CN1751025B - Diamine derivatives - Google Patents

Diamine derivatives Download PDF

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CN1751025B
CN1751025B CN200380109746.6A CN200380109746A CN1751025B CN 1751025 B CN1751025 B CN 1751025B CN 200380109746 A CN200380109746 A CN 200380109746A CN 1751025 B CN1751025 B CN 1751025B
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CN1751025A (en
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太田敏晴
小森谷聡
吉野利治
魚戸浩一
中本有美
内藤博之
望月明慶
永田勉
菅野英幸
萩野谷憲康
吉川謙次
永持雅敏
小林祥三
小野誠
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Daiichi Pharmaceutical Co Ltd
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Daiichi Pharmaceutical Co Ltd
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Abstract

A compound represented by the following general formula (1): Q<1>-Q<2>-T<0>-N(R<1>)-Q<3>-N(R<2>)-T<1>-Q<4> (1) wherein R<1> and R<2> represent each hydrogen, etc.; Q<1> represents optionally substituted and saturated or unsaturated 5- to 6-membered cyclic hydrocarbyl, etc.; Q<2> represents a single bond, etc.; Q<3> represents a group of the following formula: (wherein Q<5> represent C1-8 alkylene,etc.); and T<0> and T<1> represent each carbonyl, etc.; its salt, solvates thereof or N-oxides of the same. These compounds are useful as preventives and/or remedies for cerebral infarction, cerebralembolism, myocardial infarction, angina, pulmonary infarction, pulmonary embolism, Burger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve/joint replacement, thrombosis and reocclusion after reconstructing blood circulation, systemic inflammatory response syndrome (SIRS), multiorgan dysfunction syndrome (MODS), thrombosis in extracorporeal circulation and blood coagulation in blood collection.

Description

Diamine derivative
Technical field
The present invention relates to suppress activated form factor X (hereinafter referred to as FXa), the blood coagulation resisting function for showing strength, orally available novel compound or the Coagulative inhibitors agent using it as active ingredient or prevention and/or the therapeutic agent of thrombus or embolism.
Background technology
Unstable angina, cerebral infarction, cerebral embolism, miocardial infarction, lung blocks, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve replacement, blood flow build again after occlusion and thrombosis during extracorporal circulatory system etc. again, hyperfunction coagulation function is one of major reason, so needing dose response excellent, with continuation, bleeding it is dangerous relatively low, few side effects, even if orally can also obtaining good anticoagulation (the Thrombosis Research of sufficient effect at once, volume 68, 507-512 pages, 1992).
In the research of the anticoagulation based on various mechanism of action, FXa inhibitor has been pointed out to turn into the possibility of good anticoagulation.Blood coagulation system is by amplification process, the series reaction for producing substantial amounts of fibrin ferment, generating insoluble fibrin by multistage enzyme reaction.Continue multistage reaction in endogenous sexual system after the activation of contact factor, then in the presence of activated form Factor VIII, calcium ion, activated form factor IX activates factor X on phosphatide plasma membrane.In addition, activated form factor VII activates factor X in the presence of tissue factor in external source sexual system.That is, the factor X in blood coagulation system reacts necessary to being generation fibrin ferment to FXa activation.The factor X (FXa) being activated in two systems, which is limited, decomposes factor, generates fibrin ferment.Because the fibrin ferment of generation activates the clotting factor of upstream, so the generation of fibrin ferment is further magnified.As described above, the blood coagulation system in FXa upstreams is divided into endogenous sexual system and external source sexual system, so FXa generation can not fully be suppressed by suppressing the blood coagulation system enzyme of FXa upstreams, the result is that generation fibrin ferment.Further, since blood coagulation system is the reaction of self amplification, so the fibrin ferment for suppressing generation by the rejection ratio of the FXa positioned at upstream can realize the suppression (Thrombosis Research, volume 15,617-629 pages, 1979) of more effective blood coagulation system.Another advantage of FXa inhibitor is effective dose in thrombus model and makes the deviation of the consumption of the prolonged bleeding time of experiment Hemorrhage Model larger, and the dangerous less anticoagulation that FXa inhibitor is bleeding is believed that from the result of the experiment.
