMR(600MHz，DMSO-d
6)：δ?1.27(3H，t，J＝7.2Hz)，3.48-3.57(1H，m)，4.18(2H，q，J＝9.3Hz)，4.21(2H，q，J＝7.2Hz)，4.28-4.34(2H，m)，4.38-4.46(2H，m)，4.70(2H，brs)，4.97(2H，s)，7.28-7.36(5H，m)，8.32(1H，s)。
MS?m/Z：541(M+1)。
Embodiment 126
6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-[(2,2, the 2-trifluoro ethoxy) methyl] Nikithan
According to method described in the embodiment 125; with 6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-2-(chloromethyl)-5-cyano group Nikithan preparation; obtain 6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-[(2; 2, the 2-trifluoro ethoxy) methyl] Nikithan.Output: 7.3mg (24%).
1H?NMR(600MHz，DMSO-d
6)：δ?1.27(3H，t，J＝7.1Hz)，1.58-1.66(2H，m)，1.78-1.85(2H，m)，3.13-3.21(2H，m)，4.17(2H，q，J＝9.1Hz)，4.22(2H，q，J＝6.9Hz)，4.52-4.58(2H，m)，4.66(2H，s)，4.98(2H，s)，7.24-7.28(2H，m)，7.33-7.39(3H，m)，8.35(1H，s)。
MS?m/Z：569(M+1)。
Embodiment 127
6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(difluoro-methoxy) Nikithan
(a) 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(difluoro-methoxy) Nikithan
6-{4-[allyl group (benzyl alkylsulfonyl) formamyl of in the microwave bottle, packing into] piperidines-1-yl }-5-cyano group-2-oxo-1; 2-dihydropyridine-3-ethyl formate (103mg; 0.20mmol; referring to the embodiment 124 (d) that is dissolved in acetonitrile (2.5ml)); adding 2-(fluorosulfonyl) difluoroacetic acid (0.062ml, 0.60mmol).Reaction mixture is heated to 80 ℃ reaches 5 minutes in microwave oven.LC/MS shows that 46% has the product and 20% raw material of accurate mass.(0.124ml 1.20mmol), is heated to 100 ℃ with reaction mixture and reaches 5 minutes in microwave oven to add 2-(fluorosulfonyl) difluoroacetic acid.LC/MS shows that 46% has the product and 7% raw material of accurate mass.Reaction mixture is heated to 100 ℃ reaches 15 minutes in microwave oven.LC/MS shows no change.Mixture extracts with DCM (3 x 20ml), the organism 10%Na of merging
2CO
3(20ml) washing.Need to add salt solution (about 5ml) to separate.Organic layer washs with salt solution (50ml); concentrating under reduced pressure behind anhydrous sodium sulfate drying; obtain 110mg crude product 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(difluoro-methoxy) Nikithan, need not to be further purified and just can be used for next step.
MS?m/Z：563(M+1)。
(b) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(difluoro-methoxy) Nikithan
To derive from crude product 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl of abovementioned steps] piperidines-1-yl }-5-cyano group-2-(difluoro-methoxy) Nikithan (110mg; 0.16mmol; 80%) is dissolved in DCM (3ml); add four (triphenylphosphines) successively and close palladium (18mg; 0.016mmol) and 4-toluenesulfinic acid sodium (59mg, 0.33mmol).Reaction mixture was stirred 20 hours under nitrogen atmosphere, room temperature.LC/MS shows conversion fully.After the removal of solvent under reduced pressure, crude product preparation HPLC purifying (Kromasil C
810 μ m; 50.8 x 300mm post; elutriant A:100% acetonitrile; elutriant B:0.2% acetic acid water solution (containing 5% acetonitrile); flow velocity 75ml/ minute; the acetonitrile gradient that employing increases progressively is in 17 minutes), obtain 6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(difluoro-methoxy) Nikithan.Output: 18mg (22%).
1H?NMR(300MHz，CDCl
3)：δ?1.37(3H，t，J＝7.2Hz)，1.71-1.95(4H，m)，2.40-2.53(1H，m)，3.12-3.26(2H，m)，4.32(2H，q，J＝7.2Hz)，4.48-4.59(2H，m)，4.64(2H，s)，7.29-7.42(6H，m)，8.20-8.35(1H，brs)，8.42(1H，s)。
MS?m/Z：523(M+1)。
Embodiment 128
6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
(a) 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
With 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-oxo-1, (100mg 0.16mmol) is dissolved in anhydrous DMSO (15ml) to 2-dihydropyridine-3-ethyl formate, adds Ag
2CO
3(136mg 0.49mmol), stirs mixture 5 minutes under nitrogen atmosphere, room temperature.Add 2-iodo-1, (629mg 3.28mmol), is heated to 95 ℃ with reaction mixture to the 1-C2H4F2 C2H4F2.After 5 hours, other adds the 2-iodo-1 of 5 equivalents (eq), and (157mg 0.82mmol), makes temperature reduce to 85 ℃ to the 1-C2H4F2 C2H4F2, reaction mixture is stirred down at 85 ℃ spend the night.After adding entry, mixture extracts (3 times) with DCM.After the organism of merging is concentrated, crude product 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan need not to be further purified and just can be used for next step.
MS?m/Z：577(M+1)。
(b) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
With 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2; the 2-difluoroethoxy) Nikithan (94mg; 0.16mmol) be dissolved in anhydrous DCM (10ml); add four (triphenylphosphines) and close palladium (188mg; 0.16mmol), 4-toluenesulfinic acid sodium (78mg; 0.44mmol), reaction mixture was at room temperature stirred 1.5 hours.Mixture is filtered concentrating under reduced pressure, crude product preparation HPLC purifying (Kromasil C
810 μ m; 50.8 x 300mm post; elutriant A:100% acetonitrile; elutriant B:0.2% acetic acid water solution (containing 5% acetonitrile), flow velocity 50ml/ minute, adopting gradient was the 30-100% acetonitrile; in 35 minutes); obtain 6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan, be white solid.Output: 5.9mg (6.5%).
