CN101263133A - New pyridine analogues - Google Patents
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- CN101263133A CN101263133A CNA2006800333874A CN200680033387A CN101263133A CN 101263133 A CN101263133 A CN 101263133A CN A2006800333874 A CNA2006800333874 A CN A2006800333874A CN 200680033387 A CN200680033387 A CN 200680033387A CN 101263133 A CN101263133 A CN 101263133A
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Abstract
The present invention relates to certain new pyridin analogues of Formula (I) Chemical formula should be inserted here. Please see paper copy 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, they are as the purposes of medicine, the composition that comprises them and their preparation method.
Background of invention
Thrombocyte adhesiveness and gathering are the firing events in the artery thrombosis.Although thrombocyte adhesiveness may have important effect aspect the repairing damaged vessel walls in the process of interior subcutaneous surface, but the platelet aggregation of Yin Faing can be facilitated the acute thrombotic obstruction of vitals vescular bed thus, cause the high incidence incident, for example myocardial infarction and unstable angina pectoris.The successful property that is used to prevent or alleviate the interventional therapy (for example thrombolysis and angioplasty) of these patient's condition also is subjected to platelet-mediated obstruction or the harm of obstruction again.
Hemostasis be by platelet aggregation, solidify and fibrinolysis between tight balance controlled.Thrombosis under pathological conditions (for example the arteriosclerotic thrombocyte breaks) is at first caused by thrombocyte adhesiveness, activation and gathering.This not only causes the formation of thrombocyte embolism, and causes the electronegative phosphatide of the promotion blood coagulation on the platelet membrane of the outside to expose.Expectation can reduce thrombosis and the number of times that reduces cardiovascular event to the inhibition of the structure (build-up) of initial thrombocyte embolism, is proved that as the antithrombotic effect by for example acetylsalicylic acid (BMJ 194; 308:81-106 Antiplatelet Trialists ' Collaboration.Collaborative overview ofrandomised trials of antiplatelet therapy, I:Prevention of death, myocardialinfarction, and stroke by prolonged antiplatelet therapy in various categoriesof patients).Platelet activation/gathering can be induced by various agonist.Yet, must activate by the G-Protein G
q, G
12/13And G
iThe different intracellular signal passage of mediation is to obtain platelet aggregation (Platelets, AD Michelson ed., Elsevier Science 2002, ISBN 0-12-493951-1 completely; People such as 197-213:D Woulfe, Signal transduction duringthe initiation, extension, and perpetuation of platelet plug formation).In thrombocyte, g protein coupled receptor P2Y
12(also claimed thrombocyte P in the past
2T, P2T
AcOr P2Y
CycAcceptor) transmits signal by Gi, cause the reduction of cAMP in the cell and assemble (Nature2001 completely; People such as 409:202-207G Hollopeter, Identification of the platelet ADPreceptor targeted by antithrombotic drugs.)。The ADP that discharges from dense granule is to P2Y
12Acceptor applies positive regeeration, assembles completely allowing.
(a kind of Thienopyridines prodrug, its active metabolite optionally and irreversibly are incorporated into P2Y by clinical use clopidogrel
12Acceptor, it shows that in several clinical trials the risk of cardiovascular event takes place effective reduction patient on the line) ADP-P2Y is provided
12(Lancet 1996 for the clinical evidence of the keying action of Feedback mechanism; 348:1329-39:CAPRIE Steeringcommittee, A randomised, blinded, trial of clopidogrel versus aspirin inpatients at risk of ischaemic events (CAPRIE); N Engl J Med 2001; 345 (7): 494-502): The Clopidogrel in Unstable Angina to prevent Recurrent EventsTrial Investigators.Effects of clopidogrel in addition to aspirin in patientswith acute coronary syndromes without ST-segment elevation.).In these researchs, compare hemorrhage risk (the SemThromb Haemostas 2005 that this clinical benefit has reduction with Thienopyridines; 31 (2): 195-204 JJJ van Giezen ﹠amp; RG Humphries.Preclinical and clinical studies with selective reversible direct P2Y
12Antagonists).
Therefore, the purpose of this invention is to provide effectively, reversible and P2Y optionally
12Antagonist is as the antithrombotic drug agent.
Summary of the invention
We have been surprised to find that the pyridine compounds of some formula (I) or its pharmacologically acceptable salt are reversible and P2Y optionally now
12Antagonist is hereinafter referred to as compound of the present invention.Compound of the present invention unexpectedly shows useful character, makes them be specially adapted to treat disease/patient's condition as described below (referring to p.66-67).The example of this beneficial property is efficient, highly selective and favourable treatment window.
Detailed Description Of The Invention
The invention provides the compound or pharmaceutically acceptable salt thereof of new formula (I):
Wherein
R
1Expression R
6OC (O), R
7C (O), R
16SC (O), R
17S, R
18C (S) or group gII:
Preferably, R
1Expression R
6OC (O), R
16SC (O) or group gII:
R
2Expression H, CN, halogen (F, Cl, Br, I), NO
2, randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; In addition, R
2(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
1-C
12) alkoxyl group; In addition, R
2Expression (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 (2)R
B (2)Group, R wherein
A (2)And R
B (2)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), perhaps R
A (2)And R
B (2)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
In addition, R
1+ R
2(with two carbon atoms of pyridine ring) can form 5-unit or 6-unit annular lactone;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I) is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; In addition, R
3(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
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, R wherein
A (3)And R
B (3)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or 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) is randomly by the oxygen interval and/or randomly by OH, COOH, (C
1-C
6) (the C that replaces of alkoxy carbonyl, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
12) alkyl; 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 randomly by one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or (C
1-C
6) the alkoxy carbonyl replacement; 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, R wherein
A (4)And R
B (4)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O) or 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 randomly by oxygen at interval (condition be any this oxygen must be connected in R
6Ester-the oxygen of group is at a distance of at least two carbon atoms) and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
12) alkyl, aryl or heterocyclic radical;
R
7Expression is randomly by oxygen (C at interval and/or that randomly replaced by OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
12) alkyl; In addition, R
7Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, aryl or heterocyclic radical;
R
8Expression H is randomly by oxygen (C at interval and/or that randomly replaced by aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
12) alkyl; 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 (condition be the OH group must encircle with B/any heteroatoms in the member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
12) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
12) alkyl; 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, 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, formula NR
A (14)R
B (14)Group, R wherein
A (14)And R
B (14)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkoxy C (O), or R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H, OH (condition be the OH group must encircle with B/any heteroatoms in the member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
12) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
12) alkyl; 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, 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 (15)R
B (15)Group, R wherein
A (15)And R
B (15)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O)), (C
1-C
12) alkoxy C (O) or R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; 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
17Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; 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
18Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; 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
cRepresent unsubstituted or single the replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylene oxide group or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
1-C
4) alkyl, or R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms; In addition, R
cExpression imido grpup (NH-), the imido grpup (NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylene imine base or N-
1-C
4) alkylene imine base (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is not substituted or is replaced by above-mentioned any substituting group list or polysubstituted; Preferably, R
cExpression imido grpup or (C
1-C
4) alkylene imine base or unsubstituted or replaced or polysubstituted (C by above-mentioned any substituting group list
1-C
4) alkylidene group or (C
1-C
4) the oxo alkylidene group;
R
19Expression H or (C
1-C
4) alkyl;
R
dExpression (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, and in these groups any is randomly by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
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
A (Rd)R
B (Rd)Group, R wherein
A (Rd)And R
B (Rd)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
X represents singly-bound, imido grpup (NH-), methylene radical (CH
2-), imido grpup methylene radical (CH
2-NH-) (wherein carbon is connected in B-ring/member ring systems), methylenimine base (NH-CH
2-) (wherein nitrogen is connected in B-ring/member ring systems), and any carbon in these groups and/or nitrogen can be randomly by (C
1-C
6) the alkyl replacement; In addition, X can represent group (CH
2-) n, n=2-6 wherein, it randomly is not substituted and/or by one or more halogen, hydroxyl or (C of being selected from
1-C
6) substituting group of alkyl replaces;
B is the 4-11 unit heterocycle/member ring systems of monocycle or dicyclo, comprises one or more nitrogen and optional one or more atoms that are selected from oxygen or sulphur, and described nitrogen is connected in pyridine ring (according to formula I), and B-ring/member ring systems is connected in X with its another position in addition.Substituent R
14And R
15Be connected in B-ring/member ring systems, make (by these connections) not form quaternary ammonium compound.
The preferred value of each variable group is as follows.These values can be used with any value in value, definition, claim, aspect or the embodiment of above-mentioned or following definitions in appropriate circumstances.Particularly, each value can be with the independent restriction of doing the most extensive definition of formula (I).
For fear of causing doubt, should be appreciated that in this manual, group is by " aforementioned definitions ", when " defining as described above " or " above-mentioned definition " limits, this group comprise when occurring for the first time and definition the most widely, and for each of this group and all concrete definition.
Should be appreciated that when the compound of formula I comprised chiral centre, compound of the present invention can optical activity or racemization form existence and separated.The present invention includes and play P2Y
12Any optical activity of the compound of the formula I of receptor antagonist effect or racemization form.The synthetic of optical activity form can be undertaken by organic chemistry standard technique well known in the art, for example by racemic mixture is split, by chiral chromatography, synthetic or by asymmetric synthesis from optically active starting raw material.
The compound that be also to be understood that formula I can show tautomeric phenomenon, the present invention includes as P2Y
12Any tautomeric form of the compound of the formula I of receptor antagonist.
Be also to be understood that at compound of the present invention that as solvate particularly in the situation that hydrate exists, these also are included as a part of the present invention.
Be also to be understood that common name for example " alkyl " comprise straight chain and branched group, for example butyl and the tertiary butyl.Yet when using proprietary term for example when " butyl ", it is specially the butyl of straight chain or " just ", branched chain isomer, and for example " tertiary butyl " spells out when meaning.
In one embodiment, alkyl is not substituted or by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
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, R wherein
aAnd R
bRepresent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or R
aAnd R
bRepresent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
Term " alkyl " comprises the straight or branched group, and it is randomly 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), an embodiment of alkyl is the alkyl that is for example replaced by one or more fluorine atoms.Another embodiment of the alkyl that is replaced by halogen comprises perfluoroalkyl, for example trifluoromethyl.
Replace or the unsubstituted (C of term " cycloalkyl " ordinary representation
3-C
6) cyclic hydrocarbon, unless indicate other chain length.
In one embodiment, cycloalkyl is by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
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, R wherein
aAnd R
bRepresent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or R
aAnd R
bRepresent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
Term " alkoxyl group " comprises the straight or branched group, and it is randomly replaced by one or more halogens (F, Cl, Br, I) or blended halogen atom.
Term aryl is represented (C that replace or unsubstituted
6-C
14) aromatic hydrocarbon, and include but not limited to phenyl, naphthyl, tetralyl, indenyl, 2,3-indanyl, anthryl (antracenyl), phenanthryl (fenantrenyl) and fluorenyl.
In one embodiment, aryl is by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
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, R wherein
aAnd R
bRepresent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or R
aAnd R
bRepresent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
The monocycle or the polycyclic system of 4-10 that term " heterocyclic radical " expression replaces or unsubstituted unit, one or more atoms in wherein one or more rings are the element that is different from carbon, nitrogen for example, oxygen or sulphur, 4-particularly, the aromatic series of 5-or 6-unit or aliphatic heterocyclic group, include but not limited to azetidine, furans, thiophene, the pyrroles, pyrroline, tetramethyleneimine, dioxolane, the oxa-thiacyclopentane, oxa-aza-cyclopentane oxazole, thiazole, imidazoles, tetrahydroglyoxaline, imidazolidine, pyrazoles, pyrazoline, pyrazolidine, isothiazole oxadiazole, furazan, triazole, thiadiazoles, pyrans, pyridine and pyridine-N-oxide, piperidines, dioxane, morpholine, dithian, oxathiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, thiadiazine, dithiazine, azaindole, the azepine indoline, indoles, indoline, 1,5-naphthyridine Ben Bing oxadiazole, the dihydrobenzo dioxin, thionaphthene, diazosulfide, Imidazothiazole, 2,3-Dihydrobenzofuranes isoxazole, the 3-benzoisoxazole, 1, the 2-benzoisoxazole, the pyrazoline group, and be construed as all isomer that comprise above-mentioned group.For above-mentioned group, azelidinyl for example, term " azelidinyl " and " azetidin subunit " etc. are construed as and comprise all possible regional isomer.Should be appreciated that in addition the term heterocyclic radical can be specially a selection in the possible embodiment that provides, and be specially another (perhaps identical) selection for another variable for a variable, for example when selecting as heterocyclic radical, R
4Can be furans, R
dWhen selecting as heterocyclic radical (also be) can be the pyrroles.
In one embodiment, heterocyclic radical is by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
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, R wherein
aAnd R
bRepresent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or R
aAnd R
bRepresent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms.
In another embodiment of the invention, heterocyclic radical comprise comprise one, two or three are selected from the heteroatomic aromatic series 5-unit of nitrogen, oxygen and sulphur or 6-unit heterocycle; With condense in phenyl ring comprise one, two or three are selected from the heteroatomic aromatic series 5-unit of nitrogen, oxygen and sulphur or 6-unit heterocycle;
In alternative embodiment of the present invention, heterocyclic radical be condense in phenyl ring comprise one, two or three are selected from the heteroatomic non-aromatic 5-unit of nitrogen, oxygen and sulphur or 6-unit heterocycle.
In another embodiment of the invention, heterocyclic radical is selected from following group: furyl, pyrryl, thienyl, pyridyl, the N-pyridine oxide base, 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, benzo dioxane amyl group (for example 1,3-benzo dioxane amyl group) Ben Bing oxadiazole, dihydrobenzo two oxa-glutinous rehmannias, thionaphthene, diazosulfide, Imidazothiazole, 2,3-Dihydrobenzofuranes isoxazole, pyrazoline and benzo dioxane (for example 1,4-benzo dioxane).Value comprises for example furyl, pyrryl, thienyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, benzene and oxadiazole, dihydrobenzo two oxa-glutinous rehmannias, thionaphthene, diazosulfide, Imidazothiazole, 2 more specifically, 3-Dihydrobenzofuranes, isoxazole, 1,2-benzoisoxazole, pyrazoline and benzo dioxane (for example 1,4-benzo dioxane).
In yet another embodiment of the present invention, heterocyclic radical is to be selected from following group group: furyl, pyrryl, thienyl, pyridyl, N-pyridine oxide base, pyrazinyl, pyrimidyl, pyridazinyl, benzene and oxadiazole base, dihydrobenzo two oxa-glutinous rehmannias, thionaphthene, diazosulfide, Imidazothiazole, 2,3-Dihydrobenzofuranes, isoxazole, 1,2-benzoisoxazole or pyrazoline.
In one embodiment of the invention, R
1Expression R
6OC (O).
In another embodiment of the invention, R
1Expression R
16SC (O).
In another embodiment, R
1Expression group (gII):
In another embodiment of the invention, R
1Be selected from R
6OC (O) and R
16SC (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, and R wherein
16Be ethyl.
R
1Also can specifically represent with group gII:
R wherein
8Be selected from H, (C
1-C
6) alkyl, for example methyl or ethyl.
In radicals R
8Another embodiment in, this group is selected from hydrogen, methyl, ethyl, n-propyl and normal-butyl.
R
2Embodiment comprise for example H and (C
1-C
4) alkyl.R
2Other embodiment be methyl, ethyl, sec.-propyl, phenyl, methoxyl group or unsubstituted or randomly by methyl substituted amino.
R
3Embodiment for example comprise H, methyl, methylsulfinyl, hydroxymethyl, methoxyl group or unsubstituted or randomly by one or two methyl substituted amino.
R
3Other embodiment comprise H or unsubstituted or randomly by one or two methyl substituted amino.
R
4Embodiment comprise H, halogen (for example chlorine), methyl, cyano group, nitro, unsubstituted or randomly by one or two methyl substituted amino, and comprise 4-methoxyl group-4-oxo butoxy, 3-carboxyl-propoxy-and methyl carbonyl in addition.
In one embodiment of the invention, Z does not exist.
In another embodiment of the invention, Z represents O.
In one embodiment, R
5Expression hydrogen or methyl.In another embodiment, R
5Be hydrogen.
R
8Other embodiments comprise hydrogen, methyl and ethyl.
R
14Other embodiments comprise for example hydrogen, methyl, amino, tert-butoxycarbonyl, tert-butoxycarbonyl-imido grpup, 2-carboxy ethyl and 3-tert.-butoxy-3-oxo-propyl group.
R
14Other embodiment comprise for example hydrogen, methyl, tert-butoxycarbonyl-imido grpup and amino.
In one embodiment of the invention, R
15Expression H.
R
dOther embodiments comprise aryl or heterocyclic radical, more specifically, comprise aryl or aromatic heterocycle.
R
dAnother embodiment comprise aryl, phenyl and aromatic heterocycle thienyl for example for example.
R
dOther embodiment comprise phenyl, it can randomly be substituted.
In a specific embodiment, R
dExpression aryl, heterocyclic radical or (C
3-C
6) cycloalkyl, and in these groups any is randomly by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom or blended halogen atom and/or the following group
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
A (Rd)R
B (Rd)Group, R wherein
A (Rd)And R
B (Rd)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
dOther embodiments comprise randomly 2,3,4 or 5-position and the substituted phenyl of any combination thereof.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 position adjacent (for example 2,3) also can connect to form ring.This substituent example is the 2-naphthyl.Other more specifically value for heteroaryl is a 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 two oxa-s glutinous rehmannia-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
cRepresent unsubstituted mono-substituted or dibasic (C
1-C
4) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
1-C
4) alkyl, or R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms, and R
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
cRepresent unsubstituted mono-substituted or dibasic (C
1-C
3) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms, and R
dExpression aryl, i.e. R
cR
dExpression has above-mentioned any substituent aryl-(C
1-C
3) alkylidene group.
In another embodiment of the invention, R
cRepresent unsubstituted mono-substituted or dibasic (C
1-C
4) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
1-C
4) alkyl, perhaps R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms, and R
dExpression heterocyclic radical, i.e. R
cR
dExpression has above-mentioned any substituent heterocyclic radical-(C
1-C
4) alkylidene group.
In another preferred embodiment of the present invention, R
cRepresent unsubstituted mono-substituted or dibasic (C
1-C
3) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
1-C
4) alkyl or R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms, and R
dExpression heterocyclic radical, i.e. R
cR
dExpression has above-mentioned any substituent heterocyclic radical-(C
1-C
3) alkylidene group.
In particularly preferred embodiment of the present invention, R
cExpression C
1-alkylidene group, wherein any substituting group are separately respectively 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 respectively and independently of one another
1-C
4) alkyl or R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms, and R
dExpression aryl, i.e. R
cR
dExpression has above-mentioned any substituent aryl-C
1-alkylidene group.
In one embodiment of the invention, R
19Expression hydrogen.
In another embodiment of the invention, R
19The expression methyl.
In the most special embodiment of the present invention, R
cR
dExpression benzyl or according to the substituted benzyl described in the replacement of aryl.
In one embodiment of the invention, X represents singly-bound.
In another embodiment of the invention, X represents that imido grpup (NH-) or methylene radical (CH
2-).In another embodiment, X represents that imido grpup (NH-).In another embodiment, X represents methylene radical (CH
2-).
The fit value of B ring/member ring systems comprises for example inferior Diazesuberane base (diazepanylene), inferior piperazinyl (piperazinylene), piperidylidene (piperidinylene), pyrrolidinylidene (pyrrolidinylene) and inferior azelidinyl (azetidinylene), and wherein can their any isomeric forms there be (for example piperazine-tetrahydro pyridazine-tetrahydropyrimidine) in any in them.
The embodiment of B ring/member ring systems comprises for example inferior Diazesuberane base, inferior piperazinyl, piperidylidene, pyrrolidinylidene and inferior azelidinyl.Other embodiments comprise being had (C
1-C
6) R of alkyl
14These groups that replace, wherein (C
1-C
6) alkyl is randomly by OH, COOH or COOR
eGroup replaces, 2-carboxy ethyl for example, and R wherein
eExpression H, the aryl, cycloalkyl, heterocyclic radical or the (C that are randomly replaced by one or more halogens (F, Cl, Br, I) or blended halogen atom, OH, aryl, cycloalkyl and heterocyclic radical
1-C
12) alkyl.
In alternative embodiment of above-mentioned B ring/member ring systems, embodiment for example comprises being had (C
1-C
6) R of alkyl
14The inferior Diazesuberane base, inferior piperazinyl, piperidylidene, pyrrolidinylidene and inferior azelidinyl, the wherein (C that replace
1-C
6) alkyl is randomly by OH, COOH or COOR
eGroup replaces, 2-carboxy ethyl for example, and R wherein
eExpression H, the aryl, cycloalkyl, heterocyclic radical or the (C that are randomly replaced by one or more halogens (F, Cl, Br, I) or blended halogen atom, OH, aryl, cycloalkyl and heterocyclic radical
1-C
6) alkyl.
Second embodiment of formula I is defined as follows:
R
1Expression R
6OC (O), R
7C (O), R
16SC (O), R
17S, R
18C (S) or group gII:
R
2Expression H, CN, NO
2, randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; In addition, R
2(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
1-C
6) alkoxyl group; In addition, R
2Expression (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 (2)R
B (2)Group, R wherein
A (2)And R
B (2)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (2)And R
B (2)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
In addition, R
1+ R
2(with two carbon from pyridine ring) can form 5-unit or 6-unit annular lactone;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I) is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or the replacement of one or more halogen atom
1-C
6) alkyl; In addition, R
3(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
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, R wherein
A (3)And R
B (3)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or 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) is randomly by the oxygen interval and/or randomly by OH, COOH, (C
1-C
6) (the C that replaces of alkoxy carbonyl, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom
1-C
6) alkyl; 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 randomly by one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or (C
1-C
3) the alkoxy carbonyl replacement; 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, R wherein
A (4)And R
B (4)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or 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 randomly by oxygen at interval (condition be any this oxygen must be connected R
6Ester-the oxygen of group is at a distance of at least 1 carbon atom) and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
6) alkyl, aryl or heterocyclic radical;
R
7Expression is randomly by oxygen (C at interval and/or that randomly replaced by OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
6) alkyl; In addition, R
7Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, aryl or heterocyclic radical;
R
8Expression H is randomly by oxygen (C at interval and/or that randomly replaced by aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
6) alkyl; 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 (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; 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, 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 (14)R
B (14)Group, R wherein
A (14)And R
B (14)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O) or R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H, OH (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; 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, 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 (15)R
B (15)Group, R wherein
A (15)And R
B (15)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; 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
17Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; 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
18Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; 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
cRepresent unsubstituted or single the replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylene oxide group or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
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 imido grpup (NH-), the imido grpup (NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylene imine base or N-
1-C
4) alkylene imine base (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is not substituted or is replaced by above-mentioned any substituting group list or polysubstituted; Preferably, R
cExpression imido grpup or (C
1-C
4) alkylene imine base or unsubstituted or replaced or polysubstituted (C by above-mentioned any substituting group list
1-C
4) alkylidene group or (C
1-C
4) the oxo alkylidene group;
R
19Expression H or (C
1-C
4) alkyl;
R
dExpression (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, and in these groups any is randomly by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
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) alkyl, (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, R wherein
A (Rd)And R
B (Rd)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
X represents singly-bound, imido grpup (NH-), methylene radical (CH
2-), imido grpup methylene radical (CH
2-NH-) (wherein carbon is connected in B-ring/member ring systems), methylenimine base (NH-CH
2-) (wherein nitrogen is connected in B-ring/member ring systems), and any carbon in these groups and/or nitrogen can be randomly by (C
1-C
6) the alkyl replacement; In addition, X can represent group (CH
2-) n, n=2-6 wherein, it randomly is not substituted and/or by one or more halogen, hydroxyl or (C of being selected from
1-C
6) substituting group of alkyl replaces;
B is the 4-11 unit heterocycle/member ring systems of monocycle or dicyclo, comprises one or more nitrogen and optional one or more atoms that are selected from oxygen or sulphur, and nitrogen is connected in pyridine-ring (according to formula I) and in addition, and B-ring/member ring systems is connected in X with its another position.Substituent R
14And R
15Being connected in B ring/member ring systems makes (by these connections) not form quaternary ammonium compound.
The 3rd embodiment of formula I is defined as follows:
R
1Expression R
6OC (O), R
16SC (O) or group gII:
R
2Expression H, CN, NO
2, randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; In addition, R
2(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
1-C
6) alkoxyl group; In addition, R
2Expression (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) or formula NR
A (2)R
B (2)Group, R wherein
A (2)And R
B (2)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (2)And R
B (2)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I) is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or the replacement of one or more halogen atom
1-C
6) alkyl; In addition, R
3(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
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, R wherein
A (3)And R
B (3)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or 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) is randomly by the oxygen interval and/or randomly by the (C of OH, COOH, aryl, cycloalkyl, heterocyclic radical or the replacement of one or more halogen atom
1-C
6) alkyl; 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 randomly be replaced by 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, R wherein
A (4)And R
B (4)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or 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 randomly by oxygen at interval (condition be any this oxygen must be connected R
6Ester-the oxygen of group is at a distance of at least 1 carbon atom) and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
6) alkyl, aryl or heterocyclic radical;
R
8Expression H is randomly by oxygen (C at interval and/or that randomly replaced by aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
6) alkyl; 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 (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; 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, aryl, heterocyclic radical or formula NR
A (14)R
B (14)Group, R wherein
A (14)And R
B (14)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H, OH (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; 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, aryl, heterocyclic radical or formula NR
A (15)R
B (15)Group, R wherein
A (15)And R
B (15)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Be ethyl;
R
cRepresent unsubstituted or single the replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylene oxide group or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
1-C
4) alkyl, or R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms; In addition, R
cExpression imido grpup (NH-), the imido grpup (NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylene imine base or N-
1-C
4) alkylene imine base (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is not substituted or is replaced by above-mentioned any substituting group list or polysubstituted; Preferably, R
cExpression imido grpup or (C
1-C
4) alkylene imine base or unsubstituted or replaced or polysubstituted (C by above-mentioned any substituting group list
1-C
4) alkylidene group or (C
1-C
4) the oxo alkylidene group;
R
19Expression H or (C
1-C
4) alkyl;
R
dExpression (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, and in these groups any is randomly by one or more replacements: CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
2, (C
1-C
6) alkyl, (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) alkyl, (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, imido grpup (NH-), methylene radical (CH
2-), imido grpup methylene radical (CH
2-NH-) (wherein carbon is connected in B-ring/member ring systems), methylenimine base (NH-CH
2-) (wherein nitrogen is connected in B-ring/member ring systems), and any carbon in these groups and/or nitrogen can be randomly by (C
1-C
6) the alkyl replacement; In addition, X can represent group (CH
2-)
n, n=2-6 wherein, it randomly is not substituted and/or by one or more halogen, hydroxyl or (C of being selected from
1-C
6) substituting group of alkyl replaces;
B is the 4-11 unit heterocycle/member ring systems of monocycle or dicyclo, comprises one or more nitrogen and optional one or more atoms that are selected from oxygen or sulphur, this nitrogen be connected in pyridine-ring (according to formula I) and, in addition, B-ring/member ring systems is connected in X with its another position.Substituent R
14And R
15Being connected in B ring/member ring systems makes (by these connections) not form quaternary ammonium compound.
The 4th embodiment of formula I is defined as follows:
R
1Expression R
6OC (O), R
16SC (O) or group gII:
R
2Expression H or randomly at interval and/or (the C that is randomly replaced by OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom by oxygen
1-C
6) alkyl; In addition, R
2Expression NR
A (2)R
B (2)Group, R wherein
A (2)And R
B (2)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (2)And R
B (2)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
3Expression H or formula NR
A (3)R
B (3)Group, R wherein
A (3)And R
B (3)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (3)And R
B (3)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
4Expression CN, halogen (F, Cl, Br, I), in addition, R
4Expression (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxyl group, wherein this alkoxyl group can randomly be replaced by one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or methoxycarbonyl;
Z represents O or does not exist;
R
5Expression H;
R
6Expression randomly by oxygen at interval (condition be any this oxygen must be connected R
6Ester-the oxygen of group is at a distance of at least 2 carbon atoms) and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; In addition, R
6Expression (C
3-C
6) cycloalkyl or hydroxyl (C
2-C
12) alkyl;
R
8Expression H, randomly by oxygen (C at interval and/or that randomly replaced by aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
6) alkyl;
R
14Expression H, OH (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; In addition, R
14Expression NR
A (14)R
B (14)Group, R wherein
A (14)And R
B (14)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H;
R
16Be ethyl;
R
cRepresent unsubstituted or mono-substituted (C
1-C
4) alkylidene group, (C
1-C
4) alkylene oxide group or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately respectively and be independently selected from (C
1-C
4) alkyl; In addition, R
cExpression imido grpup (NH-), the imido grpup (NR of N-replacement
19-);
R
19Expression H or methyl;
R
dExpression (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, and in these groups any is randomly by one or more replacements: CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
2, (C
1-C
6) alkyl, (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) alkyl;
X represents that singly-bound, imido grpup are (NH-) or methylene radical (CH
2-); With
B is the 4-11 unit heterocycle/member ring systems of monocycle or dicyclo, comprises one or more nitrogen and optional one or more atoms that are selected from oxygen or sulphur, and this nitrogen is connected in pyridine-ring (according to formula I), and in addition, B-ring/member ring systems is connected in X with its another position.Substituent R
14And R
15Being connected in B ring/member ring systems makes (by these connections) not form quaternary ammonium compound.
The 5th embodiment of formula I is defined as follows:
R
1Be selected from following group: methoxycarbonyl, ethoxy carbonyl, (n-propyl)-oxygen base carbonyl, (sec.-propyl)-oxygen base carbonyl, (isobutyl-)-oxygen base carbonyl, (tertiary butyl)-oxygen base carbonyl, (2,2-dimethyl-propyl group)-oxygen base carbonyl, (cyclopropyl)-oxygen base carbonyl, (cyclobutyl)-oxygen base carbonyl, (cyclopentyl)-oxygen base carbonyl, (2-hydroxyethyl)-oxygen base carbonyl), (2,2, the 2-trifluoroethyl)-and oxygen base carbonyl, benzyl-oxygen base carbonyl, 4-luorobenzyl-oxygen base carbonyl, ethylmercapto group carbonyl and 5-ethyl-1,3-oxazole-2-base;
R
2Be selected from following group: H, methyl, ethyl, sec.-propyl and dimethylamino;
R
3Be selected from following group: H and amino;
R
4Be selected from following group: methoxyl group, chlorine, cyano group, (4-methoxyl group-4-oxo butoxy), (3-carboxyl-propoxy-) and methyl carbonyl;
Z represents O or does not exist;
R
5Be H;
R
6Be selected from following group: methyl, ethyl, 2-hydroxyethyl, (2,2, the 2-trifluoroethyl), n-propyl, sec.-propyl, cyclopropyl, isobutyl-, the tertiary butyl, cyclobutyl, 2,2-dimethyl propyl, cyclopentyl, benzyl and 4-luorobenzyl;
R
8Be ethyl;
R
14Be selected from following group: H, methyl, tert-butoxycarbonyl-imido grpup and amino;
R
15Be H;
R
16Be ethyl;
R
cBe selected from following group: methylene radical (CH
2-), methyl methylene radical (CH (CH
3)-), ethylidene (CH
2CH
2-), oxygen base propylidene (OCH
2CH
2CH
2-), imido grpup (NH-) and methylene imine base (N (CH
3)-);
R
19Be selected from following group: H and methyl;
R
dBe selected from following group: cyclopentyl, cyclohexyl, the 4-methylcyclohexyl, phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, the 4-ethylphenyl, 2-methoxycarbonyl-phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-(trifluoromethyl) phenyl, the 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, the 2-chloro-phenyl-, the 3-chloro-phenyl-, the 4-chloro-phenyl-, the 3-bromophenyl, the 4-cyano-phenyl, the 4-p-methoxy-phenyl, the 2-nitrophenyl, the 3-nitrophenyl, the 4-nitrophenyl, 3, the 4-dichlorophenyl, 3, the 5-dichlorophenyl, 3, the 4-difluorophenyl, 2, the 5-3,5-dimethylphenyl, 3, the 5-3,5-dimethylphenyl, the 4-isopropyl phenyl, 3-fluoro-4-methyl-phenyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, N-oxidation-2-pyridyl, 6-[3-benzo [d] isoxazole-3-base] and N-[(1,2-benzoisoxazole-3-yl)];
X represents that singly-bound, imido grpup are (NH-) or methylene radical (CH
2-);
B is selected from following group: 4-piperazine-1-subunit, 4-piperidines-1-subunit, 3-piperidines-1-subunit, 3-azetidine-1-subunit, and substituent R
14And R
15Be connected in B ring/member ring systems, make (by these connections) not form quaternary ammonium compound.
In the 6th embodiment of formula (I), formula (I) is defined as any compound of formula (Ia)-(Ii):
In Ig, the various values of Z and R are (except R at above-mentioned Ia
5Outside H) as defined above, and comprise aforementioned embodiment.
In the 7th embodiment, formula (I) is defined as any compound of formula (Iaa)-(Ijj):
In Ijj, the various values of Z and R are (except R at above-mentioned Iaa
5, R
14And R
15Outside, all be H) as defined above, and comprise aforementioned embodiment.
Example according to particular compound of the present invention can be selected from following:
5-cyano group-6-[3-(2-methoxycarbonyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
6-[3-({ [(3-bromobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(2-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
6-[3-(2-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
6-[3-(4-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(4-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-6-[3-(3-fluoro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(3-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
6-[3-(3-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
6-{3-[2-(3-chloro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-5-cyano group-2-methyl-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(4-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(2-phenyl-ethylsulfonylamino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-(3-o-tolyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(3-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-6-{3-[2-(4-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(2-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-6-[3-(4-fluoro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-(3-cyclopentyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-{3-[2-(2-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-[3-(3,5-two chloro-phenyl methanesulfonamide acyl amino carbonyls)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-(3-cyclohexyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-{3-[2-(3-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
6-[3-(benzo [d] isoxazole-3-base methylsulfonyl aminocarboxyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl]-N-(benzyl alkylsulfonyl) piperidines-4-methane amide
4-amino-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chlorine apellagrin (nicoticacid) ethyl ester
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid tertiary butyl ester
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl }-4-methyl piperidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
N-(benzyl alkylsulfonyl)-1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-methane amide
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopentyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid propyl diester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
N-(benzyl alkylsulfonyl)-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
N-[(1,2-benzoisoxazole-3-ylmethyl) alkylsulfonyl]-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
N-(benzyl alkylsulfonyl)-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] azetidine-3-methane amide
N-[(4-benzyl chloride base) alkylsulfonyl]-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester
5-cyano group-6-{3-[({[3-(4-methoxyl group phenoxy group) propyl group] alkylsulfonyl } amino) carbonyl] azetidine-1-yl }-2-methylnicotinic acid ethyl ester
4-amino-6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chlorine apellagrin ethyl ester
5-cyano group-2-methyl-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
5-cyano group-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
6-[4-({ [(3-bromobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclobutyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2-hydroxyethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester
5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-({ [(1-phenylethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid propyl diester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isobutyl
5-cyano group-2-methyl-6-{4-[({[4-(trifluoromethyl) benzyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid isopropyl esters
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid isopropyl esters
5-cyano group-2-methyl-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid isopropyl esters
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-{4-[({[2-(methoxycarbonyl) benzyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl }-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-{4-[({[2-(2-aminomethyl phenyl) ethyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid isopropyl esters
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
4-{[2-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(ethoxy carbonyl)-6-picoline-3-yl] the oxygen base } butyric acid
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
6-(4-{[(Phenylsulfamoyl base) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-{4-[({[methyl (phenyl) amino] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-2-methyl-6-[3-({ [(2-phenylethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-{3-[({[2-(methoxycarbonyl) benzyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl }-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid methyl ester
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid methyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] pyridine-3-carbothioic acid carbothiolic acid S-ethyl ester
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-methoxyl group-2-methylnicotinic acid ethyl ester
6-[4-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperazine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
4-{[2-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(ethoxy carbonyl)-6-picoline-3-yl] the oxygen base } butyric acid
5-cyano group-2-methyl-6-{3-[({[(1-pyridine oxide-2-yl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-({ [(pyridin-3-yl methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-{4-[({[(1-pyridine oxide-2-yl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(pyridin-3-yl methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(pyridin-4-yl methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-({ [(pyridine-2-ylmethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(3, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[4-({ [(2, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester
5-cyano group-2-methyl-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(2-phenylethyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(pyridine-2-ylmethyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(2, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[3-(2-{[(4-luorobenzyl) alkylsulfonyl] amino }-the 2-oxoethyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3-fluoro-4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 4-luorobenzyl ester
5-cyano group-6-[4-({ [(4-Ethylbenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[3-({ [(3, the 4-difluorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-methoxy-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-Ethylbenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-chloro-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3, the 4-difluorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-methoxy-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] nicotinic acid cyclopropyl ester
5-cyano group-2-methyl-6-[3-({ [(pyridin-4-yl methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester 1-oxide compound
5-ethanoyl-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-2-methylnicotinic acid ethyl ester
6-{4-{[(benzyl alkylsulfonyl) amino] carbonyl }-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-yl }-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-amino-4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-{3-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-{3-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-{3-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-(3-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl) the nicotinic acid ethyl ester
6-(3-{[(butyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-{4-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-{4-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
5-cyano group-2-(difluoromethyl)-6-(4-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl) the nicotinic acid ethyl ester
6-(4-{[(butyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-(2-oxo-2-{[(2-phenylethyl) alkylsulfonyl] amino } ethyl) tetramethyleneimine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[3-(2-{[(5-chloro-2-thienyl) alkylsulfonyl] amino }-the 2-oxoethyl) tetramethyleneimine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[3-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
6-[4-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-2-(methyl fluoride)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-(methyl fluoride)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-2-(methyl fluoride)-6-{3-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-2-(methyl fluoride)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-(methyl fluoride)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
5-cyano group-2-(methyl fluoride)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester;
And pharmacologically acceptable salt.
Method
Provide following method and intermediate as additional features of the present invention.
The a1-a8 preparation by the following method of the compound of formula (I):
A1) compound of formula (I), wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z, R
cAnd R
dAs above definition, X is singly-bound or carbon, but the compound of through type (II), wherein R
1, R
2, R
3, R
4, B, Z, R
14And R
15As above definition,
X is singly-bound or carbon, with the compound reaction formation of formula (III), wherein R
5, R
cAnd R
dAs above definition.
R
5-NHSO
2-R
c-R
d (III)
This reaction is for example carried out in envrionment temperature in the methylene dichloride in organic solvent inert usually.Reaction can be used standard conditions or carry out in the presence of the combination of TBTU, EDCI or EDCI and HOBT.Randomly, reaction can organic bases for example triethylamine or DIPEA in the presence of carry out.
A2) compound of formula (I), wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z, R
cAnd R
dAs above definition, X is nitrogen or is connected in singly-bound as the nitrogen of B ring members, but the compound of through type (IV), wherein R
1, R
2, R
3, R
4, R
14And R
15As above definition and X are nitrogen or hydrogen,
Form with the compound reaction of general formula as defined above (III).
This reaction is for example carried out among the DCM at inert solvent usually.Reaction can be carried out in the presence of CDI.Randomly, reaction can organic bases for example triethylamine or DIPEA in the presence of carry out.
A3) compound of formula (I), wherein R
1, R
2, R
3, R
4, B, R
14, R
15, Z, R
cAnd R
dAs above definition, R
5Be hydrogen, X is nitrogen or is connected in singly-bound as the nitrogen of B ring members, can be by at above-mentioned a2) in the compound of compound and formula V of formula (IV) of definition react formation,
O＝C＝N-SO
2-R
cR
d (V)
R wherein
cAnd R
dAs above-mentioned definition.
This reaction is for example carried out among the THF at inert solvent usually.Randomly, reaction can organic bases for example triethylamine or DIPEA in the presence of carry out.
A4) compound of formula (I), wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z, R
cAnd R
dAs above definition, X is nitrogen or is connected in singly-bound as the nitrogen of B ring members, the compound of formula (IV) that can be by above-mentioned definition, with the compound reaction formation of formula (VI),
R
dR
c-SO
2NR
5-COOCH
2CCl
3 (VI)
R wherein
5, R
cAnd R
dAs above definition.This reaction is for example carried out among the DMA at solvent usually.Randomly, reaction can organic bases for example triethylamine or DIPEA in the presence of carry out.
A5) formula (I) but the compound also compound of through type (VII), wherein R
1, R
2, R
3, R
4With Z as above define with L be suitable leavings group, for example chlorine, bromine, iodine, fluorine, trifluoromethane sulfonic acid ester (triflate) or tosyl group,
With the compound prepared in reaction of general formula (VIII), wherein B, R
5, R
14, R
15, R
cAnd R
dSuc as formula definition in (I).
This reaction is for example carried out among the DMA at inert solvent usually.Randomly, reaction can organic bases for example triethylamine or DIPEA in the presence of carry out.
This reaction is carried out at high temperature usually, uses standard equipment or carries out in single node microwave oven.
Usually, at R
5During for H, use the zwitter-ion of (VIII) to cause comparing the shorter reaction times with the corresponding salt (for example HCl salt) that uses the B-cyclammonium.
For some compound, advantageously organic bases for example triethylamine in the presence of in ethanol, carry out this reaction.
A6) compound of formula (I), wherein R
1Expression R
6OC (O) and R
2, R
3, R
4, B, R
5, R
14, R
15, X, Z, R
cAnd R
dSuc as formula definition in (I), can use standard method or by with R
6 '-O
-Li
+Reagent react carries out transesterify, becomes the compound of another general formula (I), wherein R
1Become R
6 'OC (O).
A7) compound of formula (I), wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z and R
dAs above define and R
cThe expression imido grpup (NH-) or (C
1-C
4) the alkyl imido grpup, wherein this imido grpup can use standard conditions or use alkylating reagent such as L-R
19Replace, wherein R
19As above definition and L are the leavings group of chlorine, bromine, iodine, trifluoromethane sulfonic acid ester or tosyl group for example, obtain the compound of formula (I), wherein R
1, R
2, R
3, R
4, B, R
5, R
14, R
15, Z and R
dAs above define and R
cImido grpup (the NR that expression N-replaces
19-) or (C that replaces of N-
1-C
4) alkyl imido grpup (N (R
19)-((C
1-C
4) alkyl), randomly highly basic for example NaH in the presence of carry out.
A8) compound of some formula (I), wherein R
2, R
3, R
4, B, R
14, R
15, R
cAnd R
dAs above definition, R
1Be R
6OC (O), wherein R
6As above definition, X is a singly-bound, Z does not exist and R
5Be hydrogen, advantageously by following steps (a8:1-a8:5) preparation;
A8:1) make formula R
1CH
2C (O) R
2Compound and dimethoxy-N, N-dimethyl methylamine reaction is to form the compound of following formula
A8:2) then, this compound and general formula R
4CH
2C (O) NH
2Compound reaction, R wherein
4Suc as formula what define in (I), obtain the compound of following general formula
R wherein
2, R
3, R
4Suc as formula what define in (I), R
1Be R
6OC (O), wherein R
6As above definition and Z do not exist.This reaction is for example carried out in the ethanol at inert solvent usually.This is reflected at highly basic and for example carries out under the existence of sodium ethylate.In addition, by with alkaline aqueous solution for example sodium hydrogen carbonate solution washing final product advantageously carry out this method.
A8:3) make from a8:2) compound and chlorination reagent for example thionyl chloride react, obtain the compound of formula (VII), wherein L is a chlorine.Further improvement to this reaction is to add dimethyl formamide.Advantageously, this reaction is for example carried out in the toluene at inert solvent usually.
A8:4) compound of general formula (VIII), wherein B, R
14, R
15, R
cAnd R
dAs above definition, X is singly-bound and R
5Be hydrogen, the compound reaction of the compound of through type (X) and formula (III) forms, and it is protected wherein to encircle nitrogen, for example protects by tertbutyloxycarbonyl.This reaction is for example carried out among the THF at inert organic solvents usually.Reaction use coupling reagent for example TBTU carries out.Randomly, this reaction can organic bases for example triethylamine or DIPEA in the presence of carry out.Further improvement to this reaction is to add LiCl.When product comprised tertbutyloxycarbonyl, this group used standard method or removes in the presence of formic acid.In an advantageous embodiment of method (a8), to about 5-9 product is separated as zwitter-ion by pH with water-soluble ammonia conditioned reaction mixture.
A8:5) product that derives from a8:3 reacts with the preferred zwitter-ion of the product that derives from a8:4, obtains the compound of formula (I), wherein R
2, R
3, R
4, B, R
14, R
15, R
cAnd R
dAs above definition, R
1Be R
6OC (O), wherein R
6As above definition, X is a singly-bound, Z does not exist and R
5Be hydrogen.Reaction is for example carried out at high temperature in the ethanol at inert solvent usually.Randomly, this reaction can organic bases for example triethylamine in the presence of carry out.In an advantageous embodiment of method (a8), by from the re-crystallizing in ethyl acetate purifying with separate final product.
Therefore, in one embodiment of the invention, provide the favorable method of the compound of production formula (I), wherein R
2, R
3, R
4, R
6, B, R
14, R
15, R
cAnd R
dAs above definition, R
1Be R
6OC (O), wherein R
6As above definition, X is a singly-bound, Z does not exist and R
5Be hydrogen, it is characterized in that this method may further comprise the steps (i-vi):
I.) make formula R
1CH
2C (O) R
2Compound and dimethoxy-N, N-dimethyl methylamine reaction is to form the compound of following formula
Ii) make from step I .) compound and general formula R
4CH
2C (O) NH
2Compound inert solvent for example in the ethanol highly basic for example sodium ethylate in the presence of react, obtain the compound of following general formula
R wherein
2, R
3, R
4As above definition, R
1Be R
6OC (O), wherein R
6As above definition and Z do not exist.
Iii) will derive from step I i) product at first with for example sodium hydrogen carbonate solution washing of alkaline aqueous solution, wash with water then, collect washed product subsequently.
Iv.) derive from step I ii) compound and chlorination reagent for example thionyl chloride in inert solvent, react, obtain the compound of formula (VII), wherein L is a chlorine.
V.) compound that makes the compound of formula (X) and formula (III) in inert organic solvents coupling reagent and optional organic bases for example triethylamine or DIPEA in the presence of react wherein B, R
14, R
15, R
cAnd R
dAs above definition, X is singly-bound and R
5Be hydrogen, under the compound of formula (III) has situation by the ring nitrogen of tertbutyloxycarbonyl protection, after the tertbutyloxycarbonyl deprotection of standard, obtain the compound of general formula (VIII).
Vi) derive from step v.) product with derive from step I v.) product in inert solvent, randomly organic bases for example triethylamine in the presence of react, obtain the compound of formula (I), wherein R
2, R
3, R
4, B, R
14, R
15, R
cAnd R
dAs above definition, R
1Be R
6OC (O) and R
6As above definition, X is a singly-bound, Z does not exist and R
5Be hydrogen.
In the independent embodiment of this method, step I v.) comprises and in reaction mixture, add dimethyl formamide.
In another independent embodiment of this favorable method, method steps iv.) comprise in reaction mixture, add dimethyl formamide and step I v.) in inert solvent be toluene.
In another independent embodiment of this favorable method, might with one or more preceding method embodiments with select step v.) inert organic solvents be the THF associating.
In another independent embodiment of this method, might with one or more preceding method embodiments with select step v.) in coupling reagent be the TBTU associating.
In another independent embodiment of this favorable method, might with one or more preceding method embodiments with to step v.) reaction mixture in add the LiCl associating.
In another independent embodiment of this favorable method, one or more preceding method embodiments and the ammonia that is dissolved in water by adding might be separated in step v.) in the product associating that obtains.
In another independent embodiment of this favorable method, might with aforementioned any preceding method embodiment with by deriving from step product associating vi) with separating from the re-crystallizing in ethyl acetate purifying.
The above-mentioned intermediate of mentioning can be by for example method/prepared of the following stated.
B) compound of formula (II), wherein R
1, R
2, R
3, R
4, B, Z, R
14And R
15As above definition, X is singly-bound or carbon, can be prepared as follows: the compound that makes formula (IX)
R wherein
1, R
2, R
3, R
4With definition and L in Z such as the above-mentioned formula (I) be suitable leavings group (for example fluorine, chlorine, bromine, iodine, trifluoromethane sulfonic acid ester or tosyl group) and the compound of general formula (X) reacts,
Wherein B, R
14, R
15As above definition and X are singly-bound or carbon.
This reaction is carried out at high temperature usually, uses standard equipment or carries out in single node microwave oven.This reaction can for example ethanol, DMA or solvent mixture for example carry out in the alcohol-water at inert solvent.Randomly, this reaction can organic bases for example TEA or DIPEA in the presence of carry out.
C) compound of formula (IV) can be prepared as follows as defined above: make compound and the compound reaction of formula (XI), wherein B, the R of corresponding formula (IX) as defined above
14, R
15As above definition, X is nitrogen or is connected in singly-bound as the nitrogen of B ring members.
This reaction is carried out at high temperature usually, uses standard equipment or carries out in single node microwave oven.This reaction can for example ethanol, DMA or solvent mixture for example carry out in the alcohol-water at inert solvent.Randomly, this reaction can organic bases for example TEA or DIPEA in the presence of carry out.
D) compound of general formula (XXX)
R wherein
2, R
3, R
4, B, R
8, R
14And R
15As above definition and X are carbon or single bonded synthetic may further comprise the steps (d1-d5):
D1) make the compound of the compound of general formula (X) and general formula (XXI) reaction accordingly as defined above
R wherein
2, R
3And R
4Suc as formula defining among the I and L is suitable leavings group, for example chlorine, bromine, iodine, trifluoromethane sulfonic acid ester or tosyl group obtain the compound of formula (XXII).
This is reflected at high temperature and carries out, and uses standard equipment or single node microwave oven to carry out.Randomly, this reaction can organic bases for example TEA or DIPEA in the presence of carry out.
D2) then, the compound of formula (XXII) can
Compound reaction with general formula (XXIII)
R wherein
10As above define, obtain the compound of general formula (XXIV).This reaction is used under standard conditions or is carried out in the presence of the combination of EDCI or EDCI and HOBT.Randomly, this reaction can organic bases for example TEA or DIPEA in the presence of carry out.
D3) this compound (XXIV) can be converted into the compound of general formula (XX) then.
D4) preparation of the compound of general formula (XX)
R wherein
2, R
3, R
4, B, R
10, R
14And R
15As above definition and X are carbon or singly-bound, use for example methylsulfonyl chloride of currently known methods or known reagent.Randomly, this reaction can organic bases for example TEA in the presence of carry out.
D5) can by use known oxidising agent for example DDQ the compound oxidation of corresponding general formula (XX) is carried out R wherein
10For with R
8Related identical substituting group.
E) preparation of the compound of general formula (XXX) further comprising the steps of (e1-e4):
E1) make the compound of general formula (XXXI)
R wherein
2, R
3And R
4As the definition of above-mentioned compound (I), with the compound reaction of general formula (XXXII),
R wherein
8As above definition,
Use standard conditions or in the presence of the combination of EDCI or EDCI and HOBT, carry out.Randomly, this reaction can organic bases for example TEA in the presence of carry out.This reaction obtains the compound of general formula (XXXIII).
E2) then, the compound of the general formula that obtains (XXXIII)
Can be converted into the compound of general formula (XXXIV), wherein R
2, R
3, R
4And R
8As above definition is used known technology or is used for example POCl of known reagent
3Carry out.
E3) then, the compound of general formula (XXXIV) can be converted into the compound of general formula (XXXV),
R wherein
2, R
3, R
4, R
8As above definition and L are sufficient leavings group, for example chlorine, bromine, iodine, trifluoromethane sulfonic acid ester or tosyl group, and for example oxalyl chloride or thionyl chloride are carried out to use known technology or reagent.
E4) then, the compound of formula (XXXV) can with the compound reaction of general formula (X) as defined above, obtain the compound of general formula (XXX) as defined above.This is reflected at high temperature and carries out, and uses standard equipment or single node microwave oven to carry out.Randomly, this reaction can organic bases for example TEA or DIPEA in the presence of carry out.
F) preparation of the compound of general formula (XXXVI)
R wherein
2, R
3, R
4, B, R
10, R
14And R
15As above definition, X are nitrogen or are connected in singly-bound as the nitrogen of B ring members, may further comprise the steps (f1-f4):
F1) make the compound and the compound reaction of general formula (XXI) as defined above of general formula (XI) as defined above, obtain the compound of general formula (XXVIII).
This is reflected at high temperature and carries out, and uses standard equipment or single node microwave oven to carry out.Randomly, this reaction can organic bases for example TEA or DIPEA in the presence of carry out.
F2) compound of formula (XXVIII) can with the compound reaction of formula (XXIII) as defined above, obtain the compound of general formula (XXIX).This reaction is used standard conditions or is carried out in the presence of the combination of EDCI or EDCI and HOBT.Randomly, this reaction can organic bases for example TEA or DIPEA in the presence of carry out.
F3) then, this compound can be converted into the compound of general formula (XXVI), wherein R
2, R
3, R
4, B, R
10, R
14And R
15As above definition,
X is nitrogen or is connected in hydrogen as the nitrogen of B ring members, use currently known methods or fully (sufficent) reagent for example methylsulfonyl chloride carry out.Randomly, this reaction can organic bases for example TEA in the presence of carry out.
F4) then, (XXXVI) can be by the compound oxidation preparation of general formula (XXVI) as defined above.This reaction can use standard conditions or reagent such as DDQ to carry out.
The compound of general formula (II), wherein R
1Be R
7C (O), R
2, R
3, R
4, B, R
14And R
15As above definition, X is a singly-bound, may further comprise the steps (g1-g2):
G1) make the compound and the N of general formula (XXII) as defined above, the reaction of O-dimethyl hydroxyl amine.This reaction can use known reagent such as CDI to carry out, and obtains the compound of general formula (XXXVIII).
G2) make the compound and the general formula R of general formula (XXXVIII) as defined above
7The reagent react of-MgX, wherein R
7As above the definition and X be halogen, or with formula R
7The reagent react of-M, wherein M is a metal, for example Zn and Li.
The compound of general formula (IV), wherein R
1Be R
7C (O), R
2, R
3, R
4, B, R
14And R
15As above definition, X is nitrogen or is connected in singly-bound as the nitrogen of B ring members, may further comprise the steps (h1-h2).
H1) make the compound and the N of general formula (XXVIII) as defined above, the reaction of O-dimethyl hydroxyl amine.This reaction can use known reagent such as CDI to carry out, and obtains the compound of general formula (XLI).
H2) as defined above the compound of general formula (XLI) can with general formula R
7The reagent react of-MgX, wherein R
7As above the definition and X be halogen, or with formula R
7The reagent react of-M, wherein M is a metal, for example Zn and Li.
The compound of general formula (VIII) can form in one of method (i1-i5).The compound of formula (VIII), wherein R
5Be hydrogen, advantageously separate as zwitter-ion.The ring nitrogen that is used for the formula (X) of following steps and compound (XI) can be by for example tertbutyloxycarbonyl protection of blocking group.
I1) compound of general formula (VIII), wherein B, R
5, R
14, R
15, R
cAnd R
dAs above definition, X is singly-bound or carbon, the compound that can be by making formula (X) and the compound reaction formation of formula (III).This reaction usually in organic solvent inert for example in the methylene dichloride, carry out in envrionment temperature.This reaction can be used standard conditions or carry out in the presence of the combination of EDCI or EDCI and HOBT.Randomly, this reaction can organic bases for example triethylamine or DIPEA in the presence of carry out.
I2) compound of general formula (VIII), wherein B, R
5, R
14, R
15, R
cAnd R
dAs above definition, X is singly-bound or carbon, the compound that also can be by making formula (X) and the compound reaction formation of formula (III), its B-nuclear nitrogen is protected, is for example protected by tertbutyloxycarbonyl.This reaction is for example carried out among the THF at inert organic solvents usually.This reaction can be used standard conditions or carry out in the presence of TBTU.Randomly, this reaction can organic bases for example triethylamine or DIPEA in the presence of carry out.Advantageously, can use for example LiCl of reagent.When product comprises tertbutyloxycarbonyl, use standard method or in the presence of formic acid, be removed.Work as R
5During for hydrogen, compound (VIII) can be used as zwitter-ion to be separated.