Various compounds are reported as FXa inhibitor, but factor combined enzyme agent that known general Antithrombin III and the pentasaccharides of Antithrombin III dependence etc. will not suppress to have thrombosis in body practical function (Thrombosis Research, volume 68,507-512 pages, Journal of Clinical Investigation in 1992, volume 71,1383-1389 pages, nineteen eighty-three, Mebio, volume 14, August number, 92-97 pages), and orally do not show validity.From tick anticoagulation peptide (the TAP) (Science separated as bloodsucking acarid and leech, volume 248,593-596 pages, nineteen ninety) and hirudin (AST) (Journal of Biological Chemistry, volume 263,10162-10167 pages, 1988) also there is inhibitory action to FXa, antithrombotic effect is all shown from venous thrombosis models to arterial thrombus model, but they are all macromolecule peptides, it is oral invalid.Therefore, the exploitation of the orally available low molecular FXa inhibitor of direct suppression Antithrombin III dependent/non-dependent clotting factor has been carried out.
The announcement of invention
It is therefore an object of the present invention to provide the FXa inhibitory action with strength, can orally show the novel compound of abundant and lasting antithrombotic effect rapidly.
Synthesis and pharmacological action of the present invention to new FXa inhibitor have found the diamine derivative for showing strength FXa inhibitory action and strength anticoagulation, its salt, their solvate or their N- oxides after inquiring into.Further, since these oral compounds at once and continue, effectively suppress FXa, show the anticoagulation and anti thrombotic action of strength, it is found that they are useful as the prophylactic and therapeutic agent of the various diseases based on thromboembolism, the present invention is thereby completed.
That is, the invention provides formula (1)
Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4(1)
The compound of expression, its salt, their solvate or their N- oxides；
In formula, R1And R2It is each independent, represent hydrogen atom, hydroxyl, alkyl or alkoxy；
Q1The saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups can with substituent are represented, can have the saturation or undersaturated 5~7 circle heterocycles base of substituent, can have the saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q2Represent singly-bound, the alkylidene of the carbon number 1~6 of straight-chain or branched, the alkenylene of the carbon number 2~6 of straight-chain or branched, the alkynylene of the carbon number 2~6 of straight-chain or branched, can have the divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups of substituent, can have the divalent saturation or undersaturated 5~7 circle heterocycles base of substituent, can have the divalent saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the divalent saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q3By following radicals
Figure G2003801097466D00021
Represent, the Q in the group5For the alkylidene of carbon number 1~8, the alkenylene of carbon number 2~8 or base-(CH2)m-CH2-A-CH2-(CH2)n- (m and n in group are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2-NH-)；
R3And R4Containing Q5Ring on carbon atom,Replaced on nitrogen-atoms or sulphur atom,It is each independent,Represent hydrogen atom,Hydroxyl,Alkyl,Alkenyl,Alkynyl,Halogen atom,Haloalkyl,Cyano group,Cyanoalkyl,Amino,Aminoalkyl,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,Acyl,There can be the acyl amino of substituent,Alkoximino,Oxyimino,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Carboxyalkyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxy carbonyl alkyl amino,Carboxyalkylamino,Alkoxycarbonyl amino,Alkoxycarbonylamino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkoxycarbamoyl alkyl,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,Carbamoylalkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Carbamoyloxy alkyl,N- alkyl carbamoyloxy base alkyl,N,N- dialkylcarbamoyloxy alkyl,There can be 3~6 circle heterocycles carbonylic alkyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,Aryl,Aralkyl,There can be 3~6 circle heterocycles bases of substituent,There can be 3~6 circle heterocycles alkyl of substituent,Alkyl sulfonyl amino,Arenesulfonyl amino,Alkyl sulfonyl amino alkyl,Arenesulfonyl amino alkyl,Alkylsulphonylaminocarbonyl,Arenesulfonyl amino