1H?NMR(400MHz，DMSO-d
6)：δ?1.26(3H，t，J＝7.3Hz)，1.58-1.70(2H，m)，1.79-1.87(2H，m)，2.97-3.03(1H，m)，3.13-3.22(2H，m)，4.19(2H，q，J＝7.2Hz)，4.46-4.54(2H，m)，4.56-4.69(4H，m)，6.38(1H，t，J＝52.6Hz)，7.24-7.40(5H，m)，8.32(1H，s)，11.59(1H，br?s)。
MS?m/Z：537(M+1)，535(M-1)。
Embodiment 129
6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) Nikithan
(a) 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-{[(trifluoromethyl) alkylsulfonyl] the oxygen base } Nikithan
Under nitrogen atmosphere, with 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-oxo-1, (308mg 0.60mmol) is dissolved in DCM (7ml) and be cooled to 0 ℃ to 2-dihydropyridine-3-ethyl formate.Add triethylamine (0.37ml, 2.7mmol) after, drip trifluoromethanesulfanhydride anhydride.Reaction mixture was stirred 1 hour down at 0 ℃.Add NaHCO
3(saturated aqueous solution) (10ml), organic layer is after separating, water layer is with DCM extraction (2 times).The organism that merges is through anhydrous sodium sulfate drying; filter the back concentrating under reduced pressure; obtain crude product 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-{[(trifluoromethyl) alkylsulfonyl] the oxygen base } Nikithan; need not to be further purified and just can be used for next step, be assumed to quantitative output.
MS?m/Z：645(M+1)。
(b) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) Nikithan
With 6-{4-[allyl group (benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-{[(trifluoromethyl) alkylsulfonyl] the oxygen base } Nikithan (150mg, 0.23mmol), Pd
2(dba)
3(21.3mg, 0.023mmol), 9,9-dimethyl-4, two (diphenyl phosphine) xanthenes of 5-(13.5mg 0.023mmol) mixes in the Zai diox (3ml), add DIPEA (0.1ml, 0.57mmol) and 2,2,2 tfifluoroethyl alcohol (100mg, 1.0mmol).Reaction mixture is heated to 160 ℃ reaches 10 minutes in microwave oven.LCMS shows that raw material transforms fully.Add NaHCO
3(aqueous solution), mixture extracts (3 times) with DCM.The organic layer that makes merging evaporates after by phase splitter.Crude product preparation HPLC purifying (Kromasil C
810 μ m, 21.5 x 250mm posts, elutriant A:100% acetonitrile, elutriant B:0.1M NH
4The aqueous solution of OAc (containing 5% acetonitrile), flow velocity 25ml/ minute, adopting gradient was 20-55% elutriant A; in 35 minutes), obtain 6-{4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-yl }-5-cyano group-2-(2,2; the 2-trifluoro ethoxy) Nikithan is solid.Output: 24mg (19%).
1H?NMR(500MHz，DMSO-d
6)δ?1.27(3H，t，J＝7.1Hz)，1.62-1.71(2H，m)，1.82-1.88(2H，m)，2.57-2.64(1H，m)，3.16-3.23(2H，m)，4.22(2H，q，J＝7.1Hz)，4.53-4.59(2H，m)，4.69(2H，s)，5.05(2H，q，J＝8.8Hz)，7.28-7.32(2H，m)，7.38-7.42(3H，m)，8.36(1H，s)，11.61(1H，br?s)。
MS?m/Z：555(M+1)，MS?m/z：553(M-1)。
Embodiment 130
5-cyano group-2-(difluoromethyl)-6-[3-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) azetidine-1-yl] Nikithan
(a) tertiary butyl { [4-(chloromethyl) benzyl] oxygen base } dimethylsilane
With 4-chloromethylbenzene methyl alcohol (1.35g, 8.6mmol) and imidazoles (763mg 11.2mmol) is dissolved in CH
2Cl
2And be cooled to 0 ℃, add in batches TBDMSCl (1.43g, 9.5mmol).Form white depositions, reaction mixture was stirred 1 hour.Add entry (30ml) and 1MKHSO
4(30ml), with mixture restir 3 minutes.Organic layer separates the back evaporation with phase splitter, obtains the tertiary butyl { [4-(chloromethyl) benzyl] oxygen base } dimethylsilane, is oily matter, need not to be further purified just and can use.Output: 2.4g (103%).
(b) 3-{[4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) benzyl] alkylsulfonyl } methyl propionate
With ultra sonic bath with SMOPS (1.76g, 10.1mmol, Wang etc., TetrahedronLetters 43,2002,8479-8483) be dissolved in DMSO (20ml), add the tertiary butyl { [4-(chloromethyl) benzyl] oxygen base } dimethylsilane (2.4g that is dissolved in DMSO (5ml), 8.4mmol), reaction mixture at room temperature stirred spend the night.After adding entry (30ml), mixture EtOAc extracting twice.The organism that merges is through anhydrous Na
2SO
4Drying is filtered the back evaporation.
1H NMR shows residual a little DMSO.In order to remove DMSO, crude product is dissolved in CH
2Cl
2(40ml), add entry (20ml) after, biphasic system was stirred 30 minutes.Organic layer separates the back evaporation with phase splitter, obtains 3-{[4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) benzyl] alkylsulfonyl } methyl propionate, be solid.Output: 3.1g (95%).
MS m/Z:404 (NH+ adducts).
(c) 1-[4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) phenyl] Toluidrin
Under nitrogen atmosphere, room temperature; with 3-{[4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) benzyl] alkylsulfonyl } methyl propionate (3.1g; 8.0mmol) be dissolved in anhydrous THF (20ml); (221mg 9.6mmol) is dissolved in anhydrous methanol (3ml) and the sodium methoxide solution of prepared fresh by sodium in adding.After 30 minutes, LCMS checks that still there is about 10% raw material in demonstration.Adding sodium methoxide solution again falls up to all raw material consumption.In this reaction mixture, add azanol O-sulfonic acid (2.27g, 20mmol) and sodium acetate (2.5g, water 30mmol) (30ml) solution (as damping fluid) spends the night the reactant stirring.With EtOAc extraction (2 times), through anhydrous Na
2SO
4Drying concentrates, and removes acetate with vacuum pump at last, obtains 1-[4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) phenyl] Toluidrin, be white solid.Crude product need not to be further purified just and can use.Output: 2.5g (99%).
MS?m/Z：314(M+1)。
(d) 6-[3-({ [4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) benzyl] alkylsulfonyl } formamyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
With 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid (100mg, 0.31mmol, referring to embodiment 9 (a)) and 1-[4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) phenyl] Toluidrin (116mg, 0.37mmol) and PyBrop (215mg, 0.46mmol) in the glass flask of packing into together (16ml pipe), add CH this moment
2Cl
2(4.5ml).(0.54ml, 3.1mmol), reaction mixture becomes clear solution to add DIPEA in these stirring slurries.After 1 hour, LCMS shows that raw material transforms fully.Add entry, organic layer concentrates in vacuum centrifuge after separating with phase splitter.Crude product preparation HPLC purifying obtains 6-[3-({ [4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) benzyl] alkylsulfonyl } formamyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan, be white solid.Output: 103mg (48%).