I3) compound of general formula (VIII), wherein R
5Be hydrogen, B, R
14, R
15, R
cAnd R
dAs above definition, X is nitrogen or is connected in singly-bound as the nitrogen of B ring members, can form by the compound of formula (XI) as defined above and the compound reaction of formula V as defined above.This reaction is for example carried out among the THF at inert solvent usually.Randomly, this reaction also can organic bases for example triethylamine or DIPEA in the presence of carry out.
I4) compound of general formula (VIII), wherein B, R
5, R
14, R
15, R
cAnd R
dAs above definition, X is nitrogen or is connected in singly-bound as the nitrogen of B ring members, compound that also can be by making formula (XI) forms with the compound reaction of formula (VI) as defined above.This reaction is for example carried out among the DMA at solvent usually.This reaction also can organic bases for example triethylamine or DIPEA in the presence of carry out.
I5) with the compound of the formula (VIII) of tertbutyloxycarbonyl protection can use standard method or reagent for example formic acid be converted into the compound of unprotect group.
(j) compound of general formula (VII) can form by the compound reaction that makes formula (XLVI) as defined above, uses standard conditions or uses chlorination reagent for example thionyl chloride or POCl
3Carry out.Advantageously, can use dimethyl formamide.This reaction can be carried out in inert solvent.Advantageously, inert solvent is a toluene.
The preparation of the compound of general formula (XLVII) may further comprise the steps (k1-k3) as defined above:
K1) make the compound of general formula (XLVIII)
(it has R with the compound of general formula (XXIII)
8Replace R
10, other as above defines) react, obtain the compound of formula (IL).This reaction is carried out in envrionment temperature in DCM usually.This reaction can be used standard conditions or carry out in the presence of the combination of EDCI or EDCI and HOBT.Randomly, this reaction can organic bases for example TEA or DIPEA in the presence of carry out.
K2) can use standard conditions or oxygenant for example the mixture of oxalyl chloride and DMSO make the compound of formula (IL) be converted into compound (L):
K3) then, can use standard conditions or in the presence of (methoxycarbonyl amino-sulfonyl) triethyl ammonium hydroxide (Burgess reagent), the compound of formula (L) is converted into the compound of general formula (XLVII).This reaction is for example carried out among the THF at inert solvent usually.This is reflected at high temperature and carries out, and uses standard equipment or single node microwave oven to carry out.
The compound of general formula (III) can use known method to make corresponding SULPHURYL CHLORIDE and ammonia for example react formation in the methyl alcohol at inert solvent.
L) prepare the compound of general formula (XLVIII) as defined above, difference is R
3Be hydrogen, may further comprise the steps (l
1-l
3):
L1) make the compound of formula (LI), wherein R
2And R
6Suc as formula what define in (I), with dimethoxy-N, the reaction of N-dimethyl methylamine is to form
The compound of formula (LII).
L2) then, this compound (LII) can be further and general formula R
4CH
2C (O) NH
2Compound reaction,
R wherein
4Suc as formula what define in (I), obtain the compound of general formula (LIII).This reaction is for example carried out in the ethanol at inert solvent usually, randomly highly basic for example sodium ethylate in the presence of carry out.
(l3) then, the compound of general formula (LIII) can be converted into the compound of general formula (XLVIII).This reaction usually protonic solvent for example water for example carry out in THF or the methyl alcohol together with cosolvent.This reaction can be used standard reagent or carry out in the presence of LiOH, NaOH or KOH.
(m) formation of the compound of general formula (XXX) can followingly be synthesized as defined above:
M1) compound of general formula (LIV), wherein R
8As definition in the above-mentioned formula (I),
Can be converted into the compound of formula (LV),
Use standard conditions or use Cu (II) O and quinoline to carry out.
M2) compound of general formula (LV) can react with the compound of general formula (LVI),
R wherein
2, R
3, R
4, B, R
14And R
15Suc as formula definition in (I) with X be carbon or singly-bound, obtain the compound of general formula (XXX).This reaction is for example carried out under inert atmosphere among the THF at inert solvent usually.This reaction can be used standard conditions or at lithium alkylide for example BuLi, ZnCl
2, Pd (Ph
3)
4Existence under carry out.
(n) compound of general formula (XXXVI) also can prepare by following steps:
N1) make compound and the compound reaction of general formula (LVII), the wherein R of general formula (LV) as defined above
2, R
3, R
4, B, R
14And R
15As definition in the above-mentioned formula (I), X is nitrogen or is connected in singly-bound as the nitrogen of B ring members.
O) preparation of the compound of general formula (LVIII) may further comprise the steps, wherein R
14And R
15As above-mentioned formula (I) definition, difference is R
14Be connected in same atom with X, and X is defined as singly-bound:
O1) make corresponding (LIX) and R
14-L reaction, wherein L is suitable leavings group, for example chlorine, bromine, iodine, trifluoromethane sulfonic acid ester or tosyl group,
To form the compound of general formula (LVIII), use standard conditions or in the presence of BuLi and di-isopropyl amine mixt, carry out.
The preparation of the compound of formula (III) comprises following method (p1-p3):
P1) formula LR
cR
dCompound, wherein L is suitable leavings group, for example chlorine, bromine, iodine can use following reaction sequence to be converted into corresponding compounds (III): at first to use SMOPS* (* Baskin and Wang.Tetrahedron Letters, 2002,43,8479-83.Especially referring to the 8480th page of left hand row), use alkali such as NaOMe hydrolysis at room temperature in inert solvent such as DMSO subsequently.Use NH subsequently
2OSO
3H and NaOAc handle, and obtain the compound of formula (III).
P2) formula LSO
2R
cR
dCompound, wherein L is suitable leavings group, for example chlorine, bromine, iodine, can with ammonium hydroxide or H
2NR
5For example react among the DCM at inert solvent, obtain the compound of formula (III).
P3) formula LR
cR
dCompound, wherein L is suitable leavings group, for example chlorine, bromine, iodine can use following reaction sequence to be converted into corresponding compounds (III): at first to use NaSO
3, use for example PCl of reagent subsequently
5, POCl
3Or SOCl
2, use ammonium hydroxide or H subsequently
2NR
5, obtain the compound of formula (III).
In any step of the pyridines of synthesizing the amine replacement, can use known technology that 2,4 or 6 chlorine substituent of pyridine is replaced with trinitride.Trinitride can be reduced to corresponding amine.These amine can use known method subsequently or carry out alkylation or acylations with alkyl halide or carboxylic acid halides respectively.
It should be appreciated by those skilled in the art that acid can be converted into for example acyl chlorides of corresponding Acibenzolar, subsequently with mercaptan R
16The SH reaction obtains thioesters R
16SC (O).
It should be appreciated by those skilled in the art that acid can be converted into for example acyl chlorides of corresponding Acibenzolar, subsequently with pure R
6The OH reaction obtains ester R
6OC (O).
The compound that it should be appreciated by those skilled in the art that formula (III) can use the alpha-position carbon atom alkylization of alkylogen at sulphonamide.Preferably, use highly basic for example sodium hydride under alkaline condition.
It should be appreciated by those skilled in the art that and to use known technology or R
17SSR
17With tertiary butyl nitrile, with thioether chain R
17S-replaces 3 nitrogen substituting group of pyridine.
It should be appreciated by those skilled in the art that and to use known technology or use Lawessons reagent to produce thioketones from corresponding ketone.
It should be appreciated by those skilled in the art that can by use oxygenant for example hydroperoxidation urea or hydrogen peroxide, be with or without trifluoroacetic anhydride in the presence of form pyridine N-oxides from pyridine.
Can use routine techniques that the reaction mixture of compound of the present invention from them separated.
Those skilled in the art should understand that, for with alternative mode and some the time obtain compound of the present invention in mode more easily, above mentioned various method steps can be different order carry out, and/or each reaction can be carried out (that is, can to carrying out chemical conversion with above-mentioned those different intermediates relevant with concrete reaction) in whole different stepss of routes.
It should be appreciated by those skilled in the art that in above-mentioned and following method, the functional group of midbody compound may need to protect with blocking group.
The functional group that needs protection comprises hydroxyl, amino and carboxylic acid.The suitable blocking group that is used for hydroxyl comprises randomly substituted 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 suitable blocking group that is used for carboxylic acid comprises (C
1-C
6) alkyl or benzyl ester.Be used for amino suitable blocking group and comprise tertbutyloxycarbonyl, benzyloxycarbonyl, 2-(trimethyl silyl) ethoxyl methyl or 2-trimethylsilylethoxy) carbonyl (Teoc).
The protection of functional group and deprotection can carry out before or after any reaction of aforesaid method.
Those skilled in the art should understand that, for with alternative mode and some the time obtain compound of the present invention in mode more easily, above mentioned various method steps can be different order carry out, and/or each reaction can be carried out (that is, can to adding substituting groups and/or carry out chemical conversion with above-mentioned those different intermediates relevant with concrete reaction of mentioning) in whole different stepss of routes.This may cancel the needs to blocking group, perhaps produces the needs to blocking group.
It should be appreciated by those skilled in the art that the starting raw material that is used for any aforesaid method can be commercially available in some cases.
It should be appreciated by those skilled in the art that for above-mentioned some starting raw material, aforesaid method may be a common practise.
The chemical type that relates to has determined the needs of blocking group and has finished the synthetic order.
Being applied in of blocking group " Protective groups in Organic Chemistry ", J W FMcOmie compiles, Plenum Press (1973) and " Protective Groups in OrganicSynthesis ", 3
RdVersion, T.W.Greene ﹠amp; P.G.M Wutz fully describes among the Wiley-Interscince (1999).
Protected derivative of the present invention can use the deprotection technology (for example under alkalescence or acidic conditions) of standard chemically to be converted into compound of the present invention.Those skilled in the art will appreciate that also the compound of some formula (II)-(LIX) also can be called " protected derivative ".
Compound of the present invention also can comprise one or more unsymmetrical carbons, and therefore can show opticity and/or diastereo-isomerism.Diastereomer can use routine techniques for example chromatography or Crystallization Separation.Can for example racemic mixture or other mixture of HPLC separating compound separate various steric isomers by using conventional technology.Perhaps, can be by suitable optical activity starting raw material being reacted under the condition that can not cause racemization or epimerization or separating the optically active isomer that the diastereomer derivative prepares expectation by for example passing through ordinary method (for example chromatography or the crystallization of HPLC, use silicon-dioxide) subsequently with homochiral sour derivatize.Also can introduce stereocenter by asymmetric synthesis (for example using the metal organic reaction of chiral ligand).All steric isomers all comprise within the scope of the invention.
All new intermediates form another aspect of the present invention.
The salt of the compound of formula (I) can by make free acid or its salt or free alkali or its salt, or derivatives thereof and one or how normal suitable alkali (for example optional by C
1-C
6Ammonium hydroxide or basic metal or alkaline earth metal hydroxides that-alkyl replaces) or acid (for example haloid acid (especially HCl), sulfuric acid, oxalic acid or phosphoric acid) reaction formation.This reaction can be carried out in undissolvable therein solvent of this salt or medium, perhaps therein can the dissolved solvent carries out in (for example water, ethanol, tetrahydrofuran (THF) or ether, but its vacuum is removed or removed by lyophilize) at this salt.This reaction also can be carried out on ion exchange resin.The preferred nontoxic acceptable salt of physiology is although other salt may be useful when the isolated or purified product.
Pharmacology data
Can derive from P2Y in use
12Measure P2Y in the in vitro tests of the cytolemma of the CHO-cell of transfection
12The functional inhibition of acceptor, method is as described below.
2-Me-S-ADP inductive P2Y
12The functional inhibition of signal: with the film of 5 μ g 200mM NaCl, 1mM MgCl at 200 μ l
2, dilute among 50mM HEPES (pH7.4), 0.01%BSA, 30 μ g/ml Saponin/TSM and the 10 μ M GDP.To wherein adding EC
80The test compound and the 0.1 μ Ci of the agonist of concentration (2-methyl-sulphur-adenosine diphosphate (ADP)), expectation concentration
35S-GTP γ S.Allow to be reflected at and carried out under 30 ℃ 45 minutes.Use cell harvestor sample to be transferred on the GF/B strainer and with lavation buffer solution (50mM Tris (pH7.4), 5mM MgCl then
2, 50mM NaCl) washing.Then strainer is covered with scintillator and counting is filtered that device keeps
35The amount of S-GTP γ S.After the value that deducts for non-specific determination of activity, in the presence of agonist, measure maximum activity, do not have agonist in the presence of measure minimum active.According to following equation the effect of the compound of various concentration is drawn:
y＝A+((B-A)/(1+((C/x)^D)))
With estimation IC
50, wherein
A is the curve bottom platform, promptly final minimum y value
B is the curve table top, promptly final maximum y value
C is in curve intermediary x value.When A+B=100, its expression log EC
50
D is slope factor (slope factor).
X is original known x value.
Y is original known y value.
When at described functional inhibition 2-Me-S-ADP inductive P2Y
12When measuring in the signal test, compound great majority of the present invention have activity when about 4 μ M or lower concentration.
For example, the compound of describing in embodiment 91 and 119 is at described functional inhibition 2-Me-S-ADP inductive P2Y
12Produce following test-results in the signal test.
IC
50(μM)
Embodiment 91 0.46
Embodiment 119 0.25
Compound of the present invention is as P2Y
12Receptor antagonist works, and therefore can be used for treatment.Therefore, according to another aspect of the present invention, provide the compound or pharmaceutically acceptable salt thereof of formula (I) to be used for the treatment of.
In one aspect of the method, provide the compound or pharmaceutically acceptable salt thereof of formula (I) to be used for the purposes of the medicine of production for treating platelet aggregation illness.In another aspect of the present invention, provide the compound or pharmaceutically acceptable salt thereof of formula (I) to be used for producing inhibition P2Y
12The purposes of the medicine of acceptor.
Described compound can be used for treatment, in particular for assisting therapy, especially, they are suitable as: platelet activation, the inhibitor of gathering and threshing, the promotor of thrombocyte unzipping, antithrombotic agent, or be used for the treatment of or prevent unstable angina pectoris, coronary angioplasty (PTCA), myocardial infarction, periphery thrombolysis (perithrombolysis), the thrombotic complications of atherosclerotic main artery is thrombus or embolic stroke for example, transient ischemic attack, peripheral angiopathy, be with or without thromboclastic myocardial infarction, (the angioplasty for example because interventional therapy in the atheromatosis, endarterectomy, support is placed, the transplantation of coronary artery and other blood vessel) the artery complication that causes, the thrombotic complications of operation or physical abuse (for example the tissue after chance or the operation wound is remedied), the reconstructive surgery that comprises skin and muscle flap, with the patient's condition of diffustivity thrombus/platelet consumption composition (disseminated intravascular coagulation for example, thrombus thrombocytopenic (thrombocytopaenic) purpura, the hemolytic uremic syndrome syndromes, septicemic cemia thrombotic complications, adult respiratory distress syndrome, anti-phosphatide syndromes, heparin-induced thrombocytopenia (thrombocytopaenia) and the preeclampsia/convulsions), or venous thrombosis (venous thrombosis for example, venous occlusive disease), the hematology patient's condition for example myeloproliferative disease (comprises thrombocythemia, drepanocytosis); Or be used to prevent the platelet activation of mechanical induction in the body, for example cardiopulmonary bypass and external film oxidation (prevention microthrombus embolism), the platelet activation of external mechanical induction, for example be used for the preservation of blood products (for example platelet concentrate), or for example the bypass in kidney dialysis and plasmapheresis is blocked, be secondary to vascular lesion/inflammation (vasculitis for example, arteritis, glomerulonephritis, inflammatory bowel and organ-graft refection) thrombosis, the patient's condition is migraine for example, Raynaud's phenomenon, wherein thrombocyte can help the patient's condition (atheromatous plaque formation/progress for example of basic inflammatory diseases process in the vessel wall, narrow/restenosis); Be used for other struvite patient's condition, for example asthma that wherein thrombocyte and the platelet-derived factor relate to the amynologic disease process.
According to the present invention, provide compound of the present invention to be used for the treatment of purposes in the medicine of above-mentioned illness in addition in production.Particularly, compound of the present invention can be used for treating myocardial infarction, thrombus apoplexy, transient ischemic attack, peripheral angiopathy and stenocardia, especially unstable angina pectoris.The present invention also provides the method for the above-mentioned illness of treatment, comprises the compound of the present invention of the patient who suffers from this illness being treated significant quantity.
In yet another aspect, the invention provides pharmaceutical composition, comprise the compound or pharmaceutically acceptable salt thereof of formula (I), and acceptable diluents, auxiliary and/or carrier.
Compound can solution, the form topical administration of suspension agent, HFA aerosol and dry powder formulations, for example is administered to lung and/or air flue; Perhaps system gives, give for example with the form orally give of tablet, pill, capsule, syrup, powder agent or granule, or with the form parenteral of aseptic parenteral solution or suspension agent, give by subcutaneous, or give by rectum, or transdermal administration with the form of suppository.
Compound of the present invention also can give separately or give as pharmaceutical composition (comprising the compound of the present invention with pharmaceutically acceptable diluent, auxiliary or carrier combinations).Particularly preferably be not comprise and cause for example composition of anaphylactoid material of adverse effect.
The HFA aerosol of the dry powder formulations of compound of the present invention and pressurization can give by oral or nasal inhalation.In order to suck, the expectation compound is in small, broken bits.Compound of the present invention also can give by the mode of Diskus.Sucker can be list or multi-dose inhaler, and can be the Diskus of respiration drive.
A kind of may be that for example monose, disaccharides or polysaccharide, sugar alcohol or another kind of polyvalent alcohol mix with carrier substance with compound in small, broken bits.Appropriate carriers comprises sugar and starch.Perhaps, compound in small, broken bits can be with another kind of material dressing.Powdered mixture can also be dispersed in the hard gelatine capsule, each comprises the active compound of desired amount.
Another may be that powder processing in small, broken bits is splitted spheroid in suction process.The powder of this spheroidization can be filled in the drug-reservoir of multi-dose inhaler for example known Turbuhaler
, wherein the dosage of dosage device metering expectation is sucked by the patient then.Use this system, will have or not have the active compound of carrier substance to be delivered to the patient.
The pharmaceutical composition that comprises compound of the present invention can be easily for being used for tablet, pill, capsule, syrup, powder agent or the granule of orally give; Be used for aseptic parenteral or subcutaneous solution, the suspension agent used that parenteral gives; Or be used for the suppository that rectum gives.
For orally give, active compound can be mixed with auxiliary or carrier (for example lactose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch (for example yam starch, W-Gum or amylopectin), derivatived cellulose), tackiness agent (for example gelatin or polyvinylpyrrolidone) and lubricant (for example Magnesium Stearate, calcium stearate, polyoxyethylene glycol, wax, paraffin) or the like, be compressed to tablet then.If require the tablet of dressing, can be with the core that as above prepares with dense sugar soln dressing, described sugar soln can comprise for example Sudan Gum-arabic, gelatin, talcum, titanium dioxide or the like.Perhaps, tablet can be with the polymer coating that is fit to that is dissolved in easy evaporable organic solvent or the water-containing solvent.
For the preparation of soft gelatin capsule, compound can be mixed with for example vegetables oil or polyoxyethylene glycol.But hard gelatin capsule inclusion compound particle uses any above-mentioned vehicle that is used for tablet, for example lactose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch, derivatived cellulose or gelatin.In addition, the liquid or the semi-solid preparation of medicine can be filled in the hard gelatin capsule.
The liquid preparation that is used for orally give can be the form of syrup or suspension agent, for example comprises the solution of described compound, and surplus is the mixture of sugar and ethanol, water, glycerine and propylene glycol.Randomly, this liquid preparation can comprise tinting material, seasonings, asccharin and carboxymethyl cellulose as thickening material or other vehicle well known by persons skilled in the art.
Further specify the present invention with following non-limiting example:
Embodiment
General experimental procedure
Be equipped with electron spray(ES) interface (LC-ms) or comprising on the Finnigan LCQ Duo ion trap mass spectrometer of LC-ms system of Waters ZQ (use LC-Agilent1100 LC system) and write down mass spectrum.
1H NMR measures on Varian Mercury VX 400 spectrographs of operating under 400 the 1H frequency and Varian UNITY plus 400,500 that operates under the 1H frequency 400,500 and 600 respectively and 600 spectrographs and carries out.Chemical shift provides with ppm, with solvent as interior mark.Chromatogram uses Biotage silica gel 40S, 40M, 12i or Merck silica gel 60 (0.063-0.200mm) to carry out.Flash chromatography uses the glass of standard or plastic column carries out or carry out in Biotage Horizon system.HPLC is separated in Waters YMC-ODS AQS-3120 Angstrom 3 * 500mm or on Waters Delta Prep Systems, uses Kromasil C8, and 10 μ m posts carry out.Being reflected among Personal Chemistry Smith maker, Smith synthesizer or the Emrys Optimizer of carrying out in microwave reactor carried out.
Abbreviated list:
Abbreviation
Explanation
AcOH acetate
Aq is aqueous
The br broad peak
The saturated solution of salt solution sodium-chlor in water
The BSA bovine serum albumin
The CDI carbonyl dimidazoles
D is bimodal
DCE 1, the 2-ethylene dichloride
The DCM methylene dichloride
DDQ 2,3-two chloro-5,6-dicyano-1,4-benzoquinones
DIEA N, the N-diisopropyl ethyl amine
DIPEA N, the N-diisopropyl ethyl amine
The DMA N,N-dimethylacetamide
DMAP N, N-lutidine-4-amine
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
EDCI N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride
The EtOAc ethyl acetate
EtOH ethanol
HATU O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate
HEPES [4-(2-hydroxyethyl)-1-piperazine ethyl sulfonic acid
The HFA hydrofluoroalkane
HOAc acetate
The HOBT I-hydroxybenzotriazole
The HPLC high performance liquid chromatography
The Hz hertz
The J coupling constant
The LDA lithium diisopropylamine
The M multiplet
M-CPBA 3-chloroperoxybenzoic acid
MeOH methyl alcohol
The MHz megahertz
The mL milliliter
The MS mass spectrum
NBS 1-bromine tetramethyleneimine-2,5-diketone (N-bromosuccinimide)
NCS 1-chlorine tetramethyleneimine-2, the 5-diketone
The q quartet
R.t. room temperature
S is unimodal
SMOPS 3-methoxyl group-3-oxo propane-1--sulfinic acid sodium
The t triplet
TB Tyrodes damping fluid
TBTU N-[(1H-1,2,3-benzotriazole-1-base oxygen base) (dimethylamino) methylene radical]-N-
Methyl first ammonium a tetrafluoro borate
The TEA triethylamine
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
Sulfonamides
Synthesizing of sulfonamides
Below every kind of material all be by making corresponding SULPHURYL CHLORIDE (0.75mmol) and saturated ammonia-MeOH solution (5mL) prepared in reaction.After with ammonia and MeOH evaporation, resistates is dissolved in MeOH (5mL) and adds DMF (2mL) in several samples, with the solubilizing reaction mixture.Then solution is filtered individually by comprising acidic ion exchange resin (propyl sulfonic acid type, ISOLUTE SCX-2 5g) (25mL cylinder).Use MeOH (16mL) rinsing to derive from the product of resin.Remove desolvate after, every kind of product without being further purified as use as described in the following method A.
Sulfonamides by this process preparation is set forth in the table 1.Other sulphonamide prepares by the method described in the embodiment or with described those similar methods.
Table 1
Embodiment's is synthetic
Method A:
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (referring to embodiment 1 (d)) (1Eq), sulphonamide (1.48Eq, the amount of the sulphonamide of use and structure describe in detail in following each embodiment) and DIPEA (5Eq) stir in DMF (acid that 8mL/mmol is used).Add the HATU (1.05Eq) that is dissolved in DMF (acid that 4mL/mmol is used) and will be reflected at stirred overnight at room temperature.Solvent removed in vacuo also is dissolved in DMSO (1mL) with crude product mixture, and by preparation property HPLC purifying (Kromasil C8,5 μ m particles, 100 * 21.2mm post, eluent A:100% acetonitrile, eluent B:0.1M ammonium acetate (in the water that contains 5% acetonitrile), flow velocity 30mL/min, in 8 minutes, use the acetonitrile gradient that increases, after evaporating solvent, obtain product).
Method B
To 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.21mmol) or 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] add TBTU (0.25mmol) and DIPEA (1.05mmol) in DCM (2mL) solution of azetidine-3-formic acid (0.21mmol).Reaction mixture was stirred 10 minutes, add sulphonamide (0.25mmol) subsequently, for example 5-chlorothiophene-3-sulphonamide.The reaction mixture stirring is spent the night, add 0.1M KHSO subsequently
4(2mL); separate organic phase and make crude product mixture through the product of preparation property HPLC (details is referring to the following stated) with the separation expectation, for example 6-[4-({ [(5-chloro-3-thienyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester.
The preparation HPLC system that uses is the Waters Fraction Lynx Purification System with Kromasil C8 5mm 20 * 100mm post.The moving phase of using is the CH of different gradients
3CN and and 0.1M NH
4OAc (aqueous solution) damping fluid.Flow velocity is 30mL/min.The fraction of using MS to trigger is collected.Mass spectrum is record on single four utmost points of Micromass ZQ or Micromass Quattromicro, and the both is equipped with the auxiliary electron spray(ES) of air pressure interface.
Method C
With 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (0.091g, 0.3mmol), DIPEA 0.074g, 0.6mmol) and TBTU (0.039g, 0.3mmol) solution in 1eq.DCM/1eq.DMF (2mL) joins sulphonamide (0.4mmol), for example in 4-(trifluoromethyl) benzsulfamide.Reaction mixture was stirred 48 hours, add subsequently TBTU (0.013g, 0.1mmol).After 20 hours, solvent removed in vacuo.Add NaHSO to crude product mixture
4(2mL, 1M), and because the difference of solubleness between the product uses DCM and DCM/ ethyl acetate to extract.Separate organic phase and solvent removed in vacuo.Thick material uses preparation property HPLC (details is referring to the following stated) purifying, so that separate the product of expectation, for example 5-cyano group-2-methyl-6-{3-[({[4-(trifluoromethyl) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid isopropyl esters.
Embodiment 1
5-cyano group-6-[3-(2-methoxycarbonyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
(a) 2-((dimethylamino) methylene radical)-3-ketobutyric acid ethyl ester
Under nitrogen atmosphere in room temperature with 1,1-dimethoxy-N, N-dimethyl methylamine (500g, 4195mmol) joined in the process at 13 minutes 3-ketobutyric acid ethyl ester (461.6g, 3547mmol) in (heat release faintly).Orange-red solution is stirred 22 hours and vacuum concentration.With resistates and toluene coevaporation (3 times, each 200ml), and need not to be further purified and be used for next step.
MS
m/
Z：186(M+1)。
(b) 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
((298g is 3544mmol) in the suspension in EtOH (3000mL) 3829mmol) to join the 2-malonamide nitrile of stirring in the process at 8 minutes for 1240.7g, the EtOH solution of 21wt% with sodium ethylate in room temperature under nitrogen atmosphere.Slowly adding is dissolved in the thick condensation product (slight exothermic reaction) that derives from above-mentioned steps (a) among the 950ml EtOH and is adding after about 1/3rd, add other EtOH (1000mL), so that effectively stir (suspension), add the rest part (total joining day is 30 minutes) of condensation product subsequently.After stirred overnight at room temperature, (526g 8759mmol) joins in the reaction with HOAc, and, stay dense thick orange soup compound (the about 3000mL of volume) with the mixture vacuum concentration, in 10 minutes, add 1M HCl (4628mL, 4628mmol), add entry (500mL) subsequently.Stop to stir, and leach precipitation and water (200mL)) wash.Show there is the corresponding acid of the 5-10% that has an appointment in NMR, and solid is by (1500mL+3 * 1000mL), containing saturated NaHCO with other water
3The water (600mL) of solution (400mL) and last water (1000mL) stir and wash.Cross filter solid and 80 ℃ of vacuum-dryings, obtain pure 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester.Yield: 493g (67%).
1H NMR(400MHz，DMSO-d
6)：δ1.36(3H，t，J＝7.1Hz)，2.62(3H，s)，4.25(2H，q，J＝7.1Hz)，8.71(1H，s)，12.79(1H，br s)。
(c) 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester
Under nitrogen atmosphere with toluene (4000mL) and thionyl chloride (507g, 4262mmol) join 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester (293g, add in the process 1421mmol) and with mixture heating up to 50 ℃ (oil bath temperature) and at 2 minutes DMF (100g, 1368mmol).Raise the temperature to 80 ℃ (oil bath temperatures) and continue and stirred 2 hours.With mixture vacuum concentration (evaporating about 3500ml), stay red oil.Add EtOH (1000mL, 99%) and add, then it is evaporated.Add methylene dichloride (4000mL), add 4%NaHCO subsequently
3Solution (4000mL) also stirs mixture 15 minutes.Separate organic phase and evaporation, obtain 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester, be bolarious thick solid, it is without being further purified use.Yield: 301g (75%).
1H NMR(400MHz，CDCl
3)：
1.42(3H，t，J＝7.1Hz)，2.91(3H，s)，4.40(2H，q，J＝7.1Hz)，8.49(1H，s)。
(d) 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid
With 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester (50.98g, 227mmol), azetidine-3-formic acid (24.09g, 238mmol) and DIPEA (118.9mL 681mmol) is suspended among the EtOH (250mL) and reflux 1 hour.Make the reaction mixture cool to room temperature, and be added drop-wise to and contain KHSO
4(154.5g is in water 1135mmol) (3000mL).By solid collected by filtration and vacuum-drying, obtain 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid, be solid, it is without being further purified use.Yield: 65.33g (100%).
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.1Hz)，2.72(3H，s)，3.59-3.68(1H，m)，4.31(2H，q，J＝7.1Hz)，4.55-4.68(4H，m)，8.28(1H，s)。
MS
m/
Z：290(M+1)。
(e) 5-cyano group-6-[3-(2-methoxycarbonyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (0.072g; 0.25mmol), the 2-[(amino-sulfonyl) methyl] benzoic acid methyl ester (0.085g; 0.375mmol) and triethylamine (0.55mL, 4mmol) stirring in DMF (2mL).(0.100g 0.263mmol) also will be reflected at stirred overnight at room temperature to add the HATU that is dissolved in DMF (1mL).Reaction mixture is by preparation property HPLC purifying; use Kromasil C8; 5 μ particles, 100 * 21.2mm post, eluent A:100% acetonitrile; eluent B:95%0.1M ammonium acetate; 5% acetonitrile, flow velocity 30mL/min, gradient: 25%A is to 75%A in 8 minutes; obtain 5-cyano group-6-[3-(2-methoxycarbonyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester, be solid.Yield: 0.063g (50%).
1H NMR (400MHz, DMSO-d
6) 1.26 (t, J=7.2Hz, 3H), 2.59 (s, 3H), 3.30 (m, 1H is by the water imbrication), 3.76 (s, 3H), 4.20 (q, J=7.1Hz, 2H), 4.27 (t, J=2.6Hz, 2H), 4.35 (t, J=4.3Hz, 2H), 5.12 (s, 2H), 7.40 (d, J=7.3Hz, 1H), 7.48 (t, J=3.9Hz, 1H), 7.55 (t, J=7.1Hz, 1H), 7.78 (d, J=7.7Hz, 1H), 8.26 (s, 1H)
MS
m/
Z：501(M+1)
Embodiment 2
6-[3-({ [(3-bromobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (0.257g, 0.89mmol), 1-(3-bromophenyl) Toluidrin (0.223g, 0.89mmol) and TEA (0.360g, 3.6mmol) stirring in DMF (5mL).Add HATU (0.405g, 1.07mmol) and with reaction mixture stirring at room 3.5 hours.Add additional quantity HATU (0.073g, 0.18mmol) and continue to stir 18 hours.Be dissolved in EtOAc (80mL) with the DMF evaporation and with resistates.Organic phase NH
4Cl (saturated aqueous solution) (2 * 8mL), water (5mL) washing, dry (MgSO
4), filter and evaporation, obtain the crude product of 0.658g, be solid.By purified by flash chromatography, obtain the 0.429g product, according to LC-MS, it is about 90% pure.(Kromasil C810 μ m 250mm * 50id is carried out in being further purified by preparation property HPLC of this material.Eluent A:100% acetonitrile, eluent B:95%0.1M ammonium acetate solution and 5% acetonitrile.The condition of using: flow velocity 50mL/min, use the linear gradient from 0%A to 100%A in 42 minutes processes).Product precipitates in the evaporating solvent process, and it is leached and washes with water.Obtain pure product like this, be white solid.Yield: 0.181g (39%).
1H NMR(400MHz，DMSO-d
6)：δ1.29(t，J＝7..0Hz，3H)，2.62(s，3H)，3.56(m，1H)，4.23(q，J＝7.0Hz，2H)，4.25-4.31(m，2H)，4.41(m，2H)，4.78(s，2H)，7.34(m，2H)，7.53(s，1H)，7.56-7.62(m，1H)，8.30(s，1H)，11.88(s，1H)。
MS
m/
Z：522(M+1)。
Embodiment 3
5-cyano group-2-methyl-6-[3-(2-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
According to method A preparation, and use 1-(2-nitrophenyl) Toluidrin (the 0.111g crude product, 0.37mmol).Yield: 0.031g (25%).
1H NMR (400MHz, DMSO-d
6) δ 1.24 (t, J=7.1Hz, 3H), 2.57 (s, 3H), 3.5 (m, 1H is by the water imbrication), 4.18 (q, J=7.1Hz, 2H), 4.26 (t, J=3.1Hz, 2H), 4.34 (t, J=4.2Hz, 2H), 5.04 (s, 2H), 7.51 (d, J=7.5Hz, 1H), 7.59 (t, J=7.3Hz, 1H), 7.66 (t, J=6.9Hz, 1H), 7.94 (d, J=8.1Hz, 1H), 8.24 (s, 1H)
MS
m/
Z：488(M+1)
Embodiment 4
6-[3-(2-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-(2-chloro-phenyl-) Toluidrin (the 0.100g crude product, 0.37mmol).Yield: 0.031g (25%).
1H NMR (400MHz, DMSO-d
6) δ 1.23 (t, J=7.1Hz, 3H), 2.57 (s, 3H), 3.52 (m, 1H is by the water imbrication), 4.18 (q, J=7.1Hz, 2H), 4.30 (t, J=7.4Hz, 2H), 4.40 (t, J=9.4Hz, 2H), 4.81 (s, 2H), 7.31-7.38 (m, 2H), 7.44 (m, 2H), 8.25 (s, 1H)
MS
m/
Z：477(M+1)
Embodiment 5
6-[3-(4-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-(4-chloro-phenyl-) Toluidrin (the 0.106g crude product, 0.37mmol).Yield: 0.057g (48%).
1H NMR (400MHz, DMSO-d
6) δ 1.24 (t, J=7.1Hz, 3H), 2.58 (s, 3H), 3.45 (m, 1H is by the water imbrication), 4.18 (q, J=7.1Hz, 2H), 4.23 (m, 2H), 4.36 (t, J=8.6Hz, 2H), 4.65 (s, 2H), 7.29 (d, J=8.5Hz, 2H), 7.37 (d, J=8.5Hz, 2H), 8.25 (s, 1H)
MS
m/
Z：477(M+1)
Embodiment 6
5-cyano group-2-methyl-6-[3-(4-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
According to method A preparation, use 1-[4-(trifluoromethyl) phenyl] and Toluidrin (the 0.057g crude product, 0.23mmol).Yield: 0.050g (39%).
1H NMR (400MHz, DMSO-d
6) δ 1.24 (t, J=7.1Hz, 3H), 2.57 (s, 3H), 3.49 (m, 1H is by the water imbrication), 4.2 (q, J=7.1Hz, 2H), 4.24 (m, 2H), 4.36 (t, J=8.8Hz, 2H), 4.75 (s, 2H), 7.51 (d, J=7.9Hz, 2H), 7.68 (d, J=8.1Hz, 2H), 8.24 (s, 1H)
MS
m/
Z：511(M+1)
Embodiment 7
5-cyano group-6-[3-(3-fluoro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-(3-fluorophenyl) Toluidrin (the 0.095g crude product, 0.37mmol).Yield: 0.065g (56%).
1H NMR (400MHz, DMSO-d
6) δ 1.24 (t, J=7.1Hz, 3H), 2.57 (s, 3H), 3.48 (m, 1H is by the water imbrication), 4.23-4.15 (m, 4H), 4.36 (t, J=9.1Hz, 2H), 4.69 (s, 2H), 7.18-7.09 (m, 3H), 7.36 (q, J=7.5Hz, 1H), 8.24 (s, 1H)
MS
m/
Z：461(M+1)
Embodiment 8
5-cyano group-2-methyl-6-[3-(3-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
According to method A preparation, use 1-[3-(trifluoromethyl) phenyl] and Toluidrin (the 0.105g crude product, 0.37mmol).Yield: 0.050g (39%).
1H NMR(400MHz，DMSO-d
6)δ1.24(t，J＝7.1Hz，3H)，2.57(s，3H)，3.48(m，1H)，4.18(m，4H)，4.35(t，J＝8.8Hz，2H)，4.78(s，2H)，7.57(m，3H)，7.69(d，J＝6.6Hz，1H)，8.24(s，1H)
MS
m/
Z：511(M+1)
Embodiment 9
6-[3-(3-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-(3-chloro-phenyl-) Toluidrin (the 0.096g crude product, 0.37mmol).Yield: 0.050g (42%).
1H NMR (400MHz, DMSO-d
6) δ 1.24 (t, J=7.1Hz, 3H), 2.57 (s, 3H), 3.46 (m, 1H is by the water imbrication), 4.23-4.15 (m, 4H), 4.35 (d, J=9.3Hz, 2H), 4.68 (s, 2H), 7.24 (d, J=7.3Hz, 1H), 7.38-7.31 (m, 3H), 8.24 (s, 1H)
MS
m/
Z：477(M+1)
Embodiment 10
6-{3-[2-(3-chloro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-5-cyano group-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 2-(3-chloro-phenyl-) ethyl sulfonamide (the 0.102g crude product, 0.37mmol).Yield: 0.055g (45%).
1H NMR (400MHz, DMSO-d
6) δ 1.23 (t, J=7.1Hz, 3H), 2.56 (s, 3H), 2.98 (t, J=7.5Hz, 2H), 3.45 (m, 2H), 3.8-3.5 (m, 2H is by the water imbrication), 4.17 (m, 3H), 4.34 (t, J=8.5Hz, 2H), 7.17 (d, J=7.1Hz, 2H), 7.29-7.24 (m, 2H), 8.23 (s, 1H)
MS
m/
Z：491(M+1)
Embodiment 11
5-cyano group-2-methyl-6-[3-(4-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
According to method A preparation, and use 1-(4-nitrophenyl) Toluidrin (the 0.099g crude product, 0.37mmol).Yield: 0.032g (26%).
1H NMR(400MHz，DMSO-d
6)
1.24(t，J＝7.2Hz，3H)，2.56(s，3H)，3.44(m，1H)，4.18(m，4H)，4.33(t，J＝8.4Hz，2H)，4.79(s，2H)，7.56(d，J＝8.7Hz，2H)，8.15(d，J＝8.7Hz，2H)，8.23(s，1H)
MS
m/
Z：488(M+1)
Embodiment 12
5-cyano group-2-methyl-6-[3-(2-phenyl-ethylsulfonylamino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
According to method A preparation, use 2-phenyl ethyl sulfonamide (0.078g crude product, 0.37).Yield: 0.044g (39%).
1H NMR (400MHz, DMSO-d
6) δ 1.23 (t, J=7.2Hz, 3H), 2.55 (s, 3H), 2.95 (t, J=7.7Hz, 2H), 3.45 (m, 1H), 4.17 (q, J=7.1Hz, 4H), 4.34 (t, J=8.6Hz, 2H), 7.25-7.12 (m, 5H), 8.23 (s, 1H) (adjacent with sulfone two protons and DMSO signal overlaps)
MS
m/
Z：457(M+1)
Embodiment 13
5-cyano group-2-methyl-6-(3-o-tolyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-nicotinic acid ethyl ester
According to method A preparation, and use 1-(2-aminomethyl phenyl) Toluidrin (the 0.010g crude product, 0.05mmol).Yield: 0.002g (2%).
1H NMR (400MHz, DMSO-d
6) δ 1.24 (t, J=7.2Hz, 3H), 2.32 (s, 3H), 2.57 (s, 3H), 3.4 (m, 1H is by the water imbrication), 4.18 (m, 2H), 4.30 (m, 2H), 4.39 (m, 2H), 4.63 (s, 2H), 7.15 (m, 4H), 8.24 (s, 1H)
MS
m/
Z：457(M+1)
Embodiment 14
5-cyano group-2-methyl-6-[3-(3-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
According to method A preparation, and use 1-(3-nitrophenyl) Toluidrin (the 0.097g crude product, 0.37mmol).Yield: 0.055g (45%).
1H NMR(400MHz，DMSO-d
6)δ1.24(t，J＝7.2Hz，3H)，2.57(s，3H)，3.46(m，1H)，4.18(m，4H)，4.32(t，J＝9.2Hz，2H)，4.82(s，2H)，7.63(t，J＝8.0Hz，1H)，7.75(d，J＝7.7Hz，1H)，8.10(s，1H)，8.17(d，J＝8.1Hz，1H)，8.23(s，1H)
MS
m/
Z：488(M+1)
Embodiment 15
5-cyano group-6-{3-[2-(4-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 2-(4-fluorophenyl) ethyl sulfonamide (the 0.082g crude product, 0.37mmol).Yield: 0.051g (43%).
1H NMR(400MHz，DMSO-d
6)δ1.23(t，J＝7.2Hz，3H)，2.55(s，3H)，2.95(t，J＝7.6Hz，2H)，3.48(m，1H)，3.70-3.50(m，2H)，4.17(q，J＝7.2Hz，4H)，4.36(t，J＝9.0Hz，2H)，7.04(t，J＝8.9Hz，2H)，7.24(dd，J＝8.6，5.5Hz，2H)，8.23(s，1H)
MS
m/
Z：475(M+1)
Embodiment 16
5-cyano group-2-methyl-6-[3-(2-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
According to method A preparation, use 1-[2-(trifluoromethyl) phenyl] and Toluidrin (the 0.100g crude product, 0.37mmol).Yield: 0.045g (35%).
1H NMR(400MHz，DMSO-d
6)δ1.23(t，J＝7.1Hz，3H)，2.57(s，3H)，3.58(m，1H)，4.18(q，J＝7.1Hz，2H)，4.31(t，J＝6.9Hz，2H)，4.41(t，J＝8.8Hz，2H)，4.83(s，2H)，7.68-7.54(m，3H)，7.74(d，J＝8.1Hz，1H)，8.24(s，1H)
MS
m/
Z：511(M+1)
Embodiment 17
5-cyano group-6-[3-(4-fluoro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-(4-fluorophenyl) Toluidrin (the 0.078g crude product, 0.37mmol).Yield: 0.050g (43%).
1H NMR(400MHz，DMSO-d
6)δ1.24(t，J＝7.1Hz，3H)，2.57(s，3H)，3.49(m，1H)，4.20(m，4H)，4.36(t，J＝9.0Hz，2H)，4.65(s，2H)，7.13(t，J＝8.8Hz，2H)，7.32(dd，J＝8.6，5.5Hz，2H)，8.25(s，1H)
MS
m/
Z：461(M+1)
Embodiment 18
5-cyano group-6-(3-cyclopentyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-cyclopentyl Toluidrin (the 0.074g crude product, 0.37mmol).Yield: 0.013g (12%).
1H NMR (400MHz, DMSO-d
6) δ 1.21 (m, 2H), 1.23 (t, J=7.1Hz, 3H), 1.44 (m, 2H), 1.52 (m, 2H), 1.79 (m, 2H), 2.13 (m, 1H), 2.56 (s, 3H), 3.38 (d, J=6.8Hz, 2H), 3.51 (m, 1H is by the water imbrication), 4.17 (q, J=7.1Hz, 2H), 4.29 (m, 2H), 4.41 (t, J=9.0Hz, 2H), 8.23 (s, 1H)
MS
m/
Z：435.0(M+1)
Embodiment 19
5-cyano group-6-{3-[2-(2-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 2-(2-fluorophenyl) ethyl sulfonamide (the 0.084g crude product, 0.37mmol).Yield: 0.060g (51%).
1H NMR (400MHz, DMSO-d
6) δ 1.23 (t, J=7.1Hz, 3H), 2.56 (s, 3H), 2.99 (t, J=7.7Hz, 2H), 3.46 (m, 1H, by the water imbrication), 3.67-3.54 (m, 2H is by the water imbrication), 4.17 (m, 4H), 4.36 (t, J=8.8Hz, 2H), 7.08 (t, J=8.0Hz, 2H), 7.21 (m, 1H), 7.30 (t, J=7.7Hz, 1H), 8.23 (s, 1H)
MS
m/
Z：475(M+1)
Embodiment 20
5-cyano group-6-[3-(3,5-two chloro-phenyl methanesulfonamide acyl amino carbonyls)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-(3, the 5-dichlorophenyl) Toluidrin (the 0.181g crude product, 0.37mmol).Yield: 0.053g (41%).
1H NMR(400MHz，DMSO-d
6)δ1.23(t，J＝7.2Hz，3H)，2.56(s，3H)，3.47(m，1H)，4.18(m，2H)，4.18(q，J＝7.1Hz，2H)，4.35(t，J＝9Hz，2H)，4.69(s，2H)，7.30(s，2H)，7.55(s，1H)，8.23(s，1H)
MS
m/
Z：511(M+1)
Embodiment 21
5-cyano group-6-(3-cyclohexyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-cyclohexyl Toluidrin (the 0.065g crude product, 0.37mmol).Yield: 0.012g (11%).
1H NMR(400MHz，DMSO-d
6)δ0.98-1.25(m，8H)，1.60-1.50(m，3H)，1.74(m，3H)，2.55(s，3H)，3.26(d，J＝6.0Hz，2H)，3.58(m，1H)，4.17(q，J＝7.1Hz，2H)，4.28(t，J＝7.1Hz，2H)，4.41(t，J＝8.7Hz，2H)，8.23(s，1H)
MS
m/
Z：449(M+1)
Embodiment 22
5-cyano group-6-{3-[2-(3-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 2-(3-fluorophenyl) ethyl sulfonamide (the 0.088g crude product, 0.37mmol).Yield: 0.044g (37%).
1H NMR (400MHz, DMSO-d
6) δ 1.23 (t, J=7.1Hz, 3H), 2.56 (s, 3H), 2.98 (t, J=7.7Hz, 2H), 3.45 (m, 1H is by the water imbrication), 3.69-3.56 (m, 2H is by the water imbrication), 4.17 (m, 2H), 4.17 (q, J=7.1Hz, 2H), 4.35 (t, J=8.9Hz, 2H), 6.95 (m, 1H), 7.06 (m, 2H), 7.27 (dd, J=14.4,8.0Hz, 1H), 8.23 (s, 1H)
MS
m/
Z：475(M+1)
Embodiment 23
6-[3-(benzo [d] isoxazole-3-base methylsulfonyl aminocarboxyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
According to method A preparation, and use 1-(1,2-benzoisoxazole-3-yl) Toluidrin (0.080g, 0.37mmol).Yield: 0.035g (28%).
1H NMR (400MHz, DMSO-d
6) δ 1.26 (t, J=7.1Hz, 3H), 2.58 (s, 3H), (3.27 m, 1H is by the water imbrication), 4.20 (q, J=7.1Hz, 2H), 4.84 (s, 2H), 4.27 (m, 4H), 7.28 (t, J=7.5Hz, 1H), 7.56 (t, J=7.6Hz, 1H), 7.66 (d, J=8.3Hz, 1H), 7.91 (d, J=7.9Hz, 1H), 8.24 (s, 1H)
MS
m/
Z：484(M+1)
Embodiment 24
1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl]-N-(benzyl alkylsulfonyl) piperidines-4-methane amide
(a) 5,6-two chloro-N-(2-hydroxybutyl) niacinamide
At room temperature with 5, the 6-dichloro-nicotinic acid (20.0g, 104mmol), EDCI (26.0g, 135mmol) and HOBt (18.3g 135mmol) is dissolved among the DCM (500mL).Reaction mixture is stirring at room 90 minutes, add then the amino fourth of 1--2-alcohol (15.0g, 156mmol) and DIPEA (54.4mL, 313mmol).Reaction mixture was stirring at room 18 hours.Reaction mixture with DCM (400mL) dilution and with the organism that merges with saturated NH
4Cl (2 * 100mL), saturated NaHCO
3(2 * 100mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtaining 5,6-two chloro-N-(2-hydroxybutyl) niacinamide is solid, and it is used with crude product, supposes that 100% transforms.
(b) 5,6-two chloro-N-(2-oxo butyl) niacinamide
(16.3mL 187mmol) is dissolved in DCM (500mL) and be cooled to-78 ℃ with oxalyl chloride.(26.3mL 374mmol) and at-78 ℃ stirred 10 minutes dropwise to add DMSO.With 5, (30g 94mmol) is dissolved in DCM/DMSO (3: 1) and slowly joining in this solution to 6-two chloro-N-(2-hydroxybutyl) niacinamide.Solution was stirred 30 minutes at-78 ℃.In solution, add TEA (65.2mL, 467mmol) and stirred 30 minutes.Rise again room temperature and stirring 3 hours of solution.Reaction mixture is with DCM (200mL) dilution, the organism water of merging (2 * 200mL), salt solution (2 * 200mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtaining 5,6-two chloro-N-(2-oxo butyl) niacinamide is solid, and it is used with crude product, supposes that 100% transforms.
(c) 2,3-two chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine
With 5, and 6-two chloro-N-(2-oxo butyl) niacinamide (26.7g, 78mmol) and POCl
3(59.6g, 389mmol) be dissolved in DMF (500mL) and 90 ℃ the heating 30 minutes.Reaction mixture is poured on ice.Add solid NaHCO in batches
3, be elevated to pH＞8 up to pH.Reaction mixture water (500mL) dilution and with the water that merges with EtOAc (3 * 400mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (EtOAc/ hexane, 1/9) obtains 2, and 3-two chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine is solid.Yield: 7.08g (37.5%).
1H NMR(400MHz，CDCl
3)：δ1.33(2H，t，J＝7.5Hz)，2.78(2H，q，J＝7.5Hz)，6.91(1H，s)，8.35(1H，d，J＝1.9Hz)，8.29(1H，d，J＝1.9Hz)。
MS
m/
Z：244(M+1)。
(d) 2,3-two chloro-5-(5-ethyl-1,3-oxazole-2-yl)-4-(methylthio group) pyridine
(2.5M, in hexane, 7.14mL 17mmol) dropwise joins and contains diisopropylamine (2.62mL is among THF 19mmol) (5mL) with n-Butyl Lithium at 0 ℃.Solution stirs at 0 ℃ and was cooled to-78 ℃ then in 30 minutes.Add in solution and contain 2, (3.50g, THF 14mmol) (30mL) also will be reflected at-78 ℃ of stirrings 1 hour to 3-two chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine.Add sulfo-methylsulfonic acid S-methyl ester (S-methyl methanesulfonothioate) (1.77mL, 19mmol) and make the solution room temperature of rising again.Reaction mixture was stirred 16 hours.Reaction mixture is with saturated NH
4Cl (100mL) dilution.(3 * 50mL) wash solution with EtOAc.(1 * 50mL) washs the organism that merges, dry (MgSO with salt solution
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (the 15%EtOAc/ hexane is to the 20%EtOAc/ hexane) obtains 2, and 3-two chloro-5-(5-ethyl-1,3-oxazole-2-yl)-4-(methylthio group) pyridine are solid.Yield: 2.71g (65.1%).
1H NMR(400MHz，CDCl
3)：δ1.33(2H，t，J＝7.6Hz)，2.35(3H，s)，2.79(2H，q，J＝7.6Hz)，6.98(1H，s)，8.58(1H，s)。
MS
m/
Z：290(M+1)。
(e) 1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-4-(methylthio group) pyridine-2-yl] piperidines-4-formic acid methyl ester
With 2,3-two chloro-5-(5-ethyl-1,3-oxazole-2-yl)-4-(methylthio group) pyridine (3.11g, 11mmol), piperidines-4-formic acid methyl ester (2.00g, 14mmol) and DIPEA (3.75mL 22mmol) is dissolved in DMA (50mL) and be heated to 120 ℃, keeps 2 hours.With reaction mixture cool to room temperature and concentrating under reduced pressure.Thick substance dissolves in EtOAc (100mL), is used NH
4Cl (2 * 60mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (1: 5 EtOAc/ hexane to 1: 3 EtOAc/ hexanes) obtain 1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-4-(methylthio group) pyridine-2-yl] piperidines-4-formic acid methyl ester, be solid.Yield: 4.26g (87.6%).
1H NMR(400MHz，CDCl
3)：δ1.33(2H，t，J＝7.6Hz)，1.88-2.06(4H，m)，2.32(3H，s)，2.51-2.58(1H，m)，2.76(3H，q，J＝7.6Hz)，2.93-2.99(2H，m)，3.72(3H，s)，3.81-3.92(2H，m)，6.91(1H，s)，8.43(1H，s)。
MS
m/
Z：396(M+1)。
(f) 1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-4-(methylsulfinyl) pyridine-2-yl] piperidines-4-formic acid methyl ester
With 1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-and 4-(methylthio group) pyridine-2-yl] piperidines-4-formic acid methyl ester (2.12g, 5.4mmol) be dissolved in DMF (500mL) and slowly add the 3-chloroperoxybenzoic acid that (2.64g, 10.7mmol), solution was stirring at room 4 hours in room temperature.Room temperature in 3 hours processes, slowly add the 3-chloroperoxybenzoic acid (1.32g, 5.35mmol).Add saturated Na
2S
2O
3(30mL) and with solution stirring 5 minutes.Reaction mixture CH
2Cl
2(40mL) dilution and the organism that separate to merge and with NaOH (1M, 2 * 40mL), salt solution (1 * 30mL) washing, drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (1: 2 EtOAc/ hexane) obtains 1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-4-(methylsulfinyl) pyridine-2-yl] piperidines-4-formic acid methyl ester, be solid.Yield: 2.71g (65.1%).
1H NMR(400MHz，CDCl
3)：δ1.30(1H，t，J＝7.5Hz)，1.83-2.08(4H，m)2.52-2.61(1H，m)，2.75(2H，q，J＝7.5Hz)，2.93-3.00(1H，m)，3.04-3.13(1H，m)，3.23(3H，s)，3.72(3H，s)，3.86-4.01(2H，m)，6.87(1H，s)，8.51(1H，s)。
MS
m/
Z：412(M+1)。
(g) 1-[4-azido--3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-formic acid methyl ester
With 1-[3-chloro-5-(5-ethyl-1; 3-oxazole-2-yl)-and 4-(methylsulfinyl) pyridine-2-yl] piperidines-4-formic acid methyl ester (0.150g; 0.36mmol) and sodiumazide (0.026g 0.40mmol) is dissolved in DMA (1mL) and stirring at room 48 hours.Reaction mixture with EtOAc (40mL) dilution and with the separating organic matters that merges and water (2 * 40mL), salt solution (1 * 30mL) washing, dry (MgSO
4) and concentrating under reduced pressure, obtain 1-[4-azido--3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-formic acid methyl ester, be solid, it is used with crude product, suppose that 100% transforms.
(h) 1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-formic acid methyl ester
With 1-[4-azido--3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] (0.150g 0.36mmol) is dissolved in THF (0.90mL) and be cooled to 0 ℃ to piperidines-4-formic acid methyl ester.The adding zinc powder (0.109g, 1.66mmol).Slowly add NH to solution
4Cl (0.900mL).Make the solution room temperature of rising again, kept 1.5 hours.Reaction mixture filtered (diatomite) and with EtOAc (40mL) dilution, with the organism that merges with saturated NH
4OAc (2 * 30mL), salt solution (1 * 30mL) washing, dry (MgSO
4) and concentrating under reduced pressure, obtain 1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-formic acid methyl ester, be solid, it is used with crude product, suppose that 100% transforms.