carbonyl,Alkylsulphonylaminocarbonyl alkyl,Arenesulfonyl amino carbonylic alkyl,Oxo base,Carbamoyloxy,Aralkoxy,Carboxyalkoxy,Alkoxycarbonylalkoxy,Acyloxy,Acyloxyallcyl,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Alkoxyalkoxycarbonyl,Hydroxyl acyl group,Alkoxyacyl,Halogenacyl,Carboxyacyl,Aminoacyl,Acyloxy acyl group,Acyloxyallcyl sulfonyl,Hydroxy alkyl sulfonyl,Alkoxyalkyl sulfonyl,There can be 3~6 circle heterocycles sulfonyls of substituent,There can be 3~6 circle heterocycles epoxides of substituent,N- alkyl acylaminos,N,N- dialkyl amido acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl sulphonyls,Alkyl sulphonyl acyl group,N- aryl-amino-carbonyls,The circle heterocycles carbamoyl of N-3~6,N- alkyl N- aryl-amino-carbonyls,The circle heterocycles carbamoyl of N- alkyl-N-3~6,N- aryl-amino-carbonyl alkyl,The circle heterocycles carbamoylalkyl of N-3~6,N- alkyl-N-arylamino carbamoylalkyls,The circle heterocycles carbamoylalkyl of N- alkyl-N-3~6,Aminothio formoxyl (carbothioyl),N- alkyl amino thioformyls,N,N- dialkyl amido thioformyls,Alkoxyalkyl (thiocarbonyl),Alkylthio alkyl or N- acyl group-N- alkylaminoalkyl groups or R3And R4Alkylidene, the alkenylene of carbon number 2~5, the alkylene dioxo base or carbonyldioxy of carbon number 1~5 of carbon number 1~5 are represented together；
Q4Represent the fusion alkyl of the aryl can with substituent, the aromatic yl polysulfide yl that there can be the aromatic yl alkenyl of substituent, there can be substituent, the heteroarylalkenyl groups that there can be the heteroaryl of substituent, there can be substituent, the saturation or unsaturated 2 ring can with substituent or 3 rings, can have the saturation of substituent or the annelated heterocycles base of unsaturated 2 ring or 3 rings；
T0Represent carbonyl or thiocarbonyl；
T1Represent carbonyl, sulfonyl, base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-, base-C (=S)-C (=S)-N (R ')-(R ' in group represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-A1- N (R ")-(A in group1Represent can there is the alkylidene of the carbon number 1~5 of substituent, R " represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-, base-C (=S)-NH-, base-C (=O)-NH-NH-, base-C (=O)-A2- C (=O)-(the A in group2Represent the alkylidene of singly-bound or carbon number 1~5), base-C (=O)-A3- the C (=O)-NH- (A in group3Represent carbon number 1~5 alkylidene), base-C (=O)-C (=NORa)-N(Rb)-, base-C (=S)-C (=NORa)-N(RbR in)-(groupaRepresent hydrogen atom, alkyl or alkanoyl, RbRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-N=N-, base-C (=S)-N=N-, base-C (=NORc)-C (=O)-N (RdR in)-(groupcRepresent hydrogen atom, alkyl, alkanoyl, aryl or aralkyl, RdRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=N-N- (Re)(Rf)-C (=O)-N (RgR in)-(groupeAnd RfIt is each independent, represent hydrogen atom, alkyl, alkanoyl, alkyl (thiocarbonyl), RgRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-C (=O)-, base-C (=S)-NH-C (=O)-, base-C (=O)-NH-C (=S)-, base-C (=S)-NHC (=S)-, base-C (=O)-NH-SO2-, base-SO2- NH-, base-C (=NCN)-NH-C (=O)-, base-C (=S)-C (=O)-or thiocarbonyl.
In addition, present invention also offers the compound represented containing above-mentioned formula (1), its salt, the pharmaceuticals of their solvate or their N- oxides, specifically provide activated form factor X inhibitor, Coagulative inhibitors agent, the prevention of thrombus or embolism and/or therapeutic agent, additionally provide cerebral infarction, cerebral embolism, miocardial infarction, angina pectoris, lung blocks, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve/joint replacement, blood flow build again after thrombosis and inaccessible again, systemic inflammatory reaction syndrome (SIRS), MODS (MODS), the prevention of blood coagulation when thrombosis during extracorporal circulatory system or blood sampling and/or therapeutic agent.
In addition, the invention provides the intermediate of the compound (1) for preparing formula (1) expression.
Present invention also offers application of the compound, its salt, their solvate or their N- oxides of above-mentioned formula (1) expression in the preparation of pharmaceuticals.
Present invention also offers the treatment method of thrombus or embolism, this method is characterized in take compound, its salt, their solvate or their N- oxides that the above-mentioned formula (1) of effective dose is represented.