(e) 5-cyano group-2-(difluoromethyl)-6-[3-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) azetidine-1-yl] Nikithan
At room temperature, with 6-[3-({ [4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) benzyl] alkylsulfonyl } formamyl) azetidine-1-yl]-(103mg 0.17mmol) is dissolved in TFA to 5-cyano group-2-(difluoromethyl) Nikithan.After 15 minutes, LCMS shows that raw material all changes into required product and about 15%TFA-ester.Regrettably reactant is placed to spend the night and is caused and all change into the TFA-ester.In dense TFA-ester, add NH
3(aqueous solution) 26% (1.5ml) and CH
3CN (2ml).After the cracking of TFA-ester, mixture is evaporated in vacuum centrifuge.From CH3CN/H
2Lyophilize among the O obtains white powder.With this NH that contains
4The rough solid of TFA is dissolved in H
2O/CH
3CN regulates pH to about 10 with 0.1M NaOH.With this solution be added to alkaline post (Waters, Oasis MAX, 500mg) on, use (1) 0.1M NaOH, (2) 50%CH successively
3CN/H
2O and (3) 100%CH
390%CH is used in the CN washing
3CN/2% formic acid wash-out and collection.After the lyophilize, obtain 5-cyano group-2-(difluoromethyl)-6-[3-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) azetidine-1-yl] Nikithan, be white solid.Output: 59mg (70%).
1H?NMR(400MHz，DMSO-d
6)δ?1.31(3H，t，J＝7.1Hz)，3.51-3.67(1H，m)，4.28(2H，q，J＝7.1Hz)，4.34-4.43(2H，m)，4.43-4.55(4H，m)，4.72(2H，s)，5.15-5.25(1H，m)，7.25-7.57(1H，m)，7.29(2H，d，J＝8.3Hz)，7.32(2H，d，J＝8.3Hz)，8.48(1H，s)，11.74-11.88(1H，brs)。
MS?m/Z：509(M+1)。
Embodiment 131
5-cyano group-2-(difluoromethyl)-6-[4-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) piperidines-1-yl] Nikithan
The basic embodiment 130 that presses; with the 1-[3-cyano group-6-(difluoromethyl) in the step (d)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid; subsequently by step (e) preparation; obtain 5-cyano group-2-(difluoromethyl)-6-[4-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) piperidines-1-yl] Nikithan, be white solid.Output: 66mg (76%).
1H?NMR(400MHz，DMSO-d
6)δ?1.32(3H，t，J＝7.1Hz)，1.60-1.75(2H，m)，1.82-1.94(2H，m)，2.54-2.72(1H，m)，3.12-3.31(2H，m)，4.29(2H，q，J＝7.1Hz)，4.50(2H，d，J＝5.4Hz)，4.54-4.63(2H，m)，4.67(2H，s)，5.22(1H，t，J＝5.7Hz)，7.24(2H，d，J＝8.1Hz)，7.34(2H，d，J＝8.1Hz)，7.41(1H，t，J＝54.0Hz)，8.51(1H，s)，11.53-11.70(1H，brs)。
MS?m/Z：537(M+1)。
Embodiment 132
6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
(a) 1-(trifluoroacetyl group) azetidine-3-formic acid
Under 0 ℃ (ice/water-bath cooling), with trifluoroacetic anhydride (93.5g, 445mmol) be added to solid azetidine (acetidine)-3-formic acid (15g, 148mmol) in.Mixture manually stirred 30 minutes with spatula, used mechanical restir (mixture becomes evenly after 40 minutes) 2 hours 40 minutes subsequently.With the mixture vacuum concentration, residual yellow oil is distributed between EtOAc (300ml) and water (50ml).Separate each mutually after, organic phase water (2 x 50ml) and salt solution (20ml) washing, drying (Na
2SO
4), filter the back evaporation, obtain yellow oil.Vacuum-drying is at room temperature spent the night, and obtains product, is yellow solid.Output: 29.2g (100%).
(b) 1-(trifluoroacetyl group) azetidine-3-t-butyl formate
With 1,1-two tert.-butoxies-N, (16.5g, (5g's N-dimethyl methylamine in solution 25mmol), refluxes mixture heating up 8 hours 81mmol) to be added to 1-(trifluoroacetyl group) azetidine-3-formic acid.LC-MS shows residual raw material, therefore add in addition a certain amount of 1,1-two tert.-butoxies-N, (21.2g 81mmol), continues heated overnight to N-dimethyl methylamine.LC-MS shows still residual a little raw material (feed/product about 1/2), replaces toluene (100ml) with THF, and mixture heating up to 100 ℃ (oil bath temperature) is reached 2 hours.After making solvent evaporation, resistates is dissolved in EtOAc (200ml).Organic phase NaHCO
3(saturated) (2 x 50ml), water (2 x 50ml), salt solution (50ml) washing, dry (Na
2SO
4), filter the back evaporation, obtain required product.Output: 4.5g (70%).
(c) azetidine-3-t-butyl formate
With salt of wormwood (7.37g, 53.3mmol) be added to 1-(trifluoroacetyl group) azetidine-3-t-butyl formate (4.5g, methanol 17.8mmol) (7/3,71ml) in the solution, mixture was at room temperature stirred 3.5 hours.After making the methyl alcohol evaporation, add DCM (200ml).Separate each phase, water extracts (2 x 100ml) with DCM.The organic phase water (2 x 50ml) that merges, salt solution (1 x50ml) washing, dry (Na
2SO
4), filter the back evaporation, obtain required product, be yellow oil.Output: 1.19g (40%).
(d) 1-(2-cyanoimino ethyl) azetidine-3-t-butyl formate
In the microwave bottle, pack into azetidine-3-t-butyl formate (1.1g, 6.65mmol, purity 95%), 2-cyano group ethanimidic acid ethyl ester (referring to McElvain, S.M.; Schroeder, J.P.; J.Am.Chem.Soc.71, the 40th page (1949)) (1.12g, 7.98mmol, purity 80%) and EtOH (15ml) and be heated to 100 ℃ and reach 10 minutes.Itself just can be used for next step this mixture, supposes yield 100%.