(i) 1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-formic acid
With 1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-formic acid methyl ester (0.045g, 0.123mmol) and lithium hydroxide (2M, 1.23mL 2.46mmol) are suspended among the THF (1mL) and stirring at room 16 hours.Dropwise add HCl (dense) to mixture and be reduced to pH 2 up to pH.(3 * 40mL) wash solution, dry (MgSO with EtOAc
4), and concentrating under reduced pressure, obtain 1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-formic acid, be solid, it is used with crude product, suppose that 100% transforms.
(j) 1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl]-N-(benzyl alkylsulfonyl) piperidines-4-methane amide
In room temperature with 1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-formic acid (and 0.040g, 0.11mmol), EDCI (0.026g, 0.14mmol) and HOBt (0.019g 0.14mmol) is dissolved in DCM (2mL).Reaction mixture is stirring at room 30 minutes, add then 1-phenyl methanesulfonamide acid amides (0.023g, 0.14mmol) and DIPEA (0.099mL, 0.57mmol).Reaction mixture was stirring at room 48 hours.Reaction mixture dilutes with EtOAc (50mL).The organism that merges is with saturated NH
4Cl (2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (EtOAc/ hexane 5/1 is to the EtOAc/ hexane 5/1 that contains 0.5%AcOH) obtains 1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl]-N-(benzyl alkylsulfonyl) piperidines-4-methane amide, be solid.Yield: 0.018g (30.5%).
1H NMR(400MHz，CDCl
3)：δ1.24-1.33(6H，m)，1.85-1.93(4H，m)，2.26-2.35(1H，m)，2.71-2.88(4H，m)，3.80-3.89(2H，m)，4.69(2H，s)，6.81(1H，s)，7.35-7.44(5H，m)，8.52(1H，s)。
MS
m/
Z：505(M+1)。
Embodiment 25
4-amino-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chlorine apellagrin ethyl ester
(a) 4-azido--5,6-dichloro-nicotinic acid ethyl ester
With 4,5,6-three chlorine apellagrins (1.28g, 5.65mmol) and sodiumazide (0.370g 5.69mmol) is dissolved in DMA (10mL) and stirring at room 16 hours.To reaction mixture add iodoethane (0.670mL, 6.60mmol) and salt of wormwood (3.90g, 28.25mmol), and stirring at room 16 hours.Reaction mixture with EtOAc (40mL) dilution and with the organism water that merges (2 * 40mL), salt solution (1 * 30mL) washing, dry (MgSO
4) and concentrating under reduced pressure, obtaining 4-azido--5,6-dichloro-nicotinic acid ethyl ester is solid, and it is used with crude product, supposes that 100% transforms.
(b) 4-amino-5,6-dichloro-nicotinic acid ethyl ester
With 4-azido--5, (0.700g 2.68mmol) is dissolved in 1 to 6-dichloro-nicotinic acid ethyl ester: 1THF/MeOH (10mL).(0.109g 1.66mmol) and with solution is cooled to 5 ℃ to add zinc powder.Slowly add NH to solution
4Cl (2mL).Make the solution room temperature of rising again, kept 2 hours.Filter reaction mixture (diatomite) with MeOH (50mL) washing and concentrated, obtains 4-amino-5, and 6-dichloro-nicotinic acid ethyl ester is solid, and it is used with crude product, supposes that 100% transforms.
(c) 1-[4-amino-3-chloro-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid
With 4-amino-5,6-dichloro-nicotinic acid (dichloronic) ethyl ester (0.320g, 1.36mmol), piperidines 4-formic acid (0.352g, 2.72mmol) and DIPEA (11.9mL, 68.2mmol) be dissolved in DMA (2.5mL) and 120 ℃ the heating 2 hours.With reaction mixture cool to room temperature and concentrating under reduced pressure.Thick substance dissolves in EtOAc (40mL), is used NH
4Cl (1 * 40mL) washing, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (EtOAc/ hexane 1/3 is to the EtOAc/ hexane 2/3 that contains 0.5% AcOH) obtains 1-[4-amino-3-chloro-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid, be solid.Yield: 0.154g (34.5%).
1H NMR(400MHz，CDCl
3)：δ1.37(2H，t，J＝7.1Hz)，1.88-2.07(4H，m)，2.55-2.62(1H，m)，2.92-3.01(2H，m)，3.87-3.90(2H，m)，4.33(3H，q，J＝7.1Hz)，8.60(1H，s)。
MS
m/
Z：328(M+1)。
(d) 4-amino-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chlorine apellagrin ethyl ester
In room temperature with 1-[4-amino-3-chloro-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid (and 0.070g, 0.21mmol), EDCI (0.053g, 0.28mmol) and HOBt (0.038g 0.28mmol) is dissolved in DCM (5mL).Reaction mixture is stirring at room 30 minutes, add then 1-phenyl methanesulfonamide acid amides (0.051g, 0.30mmol) and DIPEA (0.22mL, 1.3mmol).Reaction mixture in stirring at room up to falling to the starting raw material completely consumed by the HPLC analysis and observation.Reaction mixture is with DCM (30mL) dilution with saturated NH
4Cl (2 * 30mL) washings.With the organism drying (MgSO that merges
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (3: the 7EtOAc/ hexane is 3: 7 EtOAc/ hexanes that contain 0.5% AcOH then) obtains 4-amino-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chlorine apellagrin ethyl ester, be solid.Yield: 0.079g (77%).
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.4Hz)，1.83-1.88(4H，m)，2.28-2.36(1H，m)，2.81-2.88(2H，m)，3.92-3.95(2H，m)，4.33(2H，q，J＝7.4Hz)，4.69(4H，s)，7.35-7.41(5H，m)，8.59(1H，s)。
MS
m/
Z：481(M+1)。
Embodiment 26
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
(a) amino 6-{3-[(tert-butoxycarbonyl)] azetidine-1-yl }-5-cyano group-2-methylnicotinic acid
With 6-(3-(tert-butoxycarbonyl) azetidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester (1.50g, 4.16mmol) and lithium hydroxide (3.00g 8.32mmol) is suspended among the MeOH (40mL) and 90 ℃ of heating 1 hour.In mixture, dropwise add HCl (dense) and be reduced to pH2 up to pH.With sedimentation and filtration and collection.(1 * 60mL) washs mother liquor, dry (MgSO with EtOAc
4), concentrating under reduced pressure and merge with solid obtains the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl }-5-cyano group-2-methylnicotinic acid, be solid, it uses with crude product.
(b) amino 6-{3-[(tert-butoxycarbonyl)] azetidine-1-yl }-5-cyano group-2-methylnicotinic acid isopropyl esters
With the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl-5-cyano group-2-methylnicotinic acid (0.400g, 1.20mmol), 2-iodopropane (0.181mL, 1.81mmol) and salt of wormwood (0.216g 1.56mmol) is dissolved in DMA (5mL).Reaction mixture was stirring at room 16 hours.In solution, add 2-iodopropane (0.154g, 0.91mmol) and continue to stir other 8 hours.Reaction mixture dilutes with EtOAc (40mL).The organism that merges is with saturated NaHCO
3(2 * 40mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl }-5-cyano group-2-methylnicotinic acid isopropyl esters, be solid, it uses with crude product.
(c) 6-(the amino azetidine of 3--1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters two (trifluoroacetate)
With the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl }-(0.376g 1.00mmol) is dissolved in DCM (1mL) to 5-cyano group-2-methylnicotinic acid isopropyl esters.Slow adding TFA (1.16mL, 15.1mmol).Reaction mixture was stirring at room 16 hours.With the mixture concentrating under reduced pressure, obtain 6-(the amino azetidine of 3--1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters two (trifluoroacetate), be solid, it is used with crude product, suppose that 100% transforms.
(d) 6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
With 1,1 '-carbonyl two (1H-imidazoles) (0.035g, 0.216mmol) and 1-phenyl methanesulfonamide acid amides (0.037g 0.216mmol) is dissolved in DCE (2mL) and stirring at room 16 hours.In reaction mixture, add and contain 6-(the amino azetidine of 3--1-yl)-two (trifluoroacetate) (0.102g of 5-cyano group-2-methylnicotinic acid isopropyl esters, 0.216mmol) DCE (2mL) and DIPEA (0.564mL 0.740mmol) and in room temperature continue to stir 16 hours.Reaction mixture was heated 16 hours at 70 ℃.In solution, add 1,1 '-carbonyl two (1H-imidazoles) (0.035g, 0.216mmol) and 1-phenyl methanesulfonamide acid amides (0.037g, 0.216mmol) and with reaction mixture 70 ℃ of heating 16 hours.Dilute with the reaction mixture concentrating under reduced pressure and with EtOAc (40mL).The organism that merges is with saturated NaHCO
3(2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Grind (1: 1 EtOAc/ hexane) and obtain 6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters, be solid.Yield: 0.017g (16.2%).
1H NMR(400MHz，DMSO-d
6)：δ1.29(6H，d，J＝6.2Hz)，2.62(3H，s)，4.18(2H，m)，4.55(3H，m)，4.69(2H，m)，5.03-5.09(1H，m)，7.10(1H，s)，7.32-7.40(5H，m)，8.31(1H，s)，10.5(s，1H)。
MS
m/
Z：472(M+1)。
Embodiment 27
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid tertiary butyl ester
(a) amino 6-{3-[(tert-butoxycarbonyl)] azetidine-1-yl }-5-cyano group-2-methylnicotinic acid tertiary butyl ester
With the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl-5-cyano group-2-methylnicotinic acid (0.400g, 1.20mmol) and imido grpup carboxylamine tertiary butyl ester (0.964g, 4.80mmol) be dissolved in THF (5mL) and 80 ℃ the heating 27 hours.With the reaction mixture concentrating under reduced pressure.Reaction mixture filters by silicon-dioxide short column (plug) with DCM (40mL) dilution and with EtOAc.Filtrate decompression is concentrated, obtain crude product.Flash chromatography (1: 6 EtOAc/ hexane) obtains the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl }-5-cyano group-2-methylnicotinic acid tertiary butyl ester, be solid.Yield: 0.342g (73.2%).
(b) 6-(the amino azetidine of 3--1-yl)-5-cyano group-2-methylnicotinic acid tertiary butyl ester dihydrochloride
With the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl-5-cyano group-2-methylnicotinic acid tertiary butyl ester (0.342g. 0.880mmol) be dissolved in HCl (1M, in dioxane, 4.40mL, 4.40mmol).Reaction mixture obtains 6-(the amino azetidine of 3--1-yl)-5-cyano group-2-methylnicotinic acid tertiary butyl ester dihydrochloride at stirring at room 16 hours and concentrating under reduced pressure, is solid, and it uses with crude product, supposes that 100% transforms.
(c) 6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid tertiary butyl ester
With 1,1 '-carbonyl two (1H-imidazoles) (0.034g, 0.208mmol) and 1-phenyl methanesulfonamide acid amides (0.034g 0.208mmol) is dissolved in DCE (2mL) and stirring at room 16 hours.Will be at DCE (2mL) and DIPEA (2.08mL, 0.362mmol) in 6-(3-amino azetidine-1-yl)-5-cyano group-2-methylnicotinic acid tertiary butyl ester dihydrochloride (0.130g 0.208mmol) joins in this solution and stirring at room 48 hours.Reaction mixture is heated to 70 ℃, keeps 16 hours.The reaction mixture concentrating under reduced pressure is also used EtOAc (40mL) dilution.The organism that merges is with saturated NaHCO
3(2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (1: 6 EtOAc/ hexane) subsequent grinding (1: 1 EtOAc/ hexane) obtains 6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid tertiary butyl ester, be solid.Yield: 0.031g (30%).
1H NMR(400MHz，DMSO-d
6)：δ1.52(9H，s)，2.60(3H，s)，4.16(2H，m)，4.55(3H，m)，4.69(2H，m)，7.10(1H，s)，7.33-7.40(5H，m)，8.23(1H，s)，10.5(1H，s)。
MS
m/
Z：486(M+1)。
Embodiment 28
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
(a) amino 6-{3-[(tert-butoxycarbonyl)] azetidine-1-yl }-5-cyano group-2-methylnicotinic acid ethyl ester
With 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester (6.20g, 29.4mmol), azetidine-3-aminocarbamic acid tertiary butyl ester (5.07g, 29.4mmol) and DIPEA (5.13mL 29.4mmol) is dissolved in DCE (40mL) and stirring at room 1 hour.Dilute with the reaction mixture concentrating under reduced pressure and with EtOAc (40mL).The organism that merges is with saturated NaHCO
3(2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (1: 6 EtOAc/ hexane) obtains the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl }-5-cyano group-2-methylnicotinic acid ethyl ester, be solid.Yield: 7.00g (66.0%)
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.2Hz)，1.46(9H，s)，2.70(1H，s)，4.18-4.22(2H，m)，4.30(2H，q，J＝7.2Hz)，4.59(1H，s)，4.67-4.72(2H，m)，5.00(1H，s)，8.26(1H，s)。
MS
m/
Z：361(M+1)。
(b) 6-(the amino azetidine of 3--1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester two (trifluoroacetate)
With the 6-{3-[(tert-butoxycarbonyl) amino] azetidine-1-yl }-(1.00g 2.77mmol) is dissolved in DCM (10mL) to 5-cyano group-2-methylnicotinic acid ethyl ester.Slow adding TFA (6.40mL, 83.2mmol).Reaction mixture was stirring at room 30 minutes.With the mixture concentrating under reduced pressure, obtain 6-(the amino azetidine of 3--1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester two (trifluoroacetate), be solid, it is used with crude product, suppose that 100% transforms.
(c) 6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
With 1,1 '-carbonyl two (1H-imidazoles) (0.054g, 0.333mmol) and 1-phenyl methanesulfonamide acid amides (0.057g 0.333mmol) is dissolved in DCE (2mL) and stirring at room 16 hours.In this solution, add and contain 6-(the amino azetidine of 3--1-yl)-5-cyano group-2-methylnicotinic acid ester two (trifluoroacetate) (0.210g, (0.580mL is 3.33mmol) and stirring at room 2 hours for DCE 0.333mmol) (2mL) and DIPEA.The reaction mixture concentrating under reduced pressure is also used EtOAc (40mL) dilution.The organism that merges is with saturated NaHCO
3(2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Grind (1: 1 EtOAc/ hexane) and obtain 6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.073g (47.9%)
1H NMR(400MHz，DMSO-d
6)：δ1.30(3H，t，J＝7.1Hz)，2.63(3H，s)，2.70(1H，s)，4.18-4.19(2H，m)，4.24(2H，q，J＝7.1Hz)，4.56(3H，m)，4.70(2H，m)，7.1(1H，s)，7.32-7.43(5H，m)，8.31(1H，s)。
MS
m/
Z：458(M+1)。
Embodiment 29
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
(a) piperidines-3-guanidine-acetic acid sylvite
With trimethylammonium first potassium silicate (Potassium trimethylsilanoate, 0.89g, 5.2mmol) and piperidines-3-guanidine-acetic acid ethyl ester (0.87g, 6.8mmol) in DCM (50mL) stirring at room 2 days.Reaction mixture concentrated obtain solid piperidines-3-guanidine-acetic acid, be sylvite, it uses with crude product, supposes fully to transform.Yield: 0.74g (100%).
(b) 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and piperidines-3-yl } acetate
With 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester (1.00g, 4.45mmol), piperidines-3-guanidine-acetic acid (0.701g, 4.90mmol) and DIPEA (2.33mL 13.4mmol) is dissolved in DMF (30mL) and stirring at room 3 days.Reaction mixture is with EtOAc (100mL) dilution, with saturated NH
4Cl (2 * 25mL), saturated NaHCO
3(2 * 25mL), salt solution (25m) washing, dry (MgSO
4) and concentrating under reduced pressure, obtain thick material.Flash chromatography (9: 1 EtOAc/ hexanes contain 1%HOAc) obtains { 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-3-yl } acetate, is solid.Yield: 0.791g (54%).
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.1Hz)，1.39-1.44(1H，m)，1.63-1.73(1H，m)，1.78-1.85(1H，m)，1.98-2.03(1H，m)，2.16-2.24(1H，m)，2.29-2.34(1H，m)，2.40-2.46(1H，m)，2.71(3H，s)，3.08-3.13(1H，m)，3.26-3.32(1H，m)，4.31(2H，q，J＝7.1Hz)，4.44-4.50(1H，m)，4.52-4.56(1H，m)，8.33(1H，s)。
MS
m/
Z：330(M-1)。
(c) 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
Will 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and piperidines-3-yl } acetate (0.152g, 0.459mmol), EDCI (0.114g, 0.596mmol), HOBt (0.081g, 0.596mmol), 1-phenyl methanesulfonamide acid amides (0.102g, 0.596mmol) and DIPEA (0.160mL 917mmol) is dissolved in DCM (6mL) and stirring at room 18 hours.Reaction mixture is with EtOAc (50mL) dilution and with saturated NH
4Cl (2 * 40mL) and salt solution (40mL) washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (1: 4 EtOAc/ hexane 1.0%AcOH) obtains 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.065g (28%).
1H NMR(400MHz，CDCl
3)：δ1.35-1.40(3H，m)，1.53-1.58(1H，m)，1.64-1.71(1H，m)，1.73-1.80(1H，m)，1.93-2.00(1H，m)，2.11-2.22(2H，m)，2.27-2.34(1H，m)，2.68(3H，s)，3.09-3.16(1H，m)，3.30-3.38(1H，m)，4.29-4.40(4H，m)，4.68(2H，s)，7.37-7.38(5H，m)，7.70(1H，br s)，8.33(1H，s)。
MS
m/
Z：485(M+1)。
Embodiment 30
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl }-4-methyl piperidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
(a) piperidines-1, the 4-dioctyl phthalate 1-tertiary butyl-4-methyl ester
(3.00g 13mmol) is dissolved in MeOH (50mL) and dropwise add TMSCHN in room temperature with 1-(tert-butoxycarbonyl) piperidines-4-formic acid
2(the 2M hexane solution of 32.7mL, 65mmol).Add TMSCHN
2Up to producing persistent yellow, expression reagent is excessive.Dropwise add AcOH with the excessive TMSCHN of cancellation
2, and with the reaction mixture concentrating under reduced pressure and with methylbenzene azeotropic (3 * 30mL) MeOH or AcOH to remove any trace.Crude product piperidines-1,4-dioctyl phthalate 1-tertiary butyl 4-methyl ester is without being further purified use.
(b) 4-methyl piperidine-1,4-dioctyl phthalate 1-tertiary butyl 4-methyl ester
(2.40mL 17mmol) is dissolved in THF (60mL) and be cooled to 0 ℃ with DIPA.(9.81mL 16mmol) and with system stirred 1 hour at 0 ℃ dropwise to add the 1.6M hexane solution of butyllithium.Reaction mixture is cooled to-78 ℃ and in 30 minutes, dropwise add piperidines-1,4-dioctyl phthalate 1-tertiary butyl 4-methyl ester (3.18g, THF 13mmol) (30mL) solution.Reaction mixture was stirred 2 hours at-78 ℃, and disposable then adding contains methyl iodide, and (1.31mL, THF 21mmol) (10mL) also stirs reaction mixture 2 hours.Make system's ambient temperature overnight of rising again.Reaction mixture is with saturated NH
4Cl (100mL) cancellation and extracting among the EtOAc (100mL).The organism that merges washs with salt solution (70mL), dry (MgSO
4) and concentrating under reduced pressure, obtaining thick 4-methyl piperidine-1,4-dioctyl phthalate 1-tertiary butyl 4-methyl ester is solid, it is without being further purified use.
(c) 4-methyl piperidine-4-formic acid methyl ester
With 4-methyl piperidine-1,4-dioctyl phthalate 1-tertiary butyl 4-methyl ester (3.37g, 13.1mmol) be suspended among the THF (15mL) and add and contain 1 of 4M HCl, 4-dioxane (65.4mL, 262mmol), with reaction mixture in stirring at room up to falling to the starting raw material completely consumed by the TLC analysis and observation.With the reaction mixture concentrating under reduced pressure, obtain thick material.With this solid at saturated NaHCO
3And distribute between the DCM.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.(eluent 0.5%TEA, 2%MeOH/DCM-1%TEA 5%MeOH/DCM) obtain 4-methyl piperidine-4-formic acid methyl ester, are oily matter by purified by flash chromatography.Yield: 0.910g (44%).
1H NMR(400MHz，CDCl
3)：δ1.23(3H，s)，1.44-1.55(2H，m)，2.09-2.20(2H，m)，2.69-2.80(2H，m)，2.98-3.08(2H，m)，3.72(3H，s)，3.99(1H，br s)。
MS
m/
Z：158(M+1)。
(d) 4-methyl piperidine-4-formate hydrochlorate
With 4-methyl piperidine-4-formic acid methyl ester (0.300g, 1.9mmol) be suspended among the THF (30mL) and add trimethylammonium first potassium silicate (2.4g, 19mmol).System's reflux is spent the night, then cool to room temperature.Add and contain 1 of 4M HCl, (12mL 48mmol) and with system decompression concentrates the 4-dioxane, obtains thick 4-methyl piperidine-4-formate hydrochlorate, is solid, and it is without being further purified use.
(e) 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl]-4-methyl piperidine-4-formic acid
With 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester (0.28g, 1.3mmol) and 4-methyl piperidine-4-formate hydrochlorate (0.34g, 1.9mmol) be suspended among the DMF (20mL) and add DIPEA (1.1mL, 6.3mmol).Reaction mixture is in stirring at room, up to falling to the starting raw material completely consumed by the HPLC analysis and observation.Reaction mixture is with EtOAc (100mL) dilution and with saturated NH
4Cl (70mL), water (2 * 70mL) and salt solution (50mL) washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain thick material.Flash column chromatography (1: 3 EtOAc/ hexane, 0.5% AcOH to 1: 2 EtOAc/ hexanes 0.5%AcOH) obtain 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl]-4-methyl piperidine-4-formic acid, be solid.Yield: 0.179g (43%).
1H NMR(400MHz，DMSO-d
6)：δ1.20(3H，s)，1.30(3H，t，J＝7.1Hz)，1.44-1.54(2H，m)，2.02-2.11(2H，m)，2.63(3H，s)，3.39-3.48(2H，m)，4.15-4.29(4H，m)，8.32(1H，s)，12.52(1H，br s)。
MS
m/
Z：332(M+1)。
(f) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl }-4-methyl piperidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
In room temperature with 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl]-4-methyl piperidine-4-formic acid (0.074g, 0.22mmol), EDCI (0.056g, 0.29mmol) and HOBt (0.039g 0.29mmol) is dissolved in DCM (10mL).Reaction mixture is stirring at room 30 minutes, add then 1-phenyl methanesulfonamide acid amides (0.054g, 0.31mmol) and DIPEA (0.23mL, 1.3mmol).Reaction mixture in stirring at room up to falling to the starting raw material completely consumed by the HPLC analysis and observation.Reaction mixture is with DCM (20mL) dilution and with saturated NH
4Cl (20mL) washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (3: 7 EtOAc/ hexanes; 0.5%AcOH to 1: 1 EtOAc/ hexane; 0.5%AcOH), preparation property HPLC subsequently, obtain 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl-4-methyl piperidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.038g (35%).
1H NMR(400MHz，CDCl
3)：δ1.19(3H，s)，1.38(3H，t，J＝7.0Hz)，1.54-1.62(2H，m)，2.00-2.09(2H，m)，2.73(3H，s)，3.52-3.62(2H，m)，4.07-4.17(2H，m)，4.33(2H，q，J＝7.0Hz)，4.72(2H，s)，7.26-7.27(2H m)，7.37-7.39(3H，m)，7.47(1H s)，8.35(1H，s)。
MS
m/
Z：485(M+1)。
Embodiment 31
N-(benzyl alkylsulfonyl)-1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-methane amide
(a) amino 4-{[(benzyl alkylsulfonyl)] carbonyl } piperidines-1-formic acid tertiary butyl ester
Under nitrogen atmosphere in room temperature with triethylamine (591g, 5840mmol) join 1-(tert-butoxycarbonyl) piperidines-4-formic acid (448g of stirring, 1954mmol), LiCl (23.1g, 545mmol) and TBTU (657g is 2046mmol) in the suspension in THF (3000mL).(352g, in 1300mL THF, 2056mmol) solution and continuation are stirred and are spent the night to add 1-phenyl methanesulfonamide acid amides after 1.5 hours.Solvent removed in vacuo obtains dense thick ash-beige soup compound (the about 2500mL of volume).Add EtOAc (3500mL), add the HCl aqueous solution (1960mL 3.6MHCl and 1960mL water) subsequently.Remove water and organic phase is washed with 2 * 1500mL 1M HCl.Organic phase is cooled to 0 ℃, produces the HOBt precipitation, it is leached.Vacuum is removed major part and is desolvated, and obtains dense thick ash-white soup compound.Adding EtOH (50%, 4000mL) and with soup compound stirred 1.5 hours.Leach sedimentary product, with 50%EtOH (500mL+2 * 1500mL) washing and dry in 25 ℃ of vacuum drying ovens obtains 4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-formic acid tertiary butyl ester, be white solid.Yield: 584g (78%).
1H NMR(400MHz，CDCl
3)：δ1.46(9H，s)，1.54-1.61(2H，m)，1.70-1.74(2H，m)，2.19-2.27(1H，m)，2.68-2.75(2H，m)，4.07-4.12(2H，m)，4.66(2H，s)，7.32-7.41(5H，m)，7.54(1H，br s)。
(b) N-(benzyl alkylsulfonyl) piperidines-4-methane amide
Under nitrogen atmosphere with 4-[(benzyl alkylsulfonyl) formamyl] (583g 1524mmol) is suspended in the formic acid (3000mL) and will react stirring 20 minutes piperidines-1-formic acid tertiary butyl ester.Because gas is emitted, reaction produces foam, uses formic acid (500mL) that foam is washed down from reactor vessel wall.After 2 hours, foam stops, and reacts for transparent, leaves some solids.Reaction is stirred the formic acid that spends the night and remove 2500ml in a vacuum.Add entry (1000mL) and will react filtration.With clear solution evaporation and add entry (3000mL).Use saturated ammonium hydroxide aqueous solution (add total amount 390mL, pH from 3.10 to 6.10) with and acidic solution, and form a large amount of precipitations of product at terminal point (pH=6.10).Mixture stirred spend the night and precipitation leached and wash with water (1000mL).25 ℃ of vacuum-dryings, obtain N-(benzyl alkylsulfonyl) piperidines-4-methane amide, be white powder.Yield: 372.4g (87%).
1H NMR(400MHz，DMSO-d
6)：δ1.60-1.72(2H，m)，1.75-1.84(2H，m)，2.10-2.19(1H，m)，2.77-2.87(2H，m)，3.10-3.18(2H，m)，4.23(2H，s)，7.18-7.28(5H，m)，8.17(1H，br s)。
(c) N-(benzyl alkylsulfonyl)-1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-methane amide
With 2; 3-two chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine (0.300g, 1.23mmol), N-(benzyl alkylsulfonyl) piperidines-4-methane amide (0.367g; 1.30mmol) and DIPEA (0.645mL, 3.70mmol) suspension in DMA (10mL) stirred 24 hours at 80 ℃.With the reaction mixture cool to room temperature and pour into EtOAc (60mL) and saturated NH
4Among the Cl (30mL).The organism water (3 * 50mL), salt solution (1 * 50mL) washing, dry (MgSO
4) and concentrating under reduced pressure, obtain thick material.Flash chromatography (3: 7 EtOAc/ hexanes contain 0.5%AcOH) obtains N-(benzyl alkylsulfonyl)-1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-methane amide, be solid.Yield: 0.297g (49%).
1H NMR(400MHz，CDCl
3)：δ1.31(3H，t，J＝7.0Hz)，1.86-1.91(4H，m)，2.29-2.38(1H，m)，2.75(2H，q，J＝7.0Hz)，2.84-2.91(2H，m)，3.97-4.02(2H，m)，4.69(2H，s)，6.82(1H，s)，7.35-7.41(5H，m)，7.47(1H，br s)，8.15(1H，d，J＝2.0Hz)，8.74(1H，d，J＝2.0Hz)。
MS
m/
Z：489(M+1)。
Embodiment 32
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopentyl ester
(a) cyclopentanol sodium
Cyclopentanol (5mL) is cooled to 0 ℃.Slow adding sodium hydride (95%, 0.018g, 0.713mmol).Solution is used with crude product, suppose that 100% transforms.
(b) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopentyl ester
With 5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester (0.070g; 0.158mmol; referring to embodiment 46) and molecular sieve (4 dusts 0.070g) are suspended among cyclopentanol (5mL) and the DMSO (2mL) and stirring at room 10 minutes.Add and to contain cyclopentanol sodium (0.286g, cyclopentanol 3.48mmol) (5mL) and solution stirring 10 minutes.In mixture, dropwise add HCl (dense), be reduced to pH2 up to pH.Reaction mixture is filtered, then concentrating under reduced pressure.To solution add entry (10mL) and with the water that merges with EtOAc (3 * 40mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (30%EtOAc contains 0.5%AcOH) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopentyl ester, be solid.Yield: 0.031g (41%).
1H NMR(400MHz，DMSO-d
6)：δ1.56-1.64(2H，m)，1.69-1.80(4H，m)，1.84-1.95(2H，m)，2.63(3H，m)3.52-3.60(1H，m)，4.26-4.35(2H，m)，4.37-4.45(2H，m)，4.76(2H，s)5.22-5.30(1H，m)，7.31-7.43(5H，m)8.29(1H，s)，11.8(1H，s)。
MS
m/
Z：483(M+1)。
Embodiment 33
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid propyl diester
To 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-solution of 5-cyano group-2-methylnicotinic acid ethyl ester (0.078g, 0.17mmol is referring to embodiment 42) in THF (15mL) and n-propyl alcohol (15mL) adds 4 dust molecular sieves (0.5g).Reaction mixture was stirred 1 hour, be cooled to 0 ℃ then.Add NaH (60%, be dispersed in the mineral oil, 0.013g, 0.33mmol) afterwards, with rise again room temperature and stirring 2 hours of mixture.Add acetate (5.0mL), filter by diatomite, concentrate, (2 * 50mL) azeotropic obtain thick material with toluene subsequently.(1 * 25mL) grinds, and with EtOAc (1 * 25mL) grinds, and obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid propyl diester, is solid then with MeOH.Yield: 0.027g (34%).
1H NMR(400MHz，DMSO-d
6)：δ0.96(3H，t，J＝7.5Hz)，1.59-1.66(2H，m)，1.67-1.76(2H，m)，1.82-1.86(2H，m)，2.55-2.62(1H，m)，2.65(3H，s)，3.11-3.17(2H，m)，4.17(2H，t，J＝6.7Hz)，4.56-4.52(2H，m)，4.70(2H，s)，7.28-7.31(2H，m)，7.38-7.43(3H，m)，8.34(1H，s)，11.61(1H，br s)。
MS
m/
Z：485(M+1)。
Embodiment 34
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
(a) 2-((dimethylamino) methylene radical)-4-methyl-3-oxopentanoic acid ethyl ester
With 1,1-dimethoxy-N, N-dimethyl methylamine (4.96mL, 37.2mmol) dropwise join 4-methyl-3-oxopentanoic acid ethyl ester (5.00mL, 31.0mmol) in, simultaneously in stirring at room.Make reaction mixture stirring at room 18 hours, then concentrating under reduced pressure and with methylbenzene azeotropic (2 * 20mL), produce 2-((dimethylamino) methylene radical)-4-methyl-3-oxopentanoic acid ethyl ester, be oily matter, it is used for next step without being further purified.Yield: 6.61g (100%).
1H NMR(400MHz，CDCl
3)：δ1.09(6H，d，J＝6.9Hz)，1.31(3H，t，J＝7.3Hz)，3.00(6H，br s)，3.26(1H，br s)，4.21(2H，q，J＝7.3Hz)，7.60(1H，s)。
(b) 5-cyano group-2-sec.-propyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
To the 2-malonamide nitrile (2.74g, add in THF 32.6mmol) (100mL) suspension NaH (60%, be dispersed in the mineral oil, 1.36g, 34.1mmol).System in stirring at room, is emitted up to gas and to stop, at this moment, disposable adding 2-((dimethylamino) methylene radical)-4-methyl-3-oxopentanoic acid ethyl ester (6.61g, 31.0mmol).Reaction mixture obtains thick intermediate at stirring at room 18 hours and concentrating under reduced pressure.Solid is dissolved in minimum warm water, is acidified to pH1 with 5N HCl then.Filter, vacuum-drying subsequently obtains 5-cyano group-2-sec.-propyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester.Yield: 6.46g (89%).
1H NMR(400MHz，DMSO-d
6)：δ1.25(6H，d，J＝7.1Hz)，1.29(3H，t，J＝7.3Hz)，4.01-4.12(1H，m)，4.23(2H，q，J＝7.3Hz)，8.43(1H，s)，12.56(1H，br s)。
MS
m/
Z：235(M+1)。
(c) 6-chloro-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
With 5-cyano group-2-sec.-propyl-6-oxo-1, (6.46g is 27.6mmol) at POCl for 6-dihydropyridine-3-formic acid ethyl ester
3(10.1mL, 110mmol) suspension in was 100 ℃ of heating 6 hours.Reaction mixture is poured on ice, uses solid K then
2CO
3Alkalization.Water DCM (3 * 100mL) extract, and with organism drying (MgSO
4) and concentrating under reduced pressure, obtaining 6-chloro-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester, it is without being further purified use.Yield: 6.54g (93%).
1H NMR(400MHz，CDCl
3)：δ1.29(6H，d，J＝6.8Hz)，1.42(3H，t，J＝7.2Hz)，3.88-3.98(1H，m)，4.41(2H，q，J＝7.2Hz)，8.37(1H，s)。
MS
m/
Z：254(M+1)。
(d) N-(benzyl alkylsulfonyl) piperidines-4-carboxamide hydrochloride
To 4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-formic acid tertiary butyl ester (4.18g; 10.9mmol) THF (100mL) suspension in add the dioxane (54.6mL contain 4M HCl; 218mmol), and with reaction mixture stirring at room 18 hours.By solid collected by filtration and with EtOAc (100mL) washing, place then under the vacuum, obtain N-(benzyl alkylsulfonyl) piperidines-4-carboxamide hydrochloride, be solid.Yield: 2.50g (72%).
1H NMR(400MHz，DMSO-d
6)：δ1.70-1.78(2H，m)，1.83-1.88(2H，m)，2.47-2.53(1H，m)，2.80-2.89(2H，m)，3.26-3.31(2H，m)，4.71(2H，s)，7.27-7.30(2H，m)，7.39-7.41(3H，m)，8.53(1H，br s)，8.79(1H，br s)，11.70(1H，br s)。
(e) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
With 6-chloro-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester (0.184g; 0.728mmol), N-(benzyl alkylsulfonyl) piperidines-4-carboxamide hydrochloride (0.232g; 0.728mmol) and DIPEA (0.380mL, the 2.18mmol) mixture heating up to 60 in DMF (3.0mL) ℃ was kept 5 hours.Reaction mixture is with EtOAc (30mL) dilution, with saturated NH
4Cl (2 * 15mL) and salt solution (15mL) washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (DCM is subsequently with containing 1%MeOH, the DCM of 1%HOAc) obtains solid, with itself and 1: 1Et
2O/ hexane (25mL) grinds, and obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester, be solid.Yield: 0.300g (81%).
1H NMR(400MHz，CDCl
3)：δ1.22(6H，d，J＝6.5Hz)，1.38(3H，t，J＝7.3Hz)，1.74-1.90(4H，m)，2.41-2.48(1H，m)，3.11-3.18(2H，m)，3.95-4.05(1H，m)，4.32(2H，q，J＝7.3Hz)，4.64-4.69(4H，m)，7.31-7.33(2H，m)，7.37-7.43(3H，m)，8.10(1H，br s)，8.31(1H，s)。
MS
m/
Z：499(M+1)。
Embodiment 35
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester
(a) 2-((dimethylamino) methylene radical)-3-oxopentanoic acid ethyl ester
With 1,1-dimethoxy-N, N-dimethyl methylamine (5.09mL, 42.0mmol) dropwise join 3-oxopentanoic acid ethyl ester (5.0mL, 35.0mmol) in, simultaneously in stirring at room.With reaction mixture stirring at room 18 hours, then concentrating under reduced pressure and with methylbenzene azeotropic (2 * 20mL), produce 2-((dimethylamino) methylene radical)-3-oxopentanoic acid ethyl ester, be oily matter, its not purified use.Yield: 6.98g (100%).
1H NMR(400MHz，CDCl
3)：δ1.10(3H，t，J＝7.7Hz)，1.32(3H，t，J＝7.7Hz)，2.67-2.69(2H，m)，3.01(6H，br s)，4.22(2H，q，J＝7.2Hz)，7.64(1H，s)。
(b) 5-cyano group-2-ethyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
To the 2-malonamide nitrile (3.09g, 36.8mmol) add in the suspension in THF (100mL) NaH (60%, be dispersed in the mineral oil, 1.54g, 38.5mmol).Mixture is in stirring at room, emits up to gas to stop, at this moment disposable adding 2-((dimethylamino) methylene radical)-3-oxopentanoic acid ethyl ester (6.98g, 35.0mmol).Reaction mixture obtains thick intermediate at stirring at room 18 hours and concentrating under reduced pressure.Solid is dissolved in the warm water of minimum, is acidified to pH1 with 5M HCl then.Filter, vacuum-drying subsequently obtains 5-cyano group-2-ethyl-6-oxo-1, and 6-dihydropyridine-3-formic acid ethyl ester is solid.Yield: 6.28g (81%).
1H NMR(400MHz，DMSO-d
6)：δ1.18(3H，t，J＝7.3Hz)，1.29(3H，t，J＝7.0Hz)，2.95(2H，q，J＝7.3Hz)，4.24(2H，q，J＝7.0Hz)，8.45(1H，s)，12.79(1H，br s)。
MS
m/
Z：221(M+1)。
(c) 6-chloro-5-cyano group-2-ethyl nicotinic acid ethyl ester
With 5-cyano group-2-ethyl-6-oxo-1, (6.28g is 28.5mmol) at POCl for 6-dihydropyridine-3-formic acid ethyl ester
3(10.4mL, 114mmol) suspension in is heated to 100 ℃, keeps 6 hours.Reaction mixture is poured on ice, uses solid K then
2CO
3Alkalization.(3 * 100mL) extract and with organism drying (MgSO water with DCM
4) and concentrating under reduced pressure, obtain 6-chloro-5-cyano group-2-ethyl nicotinic acid ethyl ester, be solid, it is without being further purified use.Yield: 6.17g (91%).
1H NMR(400MHz，CDCl
3)：δ1.32(3H，t，J＝7.4Hz)，1.42(3H，t，J＝7.4Hz)，3.23(2H，q，J＝7.4Hz)，4.42(2H，q，J＝7.4Hz)，8.45(1H，s)。
MS
m/
Z：239(M+1)。
(d) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester
With 6-chloro-5-cyano group-2-ethyl nicotinic acid ethyl ester (0.143g; 0.599mmol), N-(benzyl alkylsulfonyl) piperidines-4-carboxamide hydrochloride (0.191g; 0.599mmol; referring to embodiment 34 (d)) and DIPEA (0.131mL; 1.80mmol) DMF (3.0mL) solution be heated to 60 ℃, kept 5 hours.Reaction mixture is with EtOAc (30mL) dilution, with saturated NH
4Cl (2 * 15mL) and salt solution (15mL) washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (DCM is subsequently with containing 1%MeOH, the DCM of 1%HOAc) obtains solid, with itself and 1: 1 Et
2O/ hexane (25mL) grinds, and obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester, be solid.Yield: 0.250g (84%).
1H NMR(400MHz，CDCl
3)：δ1.25(3H，t，J＝7.4Hz)，1.38(3H，t，J＝7.0Hz)，1.74-1.82(2H，m)，1.84-1.90(2H，m)，2.39-2.47(1H，m)，3.10-3.18(4H，m)，4.32(2H，q，J＝7.0Hz)，4.66-4.70(4H，m)，7.32-7.35(2H，m)，7.38-7.42(3H，m)，7.70(1H，br s)，8.35(1H，s)。
MS
m/
Z：485(M+1)。
Embodiment 36
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
(a) 1-{3-cyano group-5-[(2,2-dimethyl propoxy-) carbonyl]-6-picoline-2-yl } azetidine-3-formic acid
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (0.218g 0.92mmol) is suspended among THF (20mL) and the DMSO (4mL), and adds 2, and 2-dimethyl propylene-1-sodium alkoxide (3.684mL, 3.684mmol).Reaction mixture is in stirring at room, up to being converted into product by the HPLC analysis and observation fully to starting raw material.With 1N HCl (10mL) termination reaction, and reaction mixture water (50mL) diluted and extract EtOAc (in 2 * 40mL).With organism drying (MgSO
4) and concentrating under reduced pressure, obtain thick material.Flash chromatography (3: 7 EtOAc/ hexanes, 0.5%AcOH to 1: 1 EtOAc/ hexane 0.5%AcOH), obtains 1-{3-cyano group-5-[(2,2-dimethyl propoxy-) carbonyl]-6-picoline-2-yl } azetidine-3-formic acid, be solid.Yield: 0.167g (55%).
(b) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
In room temperature with 1-{3-cyano group-5-[(2,2-dimethyl propoxy-) carbonyl]-6-picoline-2-yl } azetidine-3-formic acid (0.080g, 0.24mmol), EDCI (0.060g, 0.31mmol) and HOBt (0.042g 0.31mmol) is dissolved in DCM (5mL).Reaction mixture is stirring at room 30 minutes, add then the phenyl methanesulfonamide acid amides (0.058g, 0.34mmol) and DIPEA (0.25mL, 1.45mmol).Reaction mixture in stirring at room up to falling to the starting raw material completely consumed by the HPLC analysis and observation.Reaction mixture is with DCM (20mL) dilution and with saturated NH
4Cl (20mL) washing.With the organism drying (MgSO that merges
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (3: the 7EtOAc/ hexane, 0.5%AcOH to 1: the 1EtOAc/ hexane, 0.5%AcOH); being prepared property HPLC subsequently; obtain 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester is solid.Yield: 0.016g (14%).
1H NMR(400MHz，CDCl
3)：δ1.02(9H，s)，2.74(3H，s)，3.26-3.56(1H，m)，3.97(2H，s)，4.43-4.50(4H，m)，4.69(2H，s)，7.36-7.56(5H，m)，8.27(1H，s)。
MS
m/
Z：485(M+1)。
Embodiment 37
N-(benzyl alkylsulfonyl)-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
(a) 5-cyano group-2-methyl-6-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,6-dihydropyridine-3-formic acid ethyl ester
With 5-cyano group-2-methyl-6-oxo-1, (8.81g 38.6mmol) is distributed in 8 Smith operation bottles the sodium salt of 6-dihydropyridine-3-formic acid ethyl ester fifty-fifty.To each bottle add DCM (3mL), [2-(chlorine methoxyl group) ethyl] (trimethylammonium) silicomethane (1.78g, 10.7mmol), add then DIPEA (2.07g, 16.0mmol).Each bottle was heated 10 minutes at 120 ℃ in the microwave oven of single node heating.To each bottle add other [2-(chlorine methoxyl group) ethyl] (trimethylammonium) silicomethane (0.445g, 2.68mmol) and continue 120 ℃ of single node heating 10 minutes.Reaction mixture is merged and vacuum filtration.Pass through SiO
2On purified by flash chromatography, used heptane/EtOAc 4: 1 or 3: 1, obtain pure product.Yield: 8.376g (58%).
1H NMR(400MHz，CDCl
3)：δ8.16(s，1H)，5.46(s，2H)，4.13(q，J＝7.2Hz，2H)，3.52(t，J＝8.0Hz，2H)，2.78(s，3H)，1.19(t，J＝7.2Hz，3H)，0.75(t，J＝8.0Hz，2H)，-0.18(s，9H)。
MS
m/
Z：335(M-1)。
(b) 5-cyano group-2-methyl-6-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-, 6-dihydropyridine-3-formic acid
With 5-cyano group-2-methyl-6-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1, (8.371g 24.9mmol) is dissolved in THF (50mL) to 6-dihydropyridine-3-formic acid ethyl ester, and adds 1M LiOH (100mL).With reaction mixture stirring at room 3 hours.According to LC/MS, conversion is completely.Add 4M HCl, to pH2-3.(3 * 100mL) extract water with EtOAc.Organic phase is merged and use dried over sodium sulfate, evaporate, obtain thick material.Yield: 8.35g (109%).According to LC/MS, formed 5-cyano group-2-methyl-6-{[2-(trimethyl silyl) oxyethyl group of isomery] methoxyl group } the nicotinic acid ethyl ester is as primary product, and it shows product/by product ratio of 25: 75.Do not attempt isomer separation.
MS
m/
Z：307(M-1)。
(c) 5-cyano group-N-(2-hydroxybutyl)-2-methyl-6-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,6-dihydropyridine-3-methane amide
With 5-cyano group-2-methyl-6-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,6-dihydropyridine-3-formic acid and isomer 5-cyano group-2-methyl-6-{[2-(trimethyl silyl) oxyethyl group] methoxyl group } the nicotinic acid ethyl ester is (according to LC/MS, ratio is 25: 75) mixture (7.67g 24.9mmol) is dissolved in DCM (125mL).Add EDCI (6.2g, 27.4mmol) and HOBt (5.04g, 37.3mmol) and with reaction mixture stirring at room 40 minutes.Add contain the amino propan-2-ol of 1-(2.44g, DIPEA 27.7mmol) (16.1g, 124.4mmol) and continue stirring at room 1.5 hours.According to LC/MS, at this moment have only less isomer to transform.Continuation is stirring at room 16 hours, on LC/MS without any further variation.Organic phase with 10% salt of wormwood (2 * 125mL), (2 * 125mL) extract salt solution, use dried over sodium sulfate, evaporate.Obtain the 12.21g crude product.By the purified by flash chromatography on the silica gel, using heptane/EtOAc, at first is 1: 2, is 1: 4 ratio wash-out then, obtain 5-cyano group-N-(2-hydroxybutyl)-2-methyl-6-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,6-dihydropyridine-3-methane amide.
Yield: 3.28g (35%).When all products all during wash-out, with heptane/EtOAc 1: 4+1% formic acid wash-out.Like this, obtain 5-cyano group-2-methyl-6-{[2-(trimethyl silyl) oxyethyl group of 2.46g] methoxyl group } the nicotinic acid ethyl ester.
1H NMR(400MHz，CDCl
3)：δ-0.13(s，9H)，0.87-0.77(m，5H)，1.44-1.31(m，2H)，2.58(s，3H)，3.15-3.06(m，1H)，3.46-3.38(m，1H)，3.60-3.50(m，4H)，5.41(s，2H)，7.26-7.21(m，1H)，7.77(s，1H)
MS
m/
Z：378(M-1)。
(d) 5-cyano group-2-methyl-6-oxo-N-(2-oxo butyl)-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,6-dihydropyridine-3-methane amide
(0.39g 3.05mmol) is dissolved in DCM (2mL) and solution is cooled to-78 ℃ with oxalyl chloride under nitrogen atmosphere.Dropping contains DMSO (0.37g, DCM 4.69mmol) (1mL), and mixture is less than 5 minutes-78 ℃ of stirrings.In 2 minutes processes, add and contain 5-cyano group-N-(2-hydroxybutyl)-2-methyl-6-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,6-dihydropyridine-3-methane amide (0.89g, stirred 1 hour at-78 ℃ by DCM 2.35mmol) (2mL) and continuation.Adding TEA (1.19g, 11.7mmol).After stirring 15 minutes, remove cooling bath and reaction mixture was stirred 15 minutes in envrionment temperature.Add entry (10mL) and (3 * 15mL) extract with DCM with water.With the organic phase merging and with dried over sodium sulfate and evaporation, obtain crude product, it is without being further purified use.Yield: 0.780g (88%).
1H NMR(500MHz，CDCl
3)：δ-0.12(s，9H)，0.81(t，J＝8.2Hz，2H)，0.97(t，J＝7.4Hz，2H)，2.40(q，J＝7.4Hz，2H)，2.63(s，3H)，3.55(t，J＝8.2Hz，2H)，4.09(d，J＝5.3Hz，2H)，5.45(s，2H)，7.50(t，J＝5.3Hz，1H)，7.86(s，1H)
MS
m/
Z：376(M-1)。
(e) 5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl-2-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,2-dihydropyridine-3-formonitrile HCN
With 5-cyano group-2-methyl-6-oxo-N-(2-oxo butyl)-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1, (2.761g 7.31mmol) is dissolved among the THF (9.6mL) and solution is transferred in 3 Smith operation bottles fifty-fifty 6-dihydropyridine-3-methane amide.Add (methoxycarbonyl amino-sulfonyl) triethyl ammonium hydroxide to each bottle, and inner salt (1.162g, 4.88mmol).Heated 2 minutes at 80 ℃ with the bottle sealing and in the microwave oven of single node heating.LC/MS to each bottle shows that conversion fully.Reaction mixture is merged and evaporation, obtain the thick material of 6.431g.Filter by silicon short column (10g), use heptane/EtOAc 1: 1 (100mL), obtain 5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl-2-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,2-dihydropyridine-3-formonitrile HCN.Yield: 1.766g (67%).
1H NMR(500MHz，CDCl
3)：δ-0.20(s，9H)，0.74(t，J＝8.0Hz，2H)，1.09(t，J＝7.5Hz，3H)，2.55(q，J＝7.5Hz，2H)，2.82(s，3H)，3.52(t，J＝8.0Hz，2H)，5.46(s，2H)，6.62(s，1H)，8.09(s，1H)
MS
m/
Z：358(M-1)。
(f) 5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl-2-oxo-1,2-dihydropyridine-3-formonitrile HCN
With TFA/DCM mixture (1: 1,10mL) join (5-(5-ethyl-1,3-oxazole-2-yl)-and 6-methyl-2-oxo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1,2-dihydropyridine-3-formonitrile HCN (1.682g, 4.68mmol) in and with reaction mixture stirring at room 4 hours.According to LC/MS, reaction is finished.Reaction mixture is evaporated.Add DCM (10mL) and, evaporate the mixture dried over sodium sulfate.Obtain the thick material of 0.263g.By the purified by flash chromatography on silica gel (Si-gel), use DCM/MeOH (then be 39: 1 at 69: 1), obtain title compound.Yield: 0.263g (82%).
1H NMR(300MHz，DMSO-d
6)：δ1.24(br t，J＝7.5Hz，3H)，2.68(s，3H)，2.73(br q，J＝7.5Hz，2H)，7.00(br s，1H)，8.51(s，1H)，12.97(s，1H)
MS
m/
Z：230(M+1)。
(g) 2-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl cigarette nitrile (nicotinonitrile)
With 5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl-2-oxo-1,2-dihydropyridine-3-formonitrile HCN (0.069g, 0.30mmol) be dissolved among the DCM (0.8mL) in the Smith operation bottle, add oxalyl chloride (0.573g at 0 ℃, 4.51mmol), add then DMF (0.022g, 0.3mmol).With heating in the sealed vial of reaction mixture in 50 ℃ of oil baths 2.5 hours.The expectation product of LC/MS demonstration 33% and 45% starting raw material.Continuation is stirred under identical temperature.After other 1.5 hours, add other DMF (0.022g, 0.30mmol).Under identical temperature, stirred other 7.5 hours.The expectation product of LC/MS demonstration 64% and 8% starting raw material.Mix with the reaction mixture evaporation and with the batch of material of preparation as follows:
With 5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl-2-oxo-1,2-dihydropyridine-3-formonitrile HCN (0.179g, 0.78mmol) be dissolved in the DCM (2.4mL) in the Smith operation bottle and add oxalyl chloride (1.486g at 0 ℃, 11.70mmol), add then DMF (0.057g, 0.78mmol).With heating in the sealed vial of reaction mixture in 50 ℃ of oil baths 4 hours.The expectation product of LC/MS demonstration 40% and 22% starting raw material.Add other DMF (0.057g, 0.78mmol).Under identical temperature, stirred other 16 hours.LC/MS shows 35% expectation product and does not have starting raw material.With this material evaporation.The batch of material that is combined by the flash chromatography on the silica gel carries out purifying, and use DCM/MeOH as eluent obtains 2-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl cigarette nitrile at 199: 1.Yield: 0.027g (10%).
1H NMR(400MHz，CDCl
3)：δ1.34(t，J＝7.5Hz，3H)，2.80(q，J＝7.5Hz，2H)，3.00(s，3H)，6.97(s，1H)，8.52(s，1H)
(h) 1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-formic acid
(0.056g 0.23mmol) is dissolved among the anhydrous EtOH (4mL) in the Smith operation bottle with 2-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl cigarette nitrile.(0.051g 0.40mmol) and with the bottle that seals heated 20 minutes at 120 ℃ in the microwave oven of single node heating to add piperidines-3-formic acid.LC/MS shows that reaction not exclusively.(0.233g, 2.30mmol) (0.015g, 0.11mmol), the bottle with sealing heated 20 minutes at 100 ℃ in the microwave oven of single node heating then with other piperidines-3-formic acid to add TEA.The LC/MS demonstration reacts completely.Reaction mixture is evaporated.Add 1M HCl (3mL) and use phase separator mixture DCM (3 * 3mL) extractions.Obtain crude product, it is without being further purified use.Yield: 0.086g (110%)
1H NMR(300MHz，CDCl
3)：δ1.17(t，J＝7.5Hz，3H)，1.78-1.62(m，2H)，1.99-1.86(m，2H)，2.51-2.39(m，1H)，2.67-2.57(m，5H)，3.16-3.04(m，2H)，4.43-4.32(m 2H)，6.70(br s，1H)，8.11(s，1H)
MS
m/
Z：341(M+1)。
(i) N-(benzyl alkylsulfonyl)-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
With 1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] (0.026g 0.0075mmol) is dissolved in DMF (1mL) to piperidines-4-formic acid.Add HATU (0.034g, 0.090mmol) and DIPEA (0.048g, 0.38mmol) and with reaction mixture stirring at room 15 minutes, add then 1-phenyl methanesulfonamide acid amides (0.013g, 0.075mmol).Continuation was stirring at room 4 hours.According to LC/MS, half the starting raw material of at this moment having an appointment transforms.Add other 1-phenyl methanesulfonamide acid amides (0.013g, 0.075mmol) and continue to spend weekend in stirring at room (64 hours).LC/MS shows that half the starting raw material of still only having an appointment transforms.(0.028g 0.075mmol) adds and continues to stir other 5.5 hours in room temperature to add other HATU.According to LC/MS, reaction is at this moment finished.By preparation property HPLC purifying, obtain pure product.Yield: 0.024g (64%).
1H NMR(400MHz，DMSO-d
6)：δ1.26(t，J＝7.6Hz，3H)，1.74-1.61(m，2H)，1.90-1.81(m，2H)，2.58-2.54(m，1H)，2.79-2.72(m，5H)，3.17-3.08(m，2H)，4.51-4.44(m，2H)，4.70(s，2H)，7.04(s，1H)，7.34-7.29(m，2H)，7.45-7.39(m，3H)，8.38(s，1H)，11.62(s，1H)
MS
m/
Z：494(M+1)。
Embodiment 38
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters
(a) propan-2-ol sodium
Virahol (5mL) is cooled to 0 ℃.Slow adding sodium hydride (95%, 0.088g, 3.48mmol).Solution is used with the crude product form, suppose that 100% transforms.
(b) 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] (0.400g 1.20mmol) is dissolved in Virahol (5mL) and stirring at room 10 minutes to azetidine-3-formic acid.Add and to contain propan-2-ol sodium (0.286g, Virahol 3.48mmol) (5mL) and solution stirring 10 minutes.In mixture, dropwise add HCl (dense), be reduced to pH2 up to pH.With the reaction mixture concentrating under reduced pressure.With the reaction mixture concentrating under reduced pressure.(3 * 40mL) wash water, dry (MgSO with EtOAc
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (100%EtOAc is to the 100%EtOAc that contains 0.5%AcOH) obtains 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid, be solid.Yield: 0.133g (51.0%).