The inhibitory action of activated form factor X of the cyclic diamine derivative of the present invention due to showing strength, so pharmaceuticals can be used as, activated form factor X inhibitor, Coagulative inhibitors agent, the prevention of thrombus or embolism and/or therapeutic agent, the prevention of thrombotic diseases and/or curative, it is alternatively arranged as cerebral infarction, cerebral embolism, miocardial infarction, angina pectoris, lung blocks, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve/joint replacement, blood flow build again after thrombosis and inaccessible again, systemic inflammatory reaction syndrome (SIRS), MODS (MODS), the prevention of blood coagulation when thrombosis during extracorporal circulatory system or blood sampling and/or therapeutic agent.
The best mode carried out an invention
Hereinafter, the substituent in the diamine derivative of the invention that mutual-through type (1) is represented is illustrated.
(on group Q4)
Group Q4Represent the fusion alkyl of the aryl can with substituent, the aromatic yl polysulfide yl that there can be the aromatic yl alkenyl of substituent, there can be substituent, the heteroarylalkenyl groups that there can be the heteroaryl of substituent, there can be substituent, the saturation or unsaturated 2 ring can with substituent or 3 rings, can have the saturation of substituent or the annelated heterocycles base of unsaturated 2 ring or 3 rings.
Group Q4In, aryl refers to the aryl of carbon number 6~14, for example, phenyl, naphthyl, anthryl, phenanthryl etc. can be enumerated.The group that aryl alkenyl basis representation is made up of the aryl of carbon number 6~14 and the alkenylene of carbon number 2~6, for example, can enumerate styryl.Aromatic yl polysulfide yl represents the group that the aryl of carbon number 6~14 and the alkynylene of carbon number 2~6 are constituted, such as can enumerate phenylene-ethynylene.
Heteroaryl basis representation has 1 valency group of the heteroatomic aromatic series of at least one selected from oxygen atom, sulphur atom and nitrogen-atoms, the heteroaryl that total annular atom number is 5 or 6, can enumerate pyridine radicals, pyridazinyl, pyrazinyl, furyl, thienyl, pyrrole radicals, thiazolyl, oxazolyls, pyrimidine radicals, tetrazole radical etc..The group that Heteroarylalkenyl basis representation is made up of the alkenylene of above-mentioned heteroaryl and carbon number 2~6, can enumerate thienyl vinyl, pyridine radicals vinyl etc..
The fusion alkyl of saturation or undersaturated 2 ring or 3 rings represents 1 valency group of the fusion hydrocarbon formation of saturation or undersaturated 2 ring or 3 rings, the fusion hydrocarbon of the saturation or undersaturated 2 ring or 3 rings be of the same race or xenogenesis saturation or undersaturated 5~6 yuan 2~3 fusions of cyclic hydrocarbon formed by 2 rings or 3 rings fusion hydrocarbon.The saturation or undersaturated 5~6 yuan of cyclic hydrocarbons can enumerate pentamethylene, cyclopentene, hexamethylene, cyclohexene, cyclohexadiene, benzene etc..The specific example of the fusion alkyl of saturation or undersaturated 2 ring or 3 rings can enumerate indenyl, indanyl, tetralyl, naphthyl etc..To the fusion alkyl of saturation or undersaturated 2 ring or 3 rings and the T in formula (1)1Binding site be not particularly limited.
The annelated heterocycles base of saturation or undersaturated 2 ring or 3 rings is 1 valency group of the annelated heterocycles formation of saturation or undersaturated 2 ring or 3 rings, the annelated heterocycles of the saturation or undersaturated 2 ring or 3 rings be shown in it is following 1)~3).
1) saturation of the same race or xenogenesis or undersaturated 5~7 yuan 2~3 fusions of heterocycle are formed 2 rings or the annelated heterocycles of 3 rings；
2) 1 saturation or undersaturated 5~7 circle heterocycles and 1~2 saturation or undersaturated 5~6 yuan of cyclic hydrocarbons condense the annelated heterocycles of 2 rings to be formed or 3 rings；And
3) 2 saturations or undersaturated 5~7 circle heterocycles and 1 saturation or undersaturated 5~6 yuan of cyclic hydrocarbons condense the annelated heterocycles for 3 rings to be formed.
To the annelated heterocycles bases of above-mentioned saturation or undersaturated 2 ring or 3 rings and the T in formula (1)1Binding site be not particularly limited.