(e) 6-[3-(tert-butoxycarbonyl) azetidine-1-yl]-5-cyano group-2-oxo-1,2-dihydropyridine-3-ethyl formate
With (oxyethyl group methylene radical) diethyl malonate (2.16g, 9.98mmol) be added in the solution that derives from above-mentioned steps (d), reaction mixture was at room temperature stirred 18 hours, and with the heating of microwave single-unit, heating is following 10 minutes at 110 ℃ after 10 minutes down at 100 ℃ subsequently.After making solvent evaporation, resistates is dissolved in DCM, by silica gel plug (with DCM (100%), DCM/MeOH (10/1), (5/1) and (1/1) wash-out).Collection is evaporated after containing the flow point of product, obtains crude product (3.1g).Crude product preparation HPLC purifying (Kromasil C
8, 10 μ m, the employing gradient is 25-70%CH
3The aqueous solution of CN/0.2%AcOH), obtain 6-[3-(tert-butoxycarbonyl) azetidine-1-yl]-5-cyano group-2-oxo-1,2-dihydropyridine-3-ethyl formate is solid.Output: 1.043g (36%).
(f) 6-[3-(tert-butoxycarbonyl) azetidine-1-yl]-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
With 6-[3-(tert-butoxycarbonyl) azetidine-1-yl]-5-cyano group-2-oxo-1, and 2-dihydropyridine-3-ethyl formate (200mg, 0.576mmol) and Ag
2CO
3(397mg 1.44mmol) is dissolved in DMSO (15ml), after at room temperature 5 minutes, adds 2-iodo-1, and the 1-C2H4F2 C2H4F2 (2.21g, 11.5mmol).Reaction mixture is heated to 95 ℃ to spend the night.LCMS shows product and noresidue SM.Mixture is filtered, behind the dilute with water, with DCM (3 times) and EtOAc (1 time) extraction.The organism that makes merging obtains required product by concentrating under reduced pressure behind the phase splitter.Crude product need not to be further purified just and can use.Suppose quantitative output.
MS?m/Z：412(M+1)。
(g) 1-[3-cyano group-6-(2, the 2-difluoroethoxy)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid
With 6-[3-(tert-butoxycarbonyl) azetidine-1-yl]-(237mg 0.576mmol) is dissolved in 90% formic acid (9ml) to 5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan, reaction mixture is at room temperature stirred spend the night.After concentrating, concentrate altogether from DCM, lyophilize obtains 1-[3-cyano group-6-(2, the 2-difluoroethoxy)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid, be solid.Output: 194mg (95%).
1H?NMR(500MHz，DMSO-d
6)：δ?1.25(3H，t，J＝7.1Hz)，3.53-3.61(1H，m)，4.17(2H，q，J＝7.1Hz)，4.32-4.42(2H，m)，4.46-4.56(2H，m)，4.60(2H，td，J＝14.8，3.5Hz)，6.37(1H，tt，J＝54.6，3.5Hz)，8.27(1H，s)，12.83(1H，s)。
MS?m/Z：356(M+1)。
(h) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
With 1-phenyl methanesulfonamide acid amides (18.8mg 0.11mmol) packs in the 16ml bottle, add the PyBrop that is dissolved in DCM (1ml) (70mg, 0.15mmol).Add be dissolved in DCM (2ml) and DIPEA (0.17ml, 1-[3-cyano group-6-1.0mmol) (2, the 2-difluoroethoxy)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid (35.5mg, 0.11mmol).Reaction mixture was at room temperature stirred 40 minutes.Mixture 1%KHSO
4After solution (1ml) washing, water extracts with DCM (0.5ml).The organism that makes merging evaporates in vacuum centrifuge by behind the phase splitter.Crude product preparation HPLC purifying (Waters Fraction Lynx II purification system.Post: Sunfire Prep C
18, 5 μ m OBD, 19 x 150mm posts.The 0.1mM HCOOH solution of gradient: 5-95%MeCN, pH3.The flow point that adopts MS to trigger is collected.Single four utmost points of Micromass ZQ or the Micromass Quattromicro record mass spectrum at pneumatic auxiliary electrical spraying interface have been equipped with the both); obtain 6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan.Output: 28.3mg (50%).
1H?NMR(600MHz，DMSO-d
6)：δ?1.24(3H，t，J＝7.1Hz)，3.50-3.56(1H，m)，4.16(2H，q，J＝7.1Hz)，4.23-4.43(4H，m)，4.56-4.63(2H，m)，4.72(2H，s)，6.37(1H，t，J＝55.5Hz)，7.29-7.36(5H，m)，8.28(1H，s)。
MS?m/Z：509(M+1)。
Embodiment 133
5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
According to method described in the embodiment 132 (h),, obtain 5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(4-luorobenzyl) alkylsulfonyl with the preparation of 1-(4-fluorophenyl) Toluidrin] formamyl } azetidine-1-yl) Nikithan.Output: 32mg (55%).
1H?NMR(600MHz，DMSO-d
6)：δ1.24(3H，t，J＝7.1Hz)，3.51-3.57(1H，m)，4.16(2H，q，J＝7.1Hz)，4.24-4.33(2H，m)，4.35-4.46(2H，m)，4.56-4.63(2H，m)，4.73(2H，s)，6.37(1H，t，J＝55.0Hz)，7.17-7.21(2H，m)，7.35-7.40(2H，m)，8.27(1H，s)。
MS?m/Z：527(M+1)。
Embodiment 134
5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
According to method described in the embodiment 132 (h),, obtain 5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(2-luorobenzyl) alkylsulfonyl with the preparation of 1-(2-fluorophenyl) Toluidrin] formamyl } azetidine-1-yl) Nikithan.Output: 33.2mg (57%).
1H?NMR(600MHz，DMSO-d
6)：δ?1.24(3H，t，J＝7.3Hz)，3.54-3.60(1H，m)，4.16(2H，q，J＝7.3Hz)，4.29-4.50(4H，m)，4.57-4.64(2H，m)，4.78(2H，s)，6.37(1H，t，J＝54.2Hz)，7.20-7.25(2H，m)，7.41-7.46(2H，m)，8.28(1H，s)。
MS?m/Z：527(M+1)。
Embodiment 135
5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(2, the 2-difluoroethoxy) Nikithan
According to method described in the embodiment 132 (h),, obtain 5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl with the preparation of 1-(2,4 difluorobenzene base) Toluidrin] formamyl } azetidine-1-yl) Nikithan.Output: 33.4mg (55%).