1H NMR(400MHz，CDCl
3)：δ1.34(6H，d，J＝6.2Hz)，2.71(3H，s)，3.59-3.67(1H，m)，4.57-4.64(4H，m)，5.15-5.24(1H，m)，8.26(1H，s)。
MS
m/
Z：304(M+1)。
(c) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters
In room temperature with 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (and 0.047g, 0.153mmol), EDCI (0.035g, 0.184mmol) and HOBt (0.025g 0.184mmol) is dissolved among the DCM (1mL).With reaction mixture stirring at room 30 minutes, add then 1-phenyl methanesulfonamide acid amides (0.032g, 0.184mmol) and DIPEA (0.134mL, 0.767mmol).Reaction mixture was stirring at room 18 hours.Reaction mixture dilutes with EtOAc (40mL).The organism that merges is with saturated NH
4Cl (2 * 40mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Grind (4: 1 hexane/CH
2Cl
2), obtain 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters, be solid.Yield: 0.031g (44.3%).
1H NMR(400MHz，DMSO-d
6)：δ1.30(6H，d，J＝6.2Hz)，2.64(3H，s)，3.52-3.59(1H，m)，4.29-4.44(4H，m)，4.75(2H，m)，5.04-5.10(1H，m)，7.32-7.40(5H，m)，8.29(1H，s)，11.8(1H，s)。
MS
m/
Z：457(M+1)。
Embodiment 39
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters
(a) 2-((dimethylamino) methylene radical)-3-ketobutyric acid isopropyl esters
With 3-ketobutyric acid isopropyl esters (200mL, 1365mmol) in stirring at room and drip dimethoxy-N, N-dimethyl methylamine (242mL, 1706mmol).Make reaction mixture in stirred overnight at room temperature.With the reaction mixture vacuum concentration, (3 ' 300mL) azeotropic, and placing under the high vacuum obtain 2-((dimethylamino) methylene radical)-3-ketobutyric acid isopropyl esters, are oily matter, and it is without being further purified use with toluene then.Yield: 272g (100%).
1H NMR(400MHz，CDCl3)：δ1.30(6H，d，J＝6.2Hz)，2.32(3H，s)，5.07-5.17(1H，m)，7.64(1H，s)。
(b) 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid isopropyl esters
With NaH (33.359g, 834.07mmol) be suspended among the THF (700mL) and room temperature add in batches the 2-malonamide nitrile (58.905g, 700.62mmol).Emit when stopping when gas, add 2-((dimethylamino) methylene radical)-3-ketobutyric acid isopropyl esters (147.72g, THF 667.25mmol) (300mL) solution, and with system in stirred overnight at room temperature.With the reaction mixture concentrating under reduced pressure and solid is dissolved in the hot water of minimum.In solution, add 1N HCl, up to pH1, by the filtering separation solid.Solid is dry under high vacuum, obtain 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid isopropyl esters is solid, it is without being further purified use.Yield: 123g (84%).
1H NMR(400MHz，CDCl3)：δ1.37(6H，d，J＝6.2Hz)，2.84(3H，s)，5.18-5.28(1H，m)，8.50(1H，s)，13.04(1H，s)。
MS
m/
Z：221(M+1)。
(c) 6-chloro-5-cyano group-2-methylnicotinic acid isopropyl esters
With 5-cyano group-2-methyl-6-oxo-1, (123.04g, (204.58mL 2234.8mmol) and at 100 ℃ heated 5 hours 6-dihydropyridine-3-formic acid isopropyl esters 558.70mmol) to be suspended in POCl3.With reaction mixture cool to room temperature and concentrating under reduced pressure.Resistates dilutes with DCM and is poured on ice.With biphase mixture in stirring at room and use solid K lentamente
2CO
3Cancellation is up to all POCl
3All hydrolysis.With aqueous extraction in DCM, and with organism drying (MgSO
4) and by the silicon-dioxide short column.With the organism concentrating under reduced pressure, obtain 6-chloro-5-cyano group-2-methylnicotinic acid isopropyl esters, be solid, it is without being further purified use.Yield: 106g (79%).
1H NMR(400MHz，CDCl3)：δ1.40(6H，d，J＝6.2Hz)，2.90(3H，s)，5.23-5.30(1H，m)，7.26(1H，s)，8.46(1H，s)。
MS
m/
Z：239(M+1)。
(d) 1-(3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid
With 6-chloro-5-cyano group-2-methylnicotinic acid isopropyl esters (25.000g, 104.75mmol), piperidines-4-formic acid (14.205g, 109.98mmol) and DIPEA (d 0.742) (54.735mL 314.24mmol) is suspended among the EtOH (200mL) and reflux 1 hour.With the reaction mixture cool to room temperature and be added drop-wise to and contain KHSO
4(71.316g is in water 523.74mmol) (2000mL).By solid collected by filtration and vacuum-drying, obtain 1-(3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid, be solid, it is without being further purified use.Yield: 35g (100%).
1H NMR(400MHz，CDCl3)：δ1.35(6H，d，J＝6.2Hz)，1.81-1.93(2H，m)，2.04-2.12(2H，m)，2.67-2.74(4H，m)，3.26-3.36(2H，m)，4.53-4.62(2H，m)，5.15-5.23(1H，m)，8.32(1H，s)。
MS
m/
Z：332(M+1)。
(e) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters
With 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (30.00g, 90.534mmol), EDCI (26.03g, 135.80mmol), 1-phenyl methanesulfonamide acid amides (20.15g, 117.69mmol), HOBt (13.46g, 99.59mmol) and DIPEA (47.308mL, 271.60mmol) be suspended among the DCM (400mL) and stirred 5 minutes, up to evenly.Made reaction mixture refluxed then 4 hours.With reaction mixture cool to room temperature and concentrating under reduced pressure.Crude product mixture is dissolved in EtOH (300mL) and is added drop-wise to the KHSO of quick stirring
4(61.64g, 452.67mmol) (3000mL) in the aqueous solution.Collect product by filtering, water (3 * 400mL) washing and vacuum-dryings (44.00g dry labor thing).The dry labor thing pulled an oar in Virahol (2000mL) and stir and heated 2 hours at 50 ℃.Compound by filtering separation and dry under high vacuum, is obtained 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters, be solid.Yield: 37.41g (85%).
1H NMR(400MHz，CDCl
3)：δ1.35(6H，d，J＝6.2Hz)，1.74-1.90(4H，m)，2.37-2.45(1H，m)，2.73(3H，s)，3.10-3.17(2H，m)，4.63-4.67(4H，m)，5.17-5.23(1H，m)，7.33-7.42(5H，m)，7.48(1H，br s)，8.33(1H，s)。
MS
m/
Z：485(M+1)。
The crystalline form that obtains characterizes by the existence and the relative intensity value at the peak of the 2-θ scope that describes in detail in following table 2 when X-ray powder diffraction (XRPD) is measured.
| The peak mark | The angle (2-θ, °) | Relative intensity (%) |
| a | 4.945 | 100.0 |
| b | 7.142 | 3.4 |
| c | 9.337 | 26.8 |
| d | 9.863 | 15.9 |
| e | 10.324 | 18.1 |
| f | 12.960 | 2.9 |
| g | 13.398 | 17.6 |
| h | 14.327 | 60.9 |
| i | 14.800 | 4.1 |
| j | 17.096 | 4.6 |
| k | 18.344 | 6.5 |
| l | 18.668 | 5.0 |
| m | 19.094 | 9.6 |
| n | 19.800 | 5.2 |
| o | 20.130 | 15.1 |
| p | 20.674 | 20.2 |
| q | 21.073 | 7.3 |
| r | 21.865 | 25.6 |
| s | 22.563 | 7.8 |
| t | 23.033 | 18.4 |
| u | 23.849 | 13.7 |
| v | 24.209 | 6.4 |
| x | 24.789 | 17.9 |
| y | 25.458 | 6.1 |
| z | 26.055 | 5.0 |
| aa | 26.390 | 4.3 |
| ab | 27.072 | 6.3 |
| ac | 27.718 | 4.8 |
| ad | 28.721 | 9.8 |
| af | 29.783 | 10.5 |
| ag | 30.260 | 4.8 |
| ah | 30.840 | 4.8 |
| ai | 31.250 | 4.3 |
| ak | 34.511 | 4.3 |
| al | 36.014 | 4.4 |
| am | 37.174 | 4.1 |
| an | 37.855 | 3.5 |
| ao | 41.783 | 3.2 |
| ap | 43.320 | 4.9 |
| aq | 44.472 | 3.8 |
| ar | 45.346 | 3.1 |
Table 2:6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-the XRPD peak of the I shape of 5-cyano group-2-methylnicotinic acid ethyl ester
Embodiment 40
5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester and [(4-cyano group benzyl) alkylsulfonyl] (1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and piperidin-4-yl } carbonyl) sodium amide (Sodium...azanide)
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid
With 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester (3.00g, 13.35mmol), piperidines-4-formic acid (1.897g, 14.69mmol) and TEA (2.703g 26.71mmol) mixes and mixture was refluxed 10 minutes.LC/MS shows conversion fully.With reaction mixture evaporation, add entry/EtOAc1: 1 (100mL) and with aqueous phase as acidified to pH3.Separating EtOAc extracts with other EtOAc (40mL) mutually and with water.With the organic phase drying (Na that merges
2SO
4), filter and evaporation, obtain the thick material of 3.8g.
With preparation property HPLC at pH=7 (0.1M NH
4OAc/CH
3CN), subsequently transfer the pH=3 purifying to, obtain pure product.Yield: 1.9g (45%).
1H NMR(400MHz，CDCl
3)：δ1.38(t，J＝7.1Hz，3H)，1.94-1.82(m，2H)，2.13-2.05(m，2H)，2.75-2.66(m，5H)，3.37-3.27(m，2H)，4.33(q，J＝7.1Hz，2H)，4.63-4.55(m，2H)，8.36(s，1H)
MS
m/
Z：318(M+1)。
(b) 5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester and [(4-cyano group benzyl) alkylsulfonyl] (1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and piperidin-4-yl } carbonyl) sodium amide
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.253g, 0.8mmol), 1-(4-cyano-phenyl) Toluidrin (0.188g, 0.96mmol) and HATU (0.425g, 1.12mmol) be dissolved in DMF and add TEA (0.161g, 1.6mmol).After other 30 minutes, (0.243g 1.6mmol) also will be reflected at stirred overnight at room temperature to add DBU.Reaction mixture is evaporated to dry doubling to be distributed resistates between EtOAc (40mL) and water (40mL).Separate organic phase, dry (Na
2SO
4), filter and evaporation, obtain yellow oil.By preparation property-HPLC (Kromasil C8 10uM; 50 * 300mm, 100mL/min, pH=7) purifying; obtain the pure 5-cyano group-6-[4-of 0.091g ({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester, be white solid.With this solid at CH
3Dilution and lyophilize among CN (6mL) and the 0.1MNaOH (1.9mL) obtain [(4-cyano group benzyl) alkylsulfonyl] ({ 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidin-4-yl } carbonyl) sodium amide, are white solid.Yield: 0.101g (24%).
1H NMR(400MHz，DMSO-d
6)：δ1.32(t，J＝7.2Hz，3H)，1.64-1.52(m，2H)，1.84-1.76(m，2H)，2.30-2.20(m，1H)，2.65(s，3H)，3.25-3.16(m，2H)，4.30-4.22(q，J＝7.2Hz，2H)，4.36(s，2H)，4.48-4.40(m，2H)，7.43(d，J＝8.2Hz，2H)，7.74(d，J＝8.2Hz，2H)，8.32(s，1H)
MS
m/
Z：496(M+1)
Embodiment 41
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester and [(4-benzyl chloride base) alkylsulfonyl] (1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and piperidin-4-yl } carbonyl) sodium amide
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.250g, 0.79mmol), 1-(4-chloro-phenyl-) Toluidrin (0.0.194g, 0.94mmol) and HATU (0.419g, 1.10mmol) be dissolved in DMF (5mL) and add TEA (0.161g, 1.60mmol).After other 30 minutes, (0.432g 1.58mmol) also will be reflected at stirred overnight at room temperature to add BEMP.Reaction mixture is evaporated to dry doubling to be distributed resistates between EtOAc (30mL) and water (40mL).To respectively be separated and water will be extracted with EtOAc (30mL).Separate the organic phase that merges, dry (Na
2SO
4), filter and evaporation, obtain oily matter.At preparation property-HPLC (Kromasil C810uM; 50 * 300mm, 100mL/min pH=7) goes up purifying; obtain the pure 6-[4-of 0.101g ({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester, be white solid.This solid is dissolved in CH
3Among CN (6mL) and the 0.1M NaOH (2.5mL) and lyophilize, obtain [(4-benzyl chloride base) alkylsulfonyl] ({ 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidin-4-yl } carbonyl) sodium amide 101mg, be white solid.Yield: 0.118g (28%).
1H NMR(400MHz，DMSO-d
6)：δ1.32(t，J＝7.2Hz，3H)，1.66-1.53(m，2H)，1.85-1.76(m，2H)，2.32-2.22(m，1H)，2.65(s，3H)，3.25-3.16(m，2H)，4.30-4.22(m，4H)，4.49-4.41(m，2H)，7.26(d，J＝8.4Hz，2H)，7.33(d，J＝8.4Hz，2H)，8.32(s，1H)
MS
m/
Z：505(M+1)。
Embodiment 42
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
In room temperature with 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester (47.5g; 211mmol) and triethylamine (58.36g; EtOH 577mmol) (314ml) solution joins N-(benzyl alkylsulfonyl) piperidines-4-methane amide (53.55g of stirring; 189.7mmol; referring to embodiment 31 (b)) and the mixture of EtOH (100ml) in, and mixture heating up to 100 ℃ 15 minutes (bathed temperature, in the process was 20-100 ℃ at 40 minutes; 100 ℃ kept 15 minutes, then cool to room temperature).Add KHSO
4The solution of (142.93g is in 900mL water) makes product be precipitated out.(2 * 250mL) washings obtain 87g crude product (84% is pure) to leach precipitation and water.Crude product pulled an oar in 50%EtOH (1200mL) and be heated to 50 ℃ (bathing temperature), kept 2 hours 45 minutes, subsequently stirred overnight at room temperature.Filtration obtains crude product, and it is passed through at 50 ℃ with 25%EtOH (1600mL) stirring 2 hours, subsequently 50 ℃ and 20%EtOH (1000mL) stirring further washing in 2 hours.(by the not success of trial of using this material of 50%EtOH/ purifying aqueous solutions, because it dissolves too many product).To be dissolved among the 700mL EtOAc through the solid (89% is pure) that above-mentioned washing obtains and solution crystallization is at room temperature spent the night at 70 ℃.Leach crystal and, after drying, obtain pure 6-(4-{[(benzyl alkylsulfonyl) amino with EtOAc (200mL) washing] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester, be orange solids (fine acicular).Yield: 54.94g.Use EtOAc to make this solid, obtain another part 10.50g from the mother liquor recrystallization.Yield: 65.44g (73%).Product also can be from CHCl
3Crystallization.
1H NMR(400MHz，CDCl
3)：δ1.38(3H，t，J＝7.0Hz)，1.77-1.91(4H，m)，2.37-2.44(1H，m)，2.73(3H，s)，3.10-3.17(2H，m)，4.33(2H，q，J＝7.0Hz)，4.64-4.68(4H，m)，7.36-7.41(5H，m)，8.36(1H，s)。
MS
m/
Z：471(M+1)。
The product (I shape) that obtains from the EtOAc crystallization is by the existence and the relative intensity value sign at the peak of the 2-θ scope that describes in detail following table 3 when X-ray powder diffraction (XRPD) is measured, from CHCl
3The product (II shape) that middle crystallization obtains characterizes in following table 4.
| The peak mark | The angle (2-θ, °) | Relative intensity (%) |
| a | 6.763 | 100.0 |
| b | 9.500 | 3.4 |
| c | 9.661 | 3.6 |
| d | 10.019 | 6.1 |
| e | 13.377 | 4.7 |
| f | 13.540 | 3.7 |
| g | 14.381 | 7.4 |
| h | 14.764 | 5.3 |
| i | 19.070 | 6.6 |
| j | 19.437 | 6.5 |
| k | 20.380 | 37.1 |
| l | 21.604 | 4.6 |
| m | 22.902 | 4.5 |
| n | 23.252 | 3.5 |
| o | 24.878 | 5.0 |
| p | 25.459 | 6.0 |
| q | 25.762 | 24.3 |
| r | 25.821 | 12.5 |
| s | 27.298 | 3.7 |
| t | 27.736 | 4.4 |
| u | 34.301 | 4.2 |
| v | 41.444 | 4.4 |
Table 3:6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-the XRPD peak of the I shape of 5-cyano group-2-methylnicotinic acid ethyl ester
| The peak mark | The angle (2-θ, °) | Relative intensity (%) |
| A | 3.530 | 100.0 |
| B | 7.097 | 12.7 |
| C | 13.363 | 5.6 |
| D | 10.782 | 2.4 |
| E | 14.038 | 3.0 |
| F | 14.762 | 3.6 |
| G | 17.849 | 2.8 |
| H | 18.332 | 8.9 |
| I | 18.596 | 6.0 |
| J | 19.601 | 4.2 |
| K | 20.733 | 3.4 |
| L | 21.500 | 5.6 |
| M | 21.674 | 7.0 |
| N | 23.178 | 3.7 |
| O | 25.057 | 3.1 |
| P | 26.256 | 3.6 |
| Q | 26.738 | 2.9 |
| R | 33.755 | 2.5 |
| S | 41.031 | 2.9 |
Table 4:6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-the XRPD peak of the II shape of 5-cyano group-2-methylnicotinic acid ethyl ester
Crystalline form in addition can be further existence by following one or more additional properties characterize:
(i) for I shape
(I) when characterizing by thermogravimetric analysis, at 25 ℃ about 0.8% weight loss is arranged in 205 ℃ scope, and/or
(II) when characterizing, under nitrogen gas stream, have in the sealing cup of pin hole under the heating rate of 10 ℃ of per minutes, the about 194 ℃ fusions heat absorptions that begin melt temperature (Tm) to occur and/or follow about 96J/g by dsc; And/or
(III) when when 80%RH (environment) stores, absorption is less than 0.2% moisture.
(i) for II shape
(I) when characterizing by thermogravimetric analysis, at 25 ℃ about 0.2% weight loss is arranged in 205 ℃ scope, and/or
(II) when characterizing, under nitrogen gas stream, have in the sealing cup of pin hole under the heating rate of 10 ℃ of per minutes, the about 193 ℃ fusions heat absorptions that begin melt temperature (Tm) to occur and/or follow about 105J/g by dsc.
Embodiment 43
N-[(1,2-benzoisoxazole-3-ylmethyl) alkylsulfonyl]-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
With 1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] (0.026g 0.076mmol) is dissolved in DMF (1mL) to piperidines-4-formic acid.Add HATU (0.044g, 0.057mmol) and DIPEA (0.049g, 0.11mmol) and with reaction mixture stirring at room 15 minutes, add then 1-(1,2-benzoisoxazole-3-yl) Toluidrin (0.012g, 0.057mmol).Continuation was stirring at room 20 hours.By preparation property HPLC purifying, obtain title compound.Yield: 0.014g (46%).
1H NMR(400MHz，DMSO-d
6)：δ1.24(t，J＝7.5Hz，3H)，1.66-1.54(m，2H)，1.84-1.77(m，2H)，2.29-2.20(m，1H)，2.77-2.70(m，5H)，3.21-3.12(m，2H)，4.40-4.32(m，2H)，4.72(s，2H)，7.01(s，1H)，7.34(t，J＝7.8Hz，1H)，7.60(t，J＝7.8Hz，1H)，7.68(d，J＝8.1Hz，1H)，7.97(d，J＝8.1Hz，1H)，8.31(s，1H)
MS
m/
Z：535(M+1)。
Embodiment 44
N-(benzyl alkylsulfonyl)-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] azetidine-3-methane amide
(a) 1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] azetidine-3-formic acid
(0.028g 0.11mmol) is dissolved among the anhydrous EtOH (2mL) in Smith operation bottle with 2-chloro-5-(5-ethyl-1,3-oxazole-2-yl)-6-methyl cigarette nitrile.Add azetidine-3-formic acid (0.023g, 0.23mmol) and TEA (0.114g 1.13mmol) and with the bottle of sealing heated 20 minutes at 120 ℃ in the microwave oven of single node heating.LC/MS shows conversion fully.Reaction mixture is evaporated.Add 1M HCl (2mL).(3 * 2mL) extract with DCM with mixture to use phase separator.Organic phase is merged, with dried over sodium sulfate and evaporation.Obtain the 0.033g crude product.By the purified by flash chromatography on the silica gel, use DCM/MeOH 39: 1+1% formic acid obtains pure product as eluent.Yield: 0.026g (74%).
1H NMR(300MHz，CDCl
3)：δ1.31(t，J＝7.5Hz，3H)，2.80-2.70(m，5H)，3.70-3.57(m，1H)，4.68-4.57(m，4H)，6.88(br s，1H)，8.20(s，1H)
MS
m/
Z：313(M+1)。
(b) N-(benzyl alkylsulfonyl)-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] azetidine-3-methane amide
With 1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] (0.012g 0.038mmol) is dissolved in DMF (0.5mL) to piperidines-4-formic acid.Add HATU (0.018g, 0.046mmol) and DIPEA (0.025g, 0.19mmol) and with reaction mixture stirring at room 30 minutes, add then 1-phenyl methanesulfonamide acid amides (0.008g, 0.046mmol).Continuation was stirring at room 18 hours.According to LC/MS, at this moment do not form product.Add EDCI ((0.007g, 0.038mmol) and HOBt (0.008g, 0.058mmol) and continuation other 28 hours of stirring at room.(0.005g 0.029mmol) also continues to spend weekend in stirring at room (64 hours) to add other 1-phenyl methanesulfonamide acid amides.According to LC/MS, reaction is at this moment finished.By preparation property HPLC purifying, obtain pure product.Yield: 0.0005g (5%).
1H NMR(400MHz，CD
3Cl)：δ1.30(t，J＝7.6Hz，3H)，2.74(q，J＝7.6Hz，2H)，2.79(s，3H)，3.38-3.28(m，1H)，4.45-4.40(m，4H)，4.66(s，2H)，6.82(s，1H)，7.42-7.34(m，5H)，8.21(s，1H)
MS
m/
Z：466(M+1)。
Embodiment 45
N-[(4-benzyl chloride base) alkylsulfonyl]-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
With 1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] (0.026g 0.075mmol) is dissolved in DMF (1mL) to piperidines-4-formic acid.Add HATU (0.019g, 0.090mmol) and DIPEA (0.048g, 0.38mmol) and with reaction mixture stirring at room 15 minutes, add then 1-(4-chloro-phenyl-) Toluidrin (0.019g, 0.090mmol).Continuation was stirring at room 27.5 hours.According to LC/MS, reaction at this moment not exclusively.Add other HATU (0.028g, 0.075mmol) and 1-(4-chloro-phenyl-) Toluidrin (0.014g, 0.068mmol) and continue other 26 hours of stirring at room.LC/MS shows that reaction is complete nearly.By preparation property HPLC purifying, obtain pure product.Yield: 0.008g (18%).
1H NMR(400MHz，DMSO-d
6)：δ1.30-1.22(t，J＝7.5Hz，3H)，1.74-1.61(m，2H)，1.91-1.82(m，2H)，2.64-2.55(m，1H)，2.80-2.71(m，5H)，3.18-3.08(m，2H)，4.52-4.44(m，2H)，4.74(s，2H)，7.04(s，1H)，7.34(d，J＝8.3Hz，2H)，7.52(d，J＝8.3Hz，2H)，8.35(s，1H)，11.65(s，1H)。
MS
m/
Z：528(M+1)。
Embodiment 46
5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (20.00g, 69.14mmol), EDCI (19.88g, 103.7mmol), 1-phenyl-Toluidrin (15.39g, 89.88mmol), HOBt (10.276g, 76.049mmol) and DIPEA (36.127mL, 207.41mmol) be suspended among the DCM (500mL) and stirring at room 5 minutes, up to evenly.Made reaction mixture refluxed then 3 hours.With reaction mixture cool to room temperature and concentrating under reduced pressure.Crude product mixture is dissolved in EtOH (400mL) and is added drop-wise to the KHSO of quick stirring
4(47.07g is 345.68mmol) in the aqueous solution (4000mL).Collect product by filtering, water (3 * 500mL) washings and drying (30.61g desciccate) under vacuum.With desciccate at EtOH (1500mL)) in making beating and stir and 50 ℃ of heating 1 hour.By filtering separation compound and dry under high vacuum, the material that obtains expecting is crystal.Yield: 27.65g (90%).
1H NMR(400MHz，DMSO-d
6)δ1.23(t，J＝7.2Hz，3H)，2.57(s，3H)，3.43(m，1H)，4.17(q，J＝7.1Hz，2H)，4.23(t，J＝7.1Hz，2H)，4.34(t，J＝8.9Hz，2H)，4.68(s，2H)，7.29(m，5H)，8.33(s，1H)，11.75(s，1H)
MS
m/
Z：443(M+1)
Crystal characterizes by the existence and the relative intensity value at the peak of the 2-θ scope that describes in detail in following table 5 when X-ray powder diffraction (XRPD) is measured.
| The peak mark | The angle (2-θ, °) | Relative intensity (%) |
| a | 5.388 | 100.0 |
| b | 7.293 | 12.0 |
| c | 10.049 | 6.2 |
| d | 10.796 | 28.8 |
| e | 13.263 | 4.1 |
| f | 13.949 | 16.4 |
| g | 14.597 | 21.8 |
| h | 16.177 | 3.1 |
| i | 17.691 | 3.8 |
| j | 18.888 | 5.0 |
| k | 20.053 | 10.7 |
| l | 20.477 | 12.6 |
| m | 20.990 | 15.9 |
| n | 21.608 | 26.7 |
| o | 22.577 | 9.1 |
| p | 23.991 | 16.0 |
| q | 24.872 | 9.6 |
| r | 26.203 | 7.9 |
| s | 26.761 | 7.7 |
| t | 27.188. | 11.8 |
| u | 31.221 | 4.9 |
| v | 34.030 | 5.6 |
The XRPD peak of the I shape of table 5:5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester
Embodiment 47
5-cyano group-6-{3-[({[3-(4-methoxyl group phenoxy group) propyl group] alkylsulfonyl } amino) carbonyl] azetidine-1-yl }-2-methylnicotinic acid ethyl ester
According to method A preparation, and use 3-(4-methoxyl group phenoxy group) propane-1-sulphonamide (the 0.105g crude product, 0.37mmol).Yield: 0.041g (32%).
1H NMR (400MHz, DMSO-d
6) δ 1.23 (t, J=7.1Hz, 3H), 2.03 (quintet, J=6.6Hz, 2H), 2.54 (s, 3H), 3.59 (s, 3H), (3.6-3.4 m, 3H is by the water imbrication), 3.94 (t, J=6.0Hz, 2H), 4.16 (q, J=7.1Hz, 2H), 4.27 (m, 2H), 4.38 (t, J=8.6Hz, 2H), 6.75 (m, 4H), 8.21 (s, 1H)
MS
m/
Z：517(M+1)
Embodiment 48
4-amino-6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chlorine apellagrin ethyl ester
(a) 4-amino-6-(3-(tert-butoxycarbonyl) azetidine-1-yl)-5-chlorine apellagrin ethyl ester
With 4-amino-5,6-dichloro-nicotinic acid ethyl ester (0.560g, 2.38mmol) be dissolved in DMA (5mL) and add azetidine-3-formic acid tertiary butyl ester (0.65g, 4.1mmol) and DIPEA (1.2mL, 7.1mmol).To be reflected at 90 ℃ of heating.After 4 hours, add other azetidine-3-formic acid tertiary butyl ester (0.32g, 2.0mmol) and DIPEA (1.0mL, 5.9mmol) and continue heating.After 2 hours, add other azetidine-3-formic acid tertiary butyl ester (0.45g, 2.9mmol) and DIPEA (1.0mL, 5.9mmol).With other 1.5 hours of reaction heating, will react cooling and concentrating under reduced pressure then.Resistates is dissolved in EtOAc (150mL) also with saturated NH
4Cl (2 * 75mL), the salt water washing, and dry (MgSO
4).Then solution decompression is concentrated and with crude product with flash chromatography (DCM is to 5%EtOAc/DCM) purifying, obtain 4-amino-6-(3-(tert-butoxycarbonyl) azetidine-1-yl)-5-chlorine apellagrin ethyl ester, be solid.Yield: 0.38g (45%).
1H NMR(400MHz，CDCl
3)：δ1.35(3H，t，J＝7.1Hz)，1.48(9H，s)，3.34-3.42(1H，m)，4.30(2H，q，J＝7.1Hz)，4.40-4.48(4H，m)，8.53(1H，s)。
MS
m/
Z：356(M+1)。
(b) 1-(4-amino-3-chloro-5-(ethoxy carbonyl) pyridine-2-yl) azetidine-3-formate hydrochlorate
(0.37g 1.0mmol) is dissolved in the dioxane solution (5mL) that contains 4M HCl with 6-(3-(tert-butoxycarbonyl) azetidine-1-yl)-4-amino-5-chlorine apellagrin ethyl ester.After at room temperature 14 hours, to react concentrating under reduced pressure and with DCM and EtOAc azeotropic, obtain 1-(4-amino-3-chloro-5-(ethoxy carbonyl) pyridine-2-yl) azetidine-3-formate hydrochlorate, it is without being further purified use. yield: 0.35g, (100%).
(c) 4-amino-6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chlorine apellagrin ethyl ester
With 1-(4-amino-3-chloro-5-(ethoxy carbonyl) pyridine-2-yl) azetidine-3-formate hydrochlorate (0.077g, 0.23mmol) with contain EDCI (0.057g, 0.30mmol) and HOBt (0.040g, DCM 0.30mmol) (4mL) mixing.Add then the phenyl methanesulfonamide acid amides (0.055g, 0.32mmol), add subsequently DIPEA (0.24mL, 1.4mmol).To react and stir 14 hours.To be reflected at EtOAc (75mL) and NH then
4Distribute between the Cl solution (20mL).Organism NH
4Salt solution (20mL) washing is used in Cl (20mL) washing then.With organic phase drying (MgSO
4) and concentrate.Crude product mixture is by column chromatography purifying (30 to the 50%EtOAc/ hexane, adds 0.5%HOAc then).Separate and obtain 4-amino-6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chlorine apellagrin ethyl ester, be solid.Yield: 0.070g (67%).
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.1Hz)，3.19-3.26(1H，m)，4.28-4.38(6H，m)，4.70(2H，s)，7.38-7.40(5H，m)，8.53(1H，s)。
MS
m/
Z：453(M+1)。
Embodiment 49
5-cyano group-2-methyl-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (0.058g, 0.2mmol) be dissolved in DMF (1mL) and add HATU (0.099g in room temperature, 0.26mmol), DIPEA (0.170mL, 1mmol) and 1-(3-aminomethyl phenyl) Toluidrin (0.037g, 0.2mmol), will react and stir 30 hours.Solvent removed in vacuo and with resistates (flow velocity: 30mL/min uses 0.1M NH for Kromasil C8 10 μ M, 20 * 100mm post by preparation property HPLC purifying
4OAc and CH
3The gradient of CN), obtain pure product.Yield: 0.019g (15%).
1H NMR(400MHz，DMSO-d
6)：δ1.32(t，J＝7.1Hz，3H)，2.33(s，3H)，2.65(s，3H)，3.53-3.62(m，1H)，4.21-4.34(m，4H)，4.39-4.47(m，2H)，4.72(s，2H)，7.13-7.32(m，4H)，8.33(s，1H)，11.81(br s，1H)。
MS
m/
Z：457(M+1)。
Embodiment 50
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
(a) 6-(4-(tert-butoxycarbonyl) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
With 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester (6.00g, 26.7mmol), piperidines-4-formic acid tertiary butyl ester hydrochloride (6.51,29.4mmol) and DIPEA (23.3mL, DMA 134mmol) (50mL) solution is heated to 80 ℃, keeps 2 hours.After cool to room temperature, reaction mixture is with EtOAc (300mL) dilution, with saturated NH
4Cl (4 * 50mL), salt solution (50mL) washing, dry (MgSO
4), by silica gel and concentrated.Flash chromatography produces 6-(4-(tert-butoxycarbonyl) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester, is solid.Yield: 8.85g (89%).
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.1Hz)，1.45(9H，s)，1.75-1.84(2H，m)，1.99-2.03(2H，m)，2.49-2.57(1H，m)，2.72(3H，s)，3.24-3.31(2H，m)，4.31(2H，q，J＝7.1Hz)，4.55-4.60(2H，m)，8.34(1H，s)。
MS
m/
Z：374(M+1)。
(b) 6-(4-(tert-butoxycarbonyl) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid
(6.65g, (1.0M, 107mL 107mmol) and with mixture heating up arrive backflow 5 hours to add the LiOH aqueous solution in THF 50mL solution 17.8mmol) to 6-(4-(tert-butoxycarbonyl) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester.After cool to room temperature, reaction is acidified to pH3.5 and extracts EtOAc (in 4 * 50mL) with 2M HCl.Organic extraction salt water washing, dry (MgSO
4), by silica gel and concentrated.Flash chromatography (the 20%EtOAc/ hexane contains 1%HOAc) obtains 6-(4-(tert-butoxycarbonyl) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid, is solid.Yield: 1.8g (29%)
1H NMR(400MHz，DMSO-d
6)：δ1.41(9H，s)，1.53-1.63 92H，m)，1.90-1.94(2H，m)，2.55-2.60(1H，m)，2.64(3H，s)，3.21-3.28 2H，m)，4.40-4.44(2H，m)，8.30(1H，s)，12.91(1H，br s)。
MS
m/
Z：350(M+1)。
(c) 6-[4-(tert-butoxycarbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
With 6-(4-(tert-butoxycarbonyl) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid (0.845g, 2.45mmol), neopentyl alcohol (1.30g, 14.7mmol), EDCI (2.11g, 11.0mmol), HOBt (0.496g, 3.67mmol) and DIPEA (0.852mL, 4.89mmol) solution be heated to 80 ℃, kept 2 days.Reaction mixture is with EtOAc (50mL) dilution, with saturated NH
4Cl (3 * 30mL), the salt water washing, dry (MgSO
4), by silica gel and concentrated.Flash chromatography (3%EtOAc/ hexane) obtains 6-[4-(tert-butoxycarbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester is solid.Yield: 1.02g (41%).
1H NMR(400MHz，CDCl
3)：δ1.02(9H，s)，1.46(9H，s)，1.76-1.85(2H，m)，2.00-2.03(2H，m)，2.49-2.57(1H，m)，2.73(3H，M)，3.25-3.31(2H，m)，3.96(2H，s)，4.56-4.60(2H，m)，8.32(1H，s)。
MS
m/
Z：416(M+1)。
(d) 1-{3-cyano group-5-[(2,2-dimethyl propoxy-) carbonyl]-6-picoline-2-yl } piperidines-4-formic acid
At 0 ℃ to 6-[4-(tert-butoxycarbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid 2, (0.415g adds TFA (10mL) and reaction mixture was stirred 2 hours 2-dimethyl propyl ester in DCM 0.999mmol) (10mL) solution.Concentrate and obtain 1-{3-cyano group-5-[(2,2-dimethyl propoxy-) carbonyl]-6-picoline-2-yl } piperidines-4-formic acid, it uses with crude product, supposes that 100% transforms.
MS
m/
Z：513(M+1)。
(e) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
With 1-{3-cyano group-5-[(2,2-dimethyl propoxy-) carbonyl]-6-picoline-2-yl } piperidines-4-formic acid (0.120g, 0.334mmol), EDCI (0.0832g, 0.434mmol) and DIPEA (0.291mL, DCM 1.67mmol) (3mL) solution was stirring at room 30 minutes.(0.0686g 0.401mmol) also continues to stir 18 hours to add the phenyl methanesulfonamide acid amides.(0.0832g, 0.434mmol) (0.0686g 0.401mmol) and with reaction mixture stirred 3 days, with EtOAc (50mL) dilution, with saturated NH with the phenyl methanesulfonamide acid amides to add other EDCI
4Cl (3 * 30mL), the salt water washing, dry (MgSO
4) and concentrate.Flash chromatography (1: 4 EtOAc/ hexane contains 1%HOAc) obtains 6-(4-{[(benzyl alkylsulfonyl) amino by the reversed-phase HPLC purifying subsequently] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester is solid.Yield: 0.0175g (10%).
1H NMR(400MHz，CDCl
3)：δ1.03(9H，s)，1.78-1.91(4H，m)，2.83-2.46(1H，m)，2.74(3H，s)，3.11-3.18(2H，s)，3.97(2H，s)，4.65-4.70(4H，m)，7.34-7.35(2H，m)，7.39-7.41(3H，m)，8.34(1H，s)。
MS
m/
Z：513(M+1)。
Embodiment 51
5-cyano group-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
At 0 ℃ with thionyl chloride (0.119g, 1mmol) joining 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] (0.058g is in DCM 0.2mmol) (1mL) solution and make rise again room temperature and stirring 30 minutes of reaction mixture for azetidine-3-formic acid.With DCM and excessive thionyl chloride evaporation (resistates is dissolved in DCM (1mL) and evaporation again, repeats once), at 0 ℃ resistates is dissolved in pyridine, add subsequently 1-(4-aminomethyl phenyl) Toluidrin (0.044g, 0.24mmol).After stirring at room 2 hours, add DMAP (a little crystal) and continue and stirred 19 hours.Add BEMP (0.055g, 0.2mmol) and continue stirring at room 22 hours.LC/MS shows to have only starting raw material to exist.Room temperature to mixture add HATU (0.152g, 0.4mmol) and DIPEA (0.259g 2mmol), and continues stirring at room 20 hours.Solvent removed in vacuo and with resistates (flow velocity: 30mL/min uses 0.1M NH for Kromasil C8 10 μ M, 20 * 100mm post by preparation property HPLC purifying
4OAc and CH
3The gradient of CN), obtain pure product.Yield: 0.019g (15%).
1H NMR(400MHz，DMSO-d
6)：δ1.32(t，J＝7.0Hz，3H)，2.32(s，3H)，2.66(s，3H)，3.51-3.60(m，1H)，4.20-4.37(m，4H)，4.38-4.47(m，2H)，4.70(s，2H)，7.17-7.28(m，4H)，8.34(s，1H)，11.77(br s，1H)。
MS
m/
Z：457(M+1)。
Embodiment 52
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester and ({ 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidin-4-yl } carbonyl) [(4-luorobenzyl) alkylsulfonyl] sodium amide
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.350g, 1.10mmol), EDCI (0.274g, 1.43mmol)), 1-(4-fluorophenyl) Toluidrin (0.271g, 1.43mmol) and HOBt (0.194g, 1.43mmol) be suspended among the DCM (8mL) and in soup compound, add DIPEA (0.713g, 5.51mmol).Reaction becomes homogeneous after 30 minutes, continues to stir and spends the night.Solvent removed in vacuo also is dissolved in EtOAc (20mL) with resistates.Organic phase 0.5M KHSO
4(5mL), water (5mL) washs and evaporation, obtains crude product.By preparation property HPLC (Kromasil C8) purifying, obtain 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl of 0.429g]-2-methylnicotinic acid ethyl ester, be white solid.
1H NMR(400MHz，DMSO-d
6)
1.30(t，J＝7.2Hz，3H)，1.56-1.69(m，2H)，1.80-1.88(m，2H)，2.57(m，1H)，2.64(s，3H)，3.13(m，2H)，4.24(q，J＝7.2Hz，2H)，4.53(m，2H)，4.68(s，2H)，7.20-7.27(m，2H)，7.30-7.35(m，2H)，8.33(s，1H)，11.60(br s，1H)。
This solid is dissolved in CH
3CN (3mL), 0.1M NaOH (8.5mL) and last lyophilize, obtain (1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and piperidin-4-yl } carbonyl) [(4-luorobenzyl) alkylsulfonyl] sodium amide, be white solid.Yield: 0.444g (76%).
Embodiment 53
6-[4-({ [(3-bromobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
At 1-[3-cyano group-5-(the ethoxy carbonyl)-6-picoline-2-yl of room temperature to stirring] piperidines-4-formic acid (0.095g, 0.30mmol) DMF (1.5mL) solution in add HATU (0.205g, 0.54mmol) and DIPEA (0.194g, 1.5mmol), add subsequently 1-(3-bromophenyl) Toluidrin (0.090g, 0.36mmol) and reaction stirred 16 hours.Except that desolvating and crude product being passed through preparation property HPLC purifying (Kromasil C8,250mm * 50mm i.d., flow velocity 50mL/min, use 0.1M NH in 40 minutes
4OAc/CH
3The gradient of CN 95/5 to 0/100).Yield: 0.035g (21%).
1H NMR(300MHz，DMSO-d
6)：δ1.32(t，J＝7.0Hz，3H)，1.58-1.74(m，2H)，1.80-1.90(m，2H)，2.00-2.15(m，1H)，2.66(s，3H)，3.10-3.22(m，2H)，4.27(q，J＝7.0Hz，2H)，4.51-4.61(m，2H)，4.75(s，2H)，7.29-7.35(m，1H)，7.37-7.44(m，1H)，7.47-7.51(m，1H)，7.60-7.66(m，1H)，8.36(s，1H)，11.68(br s，1H)。
MS
m/
Z：550(M+1)。
Embodiment 54
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester
(a) methylene radical 2-[(dimethylamino)]-3-ketobutyric acid benzyl ester
With 3-ketobutyric acid benzyl ester (82mL, 475mmol) in stirring at room and dropwise add 1,1-dimethoxy-N, N-dimethyl methylamine (76mL, 570mmol).With the reaction mixture stirred overnight at room temperature.With the reaction mixture vacuum concentration, then with methylbenzene azeotropic (3 * 200mL), and place under the high vacuum, obtain the 2-[(dimethylamino) methylene radical]-3-ketobutyric acid benzyl ester, be oily matter, it is without being further purified use.Yield: 117g (100%).
1H NMR(400MHz，CDCl
3)：δ2.32(3H，s)，3.02(6H，br s)，5.22(2H，s)，7.29-7.43(5H，m)，7.70(1H，s)。
(b) 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid benzyl ester
(19.9g, (39.9g is in THF 475mmol) (1L) suspension 498mmol) to join the 2-malonamide nitrile of stirring at room with NaH.Reaction mixture emitted up to gas in stirring at room stop.Add the 2-[(dimethylamino in batches) methylene radical]-3-ketobutyric acid benzyl ester (117.4g, 474.7mmol) and with reaction mixture in stirred overnight at room temperature.Add 1N HCl and with system stirring at room 1 hour, then with reaction mixture with the EtOAc dilution and extract.With organism drying (MgSO
4) and concentrating under reduced pressure, obtaining 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid benzyl ester is solid, it is without being further purified use.Yield: 111g (88%).
1H NMR(400MHz，DMSO-d
6)：δ2.63(3H，s)，5.29(2H，s)，7.34-7.47(5H，m)，8.72(1H，s)，12.82(1H，s)。
MS
m/
Z：267(M-1)。
(c) 6-chloro-5-cyano group-2-methylnicotinic acid
With 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid benzyl ester is suspended in POCl
3(43.44mL is 474.5mmol) and 100 ℃ of heated overnight.Reaction mixture cool to room temperature and being poured on ice.Water solid NaHCO
3The neutralization and extract among the DCM.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain this material.(gradient elution 30-50%EtOAc/ hexane 0.5%AcOH), obtains thick 6-chloro-5-cyano group-2-methylnicotinic acid to flash chromatography, is solid.Yield: 24.2g (26%).
1H NMR(400MHz，CDCl
3)：δ3.00(3H，s)，8.50(1H，s)。
MS
m/
Z：195(M-1)。
(d) 6-chloro-5-cyano group-2-methyl nicotinoyl chlorine
With 6-chloro-5-cyano group-2-methylnicotinic acid (4.00g, 20.4mmol) and oxalyl chloride (2.66mL, 30.5mmol) be suspended in DCM (75mL) and 80 ℃ the heating 1 hour.With reaction mixture concentrating under reduced pressure and with hexane and methylbenzene azeotropic.With the reaction mixture concentrating under reduced pressure, obtain thick 6-chloro-5-cyano group-2-methyl nicotinoyl chlorine then, it is without being further purified use.
(e) ring propyl alcohol
The ring propyl alcohol prepares according to following document: J.Org.Chem.41 (7), 1237-40,1976 and J.Org.Chem 45 (21), 4129-35,1980.
(e) 6-chloro-5-cyano group-2-methylnicotinic acid cyclopropyl ester
With 6-chloro-5-cyano group-2-methyl nicotinoyl chlorine (2.00g, 9.30mmol), the ring propyl alcohol (0.54mL, 9.30mmol) and DIPEA (1.62mL 9.30mmol) is suspended in DCM (40mL) and stirring at room 16 hours.Add entry (40mL) and stirred 5 minutes to this solution.With each layer separation and with organism water (2 * 40mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (hexane that contains 40%DCM) obtains 6-chloro-5-cyano group-2-methylnicotinic acid cyclopropyl ester, is solid.Yield: 0.500g (23%).
1H NMR(400MHz，CDCl
3)：δ0.85-0.92(4H，m)，2.90(3H，s)，4.38-4.45(1H，m)，8.41(1H，s)。
(f) 1-(3-cyano group-5-(ring propoxycarbonyl)-6-picoline-2-yl) azetidine-3-formic acid
With 6-chloro-5-cyano group-2-methylnicotinic acid cyclopropyl ester (0.084g, 0.354mmol), 3-azetidine formic acid (0.090g, 0.887mmol) and DIPEA (0.442mL 2.54mmol) is suspended in EtOH (4mL), refluxes then 1 hour.With reaction mixture cool to room temperature and concentrating under reduced pressure.Add EtOAc (50mL) and with reaction mixture with saturated NH
4Cl (2 * 50mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (hexane that contains 20%EtOAc contains the hexane that contains 20%EtOAc of 0.1%AcOH then) obtains 1-(3-cyano group-5-(ring propoxycarbonyl)-6-picoline-2-yl) azetidine-3-formic acid, is solid.Yield: 0.180g (71%).
1H NMR(400MHz，DMSO-d
6)：δ0.73-0.83(4H，m)，2.61(3H，s)，3.50-3.60(1H，m)，4.21-4.27(1H，m)，4.31-4.39(2H，m)，4.45-4.54(2H，m)，8.26(1H，s)，12.8(1H，s)。
(g) 6-(3-(benzyl sulfuryl amino formyl radical) azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester
With 1-(3-cyano group-5-(ring propoxycarbonyl)-6-picoline-2-yl) azetidine-3-formic acid (0.165g, 0.548mmol), EDCI (0.157g, 0.821mmol), phenyl methanesulfonamide acid amides (0.113g, 0.657mmol), HOBt (0.081g, 0.602mmol) and DIPEA (0.286mL, 1.64mmol) be suspended among the DCM (10mL), refluxed then 3 hours.With reaction mixture cool to room temperature and concentrating under reduced pressure.Crude product mixture is dissolved in IPA (10mL) and dropwise joins the KHSO of quick stirring
4(0.373g is 2.74mmol) in the aqueous solution (100mL).Collect product by filtering, water (3 * 20mL) washing and vacuum-dryings.Desciccate is pulled an oar in IPA (100mL), stir and 50 ℃ of heating 1 hour.Then solution was cooled off 3 hours at 0 ℃.By this material of filtering separation and dry under high vacuum, obtain 6-(3-(benzyl sulfuryl amino formyl radical) azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester, be solid, it is without being further purified use.Yield: 0.146g (53%).
1H NMR(400MHz，DMSO-d
6)：δ0.73-0.83(4H，m)，2.63(3H，s)，3.52-3.59(1H，m)，4.22-4.47(5H，m)，4.75(2H，s)，7.31-7.43(5H，m)，8.28(1H，s)，11.8(1H，s)。
MS
m/
Z：455(M+1)。
Embodiment 55
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
(a) 6-chloro-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
With thick 6-chloro-5-cyano group-2-methyl nicotinoyl chlorine (0.500g, 2.32mmol), 2,2,2-trifluoroethanol (1.69mL, 23.2mmol) and DIPEA (2.02mL, 11.63mmol) be suspended among the DCM (10mL) and in stirring at room, up to falling to the starting raw material completely consumed by the HPLC analysis and observation.Reaction mixture is with DCM dilution and with saturated NaHCO
3Washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain thick material.Flash chromatography (100%DCM) obtains 6-chloro-5-cyano group-2-methylnicotinic acid 2,2, and 2-trifluoroethyl ester is solid.Yield: 0.155g (24%).
(b) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
With 6-chloro-5-cyano group-2-methylnicotinic acid 2; 2; 2-trifluoroethyl ester (0.057g; 0.204mmol), N-(benzyl alkylsulfonyl) piperidines-4-carboxamide hydrochloride (0.085g; 0.266mmol; referring to embodiment 34 (d)) and DIPEA (0.18mL 1.023mmol) is suspended in DMF (5mL) and stirring at room 4 hours.Reaction mixture is dropwise joined the KHSO of stirring
4(0.195g is 1.43mmol) in the aqueous solution (50mL).By filtration collection product and dry under high vacuum, obtain 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester is a solid.Yield: 0.095g (88%).
1H NMR(400MHz，DMSO-d
6)：δ1.58-1.72(2H，m)，1.81-1.91(2H，m)，2.55-2.69(4H，m)，3.13-3.24(2H，m)，4.54-4.64(2H，m)，4.70(2H，s)，4.90-4.98(2H，m)，7.26-7.33(2H，m)，7.36-7.45(3H，m)，8.34(1H，s)，11.61(1H，s)。
MS
m/
Z：525(M+1)。
Embodiment 56
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
(a) 1-(3-cyano group-6-methyl-5-((2,2, the 2-trifluoro ethoxy) carbonyl) pyridine-2-yl) azetidine-3-formic acid
With 6-chloro-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester (0.155g, 0.556mmol), azetidine-3-formic acid (0.068g, 0.67mmol) and DIPEA (0.485mL 2.78mmol) was suspended in EtOH (10mL) and reflux 1 hour.With the reaction mixture cool to room temperature and dropwise join KHSO
4(0.53g is 3.89mmol) in the aqueous solution (100mL).By solid collected by filtration and vacuum-drying, the thick material that obtains expecting.Flash chromatography (eluent 30-50%EtOAc/ hexane 0.5%AcOH) obtains 1-(3-cyano group-6-methyl-5-((2,2, the 2-trifluoro ethoxy) carbonyl) pyridine-2-yl) azetidine-3-formic acid, is solid.Yield: 0.136g (71%).
1H NMR(400MHz，CDCl
3)：δ2.72(3H，s)，3.60-3.69(1H，m)，4.58-4.70(6H，m)，8.29(1H，s)。
MS
m/
Z：344(M+1)。
(b) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
With 1-(3-cyano group-6-methyl-5-((2,2, the 2-trifluoro ethoxy) azetidine-3-formic acid (0.068g pyridine-2-yl carbonyl)), 0.198mmol), phenyl methanesulfonamide acid amides (0.044g, 0.258mmol), EDCI (0.057g, 0.297mmol), HOBt (0.029g, 0.218mmol) and DIPEA (0.10mL 0.59mmol) was suspended in DCM (5mL) and reflux 4 hours.Reaction mixture is with DCM dilution and with saturated NH
4The Cl washing, organism drying (MgSO
4) and concentrating under reduced pressure, obtain thick material.Flash chromatography (gradient elution 30-50%EtOAc/ hexane 0.5%AcOH) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester is solid.Yield: 0.061g (62%).
1H NMR(400MHz，DMSO-d
6)：δ2.65(3H，s)，3.52-3.62(1H，m)，4.28-4.38(2H，m)，4.39-4.51(2H，m)，4.76(2H，s)，4.86-4.97(2H，m)，7.30-7.43(5H，m)，8.13(1H，s)，11.83(1H，s)。
MS
m/
Z：497(M+1)。
Embodiment 57
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
With 1-(3-cyano group-6-methyl-5-((2,2, the 2-trifluoro ethoxy) azetidine-3-formic acid (0.068g pyridine-2-yl carbonyl)), 0.198mmol), (4-chloro-phenyl-) Toluidrin (0.053g, 0.258mmol), EDCI (0.057g, 0.297mmol), HOBt (0.0294g, 0.218mmol) and DIPEA (0.104mL 0.594mmol) was suspended in DCM (5mL) and reflux 4 hours.Reaction mixture is with DCM dilution and with saturated NH
4The Cl washing is with organism drying (MgSO
4) and concentrating under reduced pressure, obtain thick material.Flash chromatography (gradient elution 30-50%EtOAc/ hexane 0.5%AcOH) obtains 6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester is solid.Yield: 0.067g (64%).
1H NMR(400MHz，DMSO-d
6)：δ2.65(3H，s)，3.54-3.64(1H，m)，4.27-4.38(2H，m)，4.41-4.52(2H，m)，4.78(2H，s)，4.85-4.97(2H，m)，7.33-7.41(2H，m)，7.42-7.50(2H，m)，8.31(1H，s)，11.85(1H，s)。
MS
m/
Z：531(M+1)。
Embodiment 58
6-(4-(benzyl sulfuryl amino formyl radical) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester
With 6-chloro-5-cyano group-2-methylnicotinic acid cyclopropyl ester (0.084g; 0.354mmol), N-(benzyl alkylsulfonyl) piperidines-4-carboxamide hydrochloride (0.100g; 0.354mmol; referring to embodiment 34 (d)) and DIPEA (0.185mL; 1.06mmol) be suspended in EtOH (3mL), refluxed then 1 hour.With reaction mixture cool to room temperature and concentrating under reduced pressure.Add EtOAc (50mL) and with reaction mixture with saturated NH
4Cl (2 * 50mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (hexane that contains 20%EtOAc is then with the hexane that contains 20%EtOAc that contains 0.1%AcOH) obtains 6-(4-(benzyl sulfuryl amino formyl radical) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester, is solid.Yield: 0.098g (57.2%).
1H NMR(400MHz，DMSO-d
6)：δ0.73-0.83(4H，m)，1.59-1.71(2H，m)，1.79-1.88(2H，m)，2.54-2.61(1H，m)，2.64(3H，s)，3.08-3.20(2H，m)，4.21-4.30(1H，m)，4.49-4.59(2H，m)，4.70(2H，s)，7.26-7.33(2H，m)，7.73-7.44(3H，m)，8.31(1H，s)，11.6(1H，s)。
MS
m/
Z：483(M+1)。
Embodiment 59
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclobutyl ester
With 5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester (0.080g, 0.181mmol) and molecular sieve (4
, 0.100g) be dissolved in cyclobutanol (1mL) and DMSO (2mL) and stirring at room 1 hour.(95%, 0.014g is 0.542mmol) and stirring at room 2 hours to add sodium hydride to reaction mixture.Add EtOAc (30mL) and reaction mixture filtered and pass through diatomite.Dropwise add HCl (dense) to mixture and be reduced to pH2 up to pH.With the reaction mixture concentrating under reduced pressure.Add entry (30mL) and with water with EtOAc (3 * 50mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (contain the hexane of 20%EtOAc, contain 0.1%AcOH) and grinding (1/1-Et
2The O/ hexane), obtain 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclobutyl ester, be solid.Yield: 0.020g (23%).
1H NMR(400MHz，DMSO-d
6)：δ1.61-1.71(1H，m)，1.77-1.85(1H，m)，2.10-2.22(2H，m)，2.29-2.40(2H，m)，2.64(3H，s)，3.53-3.60(1H，m)，4.27-4.35(2H，m)，4.38-4.46(2H，m)，4.75(2H，s)，5.04-5.13(1H，m)，7.31-7.43(5H，m)，8.35(1H，s)，11.8(1H，s)。
MS
m/
Z：469(M+1)。
Embodiment 60
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2-hydroxyethyl ester
With 5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester and molecular sieve (4
, 0.100g) be dissolved in ethylene glycol (2mL) and DMSO (2mL) and stirring at room 1 hour.(95%, 0.017g is 0.678mmol) and stirring at room 2 hours to add sodium hydride to reaction mixture.Add EtOAc (50mL) and reaction mixture filtered and pass through diatomite.Dropwise add HCl (dense) to mixture, be reduced to pH2 up to pH.With the reaction mixture concentrating under reduced pressure.Add entry (30mL) and with water with EtOAc (3 * 50mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Heating (hexane that contains 50%EtOAc, 50 ℃) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2-hydroxyethyl ester, be solid.Yield: 0.038g (37.1%).