Above-mentioned saturation or unsaturated 5~7 circle heterocycles represent that, with the heteroatomic heterocycle of at least one selected from oxygen atom, sulphur atom and nitrogen-atoms, its specific example can enumerate furans, pyrroles, thiophene, pyrazoles, imidazoles, oxazole, oxazolidines, thiazole, thiadiazoles, furazan, pyrans, pyridine, pyrimidine, pyridazine, pyrrolidines, piperazine, piperidines, oxazine, oxadiazines, morpholine, thiazine, thiadiazine, thiomorpholine, tetrazolium, triazole, triazine, thiadiazine, oxadiazines, azepine
Figure G2003801097466D00061
Diaza
Figure G2003801097466D00062
Three azepines
Figure G2003801097466D00063
ThiaOxa-
Figure G2003801097466D00065
In addition, saturation or undersaturated 5~6 yuan of cyclic hydrocarbons are the saturation or undersaturated 5~6 yuan of cyclic hydrocarbons identical compound with being illustrated in saturation or the explanation of the fusion alkyl of undersaturated 2 ring or 3 rings.The specific example of the annelated heterocycles base of saturation or undersaturated 2 ring or 3 rings can enumerate benzofuranyl,Isobenzofuran-base,Benzothienyl,Indyl,Indolinyl,Isoindolyl,Isoindoline base,Indazolyl,Quinolyl,EEDQ base,4- oxo-dihydros quinolyl (EEDQ -4- ketone),Tetrahydric quinoline group,Isoquinolyl,Tetrahydro isoquinolyl,Chromene base,Chromanyl,Isochroman base,4H-4- oxochromen bases,3,4- dihydro -4H-4- oxochromen bases,4H- quinolizine bases,Quinazolyl,Dihydroquinazoline base,Tetrahydro quinazoline base,Quinoxalinyl,Tetrahydroquinoxaline base,Cinnolines base,Indolizine base,Indolizine base,Benzothiazolyl,Tetrahydro benzothiazol base,Benzoxazolyl,Benzisothia oxazolyl,Benzoisoxazole base,Benzimidazolyl,Naphthyridines base,Naphthane piperidinyl,Thienopyridine base,Tetrahydrothieno pyridines base,Thiazolopyridinyl,Tetrahydro-thiazoles and pyridine radicals,Thiazole and pyridazinyl,Tetrahydro-thiazoles and pyridazinyl,Pyrrolopyridinyl,Pyrrolin and pyridine radicals,Nafoxidine and pyridine radicals,Pyrrolo-pyrimidine radicals,Pyrrolin and pyrimidine radicals,Pyrido quinazolyl,Dihydro pyrido quinazolyl,Pyridopyrimidine base,Tetrahydropyridine and pyrimidine radicals,Pyrans benzothiazolyl,Dihydropyran benzothiazolyl,Furopyridyl,Tetrahydrofuran and pyridine radicals,Oxazole and pyridine radicals,Si Qing oxazoles and pyridine radicals,Oxazole and pyridazinyl,Si Qing oxazoles and pyridazinyl,Pyrroles's benzothiazolyl,Pyrrolin benzothiazolyl,Bi Ka Bing oxazolyls,Pyrrolin Bing oxazolyls,Thienopyrroles base,Thiazolopyrimidinyl,4- oxo tetrahydrochysene cinnolines bases,1,2,4- benzothiadiazine bases,1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,1,2,4- Ben Bing oxadiazine bases,Cyclopenta pyranose,Thienofuran base,Furans and pyranose,Bi Ding Bing oxazinyls,Bi Zuo Bing oxazolyls,Imidazothiazole base,Imidazopyridyl,Imidazolidine and pyridine radicals,Pyrazine and pyridazinyl,Benzisoquinoline base,Furans and cinnolines base,Pyrazolo thiazole and pyridazinyl,Tetrahydro-pyrazole and thiazole and pyridazinyl,Hexahydro thiazole and pyridazine and pyridazinyl,Imidazo-triazine base,Oxazole and pyridine radicals,Benzo oxa-Base, benzo-azaBase, tetrahydro benzo azepineBase, benzodiazepineBase, the azepine of benzo threeBase, thieno azepineBase, thiophane and azepine
Figure G2003801097466D000612
Base, thieno diazaBase, the azepine of thieno threeBase, thiazole and azepine
Figure G2003801097466D000615
Base, tetrahydro-thiazoles and azepineBase, 4,5,6,7- tetrahydrochysene -5,6- tetramethylene thiazoles and pyridazinyl, 5,6- trimethylenes -4,5,6,7- tetrahydro-thiazoles and pyridazinyl etc..