1H?NMR(600MHz，DMSO-d
6)：δ?1.23(3H，t，J＝7.0Hz)，3.52-3.59(1H，m)，4.16(2H，q，J＝7.0Hz)，4.22-4.32(2H，m)，4.36-4.47(2H，m)，4.55-4.62(2H，m)，4.76(2H，s)，6.36(1H，t，J＝54.2Hz)，7.18-7.21(1H，m)，7.39-7.46(2H，m)，8.27(1H，s)。
MS?m/Z：545(M+1)。
Embodiment 136
6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(difluoromethyl) isopropyl nicotinate
(a) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(difluoromethyl) nicotinic acid
With 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan (15.5mg, 0.032mmol) be suspended in 1M NaOH (0.4ml, 0.4mmol) in, add CH
3CN (0.1ml).Reaction mixture was at room temperature stirred 1 hour.The mixture dilute with water, make it acidifying with formic acid after, with EtOAc extraction (3 times).After making the organism evaporation of merging, crude product need not to be further purified just and can use.Suppose quantitative output.
MS?m/Z：451(M+1)。
(b) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(difluoromethyl) isopropyl nicotinate
With 6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(difluoromethyl) nicotinic acid (14.6mg; 0.032mmol), DMAP (4.4mg; 0.036mmol) and EDC (6.8mg; 0.036mmol) be suspended among the IPA (2ml); adding TEA (5 μ l, 0.032mmol).Reaction mixture stirring under 50 ℃ is spent the night.(12.2mg 0.032mmol), stirs reaction mixture 4 hours down at 50 ℃ to add HATU down at 50 ℃.Mixture dilutes with DCM, uses 1%KHSO
4Behind the solution washing, water extracts (3 times) with DCM.The organism that merges is through concentrating under reduced pressure, and crude product is with preparation HPLC purifying (Kromasil C
810 μ m; 21.5 x 250mm post; elutriant A:100% acetonitrile; elutriant B:0.2% acetic acid water solution (containing 5% acetonitrile); flow velocity 25ml/ minute, adopting gradient was 30-100% elutriant A, in 30 minutes); obtain 6-{3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-yl }-5-cyano group-2-(difluoromethyl) isopropyl nicotinate, be white solid.Output: 3mg, (19%).
1H NMR (400MHz, DMSO-d
6): δ 1.30 (6H, d, J=6.3Hz), 4.34 (2H, br s), 4.37-4.49 (2H, m), 4.51-4.67 (2H, m), 5.08 (1H, quintet, J=6.3Hz), 7.31 (5H, br s), 7.38 (1H, t, J=54.3Hz), 8.43 (1H, s).Note! H signal and DMSO signal overlap.
MS?m/Z：493(M+1)，491(M-1)。
Embodiment 137
5-cyano group-6-[3-({ [(4-methylcyclohexyl) methyl] alkylsulfonyl } formamyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
According to method D by 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] preparation of azetidine-3-formic acid and 1-(4-methylcyclohexyl) Toluidrin, obtain 5-cyano group-6-[3-({ [(4-methylcyclohexyl) methyl] alkylsulfonyl } formamyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan.Output: 43mg (55%).
MS?m/z：517(M+1)。
Claims (23)
1. a formula I compound or its pharmacy acceptable salt:
Wherein:
R
1Expression R
6OC (O), R
7C (O), R
16SC (O), R
17S, R
18C (S) or following gII group:
R
2Expression is optional by the isolated (C of oxygen
1-C
12) alkyl, wherein alkyl is replaced by one or more halogens (F, Cl, Br, I) atom; In addition, R
2(the C that expression is replaced by one or more halogens (F, Cl, Br, I) atom
1-C
12) alkoxyl group;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
3Optional (the C that is replaced by one or more halogens (F, Cl, Br, I) atom of expression
1-C
12) alkoxyl group; In addition, R
3Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkylthio C (O), (C
1-C
12) alkyl C (S), (C
1-C
12) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
12) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
12) alkyl C (O), (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (3)R
B (3)Group, wherein R
A (3)And R
B (3)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
A (3)And R
B (3)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
4Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
12) alkyl: OH, COOH, (C
1-C
6) alkoxy carbonyl, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
4Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkyl-cycloalkyl, (C
1-C
12) alkoxyl group, wherein alkoxyl group can be chosen wantonly by following group and replace: one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or (C
1-C
6) alkoxy carbonyl; In addition, R
4Expression (C
1-C
12) alkylthio C (O), (C
1-C
12) alkyl C (S), (C
1-C
12) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
12) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
12) alkyl C (O), (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (4)R
B (4)Group, wherein R
A (4)And R
B (4)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
A (4)And R
B (4)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
Z represents O or does not exist;
R
5Expression H or (C
1-C
12) alkyl;
R
6Expression is optional by the isolated (C of oxygen
1-C
12) (precondition is that any this class oxygen must be apart from connecting R to alkyl
6At least 2 carbon atoms of the ester-oxygen of group) and/or the optional (C that is replaced by following group
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
12) alkyl, aryl or heterocyclic radical;
R
7Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
7Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, aryl or heterocyclic radical;
R
8Expression H, the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
12) alkyl: aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
8Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl or (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl;
R
14Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
12) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
12) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
14Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl or (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl, formula NR
A (14)R
B (14)Group, wherein R
A (14)And R
B (14)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkoxy C (O), perhaps R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
12) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
12) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
15Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (15)R
B (15)Group, wherein R
A (15)And R
B (15)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkoxy C (O), perhaps R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
16Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
17Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
17Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
18Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
12) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
18Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, (C
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
cDo not exist or represent and do not replace or single replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylidene group oxygen base or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately separately and be independently selected from (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, oxygen base-(C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, carboxyl, carboxyl-(C
1-C
4) alkyl, aryl, heterocyclic radical, nitro, cyano group, halogen (F, Cl, Br, I), hydroxyl, NR
A (Rc)R
B (Rc), R wherein
A (Rc)And R
B (Rc)Represent hydrogen, (C independent of one another and independently
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms; In addition, R
cExpression imino-(NH-), the imino-(NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylideneimino or N-
1-C
4) alkylideneimino (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is unsubstituted or is replaced by any above-mentioned substituting group list or polysubstituted;
R
19When existing, represent H or (C
1-C
4) alkyl;
R
dExpression (C
1-C
12) alkyl, (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom and/or one or more following group replacement: OH, CN, NO
2, (C
1-C
12) alkyl, (C
1-C
12) alkoxy C (O), (C
1-C
12) (the C that replaces of alkoxyl group, halogen
1-C
12) (the C that replaces of alkyl, halogen
1-C
12) alkoxyl group, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
12) alkyl sulphinyl, (C
1-C
12) alkyl sulphonyl, (C
1-C
12) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
12) alkylthio, aryl (C
1-C
12) alkyl sulphinyl, aryl (C
1-C
12) alkyl sulphonyl, heterocyclic radical (C
1-C
12) alkylthio, heterocyclic radical (C
1-C
12) alkyl sulphinyl, heterocyclic radical (C
1-C
12) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
12) alkyl sulphonyl or formula NR
A (Rd)R
B (Rd)Group, wherein R
A (Rd)And R
B (Rd)Independent expression H, (C
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
X represents singly-bound, imino-(NH-), methylene radical (CH
2-), the imino-methylene radical (CH that is connected with B ring/ring system of carbon wherein
2-NH-), the methylene radical imino-(NH-CH that is connected with B ring/ring system of nitrogen wherein
2-), any carbon and/or nitrogen in these groups can be chosen wantonly by (C
1-C
6) the alkyl replacement; X also can represent (CH
2-)
nGroup, n=2-6 wherein, this group is optional to be undersaturated and/or to be selected from following substituting group and to replace by one or more: halogen, hydroxyl or (C
1-C
6) alkyl; With
B contains one or more nitrogen and optional one or more heterocycle/ring systems that are selected from the monocycle or the dicyclo of oxygen or sulphur atom for 4-11 unit, this nitrogen is connected with pyridine ring (according to formula I), precondition is that B is not a piperazine, and in addition, B ring/ring system also is connected with other locational X in the ring; Substituent R
14And R
15(be not connected) the formation quaternary ammonium compound with B ring/ring system ways of connecting by these.