1H NMR(400MHz，DMSO-d
6)：δ2.65(3H，s)，3.54-3.60(1H，m)，3.65-3.71(2H，m)，4.16-4.23(2H，m)，4.28-4.33(2H，m)，4.39-4.48(2H，m)，4.76(2H，s)，4.91-4.99(1H，m)，7.31-7.43(5H，m)，8.46(1H，s)，11.8(1H，s)。
MS
m/
Z：459(M+1)。
Embodiment 61
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester
With 5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester (0.100g, 0.226mmol) and molecular sieve (4
, 0.100g) be dissolved in benzylalcohol (5mL) and DMSO (1mL) and stirring at room 1 hour.(95%, 0.017g is 0.678mmol) and stirring at room 60 hours to add sodium hydride to reaction mixture.Add EtOAc (50mL) and reaction mixture filtered and pass through diatomite.Dropwise add HCl (dense) to mixture and be reduced to pH2 up to pH.With the reaction mixture concentrating under reduced pressure.Add entry (30mL) and with water with EtOAc (3 * 50mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (hexane is used the hexane that contains 20%EtOAc that contains the hexane of 20%EtOAc and contain 0.1%AcOH then) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester, be solid.Yield: 0.013g (12%).
1H NMR(400MHz，DMSO-d
6)：δ2.65(3H，s)，3.51-3.59(1H，m)，4.27-4.47(4H，m)，4.75(2H，s)，5.28(2H，s)，7.29-7.52(10H，m)，8.35(1H，s)，11.8(1H，s)。
Embodiment 62
5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
(a) 1-(3, the 4-dichlorophenyl) Toluidrin
With 1-(3, the 4-dichlorophenyl) methylsulfonyl chloride (1.00g, 3.85mmol) and ammonia (1.0M, in THF, 38.5mL 38.5mmol) is suspended in THF (2mL) and stirring at room 2 hours.With the reaction mixture concentrating under reduced pressure.Add EtOAc (50mL) and with organism with saturated NaHCO
3(2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtaining crude product, it is without being further purified use.Yield: 0.900g (97.3%).
1H NMR(400MHz，DMSO-d
6)：δ4.31(2H，s)，6.90(2H，s)，7.33-7.40(1H，m)，7.59-7.70(2H，m)。
(b) 5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
In room temperature with 1-(3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid (0.200g, 0.604mmol), EDCI (0.174g, 0.905mmol), HOBt (0.090g, 0.664mmol), (3, the 4-dichlorophenyl) Toluidrin (0.174g, 0.724mmol) and DIPEA (0.315mL 1.81mmol) is suspended in DCM (10mL) and stirring 16 hours.Reaction mixture dilutes with EtOAc (40mL).The organism that merges is with saturated NH
4Cl (2 * 40mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (hexane that contains 20%EtOAc is then with the hexane that contains 20%EtOAc that contains 0.1%AcOH) obtains 5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters, be solid.Yield: 0.292g (87%).
1H NMR(400MHz，DMSO-d
6)：δ1.30(6H，d，J＝6.2Hz)，1.56-1.70(2H，m)，1.78-1.89(2H，m)，2.54-2.62(1H，m)，2.65(3H，s)，3.08-3.20(2H，m)，4.46-4.59(2H，m)，4.77(2H，s)，5.02-5.14(1H，m)，7.25-7.32(1H，m)，7.54(1H，s)，7.67-7.76(1H，m)，8.33(1H，s)，11.7(1H，s)。
MS
m/
Z：553(M+1)。
Embodiment 63
5-cyano group-6-[3-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
In room temperature with 1-(3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl) azetidine-3-formic acid (0.200g, 0.691mmol), EDCI (0.199g, 1.04mmol), HOBt (0.103g, 0.760mmol), 1-(3, the 4-dichlorophenyl) Toluidrin (0.199g, 0.830mmol) and DIPEA (0.361mL 2.07mmol) is suspended in DCM (10mL) and stirring 16 hours.Reaction mixture dilutes with EtOAc (40mL).The organism that merges is with saturated NH
4Cl (2 * 40mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (the hexane that contains 20%EtOAc; then with containing the hexane that contains 20%EtOAc of 0.1%AcOH) obtain 5-cyano group-6-[3-({ [(3; the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.248g (70%).
1H NMR(400MHz，DMSO-d
6)：δ1.30(3H，t，J＝7.1Hz)，2.64(3H，s)，3.53-3.64(1H，m)，4.19-4.35(4H，m)，4.38-4.48(2H，m)，4.82(2H，s)，7.31-7.39(1H，m)，7.59-7.70(2H，s)，8.31(1H，s)，11.9(1H，s)。
MS
m/
Z：511(M+1)。
Embodiment 64
5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
In room temperature with 1-(3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid (0.200g, 0.630mmol), EDCI (0.181g, 0.945mmol), HOBt (0.094g, 0.693mmol), (3, the 4-dichlorophenyl) Toluidrin (0.182g, 0.756mmol) and DIPEA (0.329mL 1.89mmol) is suspended in DCM (10mL) and stirring 16 hours.Reaction mixture dilutes with EtOAc (40mL).The organism that merges is with saturated NH
4Cl (2 * 40mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (hexane that contains 20%EtOAc is then with the hexane that contains 20%EtOAc that contains 0.1%AcOH) obtains 5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.273g (80.3%).
1H NMR(400MHz，DMSO-d
6)：δ1.31(3H，t，J＝7.1Hz)，1.57-1.70(2H，m)，1.80-1.88(2H，m)，2.65(3H，s)，3.10-3.18(2H，m)，4.31(1H，s)，4.25(2H，q，J＝7.1Hz)，4.50-4.58(2H，m)，4.76(2H，s)，7.25-7.32(1H，m)，7.54(1H，s)，7.68-7.75(1H，m)，8.35(1H，s)，11.7(1H，s)。
MS
m/
Z：539(M+1)。
Embodiment 65
5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
(a) (4-cyano-phenyl) methanesulfonic sodium
With 4-(chloromethyl) benzonitrile (5.00g, 33.0mmol) and S-WAT (4.42g 42.9mmol) is suspended in the aqueous solution (100mL) that contains 30% acetone and stirring and refluxing 4 hours.Solution decompression is concentrated.Add 95%EtOH (300mL) and with solution 50 ℃ of heating.Then solution is cooled to 0 and filter, obtains crude product, be solid, it is without being further purified use.Yield: 7.43g (103%).
1H NMR(400MHz，DMSO-d
6)：δ3.80(2H，s)，7.45-7.53(2H，m)，7.68-7.76(2H，m)。
(b) (4-cyano-phenyl) methylsulfonyl chloride
(7.43g 33.9mmol) is suspended in DCM (250mL) and 0 ℃ of stirring with (4-cyano-phenyl) methanesulfonic sodium.(17.7g 84.7mmol), makes solution rise again and stirring at room 16 hours then to add phosphorus pentachloride.Add entry (100mL) and stirred 5 minutes.(2 * 100mL) wash, dry (MgSO with salt solution with each layer separation and with organism
4), filtering and simmer down to oily matter, it solidifies when leaving standstill, and without being further purified use.Yield: 7.00g (96%).
1H NMR(400MHz，DMSO-d
6)：δ3.86(2H，s)，7.43-7.54(2H，m)，7.70-7.79(2H，m)。
(c) 1-(4-cyano-phenyl) Toluidrin
(1.00g 4.64mmol) is suspended in DCM (25mL) and in stirring at room with 1-(4-cyano-phenyl) methylsulfonyl chloride.Add ammonium hydroxide (6.00mL, 46.4mmol) and with solution stirring at room 3 hours.(2 * 40mL) wash with DCM with each layer separation and with water.Organism drying (the MgSO that merges
4), filtering and the simmer down to solid, it is without being further purified use.Yield: 0.888g (98%).
1H NMR(400MHz，DMSO-d
6)：δ4.40(2H，s)，6.94(2H，s)，7.51-7.61(2H，m)，7.82-7.92(2H，m)。
(d) 5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
In room temperature with 1-(3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid (0.200g, 0.604mmol), EDCI (0.174g, 0.905mmol), HOBt (0.090g, 0.664mmol), (4-cyano-phenyl) Toluidrin (0.118g, 0.604mmol) and DIPEA (0.315mL 1.81mmol) is suspended in DCM (10mL) and stirring 16 hours.Reaction mixture dilutes with EtOAc (40mL).The organism that merges is with saturated NH
4Cl (2 * 40mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (hexane that contains 20%EtOAc is then with the hexane that contains 20%EtOAc that contains 0.1%AcOH) obtains 5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters, be solid.Yield: 0.232g (75%).
1H NMR(400MHz，DMSO-d
6)：δ1.30(6H，d，J＝6.2Hz)，1.56-1.70(2H，m)，1.80-1.89(2H，m)，2.54-2.63(1H，m)，2.65(3H，s)，3.08-3.19(2H，m)，4.49-4.58(2H，m)，4.84(2H，s)，5.03-5.13(1H，m)，7.47-7.54(2H，m)，7.88-7.94(2H，m)，8.33(1H，s)，11.7(1H，s)。
MS
m/
Z：510(M+1)。
Embodiment 66
5-cyano group-6-[3-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
In room temperature with 1-(3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl) azetidine-3-formic acid (0.200g, 0.691mmol), EDCI (0.199g, 1.04mmol), HOBt (0.103g, 0.760mmol), (4-cyano-phenyl) Toluidrin (0.136g, 0.691mmol) and DIPEA (0.361mL 2.07mmol) is suspended in DCM (10mL) and stirring 16 hours.Reaction mixture is with diluting EtOAc (40mL).The organism that merges is with washing saturated NH
4Cl (2 * 40mL), dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (hexane that contains 20%EtOAc is then with the hexane that contains 20%EtOAc that contains 0.1%AcOH) obtains 5-cyano group-6-[3-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.235g (73%).
1H NMR(400MHz，DMSO-d
6)：δ1.30(3H，t，J＝7.1Hz)，2.64(3H，s)，3.51-3.64(1H，m)，4.18-4.35(4H，m)，4.38-4.49(2H，m)，4.90(2H，s)，7.53-7.61(2H，m)，7.82-7.90(2H，m)，8.32(1H，s)，11.9(1H，s)。
MS
m/
Z：468(M+1)。
Embodiment 67
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
(a) 1-(4-fluorophenyl) Toluidrin
At 0 ℃ the ammonia bubbling is passed through THF (50mL), kept 5 minutes.To reaction mixture add 1-(4-fluorophenyl) methylsulfonyl chloride (1.00g, 4.80mmol) and make system's room temperature of rising again.Make the ammonia bubbling by other 5 minutes of system and reaction mixture was stirred other 30 minutes.Reaction mixture is with EtOAc (100mL) dilution and with saturated NH
4Cl (2 * 50mL), the salt water washing, dry (MgSO
4) and concentrating under reduced pressure, obtain 1-(4-fluorophenyl) Toluidrin, be solid, it is without being further purified use.Yield: 0.91g (100%).
1H NMR(400MHz，DMSO-d
6)：δ4.26(2H，s)，6.82(2H，s)，7.18-7.24(2H，m)，7.38-7.42(2H，m)。
(b) 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
With 1-(3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid (0.190g, 0.573mmol), 1-(4-fluorophenyl) Toluidrin (0.141g, 0.745mmol), HOBt (0.101g, 0.745mmol) and EDCI (0.143g, 0.745mmol) be suspended in DCM (4mL) and add DIPEA (0.300ml, 1.72mmol).With reaction mixture at stirred overnight at room temperature concentrating under reduced pressure then.Crude product mixture is dissolved in MeOH (1.5mL) and dropwise joins the KHSO of quick stirring
4(0.380g is 2.865mmol) in the aqueous solution (20mL).Collect product by filtering, water (3 * 10mL) washing and vacuum-dryings.Desciccate is pulled an oar in IPA (4mL) and is stirred and heated 1 hour at 50 ℃.By filtration collection compound and dry under high vacuum, obtain 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters, be solid.Yield: 0.150g (54%).
1H NMR(400MHz，DMSO-d
6)：δ1.30(6H，d，J＝6.2Hz)，1.57-1.70(2H，m)，1.80-1.89(2H，m)，2.50-2.65(1H，m)，2.65(3H，s)，3.09-3.20(2H，m)，4.49-4.58(2H，m)，4.70(2H，s)，5.04-5.12(1H，m)，7.21-7.29(2H，m)，7.30-7.38(2H，m)，8.32(1H，s)，11.62(1H，s)。
MS
m/
Z：503(M+1)。
Embodiment 68
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
(a) 1-(4-chloro-phenyl-) Toluidrin
At 0 ℃ the ammonia bubbling is passed through THF (50mL), kept 5 minutes.To reaction mixture add 1-(4-fluorophenyl) methylsulfonyl chloride (1.00g, 4.80mmol) and make system's room temperature of rising again.The ammonia bubbling was stirred other 30 minutes by other 5 minutes of system and with reaction mixture.Reaction mixture is with EtOAc (100mL) dilution and with saturated NH
4Cl (2 * 50mL), the salt water washing, dry (MgSO
4) and concentrating under reduced pressure, obtain 1-(4-chloro-phenyl-) Toluidrin, be solid, it is without being further purified use.Yield: 0.91g (100%).
(b) 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
With 1-(3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid (0.178g, 0.537mmol), (4-chloro-phenyl-) Toluidrin (0.144g, 0.698mmol), HOBt (0.0944g, 0.698mmol) and EDCI (0.134g, 0.698mmol) be suspended in DCM (4mL) and add DIPEA (0.476mL, 2.69mmol).With reaction mixture stirred overnight at room temperature concentrating under reduced pressure then.Crude product mixture is dissolved in MeOH (1.5mL) and dropwise joins the KHSO of quick stirring
4(0.380g is 2.865mmol) in the aqueous solution (20mL).Collect product by filtering, water (3 * 10mL) washing and vacuum-dryings.Desciccate is pulled an oar in IPA (5mL) and is stirred and heated 1 hour at 50 ℃.By filtering separation compound and dry under high vacuum, obtain 6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters, be solid.Yield: 0.150g (52%).
1H NMR(400MHz，DMSO-d
6)：δ1.30(6H，d，J＝6.2Hz)，1.60-1.70(2H，m)，1.80-1.89(2H，m)，2.50-2.65(1H，m)，2.65(3H，s)，3.09-3.19(2H，m)，4.50-4.58(2H，m)，4.72(2H，s)，5.04-5.12(1H，m)，7.31(2H，d，J＝8.4Hz)，7.49(2H，d，J＝8.4Hz)，8.32(1H，s)，11.63(1H，s)。
MS
m/
Z：519(M+1)。
Embodiment 69
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-isopropyl pyridine-2-yl] azetidine-3-formic acid
To 6-chloro-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester (0.286g, 1.13mmol) and DIPEA (0.591mL, 3.40mmol) DMF (3.0mL) solution in add azetidine-3-formic acid (0.132g 1.31mmol) and with the non-homogeneous mixture that obtains be heated to 90 ℃, keeps 3 hours.Reaction mixture is with EtOAc (75mL) dilution, with saturated NH
4Cl (3 * 50mL), salt solution (50mL) washing, dry (MgSO
4) and filter and pass through silica gel.Concentrate, carry out flash chromatography (1%HOAc, 20%EtOAc, hexane) subsequently, obtain 1-(3-cyano group-5-(ethoxy carbonyl)-6-isopropyl pyridine-2-yl) azetidine-3-formic acid, be solid.Yield: 0.118g (33%).
1H NMR(400MHz，CDCl
3)：δ1.20(6H，d，J＝6.6Hz)，1.37(3H，t，J＝7.5Hz)，3.60-3.68(1H，m)，3.95-4.02(1H，m)，4.31(2H，q，J＝7.5Hz)，4.57-4.65(4H，m)，8.24(1H，s)。
MS
m/
Z：318(M+1)。
(b) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
With 1-(3-cyano group-5-(ethoxy carbonyl)-6-isopropyl pyridine-2-yl) azetidine-3-formic acid (0.115g, 0.362mmol), EDCI (0.0834g, 0.435mmol), HOBtxH
2O (0.0666g, 0.435mmol), 1-phenyl methanesulfonamide acid amides (0.0620g, 0.362mmol) and DIPEA (0.189mL, DCM 1.09mmol) (3.0mL) solution was stirring at room 18 hours.Reaction mixture is with EtOAc (50mL) dilution and with saturated NH
4Cl (2 * 40mL) and salt solution (40mL) washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (1%MeOH, 1%HOAc DCM) obtain 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester, be solid.Yield: 0.125g (70%).
1H NMR(400MHz，CDCl
3)：δ1.20(6H，d，J＝6.6Hz)，1.38(3H，t，J＝6.8)，3.29-3.36(1H，m)，3.96-4.02(1H，m)，4.32(2H，q，J＝6.8Hz)，4.45-4.46(4H，m)，4.69(2H，s)，7.36-7.43(5H，m)，7.56(1H，br s)，8.24(1H，s)。
MS
m/
Z：471(M+1)。
Embodiment 70
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester
(a) 1-(3-cyano group-5-(ethoxy carbonyl)-6-ethylpyridine-2-yl) azetidine-3-formic acid
To 6-chloro-5-cyano group-2-ethyl nicotinic acid ethyl ester (0.290g, 1.22mmol) and DIPEA (0.635mL, 3.65mmol) DMF (3.0mL) solution in add azetidine-3-formic acid (0.135g 134mmol) and with the non-homogeneous mixture that obtains be heated to 90 ℃, keeps 3 hours.Reaction mixture is with EtOAc (75mL) dilution, with saturated NH
4Cl (3 * 50mL), salt solution (50mL) washing, dry (MgSO
4) and filter and pass through silica gel.Concentrate, carry out flash chromatography (1%HOAc, 20%EtOAc, hexane) subsequently and obtain 1-(3-cyano group-5-(ethoxy carbonyl)-6-ethylpyridine-2-yl) azetidine-3-formic acid, be solid.Yield: 0.047g (1%).
1H NMR(400MHz，CDCl
3)：δ1.22(3H，t，J＝7.4Hz)，1.37(3H，t，J＝7.0Hz)，3.10(2H，q，J＝7.4Hz)，3.60-3.68(1H，m)，4.31(2H，q，J＝7.4Hz)，4.58-4.66(4H，m)，8.27(1H，s)。
MS
m/
Z：304(M+1)。
(b) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester
With 1-(3-cyano group-5-(ethoxy carbonyl)-6-ethylpyridine-2-yl) azetidine-3-formic acid (0.0450g, 0.148mmol), EDCI (0.0341g, 0.178mmol), HOBtx.H
2O (0.0273g, 0.178mmol), 1-phenyl methanesulfonamide acid amides (0.0254g, 0.148mmol) and DIPEA (0.0775mL, DCM 0.445mmol) (3.0mL) solution was stirring at room 18 hours.Reaction mixture is with EtOAc (50mL) dilution and with saturated NH
4Cl (2 * 40mL) and salt solution (40mL) washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (1%MeOH, 1%HOAc DCM) obtain 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester, be solid.Yield: 0.055g (77%).
1H NMR(400MHz，CDCl
3)：δ1.23(3H，t，J＝7.6Hz)，1.38(3H，t，J＝7.1Hz)，3.11(2H，q，J＝7.6Hz)，3.29-3.36(1H，m)，4.32(2H，q，J＝7.1Hz)，4.45-4.47(4H，m)，4.69(2H，s)，7.36-7.44(5H，m)，7.57(1H，br s)，8.28(1H，s)。
MS
m/
Z：457(M+1)。
Embodiment 71
5-cyano group-2-methyl-6-[3-({ [(1-phenylethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
(a) N-(tertiary butyl)-1-phenyl methanesulfonamide acid amides
0 ℃ to the phenyl methanesulfonamide acyl chlorides (10.6g, 55.7mmol) and tert-butylamine (23.6mL, add in DCM 223mmol) (200mL) solution DIPEA (29.1mL, 167mmol).Make the reaction mixture room temperature of rising again, stirred 16 hours, concentrate then.Mixture is with EtOAc (1000mL) dilution, with saturated NH
4Cl (2 * 250mL), saturated NaHCO
3(2 * 250mL), salt solution (50mL) washing, dry (MgSO
4) and filter and pass through silica gel.Thick solid is at Et
2Carry out sonication in the mixture of O (100mL) and hexane (50mL), produce crystal, with its collection and with 1: 1 Et
2O/ hexane (50mL) and pure hexane (50mL) washing.Yield: 5.32g (44%).
1H NMR(400MHz，CDCl
3)：δ1.35(9H，s)，3.93(1H，br s)，4.24(2H，s)，7.35-7.41(5H，m)。
(b) N-(tertiary butyl)-1-phenyl ethyl sulfonamide
To be cooled to-78 ℃ N-(tertiary butyl)-1-phenyl methanesulfonamide acid amides (0.918g, dropwise add in THF 4.04mmol) (40mL) solution tert-butyl lithium (1.70M, in pentane, 4.75mL, 8.08mmol).Make reaction rise again 0 ℃, kept 1 hour, be cooled to-78 ℃ then.(0.252mL 4.04mmol) produces muddy mixture, and it was stirred 15 minutes at-78 ℃, stirs 1 hour at 0 ℃ then dropwise to add methyl iodide.Reaction mixture is with saturated NH
4Cl (25mL) cancellation is with EtOAc (75mL) dilution, with saturated NH
4Cl (3 * 50mL), salt solution (50mL) washing, dry (MgSO
4) and filter and pass through silica gel.Concentrate, carry out flash chromatography (DCM) subsequently and obtain N-(tertiary butyl)-1-phenyl ethyl sulfonamide, be oily matter.Yield: 0.900g (92%).
1H NMR(400MHz，CDCl
3)：δ1.30(9H，s)，1.78(3H，d，J＝7.3Hz)，3.69(1H，br s)，4.18(1H，q，J＝7.3Hz)，7.33-7.39(3H，m)，7.42-7.45(2H，m)。
(c) 1-phenyl ethyl sulfonamide
(0.900g, solution 3.73mmol) stirred 24 hours in TFA (50mL) with N-(tertiary butyl)-1-phenyl ethyl sulfonamide.Concentrate, (2 * 50mL) azeotropic produce crude product, it is dissolved in DCM (25mL) and by silica gel, produces 1-phenyl ethyl sulfonamide, are solid with toluene subsequently.Yield: 0.210g (30%).
1H NMR(400MHz，CDCl
3)：δ1.83(3H，d，J＝7.2Hz)，4.27-4.33(3H，m)，7.38-7.42(3H，m)，7.45-7.48(2H，m)。
(d) 5-cyano group-2-methyl-6-[3-({ [(1-phenylethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
With 1-(3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl) azetidine-3-formic acid (0.0700g, 0.242mmol), EDCI (0.0649g, 0.339mmol), HOBtxH
2O (0.0519g, 0.339mmol), 1-phenyl ethyl sulfonamide (0.0628g, 0.0.339mmol) and DIPEA (0.126mL, DCM 0.726mmol) (3.0mL) solution was stirring at room 18 hours.Reaction mixture is with EtOAc (50mL) dilution and with saturated NH
4Cl (2 * 40mL) and salt solution (40mL) washing.With organism drying (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (1%MeOH, 1%HOAc DCM) obtain 5-cyano group-2-methyl-6-[3-({ [(1-phenylethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester, be solid.Yield: 0.105g (95%).
1H NMR(400MHz，CDCl
3)：δ1.38(3H，t，J＝7.0Hz)，1.88(3H，d，J＝7.2Hz)，2.72(3H，s)，3.17-3.24(1H，m)，4.25-4.48(6H，m)，4.86(1H，q，J＝7.2Hz)，7.40-7.44(5H，m)，8.28(1H，s)。
MS
m/
Z：457(M+1)。
Embodiment 72
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid propyl diester
With 5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester (0.080g, 0.181mmol) and molecular sieve (4
, 0.100g) be dissolved in n-propyl alcohol (2mL) and DMSO (2mL) and stirring at room 1 hour.(95%, 0.014g is 0.542mmol) and in stirred overnight at room temperature to add sodium hydride to reaction mixture.Dropwise add HCl (dense) to mixture and be reduced to pH2 up to pH.With solid filtering and collection.With the reaction mixture concentrating under reduced pressure.Add entry (30mL) and with water with EtOAc (3 * 50mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid, itself and filtering solid are merged.Flash chromatography (contain the hexane of 10%EtOAc, contain 0.1%AcOH) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid propyl diester, be solid.Yield: 0.020g (24.2%).
1H NMR(400MHz，CDCl
3)：δ1.02(3H，t，J＝7.4Hz)，1.74-1.82(2H，m)，2.73(3H，s)，3.29-3.36(1H，m)，4.22(2H，t，J＝6.7Hz)，4.44-4.50(4H，m)，4.69(2H，s)，7.35-7.45(5H，m)8.29(1H，s)。
MS
m/
Z：457(M+1)。
Embodiment 73
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isobutyl
With 5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester (0.080g, 0.181mmol) and molecular sieve (4
, 0.100g) be dissolved in isopropylcarbinol (2mL) and DMSO (2mL) and stirring at room 1 hour.(95%, 0.014g is 0.542mmol) and stirring at room 4 hours to add sodium hydride to reaction mixture.Add EtOAc (30mL) and reaction mixture filtered and pass through diatomite.Dropwise add HCl (dense) to mixture and be reduced to pH 2 up to pH.With the reaction mixture concentrating under reduced pressure.Add entry (30mL) and with water with EtOAc (3 * 50mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product, be solid.Flash chromatography (hexane that contains 10%EtOAc that contains 0.1%AcOH) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isobutyl, be solid.Yield: 0.040g (47.0%).
1H NMR(400MHz，CDCl
3)：δ1.01(6H，d，J＝6.7Hz)，2.02-2.10(1H，m)，2.73(3H，s)，3.30-3.37(1H，m)，4.05(2H，d，J＝6.6Hz)，4.42-4.50(4H，m)，4.69(2H，s)，7.36-7.44(5H，m)，8.28(1H，s)。
MS
m/
Z：471(M+1)。
Embodiment 74
5-cyano group-2-methyl-6-{4-[({[4-(trifluoromethyl) benzyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid isopropyl esters
(a) 1-[4-(trifluoromethyl) phenyl] Toluidrin
With 1-(4-(trifluoromethyl) phenyl) methylsulfonyl chloride (1.00g, 3.87mmol) and ammonia (1.0M, in THF, 38.7mL 38.7mmol) is suspended in THF (2mL) and stirring at room 16 hours.With the reaction mixture concentrating under reduced pressure.Add EtOAc (50mL) and with organism with saturated NaHCO
3(2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtaining 1-(4-(trifluoromethyl) phenyl) Toluidrin, it is without being further purified use.Yield: 0.900g (97.3%).
1H NMR(400MHz，DMSO-d
6)：δ4.40(2H，s)，6.94(2H，s)，7.60(2H，d，J＝8.1Hz)，7.75(2H，d，J＝8.1Hz)。
(b) 5-cyano group-2-methyl-6-{4-[({[4-(trifluoromethyl) benzyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid isopropyl esters
With 1-(3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid (0.200g, 0.604mmol), EDCI (0.174g, 0.905mmol), 1-(4-(trifluoromethyl) phenyl) Toluidrin (0.173g, 0.724mmol), HOBt (0.090g, 0.664mmol) and DIPEA (0.315mL, 1.81mmol) be suspended in DCM (10mL), refluxed then 3 hours.With reaction mixture cool to room temperature and concentrating under reduced pressure.Crude product mixture is dissolved in IPA (10mL) and dropwise joins the KHSO of quick stirring
4(0.411g is 3.02mmol) in the aqueous solution (100mL).Collect product by filtering, water (3 * 20mL) washing and vacuum-dryings.Desciccate stirs and heats and carried out purifying in 1 hour by preparation slurry in IPA (100mL) and at 50 ℃.By filtering separation product and dry under high vacuum, obtain 5-cyano group-2-methyl-6-{4-[({[4-(trifluoromethyl) benzyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid isopropyl esters.Yield: 0.173g (52.0%).
1H NMR(400MHz，CDCl
3)：δ1.35(6H，d，J＝6.2Hz)，1.77-1.97(4H，m)，2.41-2.51(1H，m)，2.73(3H，s)，3.09-3.20(2H，m)，4.62-4.71(2H，m)，4.75(2H，s)，5.15-5.25(1H，m)，7.50(2H，d，J＝8.0Hz)，7.56(1H，s)，7.67(2H，d，J＝8.0Hz)，8.34(1H，s)。MS
m/
Z：553(M+1)。
Embodiment 75
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid isopropyl esters
To be dissolved in DCM (2mL) and DIPEA (0.155g, 1.2mmol) 1-(4-aminomethyl phenyl) Toluidrin (0.099g, 0.534mmol) join 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.124g, 0.374mmol) and TBTU (0.213g is in DCM 0.663mmol) (2mL) solution and will be reflected at stirring at room 15 hours.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.With the organic phase drying (MgSO that merges
4), filter and evaporation, obtain crude product.(flow velocity 25mL/min uses 0.1M NH for Kromasil C8,21.5 * 100mm post by preparation property HPLC
4OAc and CH
3The gradient of CN) purifying obtains pure product, is solid.Yield: 0.103g (55%).
1H NMR(500MHz，DMSO-d
6)：1.31(6H，d)，1.64(2H，m)，1.84(2H，m)，2.31(3H，s)，2.58(1H，m)，2.65(3H，s)，3.13(2H，m)，4.54(2H，m)，4.64(2H，s)，5.08(1H，m)，7.16-7.23(4H，dd)，8.33(1H，s)，11.56(1H，s)。
MS
m/
Z：499(M+1)
Embodiment 76
5-cyano group-2-methyl-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid isopropyl esters
With TBTU (0.100g, 0.311mmol) and DIPEA (0.074g, 0.574mmol) join 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] (0.104g is in DCM 0.314mmol) (2mL) solution and will be reflected at stirring at room 40 minutes for piperidines-4-formic acid.(0.071g 0.383mmol) adds with DCM (2mL) and continuation was stirred 18 hours with 1-(3-aminomethyl phenyl) Toluidrin.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.The organic phase that merges is filtered by phase separator and evaporation, obtain crude product.(flow velocity 25mL/min uses 0.1MNH for Kromasil C8,21.5 * 100mm post by preparation property HPLC
4OAc and CH
3The gradient of CN) purifying obtains pure product, is solid.Yield: 0.119g (76%).
1H NMR(500MHz，DMSO-d
6)：1.31(6H，d)，1.64(2H，m)，1.82(2H，m)，2.31(3H，s)，2.58(1H，m)，2.65(3H，s)，3.14(2H，m)，4.54(2H，m)，4.65(2H，s)，5.08(1H，m)，7.08-7.31(4H，m)，8.33(1H，s)，11.58(1H，s)。
MS
m/
Z：499(M+1)
Embodiment 77
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
With TBTU (0.097g, 0.302mmol) and DIPEA (0.074g, 0.574mmol) join 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.100g, in DCM 0.302mmol) (2mL) solution and with mixture stirring at room 2.5 hours.(0.074g 0.360mmol) adds with DCM (2mL) and continuation was stirred 18 hours with 1-(3-fluorophenyl) Toluidrin.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.The organic phase that merges is filtered by phase separator and evaporation, obtain crude product.(flow velocity 25mL/min uses 0.1MNH for Kromasil C8,21.5 * 100mm post by preparation property HPLC
4OAc and CH
3The gradient of CN) purifying obtains pure product, is solid.Yield: 0.115g (76%).
1H NMR(500MHz，DMSO-d
6)：1.31(6H，d)，1.63(2H，m)，1.83(2H，m)，2.59(1H，m)，2.65(3H，s)，3.14(2H，m)，4.54(2H，m)，4.75(2H，s)，5.08(1H，m)，7.12-7.47(4H，m)，8.32(1H，s)，11.68(1H，s)。
MS
m/
Z：503(M+1)
Embodiment 78
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
With TBTU (0.097g, 0.302mmol) and DIPEA (0.074g, 0.574mmol) join 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.100g, in DCM 0.302mmol) (2mL) solution and with mixture stirring at room 2.5 hours.Mixture joined contain 1-(2-fluorophenyl) Toluidrin (0.068g is among DCM 0.360mmol) (2mL) and continue to stir 18 hours.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.The organic phase that merges is filtered by phase separator and evaporation, obtain crude product.(flow velocity 25mL/min uses 0.1MNH for Kromasil C8,21.5 * 100mm post by preparation property HPLC
4OAc and CH
3The gradient of CN) purifying obtains pure product, is solid.Yield: 0.115g (76%).
1H NMR(500MHz，DMSO-d
6)：1.29(6H，d)，1.64(2H，m)，1.87(2H，m)，2.61(1H，m)，2.64(3H，s)，3.15(2H，m)，4.53(2H，m)，4.75(2H，s)，5.07(1H，m)，7.24-7.47(4H，m)，8.31(1H，s)，11.74(1H，s)。
MS
m/
Z：503(M+1)。
Embodiment 79
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
With TBTU (0.097g, 0.302mmol) and DIPEA (0.074g, 0.574mmol) join 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.100g, in DCM 0.302mmol) (2mL) solution and with mixture stirring at room 2.5 hours.Mixture joined contain 1-(3-chloro-phenyl-) Toluidrin (0.074g is among DCM 0.360mmol) (2mL) and continue to stir 18 hours.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.The organic phase that merges is filtered by phase separator and evaporation, obtain crude product.(flow velocity 25mL/min uses 0.1MNH for Kromasil C8,21.5 * 100mm post by preparation property HPLC
4OAc and CH
3The gradient of CN) purifying obtains pure product, is solid.Yield: 0.118g (75%).
1H NMR(500MHz，DMSO-d
6)：1.29(6H，d)，1.62(2H，m)，1.82(2H，m)，2.58(1H，m)，2.63(3H，s)，3.13(2H，m)，4.52(2H，m)，4.74(2H，s)，5.07(1H，m)，7.24-7.47(4H，m)，8.31(1H，s)，11.66(1H，s)。
MS
m/
Z：520(M+1)
Embodiment 80
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
With TBTU (0.097g, 0.302mmol) and DIPEA (0.074g, 0.574mmol) join 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.100g, in DCM 0.302mmol) (2mL) solution and with mixture stirring at room 2.5 hours.Mixture joined contain 1-(2-chloro-phenyl-) Toluidrin (0.074g is among DCM 0.360mmol) (2mL) and continue to stir 18 hours.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.The organic phase that merges is filtered by phase separator and evaporation, obtain crude product.(flow velocity 25mL/min uses 0.1MNH for Kromasil C8,21.5 * 100mm post by preparation property HPLC
4OAc and CH
3The gradient of CN) purifying obtains pure product, is solid.Yield: 0.116g (74%).
1H NMR(500MHz，DMSO-d
6)：1.29(6H，d)，1.65(2H，m)，1.89(2H，m)，2.63(1H，m)，2.63(3H，s)，3.15(2H，m)，4.53(2H，m)，4.85(2H，s)，5.07(1H，m)，7.38-7.54(4H，m)，8.31(1H，s)，11.80(1H，s)。
MS
m/
Z：520(M+1)
Embodiment 81
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] nicotinic acid ethyl ester and ({ 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidin-4-yl } carbonyl) [(4-methyl-benzyl) alkylsulfonyl] sodium amide
With TBTU (1.162g, 3.62mmol) and DIPEA (2.04g, 15.76mmol) join 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.100g, in DCM 0.302mmol) (53mL) solution and with mixture stirring at room 5 minutes.(0.67g 3.62mmol) also continues to stir to spend the night to add 1-(4-aminomethyl phenyl) Toluidrin.Reaction mixture is concentrated and distribution between EtOAc (200mL), water (50mL) and formic acid (5mL).Separate organic phase and evaporation, obtain the meal red solid, it is passed through preparation property HPLC (Kromasil C8,0.1M NH
4OAc and CH
3The gradient of CN) purifying obtains 5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester, be pale solid.Yield: 0.687g (45%).
1H NMR (400MHz, DMSO-d
6)
1.30 (3H, t, J=7.1Hz), 1.56-1.68 (2H, m), 1.79-1.87 (2H, m), 2.29 (3H, s), 2.41-2.60 (1H, m is hidden under the DMSO peak), 2.64 (3H, s), 3.09-3.18 (2H, m), 3.29 (1H, s), 4.24 (2H, q, J=7.1Hz), 4.48-4.56 (2H, m), 4.59 (2H, s), 7.13-7.21 (4H, m), 8.33 (1H, s)
MS
m/
Z：485(M+1)。
With 5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] (0.687g 1.38mmol) is dissolved in CH to the nicotinic acid ethyl ester
3CN/ water adds 1M NaOH (1.38mL) and, obtains ({ 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidin-4-yl } carbonyl) [(4-methyl-benzyl) alkylsulfonyl] sodium amide with the mixture lyophilize, is white solid.Yield: 0.726g (104%, contain some remaining water).
1H NMR(400MHz，DMSO-d
6)
1.30(3H，t，J＝7.2Hz)，1.51-1.65(2H，m)，1.74-1.82(2H，m)，2.17-2.23(1H，m)，2.25(3H，s)，2.63(3H，s)，3.14-3.25(2H，m)，4.17(2H，s)，4.24(2H，q，J＝7.1Hz)，4.37-4.45(2H，m)，7.03(2H，d，J＝8.1Hz)，7.10(2H，d，J＝8.1Hz)，8.30(1H，s)
Embodiment 82
5-cyano group-6-{4-[({[2-(methoxycarbonyl) benzyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl }-2-methylnicotinic acid ethyl ester
According to method B preparation, from the 2-[(amino-sulfonyl) methyl] benzoic acid methyl ester.Yield=77mg (69%).
1H NMR(400MHz，DMSO-d
6)δ1.30(3H，t，J＝7.1Hz)，1.56-1.71(2H，m)，1.81-1.89(2H，m)，2.48-2.53(1H，m)，2.65(3H，s)，3.08-3.20(2H，m)，3.83(3H，s)，4.25(2H，q，J＝7.1Hz)，4.46-4.61(2H，m)，5.14(2H，s)，7.35(1H，d，J＝7.5Hz)，7.46-7.68(2H，m)，7.85(1H，d，J＝7.9Hz)，8.34(1H，s)，11.58-11.66(1H，m)
MS
m/
Z：529(M+1)。
Embodiment 83
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
According to method B preparation, from 1-(3-fluorophenyl) Toluidrin.Yield=76mg (74%).
1H NMR (400MHz, DMSO-d
6) δ 1.30 (3H, t, J=7.2Hz), 1.56-1.69 (2H, m), 1.78-1.87 (2H, m), 2.41-2.60 (1H, m are hidden under the DMSO peak), 2.65 (3H, s), 3.10-3.20 (2H, m), 4.25 (2H, q, J=7.1Hz), 4.52 (2H, d, J=13.3Hz), 4.72 (2H, s), 7.08-7.16 (2H, m), and 7.19-7.29 (1H, m), 7.45 (1H, q, J=7.4Hz), 8.34 (1H, s), 11.67 (1H, s)
MS
m/
Z：489(M+1)。
Embodiment 84
5-cyano group-2-methyl-6-[4-({ [2-(2-aminomethyl phenyl) ethyl] alkylsulfonyl } formamyl) piperidines-1-yl] the nicotinic acid isopropyl esters
With TBTU (0.097g, 0.302mmol) and DIPEA (0.074g, 0.574mmol) join 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.100g, in DCM 0.302mmol) (2mL) solution and with mixture stirring at room 2.5 hours.Mixture joined contain 2-(2-aminomethyl phenyl) ethyl sulfonamide (0.074g is among DCM 0.360mmol) (2mL) and continue to stir 18 hours.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.The organic phase that merges is filtered by phase separator and evaporation, obtain crude product.(flow velocity 25mL/min uses 0.1M NH for Kromasil C8,21.5 * 100mm post by preparation property HPLC
4OAc and CH
3The gradient of CN) purifying obtains pure product, is solid.Yield: 0.098g (63%).
1H NMR(500MHz，DMSO-d
6)：1.29(6H，d)，1.59(2H，m)，1.89(2H，m)，2.24(3H，s)，2.63(1H，m)，2.63(3H，s)，2.95(2H，m)，3.15(2H，m)，3.59(2H，m)，4.52(2H，m)，5.07(1H，m)，7.11-7.18(4H，m)，8.30(1H，s)，11.80(1H，s)。
MS
m/
Z：513(M+1)，511(M-1)。
Embodiment 85
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
(a) 5-ethanoyl-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
Prepare 5-ethanoyl-2-methyl-6-oxo-1 from 3-oxo butyramide, 6-dihydropyridine-3-formic acid ethyl ester adopts and production 5-cyano group-2-methyl-6-oxo-1, the method that the 6-dihydropyridine-3-formic acid ethyl ester is identical.
(b) 5-hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
To the H that is cooled to 0 ℃
2O
2(30%, in water, 74.8mL, dropwise add in the solution of EtOH 792mmol) (500mL) TFA (89.5mL, 1.16mol).Slowly add in reaction mixture and contain 5-ethanoyl-2-methyl-6-oxo-1, (11.8g, EtOH 52.8mmol) (500mL) are heated and refluxed 24 hours 6-dihydropyridine-3-formic acid ethyl ester then, make its cool to room temperature then.In independent flask, (89.5mL 1.16mol) dropwise joins the H that is cooled to 0 ℃ with TFA
2O
2 (30%, in water, 74.8mL is in EtOH 792mmol) (100mL) solution and stirred 15 minutes.Then this solution is joined in the reaction mixture, be heated and refluxed other 18 hours.After cool to room temperature, the mixture concentrating under reduced pressure and with toluene (8 * 100mL) azeotropic.Add CH
3CN (100mL) produces solid, with its collection and washing CH
3CN (100mL).Yield: 2.50g (24%).
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.1Hz)，2.66(3H，s)，4.31(2H，q，J＝7.1Hz)，6.35(1H，br s)，7.50(1H，s)，11.75(1H，br s)。
MS
m/
Z：196(M-1)。
(c) 5-(4-methoxyl group-4-oxo butoxy)-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
To the 5-hydroxy-2-methyl-6-oxo-1 that is cooled to 0 ℃, (0.824g, (0.0385g 4.60mmol) and with the reaction mixture that obtains stirred 1.5 hours 6-dihydropyridine-3-formic acid ethyl ester to add LiH in DMF 4.18mmol) (25mL) solution.(0.005g 0.0135mmol) and with reaction is heated to 60 ℃, keeps 20 hours to add 4-bromo-butyric acid methyl ester (0.832g 4.60mmol) and TBAI.After cool to room temperature, mixture is with EtOAc (200mL) dilution, with saturated NH
4Cl (3 * 100mL), the salt water washing, dry (MgSO
4) and pass through silica gel.Flash chromatography (1: 1 EtOAc/ hexane) obtains 5-(4-methoxyl group-4-oxo butoxy)-2-methyl-6-oxo-1, and 6-dihydropyridine-3-formic acid ethyl ester is solid.Yield: 0.60g (48%)
1H NMR(400MHz，CDCl
3)：δ1.41(3H，t，J＝7.1Hz)，2.15-2.22(2H，m)，2.60(2H，t，J＝7.1Hz)，2.73(3H，s)，3.71(3H，s)，4.13(2H，t，J＝6.0Hz)，4.39(2H，q，J＝7.1Hz)，7.70(1H，s)。
MS
m/
Z：298(M+1)。
(d) 6-chloro-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
With 5-(4-methoxyl group-4-oxo butoxy)-2-methyl-6-oxo-1, (0.600g is 2.02mmol) at POCl for 6-dihydropyridine-3-formic acid ethyl ester
3Suspension (25mL) is heated to 60 ℃, keeps 5 hours.After cool to room temperature, with the reaction mixture concentrating under reduced pressure, with EtOAc (200mL) dilution, with saturated NaHCO
3(2 * 100mL), the salt water washing, dry (MgSO
4) and pass through silica gel.Concentrate, obtain 6-chloro-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester.Yield: 0.589g (92%).
1H NMR(400MHz，CDCl
3)：δ1.41(3H，t，J＝7.1Hz)，2.15-2.22(2H，m)，2.60(2H，t，J＝7.1Hz)，2.74(3H，s)，3.71(3H，s)，4.13(2H，t，J＝6.0Hz)，4.39(2H，q，J＝7.1Hz)，7.70(1H，s)。
MS
m/
Z：316(M+1)。
(e) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
With 6-chloro-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester (0.300g; 1.23mmol), N-(benzyl alkylsulfonyl) piperidines-4-carboxamide hydrochloride (0.413g; 1.30mmol) and DIPEA (0.371mL, 2.13mmol) suspension in NMP (2mL) stirred 24 hours at 80 ℃.With the reaction mixture cool to room temperature and be poured over EtOAc (60mL) and saturated NH
4Among the Cl (30mL).The organism water (3 * 50mL), salt solution (1 * 50mL) washing, dry (MgSO
4) and concentrating under reduced pressure, obtain thick material.Flash chromatography (1: the 4EtOAc/ hexane contains 1%AcOH) obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.060g (29%).
1H NMR(400MHz，CDCl
3)：δ1.38(3H，t，J＝7.1Hz)，1.78-1.84(4H，m)，2.11-2.17(2H，m)，2.32-2.40(1H，m)，2.52(2H，t，J＝7.2Hz)，2.65(3H，s)，2.80-2.87(2H，m)，3.68(3H，s)，4.01(2H，t，J＝6.2Hz)，4.29-4.36(4H，m)，4.68(2H，s)，7.35-7.40(5H，m)，7.54(1H，s)。
MS
m/
Z：562(M+1)。
Embodiment 86
4-{[2-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(ethoxy carbonyl)-6-picoline-3-yl] the oxygen base } butyric acid
With 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester (0.050g; 0.089mmol) THF (4mL) solution be cooled to 0 ℃ and with NaOH (1.00M; 0.18mL, 0.18mmol) handle.Rise again room temperature and stirring 18 hours of reaction.After with EtOAc (100mL) dilution, mixture is with saturated NH
4Cl (2 * 50mL), salt solution (50mL) washing, dry (MgSO
4) and concentrate.Flash chromatography (the 50%EtOAc/ hexane contains 1%HOAc) obtains 4-(2-(4-(benzyl sulfuryl amino formyl radical) piperidines-1-yl)-5-(ethoxy carbonyl)-6-picoline-3-base oxygen base) butyric acid, is solid.Yield: 0.036g (67%).
1H NMR(400MHz，CDCl
3)：δ1.38(3H，t，J＝7.1Hz)，1.82-1.86(4H，m)，2.06-2.13(2H，m)，2.39-2.45(1H，m)，2.50(2H，t，J＝6.9Hz)，2.65(3H，s)，2.77-2.84(2H，m)，4.02(2H，t，J＝6.6Hz)，4.24-4.27(2H，m)，4.32(2H，q，J＝7.1Hz)，4.68(2H，s)，7.36-7.40(5H，m)，7.59(1H，s)。
MS
m/
Z：548(M+1)。
Embodiment 87
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
(a) 1-[5-(ethoxy carbonyl)-3-(4-methoxyl group-4-oxo butoxy)-6-picoline-2-yl] azetidine-3-formic acid
With azetidine-3-formic acid (0.380g, 3.76mmol) and TBAH (2.3g, 3.55mmol are 40% the aqueous solution) be blended among the MeOH.Azetidin alkanoic acid dissolving, then with solution for vacuum concentration and with twice of methylbenzene azeotropic.The oily matter that obtains is aspirated under vacuum.Add NMP (9mL) and exsiccant 4
Molecular sieve.The solution that obtains is used as azetidine-3-formic acid TBuA solution of 0.35M.(0.060g 0.19mmol) is dissolved in azetidine-3-formic acid TBuA (2.0mL, nmp solution 0.70mmol) with 6-chloro-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester.To be reflected at stirring at room.After 2 hours, reaction is finished, and it is poured among the EtOAc (75mL), uses NH
4Cl (2 * 40mL) washings and dry (MgSO
4).With solution for vacuum concentration, obtain product 1-[5-(ethoxy carbonyl)-3-(4-methoxyl group-4-oxo butoxy)-6-picoline-2-yl] azetidine-3-formic acid, it is without being further purified use. yield: 0.070g (97%).
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.1Hz)，2.08-2.15(2H，m)，2.51(2H，t，J＝7.3Hz)，2.63(3H，s)，3.52-3.59(1H，m)，3.70(3H，s)，3.96(2H，t，J＝6.1Hz)，4.31(2H，q，J＝7.1Hz)，4.22-4.44(4H，m)，7.40(1H，s)。
MS
m/
Z：379(M-1)。
(b) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
With 1-(5-(ethoxy carbonyl)-3-(4-methoxyl group-4-oxo butoxy)-6-picoline-2-yl) azetidine-3-formic acid (0.070g, 0.18mmol), HOBt (0.032g, 0.24mmol), 1-phenyl methanesulfonamide acid amides (0.044g, 0.26mmol) and EDCI (0.046g, 0.24mmol) be partially dissolved in anhydrous DCM (2.5mL), add then DIPEA (0.16mL, 0.92mmol).To react stirred overnight at room temperature.To react vacuum concentration then and resistates will be dissolved in MeOH (0.5mL).The solution that obtains is slowly joined KHSO
4(0.125g is in aqueous solution 0.92mmol) (7mL).Do not form significantly precipitation, therefore mixture is distributed between EtOAc (40m) and water (10mL).Organic phase is with saturated NH
4Salt water washing and drying (MgSO are used in the Cl washing then
4).(the 30%EtOAc/ hexane is to the 50%EtOAc/ hexane with solution for vacuum concentration and by column chromatography; add 0.1%HOAc then) purifying; obtain 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester, be oily matter.Yield: 0.032g (33%).
1H NMR(400MHz，CDCl
3)：δ1.37(3H，t，J＝7.1Hz)，2.06-2.13(2H，m)，2.48(2H，t，J＝7.3Hz)，2.62(3H，s)，3.29-3.36(1H，m)，3.67(3H，s)，3.96(2H，t，J＝6.1Hz)，4.28-4.34(6H，m)，4.67(2H，s)，7.37-7.38(5H，m)，7.41(1H，s)。
MS
m/
Z：534(M+1)。
Embodiment 88
6-(4-{[(Phenylsulfamoyl base) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
(0.155g 0.488mmol) is partially dissolved in anhydrous DCE (4mL) with 1-(3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl) piperidines-4-formic acid.(0.103g 0.635mmol) and with reaction mixture heated 3 hours at 50 ℃ to add CDI.Add N-phenyl-sulfamide [Bioorganic ﹠amp; Medicinal Chemistry Letters 2003,
18, 837] and (0.101g, 0.586mmol), (0.0875mL 0.586mmol) also will be reflected at other 16 hours of 50 ℃ of heating to add DBU subsequently.To react cooling and concentrated.Resistates is at EtOAc (75mL) and NH
4Distribute between the Cl aqueous solution (50mL), organic phase is further used NH
4Cl (40mL) and salt solution (40mL) washing.With solution concentration, obtain white solid then, itself and MeOH ground the product 6-that obtains expecting (4-{[(Phenylsulfamoyl base) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester, be white solid.Yield: 0.16g (70%).
NMR(400MHz，DMSO-d
6)：δ1.30(3H，t，J＝7.1Hz)，1.36-1.46(2H，m)，1.63-1.65(2H，m)，2.45-2.50(1H，obs)，2.62(3H，s)，3.09(2H，d，J＝11.6Hz)，4.24(2H，q，J＝7.1Hz)，4.36-4.39(2H，m)，7.10(1H，t，J＝7.4Hz)，7.15(2H，d，J＝7.7Hz)，7.31(2H，t，J＝7.9Hz)，8.31(1H，s)，10.38(1H，s)，11.73(1H，s)。
MS
m/
Z：472(M+1)。
Embodiment 89
5-cyano group-2-methyl-6-{4-[({[methyl (phenyl) amino] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
(0.047g 0.10mmol) is dissolved in dry DMF (1mL) and be cooled to 0 ℃ with 5-cyano group-2-methyl-6-(4-(N-phenyl amino sulfuryl amino formyl radical) piperidines-1-yl) nicotinic acid ethyl ester.(0.010g, 60%w/w is 0.25mmol) and with the reaction room temperature of rising again to add sodium hydride.Kept 5 minutes at 35 ℃ then.Make the reaction get back to 0 ℃, add then methyl iodide (6.0 μ L, 0.010mmol).After 30 minutes, make rise again room temperature and stirring 2 hours of reaction.To react then with HOAc (0.2mL) acidifying and at EtOAc (75mL) and NH
4Distribute between the Cl aqueous solution (50mL).Organic phase NH
4Cl (30mL), water (30mL) washing, dry (MgSO
4) and vacuum concentration.Crude product is by column chromatography (30 to the 40%EtOAc/ hexane) purifying, the product 5-cyano group-2-methyl-6-that obtains expecting (4-(N-methyl-N-phenyl amino sulfuryl amino formyl radical) piperidines-1-yl) nicotinic acid ethyl ester.Yield: 0.012g (25%).
Use the NMR spectrum of NOE to confirm the desired region isomer.
1H NMR(400MHz，CDCl
3)：δ1.38(3H，t，J＝7.1Hz)，1.71-1.86(4H，m)，2.35-2.42(1H，m)，2.72(3H，s)，3.09-3.16(2H，m)，3.52(3H，s)，4.32(2H，q，J＝7.1Hz)，4.63-4.67(2H，m)，7.31-7.41(5H，m)，8.35(1H，s)。
MS
m/
Z：486(M+1)。
Embodiment 90
5-cyano group-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid isopropyl esters
According to method C preparation, from 1-(4-aminomethyl phenyl) Toluidrin.Yield=4mg. (4%) MS
m/
Z: 471 (M+1)
Embodiment 91
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
According to method C preparation, from 1-(3-fluorophenyl) Toluidrin.Yield=6.4mg. (4.5%)
1H NMR(400MHz，DMSO-d
6)：δ1.32(d，J＝6.3Hz，6H)，2.65(s，3H)，3.51-3.61(m，1H)，4.26-4.34(m，2H)，4.38-4.47(m，2H)，4.75-4.81(br s，2H)，5.04-5.12(m，1H)，7.16-7.28(m，3H)，7.39-7.48(m，1H)，8.30(s，1H)，11.88-11.94(br s，1H)。
MS
m/
Z：475(M+1)
Embodiment 92
5-cyano group-2-methyl-6-[3-({ [(2-phenylethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid isopropyl esters
According to method C preparation, from 2-phenyl ethyl sulfonamide.Yield=31mg. (22%)
1H NMR(400MHz，DMSO-d
6)：δ1.31(d，J＝6.3Hz，6H)，2.63(s，3H)，3.00-3.07(m，2H)，3.52-3.61(m，1H)，3.70-3.77(m，2H)，4.24-4.32(m，2H)，4.38-4.47(m，2H)，5.04-5.12(m，1H)，7.20-7.35(m，5H)，8.29(s，1H)，11.88-12.03(br s，1H)。
MS
m/
Z：471(M+1)
Embodiment 93
5-cyano group-6-[3-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
According to method C preparation, from 1-cyclopentyl Toluidrin.Yield=28mg. (21%)
1H NMR(400MHz，DMSO-d
6)：δ1.24-1.34(m，8H)，1.48-1.66(m，4H)，1.82-1.92(m，2H)，2.17-2.27(m，1H)，2.64(s，3H)，3.46(d，J＝6.8Hz，2H)，3.57-3.67(m，1H)，4.32-4.39(m，2H)，4.42-4.51(m，2H)，5.04-5.13(m，1H)，8.29(s，1H)，11.91(br s，1H)。
MS
m/
Z：449(M+1)
Embodiment 94
5-cyano group-6-{3-[({[2-(methoxycarbonyl) benzyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl }-2-methylnicotinic acid isopropyl esters
According to method C preparation, from the 2-[(amino-sulfonyl) methyl] benzoic acid methyl ester.Yield=46mg. (30%)
1H NMR(400MHz，DMSO-d
6)：δ1.31(d，J＝6.3Hz，6H)，2.65(s，3H)，3.50-3.60(m，1H)，3.83(s，3H)，4.29-4.36(m，2H)，4.38-4.47(m，2H)，5.03-5.14(m，1H)，5.22(s，2H)，7.45-7.48(m，1H)，7.52-7.58(m，1H)，7.59-7.65(m，1H)，7.83-7.87(m，1H)，8.31(s，1H)，11.83-11.87(br s，1H)。
MS
m/
Z：(M+1)
Embodiment 95
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
According to method C preparation, from 1-(2-fluorophenyl) Toluidrin.Yield=53mg. (37%)
1H NMR(400MHz，DMSO-d
6)：δ1.32(d，J＝6.3Hz，6H)，2.66(s，3H)，3.57-3.66(m，1H)，3.33-4.41(m，2H)，4.42-4.52(m，2H)，4.83(s，2H)，5.03-5.14(m，1H)，7.24-7.31(m，2H)，7.45-7.53(m，2H)，8.31(s，1H)，11.99(br s，1H)。
MS
m/
Z：515(M+1)
Embodiment 96
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
According to method C preparation, from 1-(4-chloro-phenyl-) Toluidrin.Yield=76mg. (52%)
1H NMR(400MHz，DMSO-d
6)：δ1.32(d，J＝6.3Hz，6H)，2.66(s，3H)，3.51-3.61(s，1H)，4.28-4.36(m，2H)，4.38-4.47(m，2H)，4.75(s，2H)，5.04-5.13(m，1H)，7.35-7.40(m，2H)，7.43-7.48(m，2H)，8.31(s，1H)，11.87(br s，1H)。
MS
m/
Z：491(M+1)
Embodiment 97
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
According to method C preparation, from 1-(4-fluorophenyl) Toluidrin.Yield=19mg. (13%)
1H NMR(400MHz，DMSO-d
6)：δ1.32(d，J＝6.3Hz，6H)，2.65(s，3H)，3.51-3.61(m，1H)，4.27-4.35(m，2H)，4.38-4.48(m，2H)，4.76(br s，2H)，5.04-5.13(m，1H)，7.14-7.26(m，2H)，7.37-7.48(m，2H)，8.31(s，1H)，11.81(br s，1H)。
MS
m/
Z：475(M+1)
Embodiment 98
5-cyano group-6-[3-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
According to method C preparation, from 1-(4-cyano-phenyl) Toluidrin.Yield=39mg. (27%)
1H NMR(400MHz，DMSO-d
6/CD
3OD 9∶1)：δ1.31(6H，d，J＝6.3H)，2.65(3H s)，3.54-3.63(1H，m)，4.28-4.35(2H，m)，4.39-4.48(2H，m)，4.77(2H，s)，5.03-5.14(1H，m)，7.19-7.25(2H，m)，7.38-7.44(2H，m)，8.30(1H，s)。
MS
m/
Z：482(M+1)
Embodiment 99
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid methyl ester
(a) 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid
With KOH (1.43g, 25.5mmol) be dissolved in EtOH (25mL, 95%), join and contain 5-cyano group-2-methyl-6-oxo-1, (1.69g among EtOH 8.2mmol) (30mL), obtains dense thick soup compound to 6-dihydropyridine-3-formic acid ethyl ester, be heated backflow (90 ℃, in oil bath) 12 hours.Mixture is concentrated and adding 2M HCl.With the sedimentation and filtration that forms, wash with water and drying, obtain 5-cyano group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid is white solid.Yield: 1.425g (98%).