Fusion form to above-mentioned annelated heterocycles base is not particularly limited,Such as naphthyridines base,Can be 1,5-,1,6-,1,7-,1,8-,2,6- or 2,Any of 7- naphthyridines bases,Thienopyridine base,It can be thieno [2,3-b] pyridine radicals,Thieno [2,3-c] pyridine radicals,Thieno [3,2-b] pyridine radicals,Thieno [3,2-c] pyridine radicals,Thieno [3,4-b] pyridine radicals,Thieno [3,Any of 4-c] pyridine radicals,Thienopyrroles base,It can be thieno [2,3-b] pyrrole radicals,Thieno [2,Any of 3-b] pyrrole radicals,Thiazolopyridinyl,It can be thiazole simultaneously [4,5-b] pyridine radicals,Thiazole simultaneously [4,5-c] pyridine radicals,Thiazole simultaneously [5,4-b] pyridine radicals,Thiazole simultaneously [5,4-c] pyridine radicals,Thiazole simultaneously [3,4-a] pyridine radicals,Thiazole simultaneously [3,Any of 2-a] pyridine radicals,Thiazole and pyridazinyl,It can be thiazole simultaneously [4,5-c] pyridazinyl,Thiazole simultaneously [4,5-d] pyridazinyl,Thiazole simultaneously [5,4-c] pyridazinyl,Thiazole simultaneously [3,Any of 2-b] pyridazinyl,Pyrrolopyridinyl,It can be pyrrolo- [2,3-b] pyridine radicals,Pyrrolo- [2,3-c] pyridine radicals,Pyrrolo- [3,2-b] pyridine radicals,Pyrrolo- [3,2-c] pyridine radicals,Pyrrolo- [3,4-b] pyridine radicals,Pyrrolo- [3,Any of 4-c] pyridine radicals,Pyridopyrimidine base,It can be pyrido [2,3-d] pyrimidine radicals,Pyrido [3,2-d] pyrimidine radicals,Pyrido [3,4-d] pyrimidine radicals,Pyrido [4,3-d] pyrimidine radicals,Pyrido [1,2-c] pyrimidine radicals,Pyrido [1,Any of 2-a] pyrimidine radicals,Pyrans benzothiazolyl,It can be pyrans simultaneously [2,3-d] thiazolyl,Pyrans simultaneously [4,3-d] thiazolyl,Pyrans simultaneously [3,4-d] thiazolyl,Pyrans simultaneously [3,Any of 2-d] thiazolyl,Furopyridyl,It can be furans simultaneously [2,3-b] pyridine radicals,Furans simultaneously [2,3-c] pyridine radicals,Furans simultaneously [3,2-b] pyridine radicals,Furans simultaneously [3,2-c] pyridine radicals,Furans simultaneously [3,4-b] pyridine radicals,Furans simultaneously [3,Any of 4-c] pyridine radicals,Oxazole and pyridine radicals,Ke Yi Shi oxazoles simultaneously [4,5-b] pyridine radicals,Oxazole simultaneously [4,5-c] pyridine radicals,Oxazole simultaneously [5,4-b] pyridine radicals,Oxazole simultaneously [5,4-c] pyridine radicals,Oxazole simultaneously [3,4-a] pyridine radicals,Oxazole simultaneously [3,Any of 2-a] pyridine radicals,Oxazole and pyridazinyl,Ke Yi Shi oxazoles simultaneously [4,5-c] pyridazinyl,Oxazole simultaneously [4,5-d] pyridazinyl,Oxazole simultaneously [5,4-c] pyridazinyl,Oxazole simultaneously [3,Any of 4-b] pyridazinyl,Pyrroles's benzothiazolyl,It can be pyrrolo- [2,1-b] thiazolyl,Pyrrolo- [1,2-c] thiazolyl,Pyrrolo- [2,3-d] thiazolyl,Pyrrolo- [3,2-d] thiazolyl,Pyrrolo- [3,Any of 4-d] thiazolyl,Bi Ka Bing oxazolyls,It can be pyrrolo- [2,1-b] oxazolyls,Pyrrolo- [1,2-c] oxazolyls,Pyrrolo- [2,3-d] oxazolyls,Pyrrolo- [3,2-d] oxazolyls,Pyrrolo- [3,Any of 4-d] oxazolyls,Benzo-aza