2. the compound of claim 1, wherein:
R
1Expression R
6OC (O), R
7C (O), R
16SC (O), R
17S, R
18C (S) or following gII group:
R
2Expression optional by oxygen the isolated and (C that replaced by one or more halogens (F, Cl, Br, I) atom of alkyl wherein
1-C
6) alkyl; In addition, R
2(the C that expression is replaced by one or more halogens (F, Cl, Br, I) atom
1-C
6) alkoxyl group;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom; In addition, R
3Optional (the C that is replaced by one or more halogens (F, Cl, Br, I) atom of expression
1-C
6) alkoxyl group; In addition, R
3Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkylthio C (O), (C
1-C
6) alkyl C (S), (C
1-C
6) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
6) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
6) alkyl C (O), (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (3)R
B (3)Group, wherein R
A (3)And R
B (3)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (3)And R
B (3)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
4Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: OH, COOH, (C
1-C
6) alkoxy carbonyl, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom; In addition, R
4Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxyl group, wherein alkoxyl group can be chosen wantonly by following group and replace: one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or (C
1-C
3) alkoxy carbonyl; In addition, R
4Expression (C
1-C
6) alkylthio C (O), (C
1-C
6) alkyl C (S), (C
1-C
6) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
6) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
6) alkyl C (O), (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (4)R
B (4)Group, wherein R
A (4)And R
B (4)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (4)And R
B (4)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
5Expression H or (C
1-C
6) alkyl;
R
6Expression is optional by the isolated (C of oxygen
1-C
6) (precondition is that any this class oxygen must be apart from connecting R to alkyl
6At least 1 carbon atom of the ester-oxygen of group) and/or the optional (C that is replaced by following group
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
6) alkyl, aryl or heterocyclic radical;
R
7Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
7Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, aryl or heterocyclic radical;
R
8Expression H, the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
8Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl, heterocyclic radical, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl or (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl;
R
14Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
6) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
14Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (14)R
B (14)Group, wherein R
A (14)And R
B (14)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), perhaps R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
6) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
15Expression aryl, heterocyclic radical, one or more halogen (F, C1, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (15)R
B (15)Group, wherein R
A (15)And R
B (15)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), perhaps R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
16Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
17Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
17Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
18Optional (the C that is replaced by the following group of the isolated and/or optional quilt of oxygen of expression
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
18Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
19When existing, represent H or (C
1-C
4) alkyl; With
R
dExpression (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom and/or one or more following group replacement: OH, CN, NO
2, (C
1-C
6) alkyl, (C
1-C
6) alkoxy C (O), (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) (the C that replaces of alkyl, halogen
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl or formula NR
A (Rd)R
B (Rd)Group, wherein R
A (Rd)And R
B (Rd)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
3. the compound of claim 2, wherein:
R
1Expression R
6OC (O), R
16SC (O) or following gII group:
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom; In addition, R
3Optional (the C that is replaced by one or more halogens (F, Cl, Br, I) atom of expression
1-C
6) alkoxyl group; In addition, R
3Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkylthio C (O), (C
1-C
6) alkyl C (S), (C
1-C
6) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
6) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
6) alkyl C (O), (C
1-C
6) alkyl sulphinyl or formula NR
A (3)R
B (3)Group, wherein R
A (3)And R
B (3)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (3)And R
B (3)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
4Expression H, CN, NO
2, halogen (F, Cl, Br, I), the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: OH, COOH, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom; In addition, R
4Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxyl group, wherein alkoxyl group can be chosen wantonly by following group and replace: one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or methoxycarbonyl; In addition, R
4Expression (C
1-C
6) alkylthio C (O), (C
1-C
6) alkyl C (S), (C
1-C
6) alkoxy C (O), (C
3-C
6) cycloalkyloxy, aryl, aryl C (O), aryl (C
1-C
6) alkyl C (O), heterocyclic radical, heterocyclic radical C (O), heterocyclic radical (C
1-C
6) alkyl C (O) or formula NR
A (4)R
B (4)Group, wherein R
A (4)And R
B (4)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), perhaps R
A (4)And R
B (4)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
8Expression H, the optional (C that is replaced by the following group of the isolated and/or optional quilt of oxygen
1-C
6) alkyl: aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom; In addition, R
8Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy, aryl or heterocyclic radical;
R
14Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
6) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
14Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy or formula NR
A (14)R
B (14)Group, wherein R
A (14)And R
B (14)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), perhaps R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H; OH, precondition is that the OH group must encircle apart from B/2 carbon atoms of any heteroatoms in the ring system at least; Optional by the isolated and/or optional (C that is replaced by one or more following groups of oxygen
1-C
6) alkyl: OH, COOH and COOR
eR wherein
eExpression aryl, cycloalkyl, heterocyclic radical or the optional (C that is replaced by one or more following groups
1-C
6) alkyl: halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and heterocyclic radical; In addition, R
15Expression aryl, heterocyclic radical, one or more halogen (F, Cl, Br, I) atom, (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyloxy or formula NR
A (15)R
B (15)Group, wherein R
A (15)And R
B (15)Independent expression H, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), perhaps R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Be ethyl; With
R
dExpression (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom and/or one or more following group replacement: CN, NO
2, (C
1-C
6) alkyl, (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) (the C that replaces of alkyl, halogen
1-C
6) alkoxyl group, (C
3-C
6) cycloalkyl, aryl, heterocyclic radical, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkylthio, (C
3-C
6) cycloalkylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio, aryl (C
1-C
6) alkylthio, aryl (C
1-C
6) alkyl sulphinyl, aryl (C
1-C
6) alkyl sulphonyl, heterocyclic radical (C
1-C
6) alkylthio, heterocyclic radical (C
1-C
6) alkyl sulphinyl, heterocyclic radical (C
1-C
6) alkyl sulphonyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkylthio, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphinyl or (C
3-C
6) cycloalkyl (C
1-C
6) alkyl sulphonyl.