1H NMR (500MHz, DMSO-d
6): keto-acid: 2.61 (3H, s), 8.40 (1H, s), 12.91 (1H, br s) ,～86%; And enol form: 2.36 (3H, s), 8.09 (1H, s), 10.50 (1H, br s) ,～14%.
MS
m/
Z：179(M+1)，177(M-1)。
(b) 6-chloro-5-cyano group-2-methyl nicotinoyl chlorine
With oxalyl chloride (3.38mL, 40mmol) dropwise join refrigerative (ice/water-bath) 5-cyano group-2-methyl-6-oxo-1, (0.710g 3.99mmol) in the suspension in anhydrous DCM (25mL), adds dry DMF (0.1mL) to 6-dihydropyridine-3-formic acid subsequently.To be reflected at 0 ℃ and stir 20 minutes, stirring at room 30 minutes, reflux subsequently 16 hours then.With the mixture evaporation and with residual black residue and anhydrous DCM co-evaporated (twice).Crude product is used for next step without being further purified.
(c) 6-chloro-5-cyano group-2-methylnicotinic acid methyl ester
(0.35mL, (0.222g is in methyl alcohol 1.03mmol) (4mL) solution 2.0mmol) to join thick 6-chloro-5-cyano group-2-methyl nicotinoyl chlorine with DIPEA.To be reflected at stirring at room 1 hour.Reaction mixture is directly used in next step without separation.
(d) 1-[3-cyano group-5-(methoxycarbonyl)-6-picoline-2-yl] piperidines-4-formic acid
With piperidines-4-formic acid (0.136g, 1.05mmol) join derive from above-mentioned solution (supposition 100% transforms, 0.210g, 1mmol) in and mixture is heated to 120 ℃ in single node microwave oven, kept 5 minutes.Add NH
4Cl (aq) also will react with DCM and extract (3 times).The organic layer that merges is separated dry and evaporation.(flow velocity 25mL/min uses 0.1M NH for Kromasil C8,21.5 * 250mm post by preparation property HPLC
4OAc and CH
3The gradient of CN) purifying obtains 1-[3-cyano group-5-(methoxycarbonyl)-6-picoline-2-yl of 0.181g] piperidines-4-formic acid.Yield: (three steps, 60%).
1H NMR(500MHz，DMSO-d
6)：1.54-1.63(2H，m)，1.85-1.92(2H，m)，2.39-2.47(1H，m)，2.62(3H，s)，3.22-3.29(2H，m)，3.77(3H，s)，4.38-4.44(2H，m)，8.30(1H，s)。
(e) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid methyl ester
With TBTU (0.106g 0.33mmol) joins 1-[3-cyano group-5-(methoxycarbonyl)-6-picoline-2-yl] piperidines-4-formic acid (0.090g, 0.297mmol) and DIPEA (0.2mL is in DCM 1.15mmol) (4mL) solution.(0.060g 0.409mmol) also will be reflected at stirring at room 20 hours to add the phenyl methanesulfonamide acid amides after 30 minutes.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.Dry and evaporation obtains crude product with the organic layer that merges, and (flow velocity 25mL/min uses 0.1M NH for Kromasil C8,21.5 * 250mm post by reversed-phase HPLC with it
4OAc and CH
3The gradient of CN) purifying obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid methyl ester, be powder.Yield: 0.040g (29%).
1H NMR (500MHz, DMSO-d
6): 1.58-1.68 (2H, m), 1.80-1.87 (2H, m) 2.54-2.61 (1H, m), 2.64 (3H, s), 3.13 (2H, tangible t), 3.78 (3H, s), 4.53 (2H, tangible d), 4.68 (2H, s), 7.26-7.31 (2H, m), and 7.36-7.42 (3H, m), 8.32 (1H, s), 11.60 (1H, bs).
Embodiment 100
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid methyl ester
With with embodiment 99 in the preparation of identical method, the phenyl methanesulfonamide acid amides is replaced with 1-(4-aminomethyl phenyl) Toluidrin.Yield: 0.034g (24%).
1H NMR (500MHz, DMSO-d
6): 1.58-1.63 (2H, m), 1.80-1.87 (2H, m), 2.30 (3H, s), 2.53-2.62 (1H, m), 2.64 (3H, s), 3.13 (2H, obviously), 3.78 (3H s), 4.53 (2H, significantly d), 4.63 (2H, s), 7.14-7.22 (4H, m), 8.33 (1H, s), 11.55 (1H, bs).
Embodiment 101
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
(a) 6-chloro-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
With EtSH (0.22mL, 3.0mmol) and DIPEA (1mL, THF 5.74mmol) (5mL) solution dropwise join in 6-chloro-5-cyano group-2-methyl nicotinoyl chlorine (0.60g, 2.29mmol is referring to the foregoing description 99) solution of cooling (0 ℃, ice/water-bath).To be reflected at 0 ℃ and stir 10 minutes, stirring at room is 50 minutes subsequently.With the mixture evaporation and with resistates and THF co-evaporated (3 times), obtain 6-chloro-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester, it is used for next step without being further purified.Yield: 0.671g (100%).
(b) carbonyl 1-{3-cyano group-5-[(ethylmercapto group)]-6-picoline-2-yl } piperidines-4-formic acid
Use single node microwave oven with piperidines-4-formic acid (0.362g, 2.80mmol), 6-chloro-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester (0.674g, 2.80mmol) and DIPEA (0.5mL, 2.87mmol) mixture in DMF (10mL) 100 ℃ the heating 5 minutes.Add NH
4Cl (aq) also extracts (3 times) with mixture with DCM.Dry and the evaporation of the organic phase that merges obtains crude product, and (flow velocity 25mL/min uses 0.1M NH for Kromasil C8,21.5 * 250mm post by reversed-phase HPLC with it
4OAc and CH
3The gradient of CN) purifying obtains 1-{3-cyano group-5-[(ethylmercapto group) carbonyl]-6-picoline-2-yl } piperidines-4-formic acid.Yield: 0.453g (48%, three step).
1H NMR(500MHz，DMSO-d
6)：1.27(3h，t，J＝7.3Hz)，1.56-1.65(2H，m)，1.92-1.98(2H，m)，2.28(3H，s)，2.57-2.64(1H，m)，2.98(2H，q，J＝7.3Hz)，3.24-3.28(2H，m)，4.42-4.48(2H，m)，8.28(1H，s)，12.31(1H，bs)。
(c) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
In room temperature with TBTU (0.104g, 0.324mmol) and DIPEA (0.1mL, 0.574mmol) join 1-{3-cyano group-5-[(ethylmercapto group) carbonyl]-6-picoline-2-yl } piperidines-4-formic acid (0.090g, 0.270mmol) DCM (4mL) solution in and will react the stirring 45 minutes, (0.055g 0.321mmol) also continues to stir other 15 hours to add 1-phenyl methanesulfonamide acid amides then.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.The organic phase that merges is dry and concentrated.Evaporation, (flow velocity 25mL/min uses 0.1M NH for Kromasil C8,21.5 * 250mm post by reversed-phase HPLC subsequently
4OAc and CH
3The gradient of CN) purifying obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester.Yield: 0.053g (40%).
1H NMR(500MHz，DMSO-d
6)：1.26(3H，t，J＝7.5)，1.65(2H，m)，1.85(2H，m)，2.56(3H，s)，2.59(1H，m)，3.00(2H，q，J＝7.5)，3.16(2H，m)，4.55(2H，m)，4.70(2H，s)，7.30(2H，m)，7.41(3H，m)，8.31(1H，s)，11.61(1H，s)。
MS
m/
Z：487(M+1)，485(M-1)。
Embodiment 102
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] pyridine-3-carbothioic acid carbothiolic acid S-ethyl ester
Method preparation with identical with embodiment 101 replaces with 1-(4-aminomethyl phenyl) Toluidrin with the phenyl methanesulfonamide acid amides.Yield: 0.065g (48%).
1H NMR(500MHz，DMSO-d
6)：1.26(3H，t，J＝7.5)，1.65(2H，m)，1.85(2H，m)，2.31(3H，s)，2.56(3H，s)，2.59(1H，m)，3.00(2H，q，J＝7.5)，3.16(2H，m)，4.55(2H，m)，4.64(2H，s)，7.17(2H，m)，7.22(2H，m)，8.31(1H，s)，11.56(1H，s)。
MS
m/
Z：501(M+1)，499(M-1)。
Embodiment 103
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
Method preparation with identical with embodiment 101 replaces with 1-(4-chloro-phenyl-) Toluidrin with the phenyl methanesulfonamide acid amides.Yield: 0.061g (43%).
1H NMR(500MHz，DMSO-d
6)：1.26(3H，t，J＝7.5)，1.65(2H，m)，1.86(2H，m)，2.56(3H，s)，2.59(1H，m)，3.00(2H，q，J＝7.5)，3.16(2H，m)，4.55(2H，m)，4.72(2H，s)，7.31(2H，m)，7.49(2H，m)，8.31(1H，s)，11.63(1H，s)。
MS
m/
Z：521(M+1)，519(M-1)。
Embodiment 104
6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
Method preparation with identical with embodiment 101 replaces with 1-(4-fluorophenyl) Toluidrin with the phenyl methanesulfonamide acid amides.Yield: 0.058g (43%).
1H NMR(500MHz，DMSO-d
6)：1.26(3H，t，J＝7.4)，1.64(2H，m)，1.86(2H，m)，2.56(3H，s)，2.59(1H，m)，3.00(2H，q，J＝7.5)，3.16(2H，m)，4.55(2H，m)，4.70(2H，s)，7.25(2H，m)，7.34(2H，m)，8.31(1H，s)，11.62(1H，s)。
MS
m/
Z：505(M+1)，503(M-1)。
Embodiment 105
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-methoxyl group-2-methylnicotinic acid ethyl ester
(a) 5-methoxyl group-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
(0.0223g 2.80mmol) joins the 5-hydroxy-2-methyl-6-oxo-1 of cooling (0 ℃), and (0.502g stirred 1.5 hours in DMF 2.55mmol) (15mL) solution and with the reaction mixture that obtains 6-dihydropyridine-3-formic acid ethyl ester with LiH.(0.175mL 2.80mmol) and with reaction is heated to 60 ℃, keeps 20 hours to add methyl iodide.After cool to room temperature, mixture is with EtOAc (200mL) dilution, with saturated NH
4Cl (3 * 100mL), the salt water washing, dry (MgSO
4) and pass through silica gel.Flash chromatography (1: 1 EtOAc/ hexane) obtains 5-methoxyl group-2-methyl-6-oxo-1, and 6-dihydropyridine-3-formic acid ethyl ester is solid.Yield: 0.140g (26%)
1H NMR(400MHz，CDCl
3)：δ1.38(3H，t，J＝7.1Hz)，2.68(3H，s)，3.88(3H，s)，4.33(2H，q，J＝7.1Hz)，7.31(1H，s)，12.07(1H，br s)。
MS
m/
Z：212(M+1)。
(b) 6-chloro-5-methoxyl group-2-methylnicotinic acid ethyl ester
With 5-methoxyl group-2-methyl-6-oxo-1, (0.065g is 0.31mmol) at POCl for 6-dihydropyridine-3-formic acid ethyl ester
3Suspension (15mL) is heated to 60 ℃, keeps 6 hours.After cool to room temperature, with the reaction mixture concentrating under reduced pressure, with EtOAc (100mL) dilution, with saturated NaHCO
3(2 * 50mL), salt solution (50mL) washing, dry (MgSO
4) and pass through silica gel.Concentrate, obtain 6-chloro-5-methoxyl group-2-methylnicotinic acid ethyl ester.Yield: 0.049g (69%).
1H NMR(400MHz，CDCl
3)：δ1.42(3H，t，J＝7.1Hz)，2.74(3H，s)，3.95(3H，s)，4.40(2H，q，J＝7.1Hz)，7.71(1H，s)。
MS
m/
Z：230(M+1)。
(c) 1-(5-(ethoxy carbonyl)-3-methoxyl group-6-picoline-2-yl) azetidine-3-formic acid
Will be at the 6-chloro-5-methoxyl group among the NMP (2.0mL)-2-methylnicotinic acid ethyl ester (0.045g, 0.20mmol), azetidine-3-formic acid (0.0258g, 0.255mmol) and DIPEA (0.205mL, mixture heating up to 110 1.18mmol) ℃ were kept 4 days.After cool to room temperature, reaction mixture is with EtOAc (100mL) dilution, with saturated NH
4Cl (3 * 50mL), salt solution (50mL) washing, dry (MgSO
4) and concentrate.Flash chromatography (the 35%EtOAc/ hexane contains 1%HOAc) obtains 1-(5-(ethoxy carbonyl)-3-methoxyl group-6-picoline-2-yl) azetidine-3-formic acid.
MS
m/
Z：295(M+1)。
(d) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-methoxyl group-2-methylnicotinic acid ethyl ester
With 1-(5-(ethoxy carbonyl)-3-methoxyl group-6-picoline-2-yl) azetidine-3-formic acid (0.0550g, 0.187mmol), the phenyl methanesulfonamide acid amides (0.352g, 0.206mmol), EDCI (0.0394g, 0.206mmol), HOBt * H
2O (0.0315g, 0.206mmol) and DIPEA (0.0977mL, DCM 0.561mmol) (2.0mL) solution was stirring at room 18 hours.Reaction mixture is with EtOAc (60mL) dilution, with saturated NH
4Cl (30mL), salt solution (50mL) washing, dry (MgSO
4) and concentrate.Flash chromatography (1: the 4EtOAc/ hexane contains 1%AcOH) obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-methoxyl group-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.025g (28%).
1H NMR(400MHz，CDCl
3)：δ1.38(3H，t，J＝7.1Hz)，2.64(3H，s)，3.24-3.31(1H，m)，3.77(3H，s)，4.21-4.35(6H，m)，4.65(2H，s)，7.36-7.41(5H，m)，7.44(1H，s)。
MS
m/
Z：448(M+1)。
Embodiment 106
6-[4-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
(a) 6-(4-(tert-butoxycarbonyl amino) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
(2.00g, 8.90mmol) (1.78g 8.90mmol) is dissolved in EtOH (50mL) with piperidin-4-yl carboxylamine tertiary butyl ester with 6-chloro-5-cyano group nicotinic acid ethyl ester in room temperature.(4.65mL 26.7mmol) and with system heated 4 hours at 94 ℃ to add DIPEA.With the reaction mixture cool to room temperature and with the solvent concentrating under reduced pressure.With material at EtOAc (50mL) and saturated NH
4The Cl aqueous solution (distributes between 2 * 30mL).Organism washs with salt solution (30mL), dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Do not carry out purifying.Yield: 3.30g (95.4%).
1H NMR(400MHz，CDCl
3)：
1.37(3H，t，J＝7.1Hz)，1.46(11H，s)，2.05-2.14(2H，m)，2.72(3H，s)，3.15-3.26(2H，m)，3.71-3.83(1H，m)，4.32(2H，q，J＝7.1Hz)，4.42-4.51(1H，m)，4.58-4.67(2H，m)，8.34(1H，s)。
MS
m/
Z：389(M+1)。
(b) 6-(4-amino piperidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester dihydrochloride
With 6-(4-(tert-butoxycarbonyl amino) piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester (3.30g, 8.50mmol) be dissolved in HCl (4M, in dioxane, 31.9mL, 127mmol).Reaction mixture at stirring at room 48 hours and concentrating under reduced pressure, is obtained 6-(4-amino piperidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester dihydrochloride, be solid, it uses with crude product, supposes that 100% transforms.
1H NMR(400MHz，d
6-DMSO)：
1.31(3H，t，J＝7.1Hz)，1.53-1.68(2H，m)，2.02-2.12(2H，m)，2.65(3H，s)，3.14-3.27(2H，m)，3.30-3.43(1H，m)，4.25(2H，q，J＝7.1Hz)，4.50-4.60(2H，m)，8.17-8.29(2H，m)，8.37(1H，s)。
MS
m/
Z：362(M+1)。
(c) 6-[4-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
With CDI (0.152g, 0.934mmol) and 1-phenyl methanesulfonamide acid amides (0.200g 1.17mmol) is dissolved in DCE (2mL) and stirring at room 16 hours.In this solution, add contain 6-(4-amino piperidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester dihydrochloride (0.200g, DCE 0.554mmol) (2mL) and DIPEA (0.482mL, 2.77mmol), and stirring at room 5 hours.Dilute with the reaction mixture concentrating under reduced pressure and with EtOAc (40mL).The organism that merges with 2N HCl (2 * 30mL), saturated NH
4Cl (2 * 30mL) and water (2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Grind (40% hexane, 40%Et
2O, and 20%DCM), obtain 6-[4-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.185g (68.8%)
1H NMR(400MHz，DMSO-d
6)：δ1.31(3H，t，J＝7.1Hz)，1.39-1.56(2H，m)，1.88-2.00(2H，m)，2.64(3H，s)，3.77-3.89(1H，m)，4.25(2H，q，J＝7.1Hz)，4.39-4.49(2H，m)，4.69(2H，s)，6.32-6.41(1H，m)，7.29-7.45(5H，m)，8.34(1H，s)，9.90(1H，s)。
MS
m/
Z：486(M+1)。
Embodiment 107
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperazine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
(a) 4-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperazine-1-formic acid tertiary butyl ester
Room temperature with 6-chloro-5-cyano group nicotinic acid ethyl ester (0.500g, 2.23mmol) and piperazine-1-formic acid tertiary butyl ester (0.623g 3.35mmol) is dissolved in EtOH (50mL).(1.16mL 6.68mmol) and with system heated 6 hours at 55 ℃ to add DIPEA.With the reaction mixture cool to room temperature and with the solvent concentrating under reduced pressure.With material at EtOAc (50mL) and saturated NH
4The Cl aqueous solution (distributes between 2 * 30mL).Organism washs with salt solution (30mL), dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Flash chromatography (20%EtOAc is in hexane) obtains 4-(3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl) piperazine-1-formic acid tertiary butyl ester.Yield: 0.743g (89.2%).
1H NMR(400MHz，CDCl
3)：δ1.38(3H，q，J＝7.1Hz)，1.49(9H，s)，2.73(3H，s)，3.53-3.61(4H，m)，3.86-3.95(4H，m)，4.32(2H，q，J＝7.1Hz)，8.36(1H，s)。
MS
m/
Z：375(M+1)。
(b) 5-cyano group-2-methyl-6-piperazine-1-base nicotinic acid ethyl ester dihydrochloride
Piperazine-1-formic acid tertiary butyl ester (3.30g.8.50mmol) is dissolved in HCl, and (2M is at Et with 4-(3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl)
2Among the O, 2.98mL, 5.95mmol).Reaction mixture at stirring at room 24 hours and concentrating under reduced pressure, is obtained 5-cyano group-2-methyl-6-(piperazine-1-yl) nicotinic acid ethyl ester dihydrochloride, be solid, it uses with crude product, supposes that 100% transforms.
1H NMR(400MHz，CD
3OD)：δ1.31(3H，t，J＝7.1Hz)，2.67(3H，s)，3.19-3.30(4H，m)，3.99-4.09(4H，m)，4.27(2H，q，J＝7.1Hz)，8.43(1H，s)，9.28(1H，m)。
MS
m/
Z：275(M+1)。
(c) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperazine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
With CDI (0.152g, 0.934mmol) and 1-phenyl methanesulfonamide acid amides (0.200g 1.17mmol) is dissolved in DCE (2mL) and stirring at room 16 hours.In this solution, add and contain 5-cyano group-2-methyl-6-(piperazine-1-yl) nicotinic acid ethyl ester dihydrochloride (0.200g, (0.502mL is 2.88mmol) and stirring at room 5 hours for DCE 0.576mmol) (2mL) and DIPEA.Dilute with the reaction mixture concentrating under reduced pressure and with EtOAc (40mL).The organism that merges with 2M HCl (2 * 30mL), saturated NH
4Cl (2 * 30mL) and H
2O (2 * 30mL) washings, dry (MgSO
4) and concentrating under reduced pressure, obtain crude product.Grind (40% hexane, 40%Et
2O, and 20%DCM are then with the Et that contains 10%MeOH
2O), obtain 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperazine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester, be solid.Yield: 0.156g (57%)
1H NMR(400MHz，DMSO-d
6)：δ1.31(3H，t，J＝7.1Hz)，2.66(3H，s)，3.52-3.62(4H，m)，3.80-3.90(4H，m)，4.26(2H，q，J＝7.1Hz)，4.76(2H，s)，7.33-7.42(5H，m)，8.35(1H，s)，10.5-10.6(1H，m)。
MS
m/
Z：472(M+1)。
Embodiment 108
4-{[2-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(ethoxy carbonyl)-6-picoline-3-yl] the oxygen base } butyric acid
With 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester (0.050g; 0.089mmol) THF (4mL) solution be cooled to 0 ℃ and with NaOH (1.00M; 0.18mL, 0.18mmol) handle.Make rise again room temperature and stirring 18 hours of reaction.After with EtOAc (100mL) dilution, mixture is with saturated NH
4Cl (2 * 50mL), salt solution (50mL) washing, dry (MgSO
4), and concentrate.Flash chromatography (the 50%EtOAc/ hexane contains 1%HOAc) obtains 4-{[2-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(ethoxy carbonyl)-6-picoline-3-yl] the oxygen base } butyric acid, be solid.Yield: 0.036g (67%).
MS
m/
Z：548(M+1)。
Embodiment 109
5-cyano group-2-methyl-6-{3-[({[(1-pyridine oxide-2-yl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
A) 1-pyridine-2-base Toluidrin
Room temperature to SMOPS (4.8g, DMSO 0.028mol) (anhydrous, 50mL) add in the solution 2-bromo methyl cycloheptapyridine HBr (5g, 0.019mol).After 40 minutes, by adding the pH to 8 of bicarbonate aqueous solution regulator solution.(4 * 100mL) extract, and organic layer is merged, and use anhydrous sodium sulfate drying, filter and solvent removed in vacuo with EtOAc with reaction mixture.Be dissolved in resistates in the solvent mixture of forming by THF (200mL) and methyl alcohol (10mL) again and in 10 minutes time, handle with the solution (4mL, 25%) of sodium methylate.After stirring 40 minutes, with the reaction mixture vacuum concentration and be dissolved in the water (20mL).Add subsequently oxyamine-O-sulfonic acid (12.66g, 0.099mol), the aqueous solution (60mL) of sodium acetate (7g), stirring at room subsequently.After 48 hours, by the pH to 9 of adding bicarbonate aqueous solution regulator solution, and with the mixture lyophilize.The solid that so obtains is handled with methyl alcohol, with methanol layer separation and concentrated.Resistates uses the sherwood oil (petether) that contains EtOAc by the purified by flash chromatography on the silicon-dioxide, uses the gradient of the EtOAc that contains MeOH subsequently then with EtOAc, obtains 1-pyridine-2-base Toluidrin.Yield: 400mg (12%).
1H NMR(400MHz，DMSO-d6)δ4.42-4.45(2H，m)，6.90-6.95(2H，m)，7.33-7.39(1H，m)，7.45-7.50(1H，m)，7.78-7.85(1H，m)，8.53-8.59(1H，m)
MS
m/
Z：173(M+1)。
B) 1-(1-pyridine oxide-2-yl) Toluidrin
With 1-pyridine-2-base Toluidrin (100mg 0.55mmol) is dissolved in DCM (2mL) and cooling off in ice bath, add then the m-CPBA that is dissolved in DCM (1ml) (184mg, 0.61mmol).To be reflected at stirring at room 2 hours, subsequently solvent removed in vacuo.Thick solid is dissolved in CH
3CN/H
2O (4mL) and at preparation property HPLC (C8,10um, 20 * 250mm, 25mL/min, 5%CH
3CN is in 0.2%HOAc) last purifying.Separate obtaining 1-(1-pyridine oxide-2-yl) Toluidrin, be light yellow solid.Yield: 65mg (60%).
MS
m/
Z：189(M+1)
C) methyl 5-cyano group-2-methyl-6-{3-[({[(1-pyridine oxide-2-yl)] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
According to method B preparation, from 1-(1-pyridine oxide-2-yl) Toluidrin.Yield=13mg (14%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.1Hz)，2.63(3H，s)，3.40-3.53(1H，m)，4.23(2H，q，J＝7.1Hz)，4.31-4.51(4H，m)，5.02(2H，s)，7.27-7.49(2H，m)，7.57-7.69(1H，m)，8.20-8.25(1H，m)，8.29(1H，s)
MS
m/
Z：460(M+1)。
Embodiment 110
5-cyano group-2-methyl-6-[3-({ [(pyridin-3-yl methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method B preparation, from 1-pyridin-3-yl Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109 step a).Yield=6mg (7%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝6.9Hz)，2.63(3H，s)，3.38-3.49(1H，m)，4.23(2H，q，J＝7.0Hz)，4.28-4.55(4H，m)，4.64(2H，s)，7.30-7.48(1H，m)，7.66-7.83(1H，m)，8.29(1H，s)，8.47(1H，s)，8.50-8.57(1H，m)
MS
m/
Z：444(M+1)。
Embodiment 111
5-cyano group-2-methyl-6-{4-[({[(1-pyridine oxide-2-yl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
According to method B preparation, from 1-(1-pyridine oxide-2-yl) Toluidrin (referring to embodiment 109a and b).Yield=27mg (28%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.2Hz)，1.56-1.72(2H，m)，1.86-1.99(2H，m)，2.47-2.55(1H，m)，2.64(3H，s)，3.12-3.24(2H，m)，4.25(2H，q，J＝7.1Hz)，4.45-4.60(2H，m)，5.02(2H，s)，7.30-7.49(2H，m)，7.55-7.65(1H，m)，8.25-8.37(2H，m)，11.62-11.92(1H，m)
MS
m/
Z：488(M+1)。
Embodiment 112
5-cyano group-2-methyl-6-[4-({ [(pyridin-3-yl methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method B preparation, from 1-pyridin-3-yl Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109 step a).Yield=32mg (34%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.1Hz)，1.55-1.71(2H，m)，1.79-1.89(2H，m)，2.46-2.56(1H，m)，2.65(3H，s)，3.09-3.21(2H，m)，4.25(2H，q，J＝7.1Hz)，4.49-4.59(2H，m)，4.73(2H，s)，7.38-7.50(1H，m)，7.66-7.78(1H，m)，8.34(1H，s)，8.47(1H，s)，8.52-8.62(1H，m)，11.58-11.85(1H，m)
MS
m/
Z：472(M+1)。
Embodiment 113
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
A) 5-cyano group-6-hydroxyl-2-oxo-1,2-dihydropyridine-3-formic acid ethyl ester
(2.76g, 120mmol) burst joins in the 22mL ethanol and at 80 ℃ and heated 45 minutes with Na.It is joined the 2-malonamide nitrile, and (4.2g is 50mmol) in the slurry in the warm ethanol of 6mL.Mixture was stirred 20 minutes, add subsequently (oxyethyl group methylene radical) diethyl malonate (10.8g, 50mmol).Made reaction mixture refluxed 16 hours, subsequently cool to room temperature.Grind with filtration of crude product and with solid matter and 2 * 20mL ether, grind with 2 * 20mL heptane subsequently.With solid vacuum-drying, obtain 5-cyano group-6-hydroxyl-2-oxo-1,2-dihydropyridine-3-formic acid ethyl ester.
1H NMR(500MHz，DMSO-d6)：δ1.05(3H，t，J＝7Hz)，3.40(2H，d，J＝7Hz)，7.88(1H，s)
B) 2,6-two chloro-5-cyano group nicotinic acid ethyl esters
To containing 5-cyano group-6-hydroxyl-2-oxo-1,2-dihydropyridine-3-formic acid ethyl ester (1.56g, add among toluene 15b mL 7.50mmol) thionyl chloride (5.35g, 45mmol), add subsequently DMF (55mg, 75mmol).Reaction mixture was heated 16 hours at 85 ℃.(5.35g, 45mmol), (55mg 75mmol), heated 4 hours at 100 ℃ subsequently to add DMF subsequently to add the thionyl chloride of measuring in addition.For a part of material that is used for subsequent step, solvent removed in vacuo.
C) 6-chloro-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
To contain 2,6-two chloro-5-cyano group nicotinic acid ethyl ester (147mg, 0.600mmol) 1.5mLMeCN be cooled to 0 ℃, add subsequently and contain N-methyl methylamine (10.5 μ L, 0.150mmol) 0.15mL MeCN, stirred 15 minutes at 0 ℃, add N-methyl methylamine (10.5 μ L, 0.15mL MeCN 0.150mmol) that contains other amount subsequently.With reaction mixture stirring at room 16 hours.Solvent removed in vacuo also is used for next step immediately with the part of material.
D) 1-[3-cyano group-6-(dimethylamino)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid
With derive from above-mentioned steps 6-chloro-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester (76mg 0.300mmol) was dissolved in the 1.5mL ethanol/water 1: 1, add subsequently piperidines-4-formic acid (116mg, 0.90mmol), add subsequently TEA (91mg, 0.90mmol).Reaction mixture was heated 20 minutes at 120 ℃ in single node microwave oven.Solvent removed in vacuo obtains the thick material of 201mg.
Carry out purifying by reversed-phase HPLC.A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=10mL/min during sample introduction.After sample introduction continuous 3 minutes are increased to flow velocity=50mL/min.Be changed to A/B/C then 5: 0: 95 and flow velocity is increased to 100mL/min.Stepping with 5% in 17 minutes is increased to 100: 0: 0.Post: Kromasil C8,250mm * 50.8ID.Eluted product when A/C is 70: 30.Obtain 1-[3-cyano group-6-(dimethylamino)-5-(ethoxy carbonyl) pyridine-2-yl like this] piperidines-4-formic acid.Yield=44mg (42%).
1H NMR(500MHz，CDCl
3)：δ1.35(3H，t，J＝7.0Hz)，1.78-1.89(2H，m)，1.99-2.01(2H，m)，2.61-2.67(1H，m)，3.3-3.5(6H，m)，3.17-3.24(2H，m)，4.28(2H，q，7.0Hz)，4.42-4.49(2H，m)，8.13(1H，s)
E) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
With 1-[3-cyano group-6-(dimethylamino)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid (24mg 0.069mmol) is dissolved in DCM (1mL), add subsequently TBTU (37mg, 0.097mmol) and DIPEA (0.047mL, 0.28mmol).After 2 minutes, and adding 1-phenyl methanesulfonamide acid amides (14mg, 0.083mmol).Reaction mixture adds .094mLDIPEA subsequently stirring at room 6 hours.Continuation was other 16 hours of stirring at room.Add 1-phenyl methanesulfonamide acid amides (14mg, 0.083mmol) and TBTU (37mg, 0.097mmol), subsequently other 22 hours of stirring at room.
Carry out purifying: A:MeCN by reversed-phase HPLC, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=10mL/min during sample introduction.Be increased to flow velocity=20mL/min behind the sample introduction immediately.Be changed to A/B/C then 5: 0: 95.In 30 minutes, be increased to 50: 0: 50 with 9 equal steppings.In 10 minutes, become 100: 0: 0 then with 5 steppings.Flow velocity: 20mL/min.Post: Kromasil C8,250mm * 20ID.Obtain 6-(4-{[(benzyl alkylsulfonyl) amino like this] carbonyl } piperidines-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester.Yield=8mg (23%).
1H NMR(500MHz，CDCl
3)：δ1.35(3H，t，J＝7.2Hz)，1.71-1.86(4H，m)，2.33-2.42(1H，m)，2.98-3.04(2H，m)，3.05(6H，s)，4.28(2H，q，J＝7.2Hz)，4.48-4.54(2H，m)，4.65(2H，s)，7.31-7.35(2H，m)，7.36-7.43(3H，m)，8.12(1H，s)。
MS
m/
Z：500(M+1)
Embodiment 114
5-cyano group-2-methyl-6-[4-({ [(pyridin-4-yl methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method B preparation, from 1-pyridin-4-yl Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109 step a).Yield=20mg (21%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.1Hz)，1.56-1.70(2H，m)，1.79-1.89(2H，m)，2.46-2.56(1H，m)，2.65(3H，s)，3.08-3.21(2H，m)，4.25(2H，q，J＝7.1Hz)，4.48-4.58(2H，m)，4.73(2H，s)，7.29-7.33(2H，m)，8.34(1H，s)，8.58-8.62(2H，m)，11.65-11.93(1H，m)
MS
m/
Z：472(M+1)。
Embodiment 115
5-cyano group-2-methyl-6-[3-({ [(pyridine-2-ylmethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method B preparation, from 1-pyridine-2-base Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109 step a).Yield=7mg (8%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.1Hz)，2.64(3H，s)，3.43-3.57(1H，m)，4.24(2H，q，J＝7.1Hz)，4.36-4.56(4H，m)，4.80(2H，s)，7.30-7.57(2H，m)，7.75-7.89(1H，m)，8.31(1H，s)，8.49-8.59(1H，m)，11.52-11.99(1H，m)
MS
m/
Z：444(M+1)。
Embodiment 116
5-cyano group-6-[3-({ [(3, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
According to method B preparation, from 1-(3, the 5-3,5-dimethylphenyl) Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109).Yield=5mg (5%).
MS
m/
Z：471(M+1)。
Embodiment 117
5-cyano group-6-[4-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
To 1-[3-cyano group-5-(isopropoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (100mg, 0.301mmol) the middle TBTU (97mg that adds, 0.302mmol), anhydrous DCM (2mL), DIPEA (0.1mL, 0.574mmol) and with mixture stirring at room 2.5 hours.With mixture join 1-cyclopentyl Toluidrin (58.8mg, 0.360mmol) in, add anhydrous DCM (2ml) and with reaction mixture stirring at room 18 hours.Add NaHCO
3(aq) and with mixture extract three times with DCM.The organic layer that makes merging is by phase separator and solvent removed in vacuo.Crude product uses that (Kromasil C8 10 μ m, the preparation HPLC purifying on 21.5 * 250mm) use the acetonitrile/NH of 25-55% gradient
4OAc water-containing buffering liquid (pH7) obtains 5-cyano group-6-[4-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters.Yield: 80mg (56%).
1H NMR(500MHz，DMSO-d6)δ1.22-1.93(12H，m)，1.30(6H，app d，J＝6.2Hz)，2.11-2.20(1H，m)，2.64(3H，s)，2.64-2.69(1H，m)，3.14-3.21(2H，m)，3.42(2H，d，.J＝7.0Hz)，4.51-4.57(2H，m)，5.08(1H，app q，J＝6.2Hz)，8.32(1H，s)，11.71(1H，s)。
MS
m/
z：477.3(M+1)，475.3(M-1)。
Embodiment 118
5-cyano group-6-[4-({ [(2, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
According to method B preparation, from 1-(2, the 5-3,5-dimethylphenyl) Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109).Yield=18mg (18%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.1Hz)，1.59-1.76(2H，m)，1.83-1.95(2H，m)，2.25(3H，s)，2.33(3H，s)，2.47-2.56(1H，m)，2.65(3H，s)，3.11-3.23(2H，m)，4.25(2H，q，J＝7.1Hz)，4.51-4.60(2H，m)，4.64(2H，s)，6.95(1H，s)，7.04-7.15(2H，m)，8.34(1H，s)，11.54-11.87(1H，m)
MS
m/
Z：499(M+1)。
Embodiment 119
5-cyano group-6-[4-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
A) (4-isopropyl phenyl) methanesulfonic sodium
With 1-(chloromethyl)-4-isopropyl benzene (2.53g, 15.0mmol) and the sulfurous acid disodium (2.46,19.5mmol) join in the mixture of water (8mL) and acetone (0.8mL).Reaction mixture was heated 5 minutes at 150 ℃ in the microwave oven of single node heating.With acetone (40mL) and water (4mL) reaction mixture is transferred in the round-bottomed flask.Mixture was refluxed 5.5 hours.Solvent removed in vacuo is also pulled an oar the solid of remnants in the hot dehydrated alcohol of 20mL, crystal is leached.Filter cake is used the rinsing of 2 * 15mL heptane subsequently with the rinsing of 10mL dehydrated alcohol, last vacuum-drying 2 hours.Obtain (4-isopropyl phenyl) methanesulfonic sodium like this.Yield=3.3g. (92%)
B) 1-(4-isopropyl phenyl) Toluidrin
(1.9g, (2.92mL 40mmol) is distributed in 4 bottles and at 100 ℃ and heated 20 minutes, uses the fixed hold-time separately for dioxane (32mL) 8.0mmol) and subsequently and thionyl chloride with (4-isopropyl phenyl) methanesulfonic sodium.Reaction mixture is merged and solvent removed in vacuo.Add ammoniated THF solution (40mL) and reaction mixture was stirred 16 hours in room temperature.Add entry (30mL) and organic phase is separated.Water is with 2 * 30mL ethyl acetate extraction.With the organic phase dried over sodium sulfate that merges, filter and solvent removed in vacuo.Crude product uses heptane/ethyl acetate 2: 1 (Rf=0.22 of product) as eluent by the purified by flash chromatography on the silica gel, obtains 1-(4-isopropyl phenyl) Toluidrin.Yield=376mg, 1.76mmol. (22%)
C) 5-cyano group-6-[4-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (159mg 0.500mmol) is dissolved in DCM (4mL) and add HATU (265mg, 0.700mmol)), add subsequently DIPEA (0.341mL, 2mmol).With reaction mixture stirring at room 5 minutes, add then 1-(4-isopropyl phenyl) Toluidrin (128mg, 0.600mmol).Continuation was stirring at room 18 hours.With the concentrated DMSO (8mL) that is dissolved in then of reaction mixture.
Carry out purifying by reversed-phase HPLC.A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=10mL/min during sample introduction.After sample introduction continuous 3 minutes are increased to flow velocity=50mL/min.Be changed to A/B/C then 5: 0: 95 and flow velocity is increased to 100mL/min.Be increased to 100: 0: 0 with the stepping that equates in 17 minutes minutes, be 5% point at every turn.The product wash-out comes out when being converted to pure acetonitrile.Post: Kromasil C8,250mm * 50.8ID.Obtain 5-cyano group-6-[4-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl like this]-2-methylnicotinic acid ethyl ester.Yield: 0.144g (56%)
1H-NMR(400MHz，DMSO-d6)δ1.18(6H，d，J＝6.8Hz)，1.32(3H，t，J＝7.1Hz)，1.54-1.67(2H，m)，1.75-1.85(2H，m)，2.20-2.30(1H，m)，2.65(3H，s)，2.80-2.89(1H，m)，3.18-3.28(2H，m)，4.19(2H，s)，4.26(2H，q，J＝7.1Hz)，4.38-4.47(2H，m)，7.09-7.18(4H，m)，8.32(1H，s)。
MS
m/
Z：513(M+1)
Embodiment 120
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester
A) 6-chloro-5-cyano group-2-methylnicotinic acid benzyl ester
(120mg 0.56mmol) is dissolved in anhydrous THF (4ml), and adds DIPEA (0.2ml) and phenyl methanol (0.059ml) with 6-chloro-5-cyano group-2-methyl nicotinoyl chlorine.With reaction mixture stirring at room 15 hours.Solvent removed in vacuo obtains 6-chloro-5-cyano group-2-methylnicotinic acid benzyl ester, and it is not purified to be used for next step.
B) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester
With 6-chloro-5-cyano group-2-methylnicotinic acid benzyl ester (129mg 0.45mmol) is dissolved in THF (2ml), and add MeOH (2ml), DIPEA (0.1mL, 0.574mmol) N-(benzyl alkylsulfonyl) piperidines-4-methane amide (140mg, 0.496mmol).Use the heating of microwave oven list node that reaction mixture is heated to 120 ℃, kept 5 minutes.Add NaHCO
3(aq) and with mixture extract three times with DCM.The organic layer that merges is by phase separator and solvent removed in vacuo.Crude product uses that (Kromasil C8 10 μ m, the preparation HPLC purifying on 21.5 * 250mm) use the acetonitrile/NH of 30-55% gradient
4Oac water-containing buffering liquid (pH7) obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester.Yield=38mg (15%).
1H NMR(500MHz，DMSO-d6)δ1.64(2H，m)，1.84(2H)，2.58(1H，m)，2.66(3H，s)，3.15(2H，m)，4.54(2H，m)，4.69(2H，s)，5.30(2H，s)，7.28-7.49(10H，m)，8.38(1H，s)，11.61(1H，s)。
MS
m/
z：533.3(M+1)，531.3(M-1)。
Embodiment 121
5-cyano group-2-methyl-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
A) 1-(4-aminomethyl phenyl) Toluidrin
Room temperature to the SMOPS that stirs (5.646g, DMSO 0.0324mol) (anhydrous, 50mL) add in the solution α-bromo-p-Xylol (5g, 0.027mol) and continue to stir 45 minutes.(4 * 100mL) extract reaction mixture, organic layer are merged, with dried over sodium sulfate and solvent removed in vacuo with EtOAc.Resistates is dissolved in THF (100mL) and methyl alcohol (25mL) again, adds sodium methylate (5.8mL, 0.027mol, 25%) subsequently.After stirring 15 minutes, reaction mixture is concentrated and is dissolved in water (10mL).In reaction mixture, add oxyamine-O-sulfonic acid (17.31g, 0.1350mol) and the H of sodium acetate (7g)
2O (40mL) solution, with it stirring at room 12 hours.By adding the pH to 9 of bicarbonate aqueous solution regulator solution, and (3 * 50ml) extract, and use the salt water washing, drying (Na with EtOAc with mixture
2SO
4) and solvent removed in vacuo.The resistates water (100mL) that so obtains was handled and stirred 10 minutes.With solid filtering and the drying that obtains, obtain 1-(4-aminomethyl phenyl) Toluidrin.Yield=3.3g, (66%).
1H NMR(300MHz，DMSO-d6)δ2.55(3H，s)，4.05(2H，s)，6.8(2H，s)，7.1-7，3(4H，m)
B) 1-(4-methylcyclohexyl) Toluidrin
In room temperature with PtO
2(2g is in acetate 0.0180mol) (50mL) solution and at H (2g) to join 1-(4-aminomethyl phenyl) Toluidrin that stirs in Pa Er (parr) vibrator
2(pressure is 6kg/cm
2) continue down to stir～48 hours.After reaction is finished, reaction mixture is filtered, with acetate (30mL) washing and concentrated.Crude product uses the flash column chromatography purifying, uses the sherwood oil that contains 10%EtOAc, obtains 1-(4-methylcyclohexyl) Toluidrin.Yield=520mg (25.2%).
1H NMR(300MHz，DMSO-d6)δ0.83-2.2(13H，m)2.84-2.94(2H m)，6.74(2H，s)
MS
m/
Z：191.8(M+1)。
C) methyl 5-cyano group-2-methyl-6-{4-[({[(4-methylcyclohexyl)] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
According to method B preparation, from 1-(4-methylcyclohexyl) Toluidrin.Yield=23mg (23%).
1H NMR(400MHz，DMSO-d6)δ0.80-0.97(4H，m)，0.99-1.21(2H，m)，1.30(3H，t，J＝7.2Hz)，1.39-1.57(4H，m)，1.57-1.73(2H，m)，1.78-1.98(3H，m)，2.00-2.11(1H，m)，2.47-2.6(1H，m)，2.64(3H，s)，3.12-3.23(2H，m)，3.22-3.40(3H，m)，4.25(2H，q，J＝7.1Hz)，4.47-4.61(2H，m)，8.33(1H，s)，11.66-11.81(1H，m)
MS
m/
Z：491(M+1)。
Embodiment 122
5-cyano group-6-[3-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] (145mg 0.500mmol) is dissolved among the 4mL DCM/DMF 1: 1 azetidine-3-formic acid.Add HBTU (0.265,0.700mmol) and DIPEA (0.341mL, 2mmol).In addition, add 2mLDMF.(128mg 0.600mmol) and with reaction mixture stirred 18 hours to add 1-(4-isopropyl phenyl) Toluidrin.Add other HBTU (0.095g, 0.25mmol) and DIPEA (0.17mL, 1mmol) and continue stirring at room 22 hours.With solution concentration, be dissolved in 8mLDMSO then.By the reversed-phase HPLC separated product.A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=10mL/min during sample introduction.After sample introduction continuous 3 minutes are increased to flow velocity=50mL/min.Be changed to A/B/C then 5: 0: 95 and flow velocity is increased to 100mL/min.Be increased to 100: 0: 0 with the stepping that equates in 17 minutes minutes, be 5% point at every turn.Post: Kromasil C8,250mm * 50.8ID.
Obtain 5-cyano group-6-[3-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl like this]-2-methylnicotinic acid ethyl ester.Yield: 0.198g, (82%)
1H-NMR(400MHz，DMSO-d6)：δ1.18(6H，d，J＝6.9Hz)，1.32(3H，t，J＝7.1Hz)，2.63(3H，s)，2.73-2.87(1H，m)，3.17-3.26(1H，m)，4.21-4.27(4H，m)，4.27-4.48(4H，m)，7.08(2H，d，J＝8.1Hz)，7.17(2H，d，J＝8.1Hz)，8.28(1H，s)。
MS
m/
Z：485(M+1)
Embodiment 123
5-cyano group-2-methyl-6-[4-({ [(2-phenylethyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method B preparation, from 2-phenyl ethyl sulfonamide.Yield=22mg (22%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.1Hz)，1.50-1.65(2H，m)，1.82-1.94(2H，m)，2.50-2.53(1H，m)，2.64(3H，s)，2.93-3.00(2H，m)，3.10-3.21(2H，m)，3.58-3.70(2H，m)，4.25(2H，q，J＝7.1Hz)，4.46-4.58(2H，m)，7.16-7.37(5H，m)，8.33(1H，s)，11.69-11.85(1H，m)
MS
m/
Z：485(M+1)。
Embodiment 124
5-cyano group-2-methyl-6-[4-({ [(pyridine-2-ylmethyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method B preparation, from 1-pyridine-2-base Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109 step a).Yield=7mg (7%).
1H NMR(400MHz，DMSO-d6)δ1.31(3H，t，J＝7.1Hz)，1.61-1.74(2H，m)，1.83-1.92(2H，m)，2.47-2.56(1H，m)，2.65(3H，s)，3.13-3.25(2H，m)，4.25(2H，q，J＝7.1Hz)，4.48-4.58(2H，m)，4.77(2H，s)，7.35-7.42(1H，m)，7.46(1H，d，J＝7.9Hz)，7.79-7.88(1H，m)，8.34(1H，s)，8.52-8.58(1H，m)，11.41-11.70(1H，m)
MS
m/
Z：472(M+1)。
Embodiment 125
5-cyano group-6-[3-({ [(2, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
According to method B preparation, from 1-(2, the 5-3,5-dimethylphenyl) Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109).Yield=6mg (6%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.2Hz)，2.24(3H，s)，2.34(3H，s)，2.63(3H，s)，3.52-3.68(1H，m)，4.24(2H，q，J＝7.1Hz)，4.31-4.41(2H，m)，4.41-4.51(2H，m)，4.70(2H，s)，7.01(1H，s)，7.05-7.15(2H，m)，8.31(1H，s)，11.76-12.09(1H，m)
MS
m/
Z：471(M+1)。
Embodiment 126
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester
A) 5-chloro-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
With 2-methyl-6-oxo-1, (2.00g, 11.0mmol) (people such as Raileanu D., Tetrahedron, Vol 30 pp 623-32,1974) are dissolved in DMF (35mL) to 6-dihydropyridine-3-formic acid ethyl ester under nitrogen atmosphere.(1.53g 11.5mmol) is absorbed among the DMF (5.0mL) with NCS in room temperature.Reaction mixture was heated 1 hour at 100 ℃.(500mg 3.8mmol) and with reaction mixture stirred 0.5 hour to add the NCS that measures in addition.Reaction mixture dilutes with DCM, and water and salt solution wash once respectively.Water extracts twice with DCM, and the organic phase that makes merging is by phase separator and solvent removed in vacuo.Crude product at first used the EtOAc/ heptane 1: 1 by the purified by flash chromatography on the silicon-dioxide (Biotage horizon), used EtOAc subsequently, obtained 5-chloro-2-methyl-6-oxo-1, and 6-dihydropyridine-3-formic acid ethyl ester is yellow solid.Yield=1.362g (52%).
1H NMR(400MHz，DMSO-d6)δ1.37(3H，t，J＝7.3Hz)，2.74(3H，s)，4.32(2H，q，J＝7.3)Hz，8.19(1H，s)
B) 5,6-two chloro-2-methylnicotinic acid ethyl esters
With 5-chloro-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester (1.2g 5.1mmol) is dissolved in DCM (25mL), add subsequently oxalyl chloride (2.2mL, 26mmol).Add two DMF and with mixture 42 ℃ of heating.After 3 hours, and the adding oxalyl chloride (2mL, 24mmol).After one hour, add other oxalyl chloride (1.1ml, 13mmol) and DMF (0.03mL) and reaction mixture spent the night 50 ℃ of stirrings.Reaction mixture dilutes with DCM and is poured on ice/water mixture.Each is separated and with the saturated NaHCO of organic phase
3Wash 2 times, use the salt water washing subsequently.The water that merges is extracted with DCM, the organic phase that merges is filtered by phase separator and solvent removed in vacuo.Crude product and DCM common " concentrating " three times obtain 5, and 6-two chloro-2-methylnicotinic acid ethyl esters are the dun solid.Yield: 0.949g (52%)
1H NMR(400MHz，DMSO-d6)
1.32(3H，t，J＝8.0Hz)，2.67(3H，s)，4.32(2H，q，J＝7.2Hz)，8.37(1H，s)
C) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester
With 5, (237mg 0.930mmol) is dissolved in EtOH (5mL), water (8mL) and MeCN (3mL) for 6-two chloro-2-methylnicotinic acid ethyl esters (202mg 0.846mmol) and N-(benzyl alkylsulfonyl) azetidine-3-methane amide.In the microwave oven of single node heating, heated 20 minutes at 120 ℃.(0.47mL 3.4mmol) and with mixture heated 20 minutes at 120 ℃ in microwave oven to add TEA.Reaction mixture is with the DCM dilution and with organism 2%KHSO
4Washed twice.The water that merges extracts with DCM.The organic phase that merges is by phase separator, solvent removed in vacuo subsequently.Crude product uses that (the preparation HPLC purifying on the Kromasil C8.50.8 * 300mm) for fear of precipitation, uses 5% acetonitrile/NH
4OAc water-containing buffering liquid (pH7) is carried in compound on the post.With the product wash-out, use the acetonitrile/NH of 5-90% gradient
4OAc water-containing buffering liquid (pH3) obtains pure 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester.Yield: 204mg (53%).
1H NMR(400MHz，DMSO-d6)δ1.28(3H，t，J＝7.3Hz)，2.58(3H，s)，3.53-3.43(1H，m)，4.15-4.42(6H，m)，4.74(2H，s)，7.25-7.43(5H，m)，7.93(1H，s)，11.77(1H，s)，
MS
m/
z：452(M+1)
Embodiment 127
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
A) azetidine-3-guanidine-acetic acid
(1.0g 4.65mmol) is dissolved in DCM (8mL), adds TFA (5mL) subsequently with [1-(tert-butoxycarbonyl) azetidine-3-yl] acetate.With reaction mixture stirring at room 2 hours.Remove and to desolvate and the not purified step b that is used for of thick azetidine-3-guanidine-acetic acid (1.31g, TFA is residual).
1H-NMR(500MHz，DMSO-d6)δ2.61-2.65(2H，m)，2.98-3.09(1H，m)，3.68-3.77(2H，m)，3.95-4.03(2H，m)
B) 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and azetidine-3-yl } acetate
(460.5mg 5.00mmol) is dissolved in EtOH (8mL) and add 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester (1.02g), DIPEA (2mL) with azetidine-3-guanidine-acetic acid of deriving from abovementioned steps.Use the heating of microwave list node that reaction mixture was heated 5 minutes at 100 ℃.Add NH
4Cl (aq) also extracts mixture three times with DCM.With organic layer process phase separator and the solvent removed in vacuo that merges.Crude product is by preparation property HPLC purifying.Post: Kromasil C810 μ m, 50.8 * 300mm, mobile phase A: 100%AcN, Mobile phase B 5%AcN, 95%NH
4AcO (aq) (pH7), gradient: 20=in 60 minutes＞60%, flow velocity: 50mL/min and UV:280nm.
Obtain like this 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-yl acetate, yield=526mg (43.3%)
1H-NMR(500MHz，DMSO-d6)δ1.29(3H，t，j＝7.1)，2.60(3H，s)，2.63-2.66(2H，m)。2.93-3.02(1H，m)，3.95-4.05(2H，m)，4.34(2H，q，j＝7.1)，4.37-4.47(2H，m)
C) 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
Will 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and azetidine-3-yl } acetate (130mg, 0.429mmol), TBTU (190mg, 0.592mmol), DIPEA (0.2mL, 1.15mmol) be dissolved in anhydrous DCM (4ml) and with mixture stirring at room 1 hour 20 minutes.With mixture join 1-phenyl methanesulfonamide acid amides (100mg, 0.584mmol) in and with reaction mixture stirring at room 25 hours.Add NaHCO
3(aq) and with mixture extract three times with DCM.The organic layer that merges is by phase separator and solvent removed in vacuo.Crude product uses that (KromasilC810 μ m, the preparation HPLC purifying on 21.5 * 250mm) use the acetonitrile/NH of 25-45% gradient
4OAc water-containing buffering liquid (pH7) obtains 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester.Yield=119mg (61%)
1H-NMR(500MHz，DMSO-d6)δ1.30(3H，t，J＝7.2Hz)，2.62(3H，s)，2.69(2H，m)，3.05(1H，m)，4.02(2H，m)，4.23(2H，q，J＝7.2Hz)，4.47(2H，m)，4.70(2H，s)，7.31(2H，m)，7.41(3H，m)，8.28(1H，s)，11.67(1H，s)。
MS
m/
z：457.1(M+1)，455.0(M-1)。
Embodiment 128
5-cyano group-6-[4-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
According to method B preparation, from 1-cyclopentyl Toluidrin.Yield=10mg (10%).