Figure G2003801097466D00071
Base, can be 1H-1- benzo-azasBase, 1H-2- benzo-azasBase, 1H-3- benzo-azasAny of base, 4,5- dihydro -1- oxo -1H-2- benzo-azas
Figure G2003801097466D00075
Base, can be the benzo-aza of dihydro-oxo-derivative type
Figure G2003801097466D00076
Base, benzodiazepineBase, can be 1H-1,3- benzodiazepinesBase, 1H-1,4- benzodiazepinesBase, 1H-1,5- benzodiazepinesAny of base, such as 4,5- dihydro -4- oxos -1H-1,3- benzodiazepines
Figure G2003801097466D000711
Base, can be the benzodiazepine of dihydro-oxo-derivative type
Figure G2003801097466D000712
Base, the azepine of benzo three
Figure G2003801097466D000713
Base, can be 1H-1, the azepine of 3,4- benzo threeBase, 1H-1, the azepine of 3,5- benzo threeAny of base, such as 4,5- dihydro -5- oxos -1H-1, the azepine of 3,4- benzo three
Figure G2003801097466D000716
Base, can be the azepine of benzo three of dihydro-oxo-derivative typeBase, thieno azepine
Figure G2003801097466D000718
Base, can be thieno [2,3-b] azepine
Figure G2003801097466D000719
Base, thieno [2,3-c] azepineBase, thieno [2,3-d] azepine
Figure G2003801097466D000721
Base, thieno [3,2-c] azepine
Figure G2003801097466D000722
Base, thieno [3,2-b] azepine
Figure G2003801097466D000723
Any of base, such as 5,6,7,8- tetrahydrochysene -4- oxo -4H- thienos [3,2-c] azepines
Figure G2003801097466D000724
Base, can be the thieno azepine of dihydro-oxo-derivative type
Figure G2003801097466D000725
Base, thieno diaza
Figure G2003801097466D000726
Base or the azepine of thieno three
Figure G2003801097466D000727
Base, equally can be any fusion type or dihydro-oxo-derivative type, benzo thia
Figure G2003801097466D000728
Base, can be 1H-1- benzo thias
Figure G2003801097466D000729
Base, 1H-2- benzo thias
Figure G2003801097466D000730
Base, 1H-3- benzo thias
Figure G2003801097466D000731
Any of base, such as 4,5- dihydro -1- oxo -1H-2- benzo thiasBase, can be the benzo thia of dihydro-oxo-derivative type
Figure G2003801097466D000733
Base, benzo oxa-
Figure G2003801097466D000734
Base, can be 1H-1- benzo oxa-s
Figure G2003801097466D000735
Base, 1H-2- benzo oxa-sBase, 1H-3- benzo oxa-sAny of base, such as 4,5- dihydro -1- oxo -1H-2- benzo oxa-sBase, can be the benzo oxa- of dihydro-oxo-derivative typeForm beyond base or these fusion forms.