4. the compound of claim 1, wherein:
R
1Expression R
6OC (O);
R
2(the C that expression is replaced by one or more halogens (F, Cl, Br, I) atom
1-C
4) alkyl;
R
3Expression H;
R
4Expression CN or halogen (F, Cl, Br, I);
Z does not exist;
R
5Expression H;
R
6Expression is optional by the isolated (C of oxygen
1-C
6) (precondition is that any this class oxygen must be apart from connecting R to alkyl
6At least 2 carbon atoms of the ester-oxygen of group) and/or the optional (C that is replaced by following group
1-C
6) alkyl: OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom;
R
14Expression H;
R
15Expression H;
R
cThere is not or represents unsubstituted (C
1-C
4) alkylidene group;
R
dExpression (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, any of these groups is optional by one or more halogens (F, Cl, Br, I) atom and/or one or more following group replacement: CN, (C
1-C
6) alkyl, (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) (the C that replaces of alkyl, halogen
1-C
6) alkoxyl group;
X represents singly-bound or methylene radical (CH
2-); With
B contains one or more nitrogen and optional one or more monocyclic heterocycles/ring systems that are selected from oxygen or sulphur atom for 4-7 unit, and this nitrogen is connected with pyridine ring (according to formula I), and precondition is that B is not a piperazine, and in addition, B ring/ring system also is connected with other locational X in the ring; Substituent R
14And R
15Can (not be connected) the formation quaternary ammonium compound with B ring/ring system ways of connecting by these.
5. the compound of claim 1, wherein;
R
1Be ethoxy carbonyl or isopropoxy carbonyl;
R
2Be selected from methyl fluoride, chloromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 1-fluoro ethyl, 2-fluorine oxyethyl group, 2,2,2-trifluoro ethoxy, difluoro-methoxy and 2,2-difluoroethoxy;
R
3Be H;
R
4Be selected from chlorine or cyano group;
Z does not exist;
R
5Be H;
R
6Be ethyl or sec.-propyl;
R
14Be H;
R
15Be H;
R
cDo not exist or be selected from methylene radical (CH
2-) or ethylidene (CH
2CH
2-);
R
dBe selected from normal-butyl, the 4-methylcyclohexyl, phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, 2-(trifluoromethoxy) phenyl, 4-(trifluoromethoxy) phenyl, the 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, the 2-chloro-phenyl-, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 2, the 4-dichlorophenyl, the 2-cyano-phenyl, the 3-cyano-phenyl, the 4-cyano-phenyl, the 3-p-methoxy-phenyl, the 2-naphthyl, 2, the 6-difluorophenyl, 4-fluoro-3-aminomethyl phenyl, 2-chloro-4-fluorophenyl, 2,3, the 6-trifluorophenyl, 2, the 4-difluorophenyl, 4-chloro-2-fluorophenyl, 5-fluoro-2-aminomethyl phenyl, 2-fluoro-5-aminomethyl phenyl, the 3-p-methoxy-phenyl, 3, the 4-difluorophenyl, 4-hydroxymethyl phenyl and 5-chloro-2-thienyl;
X represents singly-bound or methylene radical (CH
2-); With
B is selected from 4-piperidines-1-subunit, 3-tetramethyleneimine-1-subunit and 3-azetidine-1-subunit, substituent R
14And R
15Can (not be connected) the formation quaternary ammonium compound with B ring/ring system ways of connecting by these.
6. each compound among the claim 1-5, described compound is following formula (Ia) compound:
7. each compound among the claim 1-5, described compound is following formula (Ib) compound:
8. each compound among the claim 1-5, described compound is following formula (Ic) compound:
9. each compound among the claim 1-5, described compound is following formula (Id) compound:
10. each compound among the claim 1-9, wherein Z does not exist.
11. each compound among the claim 1-9, wherein Z is O.
12. each compound, wherein R among the claim 1-4
1Expression R
6OC (O).
13. the compound of claim 12, described compound are following formula (Iaa) compound:
14. the compound of claim 12, described compound are following formula (Ibb) compound:
15. the compound of claim 12, described compound are following formula (Icc) compound:
16. the compound of claim 12, described compound are following formula (Idd) compound:
17. each compound, wherein R among the claim 1-5
1Expression R
6OC (O), R
16SC (O) or following gII group:
18. a compound is selected from:
(1) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) Nikithan
(2) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(3) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(4) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(5) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(6) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(7) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(8) methyl 5-cyano group-2-(difluoromethyl)-6-{4-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(9) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(10) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(11) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(12) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(13) 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(14) 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(15) 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(16) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(17) 5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(18) 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
(19) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(20) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(21) 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(22) 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(23) 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) Nikithan
(24) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(25) 5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(26) 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
(27) methyl 5-cyano group-2-(difluoromethyl)-6-{3-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
(28) 5-cyano group-6-[3-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
(29) 5-cyano group-6-[3-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
(30) 5-cyano group-2-(difluoromethyl)-6-{3-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
(31) 5-cyano group-2-(difluoromethyl)-6-{3-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
(32) 5-cyano group-6-[3-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) Nikithan
(33) 5-cyano group-2-(difluoromethyl)-6-(3-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl) Nikithan
(34) 6-(3-{[(butyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(35) 5-cyano group-6-[4-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
(36) 5-cyano group-6-[4-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
(37) 5-cyano group-2-(difluoromethyl)-6-{4-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(38) 5-cyano group-2-(difluoromethyl)-6-{4-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(39) 5-cyano group-6-[4-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) Nikithan
(40) 5-cyano group-2-(difluoromethyl)-6-(4-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl) Nikithan
(41) 6-(4-{[(butyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(42) 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(43) 5-cyano group-6-[3-(2-oxo-2-{[(2-phenylethyl) alkylsulfonyl] amino } ethyl) tetramethyleneimine-1-yl]-2-(trifluoromethyl) Nikithan
(44) 6-[3-(2-{[(5-chloro-2-thienyl) alkylsulfonyl] amino }-the 2-oxoethyl) tetramethyleneimine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(45) 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(46) 5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(47) 5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(48) 5-cyano group-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(49) 5-cyano group-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(50) 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(51) 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(52) 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(53) 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan
(54) 6-[3-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(55) 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(56) 5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(57) 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(58) 5-cyano group-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(59) 5-cyano group-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(60) 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(61) 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(62) 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(63) 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) Nikithan