MS
m/
Z：471(M+1)。
1H NMR(400MHz，DMSO-d6)
1.18-1.28(2H，m)，1.30(3H，t，J＝7.1Hz)，1.43-1.53(2H，m)，1.54-1.69(4H，m)，1.80-1.95(4H，m)，2.08-2.22(1H，m)，2.22(3H，s)，2.65-2.69(1H，m)，3.11-3.23(2H，m)，3.38(2H，d，J＝6.8Hz)，4.25(2H，q，J＝7.1Hz)，4.48-4.59(2H，m)，8.33(1H，s)，11.48-12.17(1H，m)
MS
m/
Z：463(M+1)。
Embodiment 129
5-cyano group-6-[3-(2-{[(4-luorobenzyl) alkylsulfonyl] amino }-the 2-oxoethyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
Will 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] and azetidine-3-yl } acetate (130mg, 0.43mmol), TBTU (190mg, 0.59mmol), DIPEA (0.2mL, 1.2mmol) be dissolved in anhydrous DCM (4mL) and with reaction mixture stirring at room 1 hour 20 minutes.With mixture join 1-(4-fluorophenyl) Toluidrin (189mg, 0.53mmol) in and with reaction mixture stirring at room 25 hours.Add NaHCO
3(aq) and with mixture extract three times with DCM.The organic layer that makes merging is by phase separator and solvent removed in vacuo.Crude product uses that (Kromasil C8 10 μ m, the preparation HPLC purifying on 21.5 * 250mm) use the acetonitrile/NH of 25-45% gradient
4OAc water-containing buffering liquid (pH7) obtains 5-cyano group-6-[3-(2-{[(4-luorobenzyl) alkylsulfonyl] amino }-the 2-oxoethyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester.Yield=134mg (66%).
1H-NMR(500MHz，DMSO-d6)：
1.30(3H，t，J＝7.2Hz)，2.62(3H，s)，2.70(2H，m)，3.04(1H，m)，4.02(2H，m)，4.23(2H，q，J＝7.2Hz)，4.46(2H，m)，4.71(2H，s)，7.26(2H，m)，7.35(2H，m)，8.28(1H，s)，11.69(1H，s)。
MS(
m/
z)：475.1(M+1)，473.0(M-1)。
Embodiment 130
5-cyano group-6-[4-({ [(3-fluoro-4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
According to method B preparation, from 1-(3-fluoro-4-aminomethyl phenyl) Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109 step a).Yield=2mg (2%).
MS
m/
Z：503(M+1)。
Embodiment 131
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester
A) 1-[3-chloro-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid
With 5,6-two chloro-2-methylnicotinic acid ethyl esters (428mg 1.79mmol) is dissolved in MeCN (6mL), add subsequently piperidines-4-formic acid (255mg, 1.74mmol), water (9mL) and TEA (1.5mL, 10.8mmol).Reaction mixture was heated 15 minutes at 120 ℃ in single node microwave oven.Add in addition the piperidines-4-formic acid of amount (128mg, 0.34mmol) and TEA (0.5mL 3.60mmol) and with mixture heated 15 minutes at 120 ℃ in single node microwave oven.Reaction mixture is with the DCM dilution and use 2%KHSO
4Washing.Water extracts twice with DCM and the organic phase that merges is filtered by phase separator, solvent removed in vacuo subsequently.Crude product and DCM are concentrated jointly, obtain 1-[3-chloro-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid.Yield=391mg (60%).
1H-NMR(400MHz，DMSO-d6)
1.29(3H，t，J＝7.1Hz)，1.71-1.58(2H，m)，1.96-1.85(2H，m)，2.59(3H，s)，3.03-2.91(2H，m)，4.02-3.91(2H，m)，4.24(2H，q，J＝7.1Hz，)，8.02(1H，s)，12.43-12.07(1H，bs)。
B) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester
With 1-[3-chloro-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (391mg, 1.08mmol), DIPEA (0.9mL, 5.4mmol)) and TBTU (404mg, 1.25mmol) be dissolved in anhydrous DCM (8mL) and stirring at room 15 minutes, add subsequently 1-phenyl methanesulfonamide acid amides (221mg, 1.30mmol).Reaction mixture stirred spends the night, add then other amount TBTU (14mg, 0.044mmol) and 1-phenyl methanesulfonamide acid amides (8mg, 0.047mmol).Then reaction mixture was stirred other 3 hours, then with it with DCM dilution and use 1%KHSO
4(aq) washed twice.Water extracts twice with DCM and the organic phase that merges is passed through phase separator, solvent removed in vacuo subsequently.Crude product uses that (Kromasil C8, the preparation HPLC purifying on 55 * 300mm) for fear of precipitation, uses 5% acetonitrile/NH
4OAc water-containing buffering liquid (pH7) is carried in compound on the post.With the product wash-out, use the acetonitrile/NH of 30-100% gradient
4OAc water-containing buffering liquid (pH3).The fraction vacuum concentration that will comprise product is dissolved in ethyl acetate and uses the salt water washing.Water obtains 6-(4-{[(benzyl alkylsulfonyl) amino with twice of ethyl acetate extraction and with the organic phase vacuum concentration that merges] carbonyl } piperidines-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester, be the white/yellow solid.Yield=267mg (51%).
1H NMR(400MHz，DMSO-d6)
1.29(3H，t，J＝7.1Hz)，1.74-1.59(2H，m)，1.84-1.74(2H，m)，2.49(1H，s)，2.60(3H，s)，2.86(2H，t，J＝12.7Hz)，4.10-4.00(2H，m)，4.25(2H，q，J＝7.1Hz)，4.67(2H，s)，7.44-7.23(5H，m)，8.03(1H，s)，11.57(1H，s)
MS
m/
Z：480(M+1)。
Embodiment 132
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 4-luorobenzyl ester
A) 6-chloro-5-cyano group-2-methylnicotinic acid 4-luorobenzyl ester
With 5,6-two chloro-2-methylnicotinic acid ethyl esters (120,0.56mmol) be dissolved in anhydrous THF (4mL), add DIPEA (0.2mL, 1.15mmol) and (4-fluorophenyl) methyl alcohol (0.062mL, 0.57mmol).Reaction mixture was stirring at room 15 hours.Solvent removed in vacuo also is used for next step with crude product is not purified.
B) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 4-luorobenzyl ester
With thick 6-chloro-5-cyano group-2-methylnicotinic acid 4-luorobenzyl ester (137mg 0.47mmol) is dissolved in THF (2mL), add MeOH (2mL), DIPEA (0.1mL) and N-(benzyl alkylsulfonyl) piperidines-4-methane amide (140mg, 0.49mmol).Use the heating of microwave list node that reaction mixture is heated to 120 ℃, kept 5 minutes.Add NaHCO
3(aq) and with mixture extract three times with DCM.The organic layer that makes merging is by phase separator and solvent removed in vacuo.Crude product uses that (KromasilC8 10 μ m, the preparation HPLC purifying on 21.5 * 250mm) use the acetonitrile/NH of 30-55% gradient
4OAc water-containing buffering liquid (pH7) obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 4-luorobenzyl ester.Yield=39mg (16%).
1H NMR(500MHz，DMSO-d6)δ1.64(2H，m)，1.84(2H，m)，2.58(1H，m)，2.65(3H，s)，3.15(2H，m)，4.54(2H，m)，4.69(2H，s)，5.27(2H，s)，7.23(2H，m)，7.29(2H，m)，7.40(3H，m)，7.54(2H，m)，8.38(1H，s)，11.61(1H，s)。
LCMS
+/
z：551.2(M+1)，549.3(M-1)。
Embodiment 133
5-cyano group-6-[4-({ [(4-Ethylbenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (95mg, 0.30mmol) be dissolved in DCM (1mL) and add HATU (148mg, 0.39mmol), add subsequently DIPEA (155mg, 1.20mmol).Mixture is stirring at room 5 minutes, add then with the mode similar to embodiment 65b from 1-(4-ethylphenyl) Toluidrin of corresponding SULPHURYL CHLORIDE preparation (66mg, 0.33mmol).Reaction mixture was stirred 18 hours, add subsequently contain 1-(4-1-(4-ethylphenyl) Toluidrin (and 10mg, 0.2mL DCM 0.05mmol), add subsequently HATU (20mg, 0.053mmol) and continue stirring at room 22 hours.Solvent removed in vacuo and with thick substance dissolves in DMSO (10mL) and by anti-phase preparation HPLC purifying.The solvent that uses: A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=20mL/min during sample introduction.Be increased to flow velocity=100mL/min at sample introduction after 3 minutes.Be changed to A/B/C5 then: 0: 95.In 20 minutes, be increased to 100: 0: 0 with 9 equal steppings.Post: Kromasil C8,250mm * 50.8ID.The fraction of will being correlated with concentrates and lyophilized overnight, obtains 0.071 title compound.By this material being pulled an oar in acetonitrile (0.4mL) and adding the 0.1MNaOH (1.42mL) of 1.0eq. and some water (about 10mL) preparation Na salt.After stirring 5 minutes, nearly all material all dissolves.By solids removed by filtration and with the lyophilize of solution phase.Obtain 5-cyano group-6-[4-({ [(4-Ethylbenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl like this]-2-methylnicotinic acid ethyl ester.Yield=0.076g (49%)
1H NMR(400MHz，DMSO-d6)δ1.17(3H，t，J＝7.6Hz)，1.32(3H，t，J＝7.1Hz)，1.54-1.67(2H，m)，1.76-1.85(2H，m)，2.20-2.30(1H，m)，2.56(2H，q，J＝7.6Hz)，2.65(3H，s)，3.17-3.27(2H，m)，4.20(2H，s)，4.26(2H，q，J＝7.1Hz)，4.39-4.47(2H，m)，7.09(2H，br d，J＝8.1Hz)，7.15(2H，br d，J＝8.1Hz)，8.32(1H，s)。
MS
m/
Z：499(M+1)
Embodiment 134
According to method B preparation, from beginning with 1-(3, the 4-difluorophenyl) Toluidrin of the mode similar from corresponding SULPHURYL CHLORIDE preparation to embodiment 65b.Yield=4mg (4%).
MS
m/
Z：479(M+1)。
Embodiment 135
5-cyano group-6-[4-({ [(4-methoxy-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (40mg0.126mmol) be dissolved in 0.5mL DCM and add TBTU (57mg, 0.18mmol) and DIPEA (0.064mL, 0.38mmol).Solution stirring at room 5 minutes, is joined subsequently and comprises that (32mg is among DCM 0.16mmol) from 1-(4-p-methoxy-phenyl) Toluidrin of corresponding chlorinated thing preparation in the mode similar to embodiment 109.Reaction mixture was stirred 2.5 days, subsequently by the reversed-phase HPLC purifying.The solvent that uses: A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=10mL/min during sample introduction.Be increased to flow velocity=20mL/min after the sample introduction immediately.Be changed to A/B/C then 5: 0: 95.In 30 minutes, be increased to 50: 0: 50 with 9 equal steppings.In 10 minutes, be increased to 100: 0: 0 then with 5 steppings.Flow velocity: 20mL/min.Post: Kromasil C8,250mm * 20ID.It is 95/0/5 to 100/0/0 wash-out just that this material remains on the post up to A/B/C.
For relevant fraction, vacuum is removed organic solvent, with postlyophilization.The 0.1M NaOH that adds 1eq..With the lyophilize once more of this material, obtain 5-cyano group-6-[4-({ [(4-methoxy-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester.Yield=34mg (45%).
1H NMR(400MHz，DMSO-d6)δ1.32(3H，d，J＝7.1Hz，1.55-1.68(2H，m)，1.77-1.86(2H，m)，2.27-2.36(1H，m)，2.66(3H，s)，3.16-3.25(2H，m)，3.74(3H，s)，4.22-4.30(4H，m)，4.42-4.51(2H，m)，6.85(2H，br d，J＝8.5Hz)，7.16(2H，br d，J＝8.5Hz)，8.33(1H，s)。
MS
m/
Z：523(M+1)
Embodiment 136
5-cyano group-2-methyl-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (143mg 0.45mmol) is dissolved in anhydrous DCM (4mL), and adding TBTU (168mg, 0.52mmol)) and DIPEA (0.16ml, 0.92mmol).With mixture stirring at room 30 minutes and add 1-(3-aminomethyl phenyl) Toluidrin (103mg, 0.56mmol).With reaction mixture stirring at room 22 hours.Add NaHCO
3(aq) and with mixture extract three times with DCM.The organic layer that makes merging is by phase separator and solvent removed in vacuo.Crude product uses that (Kromasil C8 10 μ m, the preparation HPLC purifying on 21.5 * 250mm) use the acetonitrile/NH of 25-45% gradient
4OAc water-containing buffering liquid (pH7) obtains 5-cyano group-2-methyl-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester.Yield=160mg (73%).
1H NMR(500MHz，DMSO-d6)：
1.31(3H，t，J＝7.0)，1.64(2H，m)，1.82(2H，m)，2.31(3H，s)，2.59(1H，m)，2.65(3H，s)，3.14(2H，m)，4.26(2H，q，J＝7.0)，4.54(2H，m)，4.65(2H，s)，7.10(2H，m)，7.21(1H，m)，7.29(1H，m)，8.35(1H，s)，11.58(1H，s)。
MS
m/
z：485.2(M
+1)，483.2(M
-1)。
Embodiment 137
5-cyano group-6-[3-({ [(4-Ethylbenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (145mg, 0.500mmol) be dissolved in 2mL DCM/DMF 1: 1 and TBTU (265mg, 0.700mmol), DIPEA (0.34mL, 2mmol) and 1mL DMF.With mixture stirring at room 5 minutes, be added in then among the 1mL DCM with the mode similar to embodiment 65b from 1-(4-ethylphenyl) Toluidrin of corresponding SULPHURYL CHLORIDE preparation (120mg, 0.600mmol).Reaction mixture was stirred weekend, add subsequently more in 0.2mL DCM 1-(4-ethylphenyl) Toluidrin (10mg, 0.05mmol), add subsequently other TBTU (20mg, 0.05mmol) and continue other 22 hours of stirring at room.Solvent removed in vacuo adds DMSO (10mL) subsequently.
Carry out purifying by reversed-phase HPLC.The solvent that uses: A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=20mL/min during sample introduction.Be increased to flow velocity=100mL/min at sample introduction after 3 minutes.Be changed to A/B/C then 5: 0: 95.Flow velocity must be reduced to 50mL/min.(flow velocity=100mL/min is ended automatically because internal pressure increases).In 15 minutes, be increased to 50: 0: 50 with 5 steppings.In 15 minutes, be increased to 100: 0: 0 then with 5 steppings.Post: Kromasil C8,250mm * 50.8ID.With relevant fraction vacuum concentration and lyophilized overnight.Obtain the 0.111g product like this.By this material being pulled an oar in acetonitrile (1mL) and adding the 0.1MNaOH (2.36mL) of 1.0eq. and some water (about 10mL) preparation Na salt.After stirring 5 minutes, nearly all material all dissolves.Remove solid and with the liquid freezing drying by filtering (syringe+strainer).Obtain 5-cyano group-6-[3-({ [(4-Ethylbenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl like this]-2-methylnicotinic acid ethyl ester.Yield=120mg (49%).
1H NMR(400MHz，DMSO-d6)δ1.16(3H，t，J＝7.6Hz)，1.32(3H，t，J＝7.1Hz)，2.55(2H，q，J＝7.6Hz)，2.64(3H，s)，3.15-3.25(1H，m)，4.22-4.27(4H，m)，4.27-4.40(4H，m)，7.05(2H，br d，J＝8.0Hz)，7.15(2H，brd，J＝8.0Hz)，8.28(1H，s)。
MS
m/
Z：471(M+1)
Embodiment 138
5-chloro-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
With 1-[3-chloro-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (235mg, 0.788mmol), DIPEA (686 μ l, 3.94mmol) and TBTU (303mg, 0.945mmol) anhydrous DCM (5mL) solution stirring at room 10 minutes, add 1-(4-aminomethyl phenyl) Toluidrin (175mg, anhydrous DCM (1mL) solution 0.945mmol) subsequently.The reaction mixture stirring is spent the night, add 2%KHSO subsequently
4(aq), will respectively be separated and with organic phase 2%KHSO
4(aq) washing.Water extracts twice with DCM and the organic phase that merges is filtered by phase separator, solvent removed in vacuo subsequently.Crude product uses that (Kromasil C8, the preparation HPLC purifying on 50.8 * 300mm) for fear of precipitation, uses 5% acetonitrile/NH
4OAc water-containing buffering liquid (pH7) is loaded into compound on the post.With the product wash-out, use the acetonitrile/NH of 5-90% gradient
4OAc water-containing buffering liquid (pH3) obtains 5-chloro-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl after lyophilize] the nicotinic acid ethyl ester, be white solid.Yield=289mg (78%).
1H NMR(400MHz，DMSO-d6)
1.28(3H，t，J＝7.4Hz)，2.28(3H，s)，2.59(3H，s，)，3.41-3.53(1H，m)，4.16-4.29(4H，m)，4.29-4.39(2H，m)，4.67(2H，s)，7.11-7.25(4H，m)，7.93(1H，s)，11.71(1H，s)。
MS
m/
Z：466(M+1)。
Embodiment 139
5-cyano group-6-[4-({ [(3, the 4-difluorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
According to method B preparation, from beginning with 1-(3, the 4-difluorophenyl) Toluidrin of the mode similar from corresponding SULPHURYL CHLORIDE preparation to embodiment 65b.Yield=16mg (16%).
1H NMR(400MHz，DMSO-d6)δ1.30(3H，t，J＝7.1Hz)，1.53-1.70(2H，m)，1.76-1.90(2H，m)，2.47-2.54(1H，m)，2.64(3H，s)，3.15(2H，app.t，J＝11.6Hz)，4.25(2H，q，J＝7.1Hz)，4.47-4.57(2H，m)，4.67(2H，s)，7.08-7.18(1H，m)，7.30-7.40(1H，m)，7.41-7.53(1H，m)，8.34(1H，s)，11.42-12.03(1H，m)
MS
m/
Z：507(M+1)。
Embodiment 140
5-cyano group-6-[3-({ [(4-methoxy-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
With 1-[3-cyano group-5-(ethoxy carbonyl)-6-picoline-2-yl] azetidine-3-formic acid (43mg 0.150mmol) is dissolved in 0.5mL DCM, add subsequently TBTU (67mg, 0.21mmol) and DIPEA (0.076mL, 0.45mmol).With solution stirring at room 5 minutes, add subsequently be dissolved in DCM with the mode similar to embodiment 109 from 1-(4-p-methoxy-phenyl) Toluidrin of corresponding chlorinated thing preparation (80mg, 0.180mmol).Reaction mixture was stirred 18 hours, add subsequently TBTU (34mg, 0.11mmol) and DIPEA (0.152mL, 0.89mmol).Reaction mixture was stirred 5 minutes, and adding subsequently is dissolved in 1-(4-p-methoxy-phenyl) Toluidrin (27mg, 0.060mmol, 45%) of 0.2mL DMF and joins in the reaction mixture.Continuation was stirring at room 16 hours.Solvent removed in vacuo is also used 2 * 5mL 1M NaHSO with thick substance dissolves in the 5mL ethyl acetate subsequently
4With 1 * 5mL saline water extraction.Separate organic layer, use dried over sodium sulfate, filter and solvent removed in vacuo, obtain the thick material of 0.136g.
Carry out purifying by reversed-phase HPLC.The solvent that uses: A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=10mL/min during sample introduction.Be increased to flow velocity=20mL/min after the sample introduction immediately.Be changed to A/B/C then 5: 0: 95.In 30 minutes, be increased to 50: 0: 50 with 9 equal steppings.In 10 minutes, be increased to 100: 0: 0 then with 5 steppings.Flow velocity: 20mL/min.Post: Kromasil C8,250mm * 20ID.It is 95/0/5 to 100/0/0 wash-out just that this material remains on the post up to A/B/C.
The fraction of will being correlated with evaporation and lyophilize, the 0.1M NaOH of weighing (0.032g) and adding 1eq..With the material lyophilize, obtain 5-cyano group-6-[3-({ [(4-methoxy-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester.Yield=34mg (48%).
1H NMR(400MHz，DMSO-d6)
1.31(3H，t，J＝7.2Hz)，2.63(3H，s)，3.14-3.23(1H，m)，3.72(3H，s)，4.21(2H，s)，4.25(2H，q，J＝7.2Hz)，4.28-4.39(4H，m)，6.79(2H，br d，J＝8.6Hz)，7.16(2H，br d，J＝8.6Hz)，8.28(1H，s)。
MS
m/
Z：473(M+1)
Embodiment 141
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] nicotinic acid cyclopropyl ester
With 1-{3-cyano group-5-[(cyclopropyl oxygen base) carbonyl]-6-picoline-2-yl piperidines-4-formic acid (40mg 0.12mmol) is dissolved in DCM, after 10 minutes, add subsequently TBTU (46.8mg, 0.15mmol) and DIPEA (0.11mL, 0.61mmol).With reaction mixture join 1-(4-aminomethyl phenyl) Toluidrin (27mg, 0.15mmol) and stir and to spend the night.Solvent removed in vacuo and with thick material at EtOAc (5ml)/1M KHSO
4Distribute (1mL).Organic layer water (1mL) washing and solvent removed in vacuo.This compound obtains 5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl by preparation property HPLC purifying] nicotinic acid cyclopropyl ester, be white solid.Yield=11mg (97%)
1H NMR(400MHz，DMSO-d6)
0.71-0.85(4H，m)，1.56-1.70(2H，m)，1.78-1.90(2H，m)，2.31(3H，s)，2.55-2.62(1H，m)，2.63(3H，s)，3.07-3.20(2H，m)，4.23-4.28(1H，m)，4.48-4.60(2H，m)，4.64(2H，s)，7.17(2H，d，J＝8.1Hz)，7.21(2H，d，J＝8.1Hz)，8.30(1H，s)，11.55(1H，s)
MS
m/
Z：497(M+1)。
Embodiment 142
5-cyano group-2-methyl-6-[3-({ [(pyridin-4-yl methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method B preparation, from 1-pyridin-4-yl Toluidrin (it prepares from corresponding bromide in the mode similar to embodiment 109 step a).Yield=7mg (8%).
1H NMR(400MHz，DMSO-d6)
1.30(3H，t，J＝6.9Hz)，2.63(3H，s)，3.39-3.49(1H，m)，4.21-4.26(2H，m)，4.28-4.55(4H，m)，4.64(2H，s)，7.28-7.42(2H，m)，8.30(1H，s)，8.48-8.62(2H，m)
MS
m/
Z：444(M+1)。
Embodiment 143
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
A) 1-[3-cyano group-6-(dimethylamino)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid
With 6-chloro-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester (507mg 1.60mmol) was dissolved in ethanol/water 1: 1, add subsequently azetidine-3-formic acid (242mg, 2.39mmol) and TEA (0.644mL, 4.80mmol).Reaction mixture heated 20 minutes at 120 ℃ in the microwave oven of single node heating.Solvent removed in vacuo also is dissolved in 15mL DMSO with resistates.Before passing through the reversed-phase HPLC purifying, by removing by filter some insoluble substance.
A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5, C: the 50mMHCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C 5: 95: 0.Flow velocity=10mL/min during sample introduction.After sample introduction continuous 3 minutes are increased to flow velocity=50mL/min.Be changed to A/B/C then 5: 0: 95 and flow velocity is increased to 100mL/min.Stepping with 5% in 17 minutes is increased to 100: 0: 0.Post: Kromasil C8,250mm * 50.8ID.
Obtain 1-[3-cyano group-6-(dimethylamino)-5-(ethoxy carbonyl) pyridine-2-yl like this] azetidine-3-formic acid.Yield=0.064g (13%).
B) 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
With 1-[3-cyano group-6-(dimethylamino)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid (64mg, 0.200mmol) be dissolved in DCM and add TBTU (96mg, 0.300mmol) and DIPEA (0.136mL, 0.800mmol).With this mixture stirring at room 5 minutes, add then 1-phenyl methanesulfonamide acid amides (48mg, 0.28mol).With reaction mixture stirring at room 16 hours.Add 1-phenyl methanesulfonamide acid amides (48mg, 0.28mol), TBTU (96mg, 0.300mmol) and DIPEA (0.136mL, 0.800mmol) and continuation other 20 hours of stirring at room.Add bromo-tripyrrole Wan Ji Phosphonium hexafluorophosphate (93mg, 0.20mmol) and with mixture in stirring at room 3.5 days (optimizing).(0.044mL 0.600mmol) and with reaction mixture stirred other 16 hours to add thionyl chloride.
Carry out purifying by reversed-phase HPLC.A:MeCN, B:0.1M ammonium acetate/MeCN 95: 5.Beginning: A/B 5: 95.Flow velocity=10mL/min during sample introduction.Sample introduction is increased to flow velocity=20mL/min after 3 minutes.Be changed to A/B/C then 5: 0: 95.Be increased to 100: 0 in 20 minutes, per minute increases identical distance.Flow velocity: 20mL/min.Post: Kromasil C8,250mm * 20ID.Obtain product like this, it has only 71% pure.Remaining is the guanidine by product.
Carry out purifying once more by reversed-phase HPLC.A:MeCN, B:0.1M ammonium acetate/MeCN95: 5, C: the 50mM HCOOH/50mM ammonium formiate that contains 5%MeCN.Beginning: A/B/C5: 95: 0.Flow velocity=10mL/min during sample introduction.Be increased to flow velocity=20mL/min behind the sample introduction in 3 minutes.Be changed to A/B/C then 5: 0: 95.In 20 minutes, be increased to 100: 0: 0 with the stepping that equates.Flow velocity: 20mL/min. post: Kromasil C8,250mm * 20ID.
Aforesaid method obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester.Yield: 11mg (12%).
1H NMR(400MHz，CDCl
3)δ1.30-1.40(3H，m)，3.03(6H，s)，3.00-3.06(2H，m)，4.21-4.40(5H，m)，4.67(2H，s)，7.33-7.45(5H，m)，8.10(1H，s)
MS
m/
Z：472(M+1)
Embodiment 144
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester 1-oxide compound
A) 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester 1-oxide compound
(1.00g 4.45mmol) is dissolved in DCM (25mL) and cooling off on ice bath with 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester.Add urea hydrogen peroxide (2.09g, dropwise add in the process 22.3mmol) and at 2-3 minute trifluoroacetic anhydride (3.11mL, 22.3mmol).After 15 minutes, remove cooling bath and reaction mixture stirred and spend the night.Adding contains the 15mL water of 4.2g Sodium Pyrosulfite and reaction mixture was stirred 3 minutes, adds DCM (5ml) and 1MKHSO subsequently
4(2ml) and continue to stir 5 minutes.Water layer is with DCM extraction three times and with the organism dried over sodium sulfate that merges.Concentrate, obtain the light yellow sticky solid of 900mg.Thick material passes through preparation property HPLC purifying, 50 * 300mm, and C8,10um obtains 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester 1-oxide compound.Yield=356mg (33%).
1H-NMR(400MHz，DMSO-d6)δ1.34(3H，t，J＝7.1Hz)，2.68(3H，s)，4.36(2H，q，J＝7.1Hz)，8.25(1H，s)
B) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester 1-oxide compound
With 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester 1-oxide compound (50mg; 0.21mmol) and N-(benzyl alkylsulfonyl) piperidines-4-methane amide (59mg; 0.21mmol) join in the flask and be dissolved in EtOH (2mL), at this moment add DIPEA (0.072mL, 0.42mmol).After 10 minutes with the reaction mixture vacuum concentration.Crude product uses preparation property HPLC purifying, obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester 1-oxide compound.Yield=65mg:(64%)
1H NMR(400MHz，DMSO-d6)δ1.32(3H，t，J＝7.1Hz)，1.70-1.84(4H，m)，2.04-2.25(1H，m)，2.63(3H，s)，3.16-3.25(2H，m)，3.54(1H，br s)，3.71-3.80(2H，m)，4.26(2H，s)，4.30(2H，q，J＝7.1)，7.21-7.30(5H，m)，7.95(1H，s)
MS
m/
Z：487(M+1)。
Embodiment 145
5-ethanoyl-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-2-methylnicotinic acid ethyl ester
A) 5-ethanoyl-2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
(54.5g 539mmol) is suspended among the 400mL EtOH with 3-oxo butyramide.Dropwise add NaOEt/EtOH (210mL, 564mmol, 21%) and with reaction mixture stirring at room 1 hour.(100g 513mmol) and with the reaction mixture stirring spends the night dropwise to add (2E)-2-ethanoyl-3-(dimethylamino) vinylformic acid ethyl ester that is dissolved in 400mL EtOH.With the reaction mixture vacuum concentration, resistates is dissolved in water and is acidified to pH1 with dense HCl.Used solid carbonic acid potassium and saturated sodium bicarbonate to regulate pH in 2 hours subsequently the reaction stirring to～8.Extract reaction mixture among EtOAc and the DCM and with the salt water washing of every kind of organism.The organism MgSO that merges
4Drying is by the silicon-dioxide short column.Solvent removed in vacuo and use 400mL ether/hexane (1: 1) are ground remaining solid.Obtain 5-ethanoyl-2-methyl-6-oxo-1 like this, 6-dihydropyridine-3-formic acid ethyl ester is solid.
B) 5-ethanoyl-6-chloro-2-methylnicotinic acid ethyl ester
With 5-ethanoyl-2-methyl-6-oxo-1, (1.67g 7.48mmol) is dissolved in POCl to 6-dihydropyridine-3-formic acid ethyl ester
3(13mL 139mmol) and with mixture heating up to 110 ℃ and backflow spends the night.Temperature is reduced to room temperature, and POCl3 is removed in decompression subsequently.Crude product is dissolved in DCM, with saturated NaHCO
3Washed twice is used salt solution and water washing subsequently.Water extracts with DCM and organic phase is merged solvent removed in vacuo.Thick material concentrates jointly from EtOH and DCM, respectively carries out once, obtains thick 5-ethanoyl-6-chloro-2-methylnicotinic acid ethyl ester, and it is used for subsequently step immediately.
C) 1-[3-ethanoyl-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid
With 5-ethanoyl-6-chloro-2-methylnicotinic acid ethyl ester (600mg, 2.11mmol)) and piperidines-4-formic acid (299mg 2.32mmol) is dissolved in water (4ml) and MeCN (6ml), add subsequently TEA (1.18mL, 8.44mmol).Reaction mixture was heated 20 minutes at 120 ℃ in single node microwave oven.Reaction mixture dilutes with DCM.Use 1%KHSO
4Washed twice, the water of merging extracts with DCM, the organic phase that merges is filtered pass through phase separator; solvent removed in vacuo subsequently; obtain 1-[3-ethanoyl-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid, be crude product, it is used for next step immediately.Yield=2.42g (114%).
1H NMR(400MHz，DMSO-d6)δ1.63-1.47(2H，m)，1.92-1.78(2H，m)，2.46(3H，s)，2.61(3H，s)，3.13-2.99(2H，m)，3.87-3.74(2H，m)，4.24(2H，q，J＝7.0Hz)，8.21(1H，s)
D) 5-ethanoyl-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-2-methylnicotinic acid ethyl ester
With 1-[3-ethanoyl-5-(ethoxy carbonyl)-6-picoline-2-yl] piperidines-4-formic acid (872mg; 2.61mmol)), DIPEA (2.27mL; 13.0mmol) and TBTU (1.0g; 3.11mmol) anhydrous DCM (15mL) solution stirring at room 15 minutes; add subsequently 1-phenyl methanesulfonamide acid amides (536mg, 3.13mmol).Reaction mixture stirred spends the night, add subsequently TBTU (100mg, 0.31mmol) and the phenyl methanesulfonamide acid amides (53mg, 0.31mmol).Then reaction mixture was stirred 5 hours, add DCM subsequently.With reaction mixture 1%KHSO
4(aq) washed twice.Water extracts 2 times with DCM and the organic phase that merges is passed through phase separator and solvent removed in vacuo.Crude product uses that (Kromasil C8, the preparation HPLC purifying on 50.8 * 300mm) for fear of precipitation, uses 5% acetonitrile/NH
4OAc water-containing buffering liquid (pH7) is carried in compound on the post.With the product wash-out, use the acetonitrile/NH of 40-10% gradient
4OAc water-containing buffering liquid (pH3).The fraction vacuum concentration that will comprise product is dissolved in DCM and washes with water.Water extracts twice with DCM and with the organic phase vacuum concentration that merges, obtains 5-ethanoyl-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-2-methylnicotinic acid ethyl ester, be the white/yellow solid.Yield=607mg (48%).
1H NMR(400MHz，CDCl
3)δ1.36(3H，t，J＝7.2Hz)，1.67-1.85(4H，m)，2.29-2.40(1H，m)2.50(3H，s)，2.70(3H，s)，2.94-3.04(2H，m)，3.91-4.01(2H，m)，4.32(2H，q，J＝7.2Hz)，4.64(2H，s)，7.27-7.41(4H，m)，7.51(1H，s)，8.38(1H，s)，
MS
m/
Z：488(M+1)。
Embodiment 146
6-{4-{[(benzyl alkylsulfonyl) amino] carbonyl }-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-yl }-5-cyano group-2-methylnicotinic acid ethyl ester
A) amino 4-{[(benzyl alkylsulfonyl)] carbonyl }-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-formic acid benzyl ester
With the 1-[(benzyloxy) carbonyl]-the 4-[(tert-butoxycarbonyl) amino] piperidines-4-formic acid (468mg, 1.24mmol)), TBTU (440mg, 1.36mmol) and DIPEA (0.3mL 1.72mmol) is dissolved in anhydrous DCM (4mL) and stirring at room 1 hour.Add 1-phenyl methanesulfonamide acid amides (217mg, 1.27mmol) and with reaction mixture stirring at room 17 hours.Add NaHCO
3(aq) and with mixture extract three times with DCM.The organic layer that makes merging is by phase separator and solvent removed in vacuo.Crude product is by preparation property HPLC purifying, post: Kromasil C8 10 μ m, 21.5 * 250mm, mobile phase A: 100%AcN, Mobile phase B: 5%AcN, 95%NH
4AcO (aq) (pH7), gradient: in 35 minutes, 20=＞40%A, flow velocity: 25mL/min, UV:220nm obtains 4-{[(benzyl alkylsulfonyl) amino] carbonyl-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-formic acid benzyl ester.Yield=297mg (45%).
LCMS：m/z：530.4(M-1)。
B) (4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidin-4-yl) the carboxylamine tertiary butyl ester
With 4-{[(benzyl alkylsulfonyl) amino] carbonyl }-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-formic acid benzyl ester (297mg, 0.56mmol), Pd (OH)
2(96mg, 0.136mmol, 20%wt) and ammonium formiate (544mg 8.63mmol) is suspended among the MeOH (10mL) in 20-mL microwave bottle.Use the heating of microwave list node that reaction mixture is heated to 120 ℃, kept 5 minutes.Add Pd (OH)
2(50mg, 0.094mmol, 20%wt) and ammonium formiate (300mg 4.76mmol) and with reaction mixture is heated to 120 ℃, keeps 5 minutes.Add the Pd (OH) of amount in addition
2(50mg, 0.094mmol) and ammonium formiate (400mg 6.34mmol), and is heated to 120 ℃ with reaction mixture, keeps 10 minutes.Reaction mixture is filtered and evaporation.Crude product is used for next step without being further purified.
LCMS
+/
z：398.2(M+1)，396.3(M-1)。
C) amino 6-{4-{[(benzyl alkylsulfonyl)] carbonyl }-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-yl }-5-cyano group-2-methylnicotinic acid ethyl ester
With (4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidin-4-yl) (107mg, 0.27mmol) (124mg 0.55mmol) is dissolved in EtOH (7mL) and H to the carboxylamine tertiary butyl ester with 6-chloro-5-cyano group-2-methylnicotinic acid ethyl ester
2Among the O (2mL) and add DIPEA (1.3mL, 7.46mmol).Use single node heating microwave oven that reaction mixture is heated to 120 ℃, kept 5 minutes.Add NaHCO
3(aq) and with mixture extract three times with DCM.The organic layer that makes merging is by phase separator and solvent removed in vacuo.Crude product is by preparation property HPLC purifying.Post: Kromasil C810 μ m, 21.5 * 250mm, mobile phase A: 100%AcN, Mobile phase B: 5%AcN, 95%NH
4AcO (aq) (pH7); gradient: 25=＞50%A in 35 minutes; flow velocity: 25mL/min, UV:296nm obtains 6-{4-{[(benzyl alkylsulfonyl) amino] carbonyl }-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-yl }-5-cyano group-2-methylnicotinic acid ethyl ester.Yield=9mg (3%).
LCMS
+/
z：586.4(M+1)，584.4(M-1)。
Embodiment 147
6-(4-amino-4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
With 6-{4-{[(benzyl alkylsulfonyl) amino] carbonyl }-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-yl }-(7.6mg 0.013mmol) is dissolved in DCM (5mL) and adding TFA (2mL) to 5-cyano group-2-methylnicotinic acid ethyl ester.With reaction mixture in stirring at room 1 hour solvent removed in vacuo subsequently.Product is dissolved in AcN/H
2O and lyophilize obtain 6-(4-amino-4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester trifluoroacetate.Yield=8mg (100%).
LCMSm/
z：486.3(M+1)，484.3(M-1)。
Additional embodiments
General experimental procedure
Be equipped with electron spray(ES) interface (LC-ms) or comprising on the Finnigan LCQ Duo ion trap mass spectrometer of LC-ms system of Waters ZQ (use LC-Agilent1100LC system) and write down mass spectrum.
1H NMR measures on Varian Mercury VX 400 spectrographs of operating under 400 the 1H frequency and Varian UNITY plus 400,500 that operates under the 1H frequency 400,500 and 600 respectively and 600 spectrographs and carries out.Chemical shift provides with ppm, with solvent as interior mark.Proton on the heteroatoms is just reported when for example NH and OH proton only detect in NMR, therefore can be omitted.Chromatogram uses Biotage silica gel 40S, 40M, 12i or Merck silica gel 60 (0.063-0.200mm) to carry out.Flash chromatography uses the glass of standard or plastic column carries out or carry out in Biotage Horizon system.HPLC is separated in Waters YMC-ODS AQS-3120 Angstrom3 * 500mm or on Waters Delta Prep Systems, uses Kromasil C8, and 10 μ m posts carry out.
Being used for following method A ' is Waters FractionLynx II Purification System to purification system and the LC-MS system of E ': post: Sunfire Prep C18,5 μ m OBD, 19 * 100mm post.Gradient: contain 5-95%CH
3The 0.1mM HCOOH (pH=3) of CN.The fraction of using MS to trigger is collected.Mass spectrum is record on single four utmost points of Micromass ZQ or Micromass Quattro micro, and the both is equipped with the auxiliary electrospray of air pressure interface.
Being reflected among Personal Chemistry Smith maker, Smith synthesizer or the Emrys Optimizer of carrying out in microwave reactor carried out.
Used abbreviated list:
Abbreviation
Explanation
AcOH acetate
Aq is aqueous
The br broad peak
The saturated solution of salt solution sodium-chlor in water
The BSA bovine serum albumin
(Boc)
2O two dimethyl dicarbonate butyl esters
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-diisopropyl ethyl amine
The DMA N,N-dimethylacetamide
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
EDCI N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride
The EtOAc ethyl acetate
EtOH ethanol
HEPES [4-(2-hydroxyethyl)-1-piperazine] ethyl sulfonic acid
The HFA hydrofluoroalkane
HOAc acetate
The HOBT I-hydroxybenzotriazole
The HPLC high performance liquid chromatography
The Hz hertz
The J coupling constant
The LDA lithium diisopropylamine
The m multiplet
The Me methyl
The MHz megahertz
The mL milliliter
The MS mass spectrum
The NCS N-chloro-succinimide
The OAc acetate moiety
iPrOAc acetate isopropyl esters
The heavy peak of q
The r.t room temperature
S is unimodal
The t triplet
TB Tyrodes damping fluid
TBME butyl methyl ether
TBTU N-[(1H-1,2,3-benzotriazole-1-base oxygen base) (dimethylamino) methylene
Base]-N-methyl first ammonium a tetrafluoro borate
The TEA triethylamine
The Tf trifluoromethyl sulfonyl
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
The TMEDA N,N,N
The Ts p-toluenesulfonyl
Synthesizing of sulfonamides
The synthetic of sulphonamide that is used for following examples carries out according to one of three kinds of methods as described below:
I) handle with the ammonium hydroxide in the methylene dichloride by corresponding SULPHURYL CHLORIDE and ammonia being reacted in THF or MeOH or passing through.The sulfonamides that obtains is without being further purified use.
Ii) basically according to Seto, people such as T. are at J.Organic Chemistry, and Vol 68, No10 (2003), the process described in the pp.4123-4125.
Or
Iii) basically according to Wang, people such as Z are at Tetrahedron Letters, and Vol 43 (2002), the process described in the pp8479-8483.
Embodiment's is synthetic
Use following general procedure (being that method A ' is to E ') to prepare some following examples, and in each specific embodiment, mention.
Method A ': by the process example of embodiment 10
With DIPEA (64mg, 0.5mmol) join 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 and with mixture stirring at room 30 minutes, add then 1-(2-fluorophenyl) Toluidrin be dissolved in DCM (1mL) (23mg, 0.12mmol).To react to stir and spend the night.LC-MS shows starting raw material residue, in mixture, add more TBTU (19mg, 0.06mmol) and DIPEA (26mg, 0.2mmol) and continue other 2 hours of stirring.Reaction mixture 1%KHSO
4Washing, water extracts with DCM (1ml) and the organic phase that merges is evaporated by phase separator and in vacuum centrifuge.The crude product that obtains obtains 5-cyano group-2-(difluoromethyl)-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl by HPLC purifying (referring to general experimental procedure)] the nicotinic acid ethyl ester.Yield: 41mg (78%).
Method B ': by the process example of embodiment 42
With DIPEA (128mg, 1.0mmol) join 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 and with mixture stirring at room 30 minutes, add the 1-phenyl methanesulfonamide acid amides (41mg that is dissolved in DCM (1mL) then, 0.24mmol), and will react to place and spend the night.Reaction mixture 1%KHSO
4Washing, water extracts with DCM and the organic phase of merging is evaporated by phase separator and in vacuum centrifuge.The crude product that obtains obtains 6-(3-{2-[(benzyl alkylsulfonyl) amino by HPLC purifying (referring to general experimental procedure)]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester.Yield: 88mg (84%).
Method C ': by the process example of embodiment 55
With DIPEA (43mg, 0.3mmol) and TBTU (64mg, 0.20mmol) join 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid (74.2mg, 0.2mmol) DMF solution in and with mixture stirring at room 2 hours, then it is joined 1-(4-fluorophenyl) Toluidrin that is dissolved in DMF (38mg, 0.22mmol) in.Reaction mixture stirred spend the night and by the SCX-2 ion exchange column.The crude product that obtains obtains 5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl by HPLC purifying (referring to general experimental procedure)]-2-(trifluoromethyl) nicotinic acid ethyl ester.Yield: 4.3mg (4%).
Method D ': by the process example of embodiment 45
With CDI (26mg 0.16mmol) joins 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid (51mg, 0, the 15mmol) CH of (gas is emitted)
3In the CN solution and with mixture heating up to 50 ℃, kept 2 hours.Then said mixture is added to 1-(4-fluorophenyl) Toluidrin (28mg, 0.15mmol) and DBU (23mg, CH 0.15mmol)
3Also will be reflected at stirred overnight at room temperature in the CN solution.By HPLC purifying (referring to experimental arrangement), obtain 5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester.
Method E ': by the process example of embodiment 75
With DIPEA (38mg, 0.3mmol) join 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 and with mixture stirring at room 10 minutes, add then 1-(2-fluorophenyl) Toluidrin (19mg, 0.10mmol).To react to stir and spend the night.Reaction mixture 1M KHSO
4Washing also makes organic phase pass through phase separator and evaporate in vacuum centrifuge.The crude product that obtains obtains 5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl by HPLC purifying (referring to general experimental procedure)]-2-(methyl fluoride) nicotinic acid ethyl ester.Yield: 13mg (25%).
Embodiment 148
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) nicotinic acid ethyl ester
(a) 2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
Under nitrogen atmosphere with 2-methyl-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester (2.0g, 11.04mmol) (Sobczak, people such as A, Synth.Commun, Vol.35, No.23,2005, pp2993-3001) join 2-methoxyl group-N-(2-methoxy ethyl)-N-(three fluoro-λ
4-sulfane base) ethamine (7.82g, CH 22.08mmol)
3In the CN solution.To react refluxes spends the night, and adds other 2-methoxyl group-N-(2-methoxy ethyl)-N-(three fluoro-λ then
4-sulfane base) (2.73g 7.7mmol) also continues to stir to consume up to all starting raw materials ethamine.Reaction is diluted with ether, removes by filter the solid of black, water and NaHCO
3(saturated aqueous solution) washing.Once more two-phase is filtered, to remove more black solid.Water is with ether extraction (2 times) and with the organic phase drying (MgSO that merges
4), filter and concentrate and in ether, pull an oar, to remove xanchromatic impurity.With the white solid drying of remnants, obtain 2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester.Yield: 370mg (14%).
1H NMR(400MHz，CDCl
3)
1.38(3H，t，J＝7.2Hz)，4.36(2H，q，J＝7.2Hz)，6.69(1H，d，J＝10Hz)，7.56(1H，t，J＝54Hz)，7.9981H，d，J＝10Hz)。
(b) 5-chloro-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
(270mg 2.02mmol) joins 2-(difluoromethyl)-6-oxo-1, and (365mg is 1.44mmol) in the solution and reaction is heated to 100 ℃ spends the night for 6-dihydropyridine-3-formic acid ethyl ester will to be dissolved in the NCS of DMF (2mL).Because starting raw material is still remaining, add other five equilibrium NCS (135mg, 1.01mmol and add 270mg after 5 hours, 2.02mmol) and continue heating and disappear up to starting raw material.Reaction is with diluting DCM and water and salt water washing.Water extracts twice with DCM and the organic phase that merges is passed through phase separator and evaporation.By purified by flash chromatography (Horizon Flash 40+M, eluent: use EtOAc/ heptane) from 50 to 100%EtOAc gradients, obtain 5-chloro-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester, be yellow oil, it is without further analysis or purifying are used for next step.Yield: 88mg (15%).
(c) 5,6-two chloro-2-(difluoromethyl) nicotinic acid ethyl esters
With oxalyl chloride (0.1mL, 1.18mmol) join 5-chloro-2-(difluoromethyl)-6-oxo-1 with DMF (0.1mL), (85.5mg in DCM solution 0.217mmol) and with mixture heating up to 42 ℃, kept 3 hours 6-dihydropyridine-3-formic acid ethyl ester.Therefore do not detect product, add other 0.1mL (1.18mmol) oxalyl chloride and continue to stir and spend the night at 42 ℃.To react with the DCM dilution and by it being poured over cancellation on ice/water mixture.To respectively be separated, and with organic phase NaHCO
3(saturated aqueous solution) and salt water washing.The water that merges extracts with DCM and the organic phase that merges is filtered by phase separator and evaporation.Resistates and DCM are concentrated twice jointly, obtain 5,6-two chloro-2-(difluoromethyl) nicotinic acid ethyl esters are yellow oil, and it is used for next step without being further purified.Yield: 113.5mg (51%).
(d) formamyl 4-[(benzyl alkylsulfonyl)] piperidines-1-formic acid tertiary butyl ester
Under nitrogen atmosphere in room temperature with triethylamine (591g, 5840mmol) join 1-(tert-butoxycarbonyl) piperidines-4-formic acid (448g of stirring, 1954mmol), LiCl (23.1g, 545mmol) and TBTU (657g is 2046mmol) in the suspension in THF (3000mL).After 1.5 hours, add 1-phenyl methanesulfonamide acid amides (352g, in 1300mL THF, 2056mmol) solution, and continue to stir and to spend the night.Solvent removed in vacuo obtains dense thick ash-beige soup compound (the about 2500mL of volume).Add EtOAc (3500mL), add the aqueous solution (1960mL 3.6MHCl and 1960mL water) of HCl subsequently.Remove water and organic phase is washed with 2 * 1500mL 1M HCl.Organic phase is cooled to 0 ℃, obtains the precipitation of HOBT, it is filtered out.Vacuum is removed most of solvent, obtains dense thick ash-white soup compound.Adding EtOH (50%, 4000mL) and with soup compound stirred 1.5 hours.Sedimentary product is filtered out, with 50%EtOH (washing of 500mL+2 * 1500mL) and 25 ℃ of vacuum-dryings, obtain 4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-formic acid tertiary butyl ester, be white solid.Yield: 584g (78%).
(e) N-(benzyl alkylsulfonyl) piperidines-4-methane amide
Under nitrogen atmosphere with 4-[(benzyl alkylsulfonyl) formamyl] piperidines-1-formic acid tertiary butyl ester (583g, 1524mmol) be suspended in formic acid (3000mL) and will react the stirring 20 minutes.Because gas is emitted, reaction produces foam, uses formic acid (500mL) that foam is washed down from reactor vessel wall.After 2 hours, foam stops, and reacts for transparent, leaves some solids.Reaction is stirred the formic acid that spends the night and remove 2500ml in a vacuum.Add entry (1000mL) and will react filtration.With clear solution evaporation and add entry (3000mL).Use saturated ammonium hydroxide aqueous solution (add total amount 390mL, pH from 3.10 to 6.10) with and acidic solution, and form a large amount of precipitations of product at terminal point (pH=6.10).Mixture stirred spend the night and sedimentation and filtration is come out and water (1000mL) washing.Dry in 25 ℃ of vacuum chambers, obtain N-(benzyl alkylsulfonyl) piperidines-4-methane amide, be white powder.Yield: 372.4g (87%).
(f) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) nicotinic acid ethyl ester
To 5,6-two chloro-2-(difluoromethyl) nicotinic acid ethyl esters (113mg, 0.214mmol)) and N-(benzyl alkylsulfonyl) piperidines-(66mg is 0.24mmol) at CH for the 4-methane amide
3Add in the solution in CN (3mL) and the water (2mL) TEA (149 μ L, 1.07mmol).To be reflected in single node microwave 120 ℃ of heating 20 minutes.Solvent removed in vacuo and with crude mixture with DCM dilution and use 1%KHSO
4(aq) washed twice.The water that merges extracts with DCM and the organic phase that merges is passed through phase separator, solvent removed in vacuo subsequently.
Crude product uses that (Kromasil C8, the preparation HPLC purifying on 50.8 * 300mm) uses 5% acetonitrile/NH
4OAc water-containing buffering liquid (pH7) is loaded into compound on the post, uses the acetonitrile/NH of 30-100% gradient then
4OAc water-containing buffering liquid (pH3) wash-out.
Product-fraction is merged and solvent removed in vacuo, and grind subsequent filtration with DCM.Solvent removed in vacuo obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-(difluoromethyl) nicotinic acid ethyl ester, be white solid.Yield: 13mg (11%).
1H NMR(400MHz，CDCl
3)
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 149
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
(a) 5-cyano group-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
With 1,1-dimethoxy-N, N-dimethyl methylamine (4.8mL 36.1mmol) joins 4,4-two fluoro-3-ketobutyric acid ethyl esters (5.0g, 30.1mmol) in (thermopositive reaction).With orange solution in stirred overnight at room temperature, concentrate and with the toluene co-evaporated.With resistates be absorbed in EtOH (99.5%, 10mL) in, obtain red solution.With freshly prepd NaOEt (1M, 30mL) join the 2-malonamide nitrile (2.53g, EtOH 30.1mmol) (99.5%, 30mL) in the solution and will be reflected at stirring at room 1 hour, and dropwise add above-mentioned red solution.The red suspension that forms stirred spend the night and add HOAc (6mL), solution becomes transparent.With solution concentration and in water (50mL) making beating and stirred 1 hour, thereafter sedimentation and filtration is come out and dry air, obtain 5-cyano group-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester is brown solid.Yield: 3.03g (41%).
1H-NMR (400MHz, DMSO-d
6)
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) nicotinic acid ethyl ester
To 5-cyano group-2-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester (3g, 12.5mmol) add oxalyl chloride (5.3mL in the slurry in DCM (45mL), 62.6mmol), add DMF (0.097mL) subsequently and reaction is heated to 50 ℃, kept several hours, add more oxalyl chloride (1mL, 11.8mmol) and add DMF (0.2mL) twice with several hours interval, continue reflux and spend the night.With reaction mixture evaporation and be absorbed among the DCM resistates and water and NaHCO
3(saturated aqueous solution) washing, water extracts (twice) with DCM and the organic phase that merges is concentrated and by purified by flash chromatography (Horizon, the gradient of the eluent that uses: heptane/EtOAc 7/1 to 100%EtOAc), obtain 6-chloro-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester, be yellow oil.Yield: 2.0g (60%).
1H-NMR(400MHz，DMSO-d
6)
1.34(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) nicotinic acid ethyl ester
With TEA (0.4mL; 2.89mmol) join 6-chloro-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester (200mg; 0.721mmol) and N-(benzyl alkylsulfonyl) piperidines-4-methane amide (224mg is 0.793mmol) in the solution of water (2.5mL) and EtOH (2mL).With mixture in single node microwave oven 120 ℃ of heating 20 minutes, with solvent evaporation and be absorbed in resistates among the DCM and use 1%KHSO
4Washing (twice).The water that merges passes through phase separator with DCM extraction (twice) and with the organic phase filtration that merges and concentrates.By HPLC (Kromasil C8, eluent: 40%CH
3CN is to 100%CH
3The gradient of CN/(50mM HCOOH and 50mMNH
4OOCH, pH=3) purifying obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester, be white solid.Yield: 250mg (68%).
1H NMR(400MHz，DMSO-d
6)
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 150
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
(a) 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
With oxalyl chloride (12.20g, 96.1mmol) and DMF (0.744mL) join 5-cyano group-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-formic acid ethyl ester (5g, 19.22mmol) (basically according to Mosti, people such as L, Farmaco, Vol 47, No 4,1992, the preparation of method described in the pp427-437) solution in and reaction be heated to 50 ℃ spend the night.With reactive evaporation and with dissolving crude product in EtOAc and water.To respectively be separated and organic phase salt solution and NaHCO
3(saturated aqueous solution) washing.Water is with EtOAc extraction (3 times) and with the organic phase drying (Na that merges
2CO
3), filter and concentrate, obtain 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester, be brown solid, it is without being further purified use.Yield: 5.206g (95%).
1H NMR(400MHz，DMSO-d
6)δ1.31(t，J＝7.2Hz，3H)，4.38(q，J＝6.9Hz，2H)，9.07(s，1H)
(b) 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
With TEA (142mg; 1.41mmol) join 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester (140mg; 0.352mmol) and N-(benzyl alkylsulfonyl) piperidines-4-methane amide (109mg is 0.387mmol) in the solution of water (2mL) and EtOH (2.5mL).With mixture in single node microwave oven 120 ℃ of heating 20 minutes, with solvent evaporation and be absorbed in resistates among the DCM and use 1%KHSO
4Washing (twice).The water that merges passes through phase separator with DCM extraction (twice) and with the organic phase filtration that merges and concentrates.By HPLC (Kromasil C8, eluent: 30%CH
3CN is to 100%CH
3The gradient of CN/(50mM HCOOH and 50mMNH
4OOCH, pH=3) purifying obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester, be white solid.Yield: 107mg (58%).