(64) 6-[4-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) Nikithan
(65) 5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(66) 5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(67) 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(68) 6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(69) 6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(70) 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(71) 5-cyano group-2-(methyl fluoride)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(72) 5-cyano group-2-(methyl fluoride)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] Nikithan
(73) 5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) Nikithan
(74) methyl 5-cyano group-2-(methyl fluoride)-6-{3-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } Nikithan
(75) 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(76) 5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(77) 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(78) 6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(79) 6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(80) 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) Nikithan
(81) 5-cyano group-2-(methyl fluoride)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(82) 5-cyano group-2-(methyl fluoride)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] Nikithan
(83) 5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) Nikithan
(84) methyl 5-cyano group-2-(methyl fluoride)-6-{4-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } Nikithan
(85) 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(86) 5-cyano group-6-(3-{[(2-cyano group benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(87) 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(methyl fluoride) Nikithan
(88) 5-cyano group-2-(methyl fluoride)-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(89) 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(90) 5-cyano group-2-(methyl fluoride)-6-(3-{[(2,3,6-trifluoro-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(91) 5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(methyl fluoride) Nikithan
(92) 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(93) 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
(94) 5-cyano group-2-(difluoromethyl)-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(95) 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(96) 5-cyano group-2-(difluoromethyl)-6-(3-{[(5-fluoro-2-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(97) 5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
(98) 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) Nikithan
(99) 5-cyano group-6-(3-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(100) 5-cyano group-6-(3-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(101) 6-(3-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(102) 5-cyano group-6-(3-{[(5-fluoro-2-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(103) 5-cyano group-6-(3-{[(2,3,6-trifluoro-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(104) 6-(3-{[(4-chloro-2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) Nikithan
(105) 5-cyano group-6-(4-{[(2,6-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
(106) 5-cyano group-2-(difluoromethyl)-6-(4-{[(4-fluoro-3-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl) Nikithan
(107) 5-cyano group-2-(methyl fluoride)-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(108) 5-cyano group-6-(4-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(trifluoromethyl) Nikithan
(109) 5-cyano group-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(trifluoromethyl) Nikithan
(110) 5-cyano group-2-(difluoromethyl)-6-(4-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } piperidines-1-yl) Nikithan
(111) 5-cyano group-2-(difluoromethyl)-6-(3-{[(3-methoxy-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(112) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan
(113) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(pentafluoroethyl group) Nikithan
(114) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan
(115) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(1-fluoro ethyl) Nikithan
(116) 6-(4-{[(2-chloro-4-luorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) Nikithan
(117) 5-cyano group-6-(4-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(methyl fluoride) Nikithan
(118) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-2-(chloromethyl)-5-cyano group Nikithan
(119) 5-cyano group-2-(difluoromethyl)-6-(3-{[(2-fluoro-5-methyl-benzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(120) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-2-(chloromethyl)-5-cyano group Nikithan
(121) 5-cyano group-6-(3-{[(3,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(difluoromethyl) Nikithan
(122) 5-cyano group-6-(4-{[(3,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
(123) 5-cyano group-6-(4-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } piperidines-1-yl)-2-(difluoromethyl) Nikithan
(124) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2-fluorine oxyethyl group) Nikithan
(125) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-[(2,2, the 2-trifluoro ethoxy) methyl] Nikithan
(126) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-[(2,2, the 2-trifluoro ethoxy) methyl] Nikithan
(127) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(difluoro-methoxy) Nikithan
(128) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
(129) formamyl 6-{4-[(benzyl alkylsulfonyl)] piperidines-1-yl }-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) Nikithan
(130) 5-cyano group-2-(difluoromethyl)-6-[3-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) azetidine-1-yl] Nikithan
(131) 5-cyano group-2-(difluoromethyl)-6-[4-({ [4-(hydroxymethyl) benzyl] alkylsulfonyl } formamyl) piperidines-1-yl] Nikithan
(132) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(2, the 2-difluoroethoxy) Nikithan
(133) 5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(4-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(134) 5-cyano group-2-(2, the 2-difluoroethoxy)-6-(3-{[(2-luorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl) Nikithan
(135) 5-cyano group-6-(3-{[(2,4-difluorobenzyl) alkylsulfonyl] formamyl } azetidine-1-yl)-2-(2, the 2-difluoroethoxy) Nikithan
(136) formamyl 6-{3-[(benzyl alkylsulfonyl)] azetidine-1-yl }-5-cyano group-2-(difluoromethyl) isopropyl nicotinate
(137) 5-cyano group-6-[3-({ [(4-methylcyclohexyl) methyl] alkylsulfonyl } formamyl) azetidine-1-yl]-2-(trifluoromethyl) Nikithan;
And pharmacy acceptable salt.
19. a pharmaceutical composition, described pharmaceutical composition comprise among the claim 1-18 each compound and pharmaceutically acceptable auxiliary, thinner and/or carrier.
20. each compound among the claim 1-18 that is used for the treatment of.
21. each compound is used for the treatment of purposes in the medicine of platelet aggregation obstacle in preparation among the claim 1-18.
22. each compound is used to suppress P2Y in preparation among the claim 1-18
12Purposes in the medicine of acceptor.
23. a method for the treatment of the platelet aggregation obstacle, this method comprise among the claim 1-18 of the patient treatment significant quantity of suffering from this class obstacle each compound.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE06014633 | 2006-07-04 | ||
| SE0601463 | 2006-07-04 | ||
| SE06020911 | 2006-10-04 | ||
| SE07000599 | 2007-01-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101506194A true CN101506194A (en) | 2009-08-12 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800316322A Pending CN101506194A (en) | 2006-07-04 | 2007-07-02 | New pyridine analogues |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101506194A (en) |
| ZA (1) | ZA200810645B (en) |
-
2007
- 2007-07-02 CN CNA2007800316322A patent/CN101506194A/en active Pending
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2008
- 2008-12-17 ZA ZA200810645A patent/ZA200810645B/en unknown
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| Publication number | Publication date |
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| ZA200810645B (en) | 2010-05-26 |
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