1H NMR(400MHz，DMSO-d
6)
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 151
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
(a) 1-(tert-butoxycarbonyl) azetidine-3-formic acid
To be dissolved in MeOH (70mL) (Boc) in the clock time at 20 minutes in room temperature
2O (25.535g, 117mmol) dropwise join stirring azetidine-3-formic acid (10.11g, 100mmol) and Et
3N (27.8mL, 200mmol) in the slurry in MeOH (105mL) (gentle thermopositive reaction) and mixture heating up spent the night (18 hours).Reactive evaporation to dry doubling and adding THF (120mL) and evaporation, is obtained thick 1-(tert-butoxycarbonyl) azetidine-3-formic acid, and it is used for next step without being further purified.Yield: 25.89g (128%)
1H NMR(400MHz，CDCl
3)
1.43(9H，s)，3.21-3.34(1H，m)，4.00-4.13(4H，m)。
(b) formamyl 3-[(benzyl alkylsulfonyl)] azetidine-1-formic acid tertiary butyl ester
With TBTU (33.71g, 105mmol) and TEA (30.3g 300mmol) joins in the solution that derives from above-mentioned 1-(tert-butoxycarbonyl) azetidine-3-formic acid (25.89g supposes to comprise 100mmol) and will be reflected at stirring at room 30 minutes.Add 1-phenyl methanesulfonamide acid amides (17.97g, 105mmol) and LiCl (1.844g, 43.5mmol) and continuation in stirred overnight at room temperature (23 hours).Reaction is concentrated to about 1/3 residue, add EtOAc (500mL) and with organic phase with 2M HCl (1 * 150mL, 2 * 50mL), water (2 * 50mL) washings.Dry (MgSO
4), filter and evaporating solvent, obtain brown ceramic powder (48.6g).Powder is pulled an oar in 150mL TBME and stirred 3 hours.Solid filtering is come out and wash with TBME (40mL).Repeat this process twice with 100mL TBME (washing), obtain browny powder (33g), still comprise some HOBT with 25mL.With powder dissolution in about 100mL temperature EtOH and add entry (130mL) with the induced product crystallization.Leach crystal and drying, obtain pure 3-[(benzyl alkylsulfonyl) formamyl] azetidine-1-formic acid tertiary butyl ester, be pale powder.Yield: 25.4g (71%).
1H NMR (400MHz, DMSO-d
6)
1.39 (9H, s), 3.30 (1H, m is with the signal overlap of water among the DMSO), 3.78-3.9584H, 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
In room temperature with 3-[(benzyl alkylsulfonyl) formamyl] (25.4g 71.7mmol) joins among the HCOOH (300mL) and will react stirring spend the night (22 hours) azetidine-1-formic acid tertiary butyl ester.Vacuum is removed formic acid removal, adds entry (40mL) and vacuum and removes.Add entry (130mL) to resistates, add NH subsequently
4OH (aq) reaches 7.4 up to pH, at this moment begins crystallization.Leach crystal and drying, obtain pure N-(benzyl alkylsulfonyl) azetidine-3-methane amide, be white solid.Yield: 15.73g (86%).
1H NMR(400MHz，DMSO-d
6)δ3.22(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) nicotinic acid ethyl ester
With TEA (291mg; 2.88mmol) join 6-chloro-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester (200mg; 0.721mmol) and N-(benzyl alkylsulfonyl) azetidine-3-methane amide (201mg is 0.793mmol) in the solution of water (2mL) and EtOH (2.5mL).With mixture in single node microwave oven 120 ℃ of heating 20 minutes, with solvent evaporation and be absorbed in resistates among the DCM and use 1%KHSO
4Washing (twice).The water that merges passes through phase separator with DCM extraction (twice) and with the organic phase filtration that merges and concentrates.By HPLC (Kromasil C8, eluent: 40%CH
3CN is to 100%CH
3The gradient of CN/(50mM HCOOH and 50mM NH
4OOCH, pH=3) purifying obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester, be white solid.Yield: 264mg (72%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 152
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
(a) 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
With oxalyl chloride (8.13mL, 96.1mmol) and DMF (0.744mL, 9.61mmol) join 5-cyano group-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-formic acid ethyl ester (5.0g, 19.22mmol, basically according to people such as Mosti L, Farmaco, Vol 47, and No 4,1992, the described method of pp.427-437 preparation) is heated to reflux in the solution and with reaction and spends the night.Evaporating solvent also is dissolved in EtOAc/ water with resistates.To respectively be separated and with organic phase with salt solution and NaHCO
3(aq, twice) washing.Water is with EtOAc extraction (three times) and with the organic phase drying (Na that merges
2CO
3), filter and concentrate, obtain 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester, it is without being further purified use.Yield: 5.21g (95%).
1H NMR(400MHz，DMSO-d
6)
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) nicotinic acid ethyl ester
With TEA (142mg; 1.41mmol) join 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester (140mg; 0.352mmol) and N-(benzyl alkylsulfonyl) azetidine-3-methane amide (98.4mg, 0.387mmol) solution in water (2mL) and EtOH (2.5mL).Mixture was heated 20 minutes at 120 ℃ in single node microwave oven.To react and filter removing precipitation, and with solvent evaporation.Be absorbed in resistates among the DCM and use 1%KHSO
4Washing (twice).The water that merges passes through phase separator with DCM extraction (twice) and with the organic phase filtration that merges and concentrates.By HPLC (Kromasil C8, eluent: 30%CH
3CN is to 100%CH
3The gradient of CN/(0.1%HCOOH (aq)) purifying obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester, be white solid.Yield: 102mg (58%).
1H NMR(400MHz，DMSO-d
6)δ1.28(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 153
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
(a) 5-cyano group-2-(methyl fluoride)-6-oxo-1,6-dihydropyridine-3-formic acid ethyl ester
In room temperature with 1,1-dimethoxy-N, N-dimethyl methylamine (4.83g, 40.5mmol) join 4-fluoro-3-ketobutyric acid ethyl ester (5.0g, 33.75mmol) in (thermopositive reaction) and mixture stirred spend the night, concentrate and with the toluene co-evaporated.Adding EtOH (99.5%, 10mL), obtain red solution.(34.5mL, 2.35g 34.5mmol) join 2-malonamide nitrile (3.12g with freshly prepd sodium ethylate 1M solution, 37.13mmol) at EtOH (99.5%, in the solution 30mL), after stirring at room 35 minutes, dropwise add and derive from above-mentioned red solution and stirring continues to spend the night.Add AcOH (6mL) (thermopositive reaction) carefully and wash with the sedimentation and filtration that forms and with ether.Drying obtains 5-cyano group-2-(methyl fluoride)-6-oxo-1, and 6-dihydropyridine-3-formic acid ethyl ester is the beige solid.Yield: 4.42g (56%).
1H NMR(400MHz，DMSO-d
6)
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) nicotinic acid ethyl ester
With oxalyl chloride (5.49mL, 64.9mmol) and DMF (0.5mL, 6.5mmol) joining 5-cyano group-2-(methyl fluoride)-6-oxo-1, (3.0g arrives in DCM 12.98mmol) (120mL) solution and with mixture heating up and refluxed 6 hours 6-dihydropyridine-3-formic acid ethyl ester.Be dissolved in EtOAc/ water with solvent evaporation and with resistates.To respectively be separated and with organic phase with salt solution and NaHCO
3(aq) washing.Water extracts (twice) with EtOAc and the organic phase that merges is concentrated, and obtains 6-chloro-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester, is the beige solid, and it is without being further purified use.Yield: 2.92g (90%).
1H NMR(400MHz，DMSO-d
6)
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) nicotinic acid ethyl ester
With TEA (326mg, 3.23mmol) join 6-chloro-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester (200mg, 0.81mmol) and N-(benzyl alkylsulfonyl) piperidines-(251mg is 0.89mmol) at CH for the 4-methane amide
3In the solution of CN (1.5mL) and 95%EtOH (2.5mL).Mixture was heated 20 minutes at 120 ℃ in single node microwave oven.With solvent evaporation and be absorbed in resistates among the DCM and use 1%KHSO
4Washing (twice).The water that merges passes through phase separator with the DCM extraction and with the organic phase filtration that merges and concentrates.By HPLC purifying (Kromasil C8, eluent: 40%CH
3CN is to 100%CH
3The gradient of CN/(0.1%HCOOH (aq)) obtains 6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester, be the beige solid.Yield: 257mg (65%).
1H NMR(400MHz，DMSO-d
6)
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 154
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
With TEA (326mg, 3.23mmol) join 6-chloro-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester (200mg, 0.81mmol) and N-(benzyl alkylsulfonyl) azetidine-(225mg is 0.89mmol) at CH for the 3-methane amide
3In the solution of CN (1.5mL) and 95%EtOH (2.5mL).Mixture was heated 20 minutes at 120 ℃ in single node microwave oven.With solvent evaporation and be absorbed in resistates among the DCM and use 1%KHSO
4Washing.The water that merges passes through phase separator with the DCM extraction and with the organic phase filtration that merges and concentrates.(Kromasil C8, eluent: 40%CH3CN is to 100%CH by HPLC
3The gradient of CN/(0.1%HCOOH (aq)) purifying obtains 6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester, be the beige solid.Yield: 221mg (59%)
1H NMR(400MHz，DMSO-d
6)
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 155
5-cyano group-2-(difluoromethyl)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
(a) 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid
With TEA (423mg, 4.18mmol) join 6-chloro-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester (290mg, 1.05mmol) and piperidines-4-formic acid (148mg is in water/EtOH 1.15mmol) (4.5mL) solution.Mixture was heated 10 minutes at 120 ℃ in single node microwave oven.With solvent evaporation and be absorbed in resistates among the DCM and use 1%KHSO
4Washing.The water that merges passes through phase separator with DCM extraction (twice) and with the organic phase filtration that merges and concentrates, obtain 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] piperidines-4-formic acid, be white solid, it is without being further purified use.Yield: 356mg (94%).
1H-NMR(400MHz，CDCl
3)δ1.39(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 } the nicotinic acid ethyl ester
With DIPEA (64mg, 0.5mmol) join 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 and with mixture stirring at room 30 minutes, add then 1-(4-methylcyclohexyl) Toluidrin be dissolved in DCM (1mL) (23mg, 0.12mmol).To react to stir and spend the night.LC-MS shows starting raw material residue, therefore, in mixture, add more TBTU (19mg, 0.06mmol) and DIPEA (26mg, 0.2mmol) and continue other 2 hours of stirring.Reaction mixture 1%KHSO
4Washing, water extracts with DCM (1ml) and the organic phase that merges is evaporated by phase separator and in vacuum centrifuge.The crude product that obtains is by HPLC (Kromasil C
8, use 20% to 100%CH
3Gradient/0.2%HOAc of CN (aq)) purifying obtains 5-cyano group-2-(difluoromethyl)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester, be white solid.Yield: 22mg (40%).
1H NMR(400MHz，CDCL
3-d
6)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 156
5-cyano group-2-(difluoromethyl)-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
(a) 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid
With TEA (423mg, 4.18mmol) join 6-chloro-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester (290mg, 1.05mmol) and azetidine-3-formic acid (116mg is 1.15mmol) in the solution of 95%EtOH (4.5mL).Mixture was heated 10 minutes at 120 ℃ in single node microwave oven.With solvent evaporation and be absorbed in resistates among the DCM and use 1%KHSO
4Washing.The water that merges passes through phase separator with DCM extraction (twice) and with the organic phase filtration that merges and concentrates, obtain 1-[3-cyano group-6-(difluoromethyl)-5-(ethoxy carbonyl) pyridine-2-yl] azetidine-3-formic acid, be white solid, it is without being further purified use.Yield: 359mg (101%).
1H-NMR(400MHz，CDCl
3)δ1.39(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] the nicotinic acid ethyl ester
With DIPEA (64mg, 0.5mmol) join 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 and with mixture stirring at room 30 minutes, add then 1-(2-fluorophenyl) Toluidrin be dissolved in DCM (1mL) (23mg, 0.12mmol).To react to stir and spend the night.LC-MS shows starting raw material residue, therefore, in mixture, add more TBTU (19mg, 0.06mmol) and DIPEA (26mg, 0.2mmol) and continue other 2 hours of stirring.Reaction mixture 1%KHSO
4Washing, water extracts with DCM (1ml), and the organic phase that merges is evaporated by phase separator and in vacuum centrifuge.The crude product that obtains is by HPLC (Kromasil C
8, use 20% to 100%CH
3Gradient/0.2%HOAc of CN (aq)) purifying obtains 5-cyano group-2-(difluoromethyl)-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester, be white solid.Yield: 42mg (83%).
1H NMR(400MHz，CDCL
3-d
6)δ1.38(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 157
5-cyano group-2-(difluoromethyl)-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 41mg (78%).
1H NMR(600MHz，DMSO-d
6)δ1.28(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 158
5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 21mg (40%).
1H NMR(600MHz，DMSO-d
6)δ8.45(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 159
5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 19mg (36%).
1H NMR(600MHz，DMSO-d
6)δ1.28(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 160
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 36mg (67%).
1H NMR(600MHz，DMSO-d
6)
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 161
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 42mg (78%).
1H NMR(600MHz，DMSO-d
6)
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 162
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 33mg (61%).
1H NMR(400MHz，DMSO-d
6)
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 163
5-cyano group-2-(difluoromethyl)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 17mg (32%).
1H NMR(400MHz，DMSO-d
6)
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 164
5-cyano group-2-(difluoromethyl)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 19mg (36%).
1H NMR(600MHz，DMSO-d
6)
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 165
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 27mg (47%).
1H NMR(600MHz，DMSO-d
6)
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 166
5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 47mg (95%).
1H NMR(600MHz，DMSO-d
6)
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 167
5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 41mg (83%).
1H NMR(600MHz，DMSO-d
6)
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 168
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 42mg (82%).
1H NMR(400MHz，DMSO-d
6)
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 169
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 46mg (90%).
1H NMR(600MHz，DMSO-d
6)
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 170
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 45mg (88%).
1H NMR(600MHz，DMSO-d
6)
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 171
5-cyano group-2-(difluoromethyl)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 36mg (73%).
1H NMR(600MHz，DMSO-d
6)
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 172
5-cyano group-2-(difluoromethyl)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method A ' from 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] the nicotinic acid ethyl ester.Yield: 31mg (63%).
1H NMR(600MHz，DMSO-d
6)
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 173
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 7mg (12%).
1H NMR(600MHz，DMSO-d
6)
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 174
5-cyano group-2-(difluoromethyl)-6-{3-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
According to method A ' from 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 the nicotinic acid ethyl ester.Yield: 27mg (55%).
1H NMR(400MHz，DMSO-d
6)
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 175
5-cyano group-6-[3-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 47mg (64%).
MS
m/
Z：490(M+1)
Embodiment 176
5-cyano group-6-[3-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 42mg (57%).
MS
m/
Z：490(M+1)
Embodiment 177
5-cyano group-2-(difluoromethyl)-6-{3-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
According to method A ' from 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 the nicotinic acid ethyl ester.Yield: 37mg (45%).
MS
m/
Z：549(M+1)
Embodiment 178
5-cyano group-2-(difluoromethyl)-6-{3-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
According to method A ' from 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 the nicotinic acid ethyl ester.Yield: 44mg (53%).
MS
m/
Z：549(M+1)
Embodiment 179
5-cyano group-6-[3-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 52mg (69%).
MS
m/
Z：504(M+1)
Embodiment 180
5-cyano group-2-(difluoromethyl)-6-(3-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl) the nicotinic acid ethyl ester
According to method A ' from 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) the nicotinic acid ethyl ester.Yield: 48mg (62%).
MS
m/
Z：515(M+1)
Embodiment 181
6-(3-{[(butyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 44mg (65%).
MS
m/
Z：445(M+1)
Embodiment 182
5-cyano group-6-[4-({ [(3-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 9mg (12%).
MS
m/
Z：518(M+1)
Embodiment 183
5-cyano group-6-[4-({ [(4-cyano-phenyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 9mg (12%).
MS
m/
Z：518(M+1)
Embodiment 184
5-cyano group-2-(difluoromethyl)-6-{4-[({[4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
According to method A ' from 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 the nicotinic acid ethyl ester.Yield: 17mg (19%).
MS
m/
Z：577(M+1)
Embodiment 185
5-cyano group-2-(difluoromethyl)-6-{4-[({[2-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
According to method A ' from 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 the nicotinic acid ethyl ester.Yield: 50mg (58%).
MS
m/
Z：577(M+1)
Embodiment 186
5-cyano group-6-[4-({ [(2-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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 the nicotinic acid ethyl ester.Yield: 14mg (17%).
MS
m/
Z：532(M+1)
Embodiment 187
5-cyano group-2-(difluoromethyl)-6-(4-{[(2-naphthyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl) the nicotinic acid ethyl ester
According to method A ' from 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) the nicotinic acid ethyl ester.Yield: 31mg (38%).
MS
m/
Z：543(M+1)
Embodiment 188
6-(4-{[(butyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
According to method A ' from 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) nicotinic acid ethyl ester.Yield: 36mg (51%).
MS
m/
Z：473(M+1)
Embodiment 189
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } tetramethyleneimine-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] and tetramethyleneimine-3-yl } acetate
With TEA (606mg, 5.99mmol) join 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester (341mg, 1.2mmol) and tetramethyleneimine-3-guanidine-acetic acid (209mg is in water/EtOH 1.62mmol) (4.5mL) solution.Mixture was heated 20 minutes at 120 ℃ in single node microwave oven.With solvent evaporation and be absorbed in resistates among the DCM and use 1%KHSO
4Washing.The water that merges passes through phase separator with the DCM extraction and with the organic phase filtration that merges and concentrates.By HPLC (Kromasil C8, eluent: 5%CH
3CN is to 100%CH
3The gradient of CN/(0.2%HOAc (aq)) purifying, obtain 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] tetramethyleneimine-3-yl acetate, be white solid.Yield: 219mg (49%).
1H NMR(400MHz，CDCL
3)
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) nicotinic acid ethyl ester
From { 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) nicotinic acid ethyl ester.Yield: 88mg (84%).
1H NMR(600MHz，DMSO)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 190
5-cyano group-6-[3-(2-oxo-2-{[(2-phenylethyl) alkylsulfonyl] amino } ethyl) tetramethyleneimine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
From { 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] tetramethyleneimine-3-yl } acetate and the preparation of 2-phenyl ethyl sulfonamide, obtain 5-cyano group-6-[3-(2-oxo-2-{[(2-phenylethyl) alkylsulfonyl according to method B '] amino } ethyl) tetramethyleneimine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester.Yield: 73mg (68%).
1H NMR(600MHz，DMSO)δ1.25(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 191
6-[3-(2-{[(5-chloro-2-thienyl) alkylsulfonyl] amino }-the 2-oxoethyl) tetramethyleneimine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
From { 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) nicotinic acid ethyl ester.Yield: 86mg (78%).
1H NMR(500MHz，DMSO)δ1.29(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 192
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid
With TEA (0.908g, 8.97mmol) join 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester (1.0g, 3.59mmol) and azetidine-3-formic acid (0.399g 3.95mmol) heated 20 minutes in single node microwave oven in the suspension in EtOH (10mL) and with mixture.With solvent evaporation and with resistates at iPrOAc (10mL)/water and Na
2CO
3Between distribute.Water phase separated and be adjusted to acidity by adding dense HCl.(2 * 10mL) extract the tart water with iPrOAc.With the extract drying (MgSO that merges
4) and evaporation, obtain 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] azetidine-3-formic acid, be brown solid, it is without being further purified use.Yield: 1.04g (84%).
1H-NMR(500MHz，DMSO-d
6)
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) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：515(M+1)
Embodiment 193
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：515(M+1)
Embodiment 194
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：515(M+1)
Embodiment 195
5-cyano group-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：511(M+1)
Embodiment 196
5-cyano group-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：511(M+1)
Embodiment 197
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：531(M+1)
Embodiment 198
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：531(M+1)
Embodiment 199
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：531(M+1)
Embodiment 200
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：565(M+1)
Embodiment 201
6-(3-{[(5-chloro-2-thienyl) alkylsulfonyl] formamyl } azetidine-1-yl)-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method D ' from 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) nicotinic acid ethyl ester.
MS
m/
Z：523(M+1)
Embodiment 202
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid
With TEA (0.908g, 8.97mmol) join 6-chloro-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester (1.0g, 3.59mmol) and piperidines-4-formic acid (0.510g 3.95mmol) heated 15 minutes in single node microwave oven in the suspension in EtOH (10mL) and with mixture.With solvent evaporation and with resistates at iPrOAc (10mL)/water and 20%Na
2CO
3Distribute (1mL).With aqueous phase separation, it is acid adding 1mL EtOH and regulating water by the dense HCl of adding.(2 * 10mL) extract the tart water with iPrOAc.With organic phase drying (MgSO
4), filter and concentrate, obtain 1-[3-cyano group-5-(ethoxy carbonyl)-6-(trifluoromethyl) pyridine-2-yl] piperidines-4-formic acid, being brown solid, it is without being further purified use.Yield: 1.06g (79%).
1H NMR(500MHz，DMSO-d
6)δ1.28(3H，t，J＝7.1Hz)，1.61-1.71(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) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 4.3mg (4%).
1H NMR(600MHz，CDCl
3)δ1.36(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 203
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 5.7mg (5%).
1H NMR(500MHz，CDCl
3)δ1.40(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 204
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 5.1mg (5%).
1H NMR(400MHz，CDCl
3)δ1.35(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 205
5-cyano group-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 3.4mg (3%).
1H NMR(400MHz，CDCl
3)δ1.36(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 206
5-cyano group-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 2.8mg (3%).
1H NMR(400MHz，CDCl
3)δ1.31(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 207
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 6.6mg (6%).
1H NMR(600MHz，CDCl
3)δ1.20(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 208
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 7.8mg (7%).
1H NMR(600MHz，CDCl
3)δ1.35(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 209
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 7.3mg (6%).
1H NMR(500MHz，CDCl
3)δ1.40(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 210
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 5.5mg (5%).
1H NMR(600MHz，CDCl
3)δ1.35(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 211
6-[4-({ [(5-chloro-2-thienyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(trifluoromethyl) nicotinic acid ethyl ester
According to method C ' from 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) nicotinic acid ethyl ester.Yield: 19.1mg (17%).
1H NMR(400MHz，CDCl
3)δ1.34(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 212
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid
With TEA (653mg, 6.46mmol) join 6-chloro-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester (400mg, 1.61mmol) and azetidine-3-formic acid (179mg is in water/EtOH 1.78mmol) (4.5mL) solution.Mixture was heated 20 minutes at 120 ℃ in single node microwave oven.With solvent evaporation, and be absorbed in resistates among the DCM and use 1%KHSO
4Washing.Water extracts with DCM and the organic phase that merges is filtered by phase separator and concentrated.By HPLC (Kromasil C8, eluent: 5%CH
3CN is to 100%CH
3The gradient of CN/(0.2%HOAc (aq)) purifying obtains 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid, be white solid.Yield: 302mg (60%).
1H NMR(400MHz，CDCl
3)
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) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 21mg (44%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 213
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 25mg (53%).
1H NMR(400MHz，DMSO-d
6)δ1.29(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 214
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 27mg (56%).
1H NMR(400MHz，DMSO-d
6)δ1.29(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 215
6-[3-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 13mg (27%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 216
6-[3-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 28mg (58%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 217
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 33mg (68%).
1H NMR(400MHz，DMSO-d
6)δ1.29(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 218
5-cyano group-2-(methyl fluoride)-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method E ' from 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] the nicotinic acid ethyl ester.Yield: 41mg (86%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 219
5-cyano group-2-(methyl fluoride)-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
According to method E ' from 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] the nicotinic acid ethyl ester.Yield: 12mg (25%).
1H NMR(400MHz，DMSO-d
6)δ1.29(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 220
5-cyano group-6-[3-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 27mg (51%).
1H NMR 400MHz，DMSO-d
6)δ1.29(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 221
5-cyano group-2-(methyl fluoride)-6-{3-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 28mg (57%).
1H NMR(400MHz，DMSO-d
6)δ0.75-0.92(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 222
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
(a) 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] piperidines-4-formic acid
With TEA (653mg, 6.46mmol) join 6-chloro-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester (400mg, 1.61mmol) and piperidines-4-formic acid (229mg is in water/EtOH 1.78mmol) (4.5mL) solution.Mixture was heated 20 minutes at 120 ℃ in single node microwave oven.With solvent evaporation, and resistates is absorbed in DCM and uses 1%KHSO
4Washing.Water extracts with DCM and the organic phase that merges is filtered by phase separator and concentrated.By HPLC (Kromasil C8, eluent: 5%CH
3CN is to 100%CH
3The gradient of CN/(0.2%HOAc (aq)) purifying obtains 1-[3-cyano group-5-(ethoxy carbonyl)-6-(methyl fluoride) pyridine-2-yl] azetidine-3-formic acid, be white solid.Yield: 76mg (14%).
1H NMR(400MHz，CDCL
3)δ1.36(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) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 13mg (25%).
1H NMR(400MHz，DMSO-d
6)δ1.29(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 223
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 16mg (31%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 224
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 23mg (45%).
1H NMR(400MHz，DMSO-d
6)δ1.29(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 225
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.Yield: 24mg (45%).
1H NMR(400MHz，DMSO-d
6)δ1.29(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 226
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.
Yield: 24mg (46%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 227
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.
Yield: 24mg (46%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 228
5-cyano group-2-(methyl fluoride)-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method E ' from 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] the nicotinic acid ethyl ester.
Yield: 6mg (12%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 229
5-cyano group-2-(methyl fluoride)-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
According to method E ' from 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] the nicotinic acid ethyl ester.
Yield: 20mg (40%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 230
5-cyano group-6-[4-({ [(2, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-(methyl fluoride) nicotinic acid ethyl ester
According to method E ' from 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) nicotinic acid ethyl ester.
Yield: 21mg (38%).
1H NMR(400MHz，DMSO-d
6)δ1.30(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 231
5-cyano group-2-(methyl fluoride)-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
According to method E ' from 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 the nicotinic acid ethyl ester.
Yield: 18mg (36%).
1H NMR(400MHz，DMSO-d
6)δ0.80-0.90(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 232
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester
(a) amino 3-{2-[(benzyl alkylsulfonyl)]-the 2-oxoethyl } azetidine-1-formic acid tertiary butyl ester
With DIPEA (0.3mL, 1.72mmol) join [1-(tert-butoxycarbonyl) azetidine-3-yl] acetate (193mg, 0.90mmol) and TBTU (326mg is 1.02mmol) in the mixture in anhydrous DCM (4mL).With reaction mixture stirring at room 1 hour, add 1-phenyl methanesulfonamide acid amides (169mg, 0.99mmol) and continue stirring at room 19 hours.Add NaHCO
3(aq) and with mixture extract (3 times) with EtOAc.The anhydrous MgSO of organic layer that merges
4Drying is filtered and evaporation, obtains 3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-formic acid tertiary butyl ester, it is used for next step without being further purified.Yield: 383mg (116%).
MS
m/
Z：367(M-1)。
(b) 2-azetidine-3-base-N-(benzyl alkylsulfonyl) ethanamide
To derive from the thick 3-{2-[(benzyl alkylsulfonyl of abovementioned steps) amino]-the 2-oxoethyl } (383mg 0.90mmol) is dissolved in DCM (5mL) and adding TFA (4mL) to azetidine-1-formic acid tertiary butyl ester.With reaction mixture stirring at room 1.5 hours.Evaporating solvent obtains 2-azetidine-3-base-N-(benzyl alkylsulfonyl) ethanamide, and it is used for next step without being further purified.Yield: 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) nicotinic acid ethyl ester
DIPEA (1mL) is joined thick 2-azetidine-3-base-N-(benzyl alkylsulfonyl) ethanamide of deriving from abovementioned steps and 6-chloro-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester, and (180mg is in EtOH 0.69mmol) (9mL) solution.Use the heating of microwave list node that reaction mixture is heated to 120 ℃, kept 5 minutes.Add NaHCO
3(aq) and with mixture extract (3 times) with DCM.The organic layer that makes merging is by phase separator and evaporation.(Kromasil C8 10 μ m, 21.5 * 250mm use CH to crude product by HPLC
3CN/0.1M NH
4The gradient of OAc 20% to 50%, flow velocity 25mL/min) purifying, obtain 6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-(difluoromethyl) nicotinic acid ethyl ester.Yield: 156mg (46%, three step).
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, significantly br s), 4.28 (2H, q, J=7.1Hz), 4.52 (2H, significantly br s), 4.70 (2H, s), 7.29-7.32 (2H, m), 7.37-7.44 (3H, m), 7.40 (1H, t, J=53Hz ,-CHF2), 8.44 (1H, s), 11.68 (1H, s).
MS
m/
Z：493(M+1)，491(M-1)。
Claims (46)
1. the compound or pharmaceutically acceptable salt thereof of formula I:
Wherein
R
1Expression R
6OC (O), R
7C (O), R
16SC (O), R
17S, R
18C (S) or group gII:
R
2Expression H, CN, halogen (F, Cl, Br, I), NO
2, randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; In addition, R
2(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
1-C
12) alkoxyl group; In addition, R
2Expression (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 (2)R
B (2)Group, R wherein
A (2)And R
B (2)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or R
A (2)And R
B (2)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
In addition, R
1+ R
2(with two carbon atoms of pyridine ring) can form 5-unit or 6-unit annular lactone;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I) is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; In addition, R
3(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
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, R wherein
A (3)And R
B (3)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or 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) is randomly by the oxygen interval and/or randomly by OH, COOH, (C
1-C
6) (the C that replaces of alkoxy carbonyl, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
12) alkyl; 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 randomly by one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or (C
1-C
6) the alkoxy carbonyl replacement; 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, R wherein
A (4)And R
B (4)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or 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 randomly by oxygen at interval (condition be any this oxygen must be connected R
6Ester-the oxygen of group is at a distance of at least 2 carbon atoms) and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
12) alkyl, aryl or heterocyclic radical;
R
7Expression is randomly by oxygen (C at interval and/or that randomly replaced by OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
12) alkyl; In addition, R
7Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
12) alkyl, aryl or heterocyclic radical;
R
8Expression H is randomly by oxygen (C at interval and/or that randomly replaced by aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
12) alkyl; 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 (condition be the OH group must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
12) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
12) alkyl; 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, 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, formula NR
A (14)R
B (14)Group, R wherein
A (14)And R
B (14)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), (C
1-C
12) alkoxy C (O), or R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H, OH (condition be the OH group must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
12) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
12) alkyl; 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, 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 (15)R
B (15)Group, R wherein
A (15)And R
B (15)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O)), (C
1-C
12) alkoxy C (O), or R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; 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
17Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; 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
18Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; 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
cRepresent unsubstituted or single the replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylene oxide group or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
1-C
4) alkyl, or R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms; In addition, R
cExpression imido grpup (NH-), the imido grpup (NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylene imine base or N-
1-C
4) alkylene imine base (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is not substituted or is replaced by above-mentioned any substituting group list or polysubstituted;
R
19Expression H or (C
1-C
4) alkyl;
R
dExpression (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, and in these groups any is randomly by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
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
A (Rd)R
B (Rd)Group, R wherein
A (Rd)And R
B (Rd)Represent H, (C independently
1-C
12) alkyl, (C
1-C
12) alkyl C (O), or R
A (Rd)And R
B (Rd)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
X represents singly-bound, imido grpup (NH-), methylene radical (CH
2-), imido grpup methylene radical (CH
2-NH-), wherein carbon is connected in B-ring/member ring systems), methylenimine base (NH-CH
2-), wherein nitrogen is connected in B-ring/member ring systems, and any carbon in these groups and/or nitrogen can be randomly by (C
1-C
6) the alkyl replacement; In addition, X can represent group (CH
2-) n, n=2-6 wherein, it randomly is not substituted and/or by one or more halogen, hydroxyl and (C of being selected from
1-C
6) substituting group of alkyl replaces; With
B is the 4-11 unit heterocycle/member ring systems of monocycle or dicyclo, comprises one or more nitrogen and optional one or more atoms that are selected from oxygen or sulphur, and described nitrogen is connected in pyridine-ring (according to formula I), and B-ring/member ring systems is connected in X with its another position in addition.Substituent R
14And R
15Be connected in B-ring/member ring systems, make (by these connections) not form quaternary ammonium compound.
2. the compound of claim 1, wherein
R
2Expression H, CN, NO
2, randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; In addition, R
2(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
1-C
6) alkoxyl group; In addition, R
2Expression (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 (2)R
B (2)Group, R wherein
A (2)And R
B (2)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (2)And R
B (2)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
In addition, R
1+ R
2(with two carbon from pyridine ring) can form 5-unit or 6-unit annular lactone;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I) is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or the replacement of one or more halogen atom
1-C
6) alkyl; In addition, R
3(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
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, R wherein
A (3)And R
B (3)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or 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) is randomly by the oxygen interval and/or randomly by OH, COOH, (C
1-C
6) (the C that replaces of alkoxy carbonyl, aryl, cycloalkyl, heterocyclic radical or one or more halogen atom
1-C
6) alkyl; 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 randomly by one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or (C
1-C
3) the alkoxy carbonyl replacement; 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, R wherein
A (4)And R
B (4)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or 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 randomly by oxygen at interval (condition be any this oxygen must be connected R
6Ester-the oxygen of group is at a distance of at least 1 carbon atom) and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; In addition, R
6Expression (C
3-C
6) cycloalkyl, hydroxyl (C
2-C
6) alkyl, aryl or heterocyclic radical;
R
7Expression is randomly by oxygen (C at interval and/or that randomly replaced by OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
6) alkyl; In addition, R
7Expression (C
3-C
6) cycloalkyl, hydroxyl (C
1-C
6) alkyl, aryl or heterocyclic radical;
R
8Expression H is randomly by oxygen (C at interval and/or that randomly replaced by aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
6) alkyl; 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 (condition be OH must encircle with B-/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; 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, 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 (14)R
B (14)Group, R wherein
A (14)And R
B (14)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H, OH (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; 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, 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 (15)R
B (15)Group, R wherein
A (15)And R
B (15)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; 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
17Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; 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
18Expression is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; 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; With
R
dExpression (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, and in these groups any is randomly by one or more replacements: OH, CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
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) alkyl, (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, R wherein
A (Rd)And R
B (Rd)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or 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 group gII:
R
2Expression H, CN, NO
2, randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
6) alkyl; In addition, R
2(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
1-C
6) alkoxyl group; In addition, R
2Expression (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) or formula NR
A (2)R
B (2)Group, R wherein
A (2)And R
B (2)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (2)And R
B (2)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
3Expression H, CN, NO
2, halogen (F, Cl, Br, I) is randomly by the oxygen interval and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or the replacement of one or more halogen atom
1-C
6) alkyl; In addition, R
3(the C that expression is randomly replaced by one or more halogens (F, Cl, Br, I) atom
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, R wherein
A (3)And R
B (3)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or 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) is randomly by the oxygen interval and/or randomly by the (C of OH, COOH, aryl, cycloalkyl, heterocyclic radical or the replacement of one or more halogen atom
1-C
6) alkyl; 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 randomly be replaced by 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, R wherein
A (4)And R
B (4)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (4)And R
B (4)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
8Expression H is randomly by oxygen (C at interval and/or that randomly replaced by aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
6) alkyl; 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 (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; 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, aryl, heterocyclic radical or formula NR
A (14)R
B (14)Group, R wherein
A (14)And R
B (14)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H, OH (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; 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, aryl, heterocyclic radical or formula NR
A (15)R
B (15)Group, R wherein
A (15)And R
B (15)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (15)And R
B (15)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
16Be ethyl;
R
cRepresent unsubstituted or single the replacement or polysubstituted (C
1-C
4) alkylidene group, (C
1-C
4) oxo alkylidene group, (C
1-C
4) alkylene oxide group or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately respectively 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 respectively and independently of one another
1-C
4) alkyl, or R
A (Rc)And R
B (Rc)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms; In addition, R
cExpression imido grpup (NH-), the imido grpup (NR of N-replacement
19-), (C
1-C
4) (the C that replaces of alkylene imine base or N-
1-C
4) alkylene imine base (N (R
19)-((C
1-C
4) alkylidene group), wherein said alkylidene group is not substituted or is replaced by above-mentioned any substituting group list or polysubstituted; With
R
dExpression (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, and in these groups any is randomly by one or more replacements: CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
2, (C
1-C
6) alkyl, (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) alkyl, (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
16SC (O) or group gII:
R
2Expression H or randomly at interval and/or (the C that is randomly replaced by OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom by oxygen
1-C
6) alkyl; In addition, R
2Expression NR
A (2)R
B (2)Group, R wherein
A (2)And R
B (2)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (2)And R
B (2)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
3Expression H or formula NR
A (3)R
B (3)Group, R wherein
A (3)And R
B (3)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), or R
A (3)And R
B (3)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
4Expression CN, halogen (F, Cl, Br, I), in addition, R
4Expression (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxyl group, wherein this alkoxyl group can randomly be replaced by one or more halogens (F, Cl, Br, I) atom, OH and/or COOH and/or methoxycarbonyl;
R
5Expression H;
R
6Expression randomly by oxygen at interval (condition be any this oxygen must be connected R
6Ester-the oxygen of group is at a distance of at least 2 carbon atoms) and/or randomly by the (C of OH, aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom replacement
1-C
12) alkyl; In addition, R
6Expression (C
3-C
6) cycloalkyl or hydroxyl (C
2-C
12) alkyl;
R
8Expression H, randomly by oxygen (C at interval and/or that randomly replaced by aryl, cycloalkyl, heterocyclic radical or one or more halogen (F, Cl, Br, I) atom
1-C
6) alkyl;
R
14Expression H, OH (condition be OH must encircle with B/any heteroatoms of member ring systems is at a distance of at least 2 carbon atoms), randomly by oxygen at interval and/or randomly by OH, COOH and COOR
eIn (the C of one or more replacements
1-C
6) alkyl; R wherein
eExpression aryl, cycloalkyl, heterocyclic radical or randomly by the (C of one or more replacements in halogen (F, Cl, Br, I) atom, OH, aryl, cycloalkyl and the heterocyclic radical
1-C
6) alkyl; In addition, R
14Expression NR
A (14)R
B (14)Group, R wherein
A (14)And R
B (14)Represent H, (C independently
1-C
6) alkyl, (C
1-C
6) alkyl C (O), (C
1-C
6) alkoxy C (O), or R
A (14)And R
B (14)Represent piperidines, tetramethyleneimine, azetidine or aziridine with nitrogen-atoms;
R
15Expression H;
R
16Be ethyl;
R
cRepresent unsubstituted or mono-substituted (C
1-C
4) alkylidene group, (C
1-C
4) alkylene oxide group or oxygen base-(C
1-C
4) alkylidene group, wherein any substituting group is separately respectively and be independently selected from (C
1-C
4) alkyl; In addition, R
cExpression imido grpup (NH-), the imido grpup (NR of N-replacement
19-);
R
19Expression H or methyl;
R
dExpression (C
3-C
8) cycloalkyl, aryl or heterocyclic radical, and in these groups any is randomly by one or more replacements: CN, NO in one or more halogens (F, Cl, Br, I) atom and/or the following group
2, (C
1-C
6) alkyl, (C
1-C
6) (the C that replaces of alkoxyl group, halogen
1-C
6) alkyl; With
X represents that singly-bound, imido grpup are (NH-) or methylene radical (CH
2-).
5. the compound of claim 1, wherein:
R
1Be selected from following group: methoxycarbonyl, ethoxy carbonyl, (n-propyl)-oxygen base carbonyl, (sec.-propyl)-oxygen base carbonyl, (isobutyl-)-oxygen base carbonyl, (tertiary butyl)-oxygen base carbonyl, (2,2-dimethyl-propyl group)-oxygen base carbonyl, (cyclopropyl)-oxygen base carbonyl, (cyclobutyl)-oxygen base carbonyl, (cyclopentyl)-oxygen base carbonyl, (2-hydroxyethyl)-oxygen base carbonyl), (2,2, the 2-trifluoroethyl)-and oxygen base carbonyl, benzyl-oxygen base carbonyl, 4-luorobenzyl-oxygen base carbonyl, ethylmercapto group carbonyl and 5-ethyl-1,3-oxazole-2-base;
R
2Be selected from following group: H, methyl, ethyl, sec.-propyl and dimethylamino;
R
3Be selected from following group: H and amino;
R
4Be selected from following group: methoxyl group, chlorine, cyano group, (4-methoxyl group-4-oxo butoxy), (3-carboxyl-propoxy-) and methyl carbonyl;
Z represents O or does not exist;
R
5Be H;
R
6Be selected from following group: methyl, ethyl, 2-hydroxyethyl, (2,2, the 2-trifluoroethyl), n-propyl, sec.-propyl, cyclopropyl, isobutyl-, the tertiary butyl, cyclobutyl, 2,2-dimethyl propyl, cyclopentyl, benzyl and 4-luorobenzyl;
R
8Be ethyl;
R
14Be selected from following group: H, methyl, tert-butoxycarbonyl-imido grpup and amino;
R
15Be H;
R
16Be ethyl;
R
cBe selected from following group: methylene radical (CH
2-), methyl methylene radical (CH (CH
3)-), ethylidene (CH
2CH
2-), oxygen base propylidene (OCH
2CH
2CH
2-), imido grpup (NH-) and methylene imine base (N (CH
3)-);
R
19Be selected from following group: H and methyl;
R
dBe selected from following group: cyclopentyl, cyclohexyl, the 4-methylcyclohexyl, phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, the 4-ethylphenyl, 2-methoxycarbonyl-phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-(trifluoromethyl) phenyl, the 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, the 2-chloro-phenyl-, the 3-chloro-phenyl-, the 4-chloro-phenyl-, the 3-bromophenyl, the 4-cyano-phenyl, the 4-p-methoxy-phenyl, the 2-nitrophenyl, the 3-nitrophenyl, the 4-nitrophenyl, 3, the 4-dichlorophenyl, 3, the 5-dichlorophenyl, 3, the 4-difluorophenyl, 2, the 5-3,5-dimethylphenyl, 3, the 5-3,5-dimethylphenyl, the 4-isopropyl phenyl, 3-fluoro-4-methyl-phenyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, N-oxidation-2-pyridyl, 6-[3-benzo [d] isoxazole-3-base] and N-[(1,2-benzoisoxazole-3-yl)];
X represents that singly-bound, imido grpup are (NH-) or methylene radical (CH
2-); With
B is selected from following group: 4-piperazine-1-subunit, 4-piperidines-1-subunit, 3-piperidines-1-subunit, 3-azetidine-1-subunit, and substituent R
14And R
15Being connected in B ring/member ring systems makes (by these connections) not form quaternary ammonium compound.
6. each compound among the claim 1-5 is formula (Ia):
7. each compound among the claim 1-5 is formula (Ib):
8. each compound among the claim 1-5 is formula (Ic):
9. each compound among the claim 1-5 is formula (Id):
10. each compound among the claim 1-5 is formula (Ie):
11. each compound among the claim 1-5 is formula (If):
12. each compound among the claim 1-5 is formula (Ig):
13. each compound among the claim 1-12, wherein Z does not exist.
14. each compound among the claim 1-12, wherein Z is O.
15. each compound, wherein R among the claim 1-5
1Expression R
6OC (O).
16. each compound, wherein R among the claim 1-5
1Expression R
16SC (O) or group gII:
17. the compound of claim 15, it is formula (Iaa):
18. the compound of claim 15, it is formula (Ibb):
19. the compound of claim 15, it is formula (Ibc):
20. the compound of claim 15, it is formula (Ibd):
21. the compound of claim 15, it is formula (Ibe):
22. the compound of claim 15, it is formula (Icc)
23. the compound of claim 15, it is formula (Idd):
24. the compound of claim 15, it is formula (Iee):
25. the compound of claim 15, it is formula (Iff):
26. the compound of claim 16, it is formula (Igg):
27. the compound of claim 16, it is formula (Ihh):
28. the compound of claim 16, it is formula (Iii):
29. the compound of claim 16, it is formula (Ijj):
30. each compound, wherein R among the claim 1-5
1Expression R
6OC (O), R
16SC (O) or group gII:
31. the compound of claim 30, wherein R
1Expression group gII:
32. the compound of claim 30, wherein R
1Expression R
16SC (O).
33. be selected from following compound:
5-cyano group-6-[3-(2-methoxycarbonyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
6-[3-({ [(3-bromobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(2-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
6-[3-(2-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
6-[3-(4-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(4-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-6-[3-(3-fluoro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(3-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
6-[3-(3-chloro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
6-{3-[2-(3-chloro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-5-cyano group-2-methyl-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(4-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(2-phenyl-ethylsulfonylamino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-(3-o-tolyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(3-nitro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-6-{3-[2-(4-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-(2-trifluoromethyl-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-the nicotinic acid ethyl ester
5-cyano group-6-[3-(4-fluoro-phenyl methanesulfonamide acyl amino carbonyl)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-(3-cyclopentyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-{3-[2-(2-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-[3-(3,5-two chloro-phenyl methanesulfonamide acyl amino carbonyls)-azetidine-1-yl]-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-(3-cyclohexyl methylsulfonyl aminocarboxyl-azetidine-1-yl)-2-methyl-nicotinic acid ethyl ester
5-cyano group-6-{3-[2-(3-fluoro-phenyl)-ethylsulfonylamino carbonyl]-azetidine-1-yl }-2-methyl-nicotinic acid ethyl ester
6-[3-(benzo [d] isoxazole-3-base methylsulfonyl aminocarboxyl)-azetidine-1-yl]-5-cyano group-2-methyl-nicotinic acid ethyl ester
1-[4-amino-3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl]-N-(benzyl alkylsulfonyl) piperidines-4-methane amide
4-amino-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chlorine apellagrin ethyl ester
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid tertiary butyl ester
6-[3-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl }-4-methyl piperidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
N-(benzyl alkylsulfonyl)-1-[3-chloro-5-(5-ethyl-1,3-oxazole-2-yl) pyridine-2-yl] piperidines-4-methane amide
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopentyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid propyl diester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
N-(benzyl alkylsulfonyl)-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
N-[(1,2-benzoisoxazole-3-ylmethyl) alkylsulfonyl]-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
N-(benzyl alkylsulfonyl)-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] azetidine-3-methane amide
N-[(4-benzyl chloride base) alkylsulfonyl]-1-[3-cyano group-5-(5-ethyl-1,3-oxazole-2-yl)-6-picoline-2-yl] piperidines-4-methane amide
5-cyano group-2-methyl-6-(3-phenyl methanesulfonamide acyl amino carbonyl-azetidine-1-yl)-nicotinic acid ethyl ester
5-cyano group-6-{3-[({[3-(4-methoxyl group phenoxy group) propyl group] alkylsulfonyl } amino) carbonyl] azetidine-1-yl }-2-methylnicotinic acid ethyl ester
4-amino-6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chlorine apellagrin ethyl ester
5-cyano group-2-methyl-6-[3-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2-dimethyl propyl ester
5-cyano group-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
6-[4-({ [(3-bromobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid 2,2,2-trifluoroethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid cyclopropyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid cyclobutyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid 2-hydroxyethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester
5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3, the 4-dichloro benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-sec.-propyl nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-ethyl nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-({ [(1-phenylethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid propyl diester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid isobutyl
5-cyano group-2-methyl-6-{4-[({[4-(trifluoromethyl) benzyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid isopropyl esters
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid isopropyl esters
5-cyano group-2-methyl-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid isopropyl esters
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[4-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
6-[4-({ [(3-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
6-[4-({ [(2-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-{4-[({[2-(methoxycarbonyl) benzyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl }-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-{4-[({[2-(2-aminomethyl phenyl) ethyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid isopropyl esters
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
4-{[2-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-(ethoxy carbonyl)-6-picoline-3-yl] the oxygen base } butyric acid
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(4-methoxyl group-4-oxo butoxy)-2-methylnicotinic acid ethyl ester
6-(4-{[(Phenylsulfamoyl base) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-{4-[({[methyl (phenyl) amino] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(3-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-2-methyl-6-[3-({ [(2-phenylethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-{3-[({[2-(methoxycarbonyl) benzyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl }-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(2-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
6-[3-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-5-cyano group-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[3-({ [(4-cyano group benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid isopropyl esters
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid methyl ester
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid methyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] pyridine-3-carbothioic acid carbothiolic acid S-ethyl ester
6-[4-({ [(4-benzyl chloride base) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-5-cyano group-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
5-cyano group-6-[4-({ [(4-luorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-picoline-3-carbothioic acid carbothiolic acid S-ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-methoxyl group-2-methylnicotinic acid ethyl ester
6-[4-({ [(benzyl alkylsulfonyl) amino] carbonyl } amino) piperidines-1-yl]-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperazine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
4-{[2-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-(ethoxy carbonyl)-6-picoline-3-yl] the oxygen base } butyric acid
5-cyano group-2-methyl-6-{3-[({[(1-pyridine oxide-2-yl) methyl] alkylsulfonyl } amino) carbonyl] azetidine-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-({ [(pyridin-3-yl methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-{4-[({[(1-pyridine oxide-2-yl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(pyridin-3-yl methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(pyridin-4-yl methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[3-({ [(pyridine-2-ylmethyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(3, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid isopropyl esters
5-cyano group-6-[4-({ [(2, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid benzyl ester
5-cyano group-2-methyl-6-{4-[({[(4-methylcyclohexyl) methyl] alkylsulfonyl } amino) carbonyl] piperidines-1-yl } the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-isopropyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(2-phenylethyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(pyridine-2-ylmethyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(2, the 5-dimethyl benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester
6-(3-{2-[(benzyl alkylsulfonyl) amino]-the 2-oxoethyl } azetidine-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(cyclopentyl-methyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[3-(2-{[(4-luorobenzyl) alkylsulfonyl] amino }-the 2-oxoethyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3-fluoro-4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-chloro-2-methylnicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid 4-luorobenzyl ester
5-cyano group-6-[4-({ [(4-Ethylbenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[3-({ [(3, the 4-difluorobenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[4-({ [(4-methoxy-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(3-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-Ethylbenzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-chloro-2-methyl-6-[3-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
5-cyano group-6-[4-({ [(3, the 4-difluorobenzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-6-[3-({ [(4-methoxy-benzyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl]-2-methylnicotinic acid ethyl ester
5-cyano group-2-methyl-6-[4-({ [(4-methyl-benzyl) alkylsulfonyl] amino } carbonyl) piperidines-1-yl] nicotinic acid cyclopropyl ester
5-cyano group-2-methyl-6-[3-({ [(pyridin-4-yl methyl) alkylsulfonyl] amino } carbonyl) azetidine-1-yl] the nicotinic acid ethyl ester
6-(3-{[(benzyl alkylsulfonyl) amino] carbonyl } azetidine-1-yl)-5-cyano group-2-(dimethylamino) nicotinic acid ethyl ester
6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester 1-oxide compound
5-ethanoyl-6-(4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-2-methylnicotinic acid ethyl ester
6-{4-{[(benzyl alkylsulfonyl) amino] carbonyl }-the 4-[(tert-butoxycarbonyl) amino] piperidines-1-yl }-5-cyano group-2-methylnicotinic acid ethyl ester
6-(4-amino-4-{[(benzyl alkylsulfonyl) amino] carbonyl } piperidines-1-yl)-5-cyano group-2-methylnicotinic acid ethyl ester;
And pharmacologically acceptable salt.
34. the method for the compound of production formula (I), wherein R
2, R
3, R
4, B, R
14, R
15, R
cAnd R
dAs each defines among the claim 1-5, R
1Be R
6OC (O), wherein R
6As each defines among the claim 1-5, X is a singly-bound, and Z does not exist and R
5Be hydrogen, it is characterized in that this method may further comprise the steps (i-vi):
I.) make formula R
1CH
2C (O) R
2Compound and dimethoxy-N, N-dimethyl methylamine reaction, to form the compound of following formula:
Ii.) inert solvent for example in the ethanol highly basic for example sodium ethylate in the presence of make from step I) compound and general formula R
4CH
2C (O) NH
2Compound reaction, obtain the compound of following general formula:
R wherein
2, R
3, R
4As each defines among the claim 1-5, R
1Be R
6OC (O), wherein R
6As each defines and Z does not exist among the claim 1-5,
Iii) will derive from step I i) product at first with for example sodium hydrogen carbonate solution washing of alkali aqueous solution, wash with water then, collect the product of washing subsequently,
Iv.) make from step I ii) compound and chlorination reagent for example thionyl chloride in inert solvent, react, obtain the compound of formula (VII), wherein L is a chlorine,
V.) in inert organic solvents coupling reagent and optional organic bases for example triethylamine or DIPEA in the presence of, the compound that makes formula (X) reacts with the compound of formula (III), wherein B, R
14, R
15, R
cAnd R
dAs each defines among the claim 1-5, X is singly-bound and R
5Be hydrogen, the compound of same up-to-date style (III) has the ring nitrogen with the tertbutyloxycarbonyl protection, after the tertbutyloxycarbonyl deprotection of standard, obtains the compound of general formula (VIII),
Vi) make from step v.) product with derive from step I v.) product in inert solvent, randomly organic bases for example triethylamine in the presence of react, obtain the compound of formula (I), wherein R
2, R
3, R
4, B, R
14, R
15, R
cAnd R
dAccording to each definition among the claim 1-4, R
1Be R
6OC (O) and R
6As each defines among the claim 1-5, X is a singly-bound, and Z does not exist and R
5Be hydrogen.
35. the method for claim 34, wherein step I v.) comprise and in reaction mixture, add dimethyl formamide.
36. the method for claim 35, wherein step I v.) in inert solvent be toluene.
37. each method among the claim 34-36, wherein step v.) in inert organic solvents be THF.
38. each method among the claim 34-37, wherein step v.) in coupling reagent be TBTU.
39. each method among the claim 34-38 is wherein at step v.) in reaction mixture, add LiCl.
40. each method among the claim 34-39, wherein step v.) comprise the ammonia separated product that is dissolved in water by adding.
41. each method among the claim 34-40 is wherein by deriving from step product vi) from the re-crystallizing in ethyl acetate purifying with separating.
42. pharmaceutical composition, it comprises among the claim 1-33 with pharmaceutically acceptable auxiliary agent, thinner and/or carrier combinations each compound.
43. each compound is used for the treatment of among the claim 1-33.
44. each compound is used for the purposes of the medicine of production for treating platelet aggregation illness among the claim 1-33.
45. each compound is used for producing inhibition P2Y among the claim 1-33
12The purposes of the medicine of acceptor.
46. the method for treatment platelet aggregation illness comprises the compound of the patient who suffers from this illness being treated among the claim 1-33 of significant quantity each.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE05016639 | 2005-07-13 | ||
| SE0501663 | 2005-07-13 | ||
| SE05023544 | 2005-10-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101263133A true CN101263133A (en) | 2008-09-10 |
Family
ID=39962951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800333874A Pending CN101263133A (en) | 2005-07-13 | 2006-07-04 | New pyridine analogues |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101263133A (en) |
| ZA (1) | ZA200800157B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109406643A (en) * | 2017-08-18 | 2019-03-01 | 青岛谱尼测试有限公司 | The measuring method of dihydropyridine in a kind of feed |
| WO2020119590A1 (en) * | 2018-12-11 | 2020-06-18 | 中国科学院上海药物研究所 | 3-cyanopyridine compound, pharmaceutical composition comprising same, preparation method therefor, and uses thereof. |
-
2006
- 2006-07-04 CN CNA2006800333874A patent/CN101263133A/en active Pending
-
2008
- 2008-01-07 ZA ZA200800157A patent/ZA200800157B/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109406643A (en) * | 2017-08-18 | 2019-03-01 | 青岛谱尼测试有限公司 | The measuring method of dihydropyridine in a kind of feed |
| CN109406643B (en) * | 2017-08-18 | 2021-07-13 | 青岛谱尼测试有限公司 | Method for determining dihydropyridine in feed |
| WO2020119590A1 (en) * | 2018-12-11 | 2020-06-18 | 中国科学院上海药物研究所 | 3-cyanopyridine compound, pharmaceutical composition comprising same, preparation method therefor, and uses thereof. |
| CN111303146A (en) * | 2018-12-11 | 2020-06-19 | 中国科学院上海药物研究所 | 3-cyanopyridine compound, pharmaceutical composition containing same, preparation method and application thereof |
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