Above-mentioned aryl,Heteroaryl,Aromatic yl alkenyl,Heteroarylalkenyl groups,The annelated heterocycles base of the fusion alkyl and saturation or undersaturated 2 ring or 3 rings of saturation or undersaturated 2 ring or 3 rings can possess 1~3 substituent respectively,The substituent can enumerate hydroxyl,Fluorine atom,Chlorine atom,The halogen atom such as bromine atoms and iodine atom,The haloalkyl of the carbon number 1~6 of 1~3 halogen atom substitution,Amino,Cyano group,Aminoalkyl,Nitro,Hydroxy alkyl is (for example,Hydroxymethyl,2- hydroxyethyls etc.),Alkoxyalkyl is (for example,Methoxy,2- methoxy ethyls etc.),Carboxyl,Carboxyalkyl is (for example,Carboxymethyl group,2- carboxy ethyls etc.),Alkoxy carbonyl alkyl is (for example,Methoxycarbonylmethyl,Ethoxy carbonyl methyl etc.),Acyl group is (for example,Formoxyl,Acetyl group,The alkanoyls such as propiono),Amidino groups,Hydroxyl amidino groups (amino (oxyimino) methyl),Straight-chain,The alkyl of the carbon number 1~6 of branched or ring-type is (for example,Methyl,Ethyl etc.),Straight-chain,The alkoxy of the carbon number 1~6 of branched or ring-type is (for example,Methoxyl group,Ethyoxyl etc.),Straight-chain,The alkyl-substituted amidino groups of the carbon number 1~6 of branched or ring-type is (for example,Imino group (methylamino) methyl etc.),Straight-chain,The amidino groups of the alkoxy substitution of the carbon number 1~6 of branched or ring-type is (for example,Amino (methoxyimino) methyl etc.),Straight-chain,The amidino groups of the alkoxy carbonyl substitution of the carbon number 2~7 of branched or ring-type is (for example,Amino (methoxycarbonyl imino group) methyl,Amino (ethoxycarbonylimino) methyl etc.),Straight-chain,The alkenyl of the carbon number 2~6 of branched or ring-type is (for example,Vinyl,Pi-allyl etc.),The alkynyl of the carbon number 2~6 of straight-chain or branched is (for example,Acetenyl,Propinyl etc.),Straight-chain,The alkoxy carbonyl of the carbon number 2~6 of branched or ring-type is (for example,Methoxycarbonyl,Ethoxy carbonyl etc.),Carbamoyl,There is straight-chain on nitrogen-atoms,The alkyl-substituted mono- or dialkylcarbamoyl group of the carbon number 1~6 of branched or ring-type is (for example,Methylcarbamoyl,Ethylaminocarbonyl,Formyl-dimethylamino,Ethylmethylamino formoxyl etc.),By straight-chain,Alkyl-substituted one or dialkyl amido of the carbon number 1~6 of branched or ring-type are (for example,Ethylamino,Dimethylamino,Methylethylamine) and 5~6 yuan nitrogen heterocycle (for example,Pyrrolidinyl,Piperidyl,Piperazinyl,Morpholinyl etc.) etc..
The group Q that above-mentioned group is represented4In, preferably following 12 kinds of groups (a)~(1).That is, preferable group can be enumerated
Figure G2003801097466D00084
[in base, R5And R6It is each independent; represent hydrogen atom, cyano group, halogen atom, alkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, alkoxy carbonyl, alkoxy carbonyl alkyl or the phenyl that can be replaced by cyano group, hydroxyl, halogen atom, alkyl or alkoxy, R7And R8It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]
[in base, R9And R10It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]
Figure G2003801097466D00092
[in base, R11、R12And R13It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]
Figure G2003801097466D00093
[in base, X1Represent CH2, CH, NH, NOH, N, O or S, R14、R15And R16It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]
Figure G2003801097466D00101
[in base, X2Represent NH, N, O or S, X3Represent N, C or CH, X4Represent N, C or CH, R17And R18It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl, X3And X4Situation for C and CH combination and be C or CH situation except],
[in base, N represents R191 of the carbon atom of substituted ring or 2 is replaced by nitrogen-atoms, R19、R20And R21It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]
Figure G2003801097466D00103
[in base, X5Represent CH2, CH, N or NH, Z1 represents N, NH or O, Z2Represent CH2, CH, C or N, Z3Represent CH2、CH、S、SO2Or C=O, X5-Z2Represent X5And Z2Combined with singly-bound or double bond, R22And R23It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl, R24Represent hydrogen atom or alkyl],
[in base, X6Represent O or S, R25And R26It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]
Figure G2003801097466D00112
[in base, R27And R28It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]
[in base, E1And E2It is each independent, represent N or CH, R29And R30It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]
[in base, Y1Represent CH or N, Y2Expression-N (R33In)-(base, R33Represent the alkyl of hydrogen atom or carbon number 1~6), O or S, R31And R32It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl], and following radicals
Figure G2003801097466D00121
[in base, 1~8 numeral represents position, and each N represents that any one and 5~8 any one of carbon atom of 1~4 carbon atom are replaced by 1 nitrogen-atoms respectively, R34、R35And R36It is each independent; represent hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N, N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl].
Hereinafter, these groups are illustrated.
R in above-mentioned base5~R36Explanation in halogen atom represent fluorine atom, chlorine atom, bromine atoms or iodine atom, the group of the carbon number 1~6 of Alkyl means straight shape, branched or ring-type, the group of the carbon number 2~6 of alkene basis representation straight-chain, branched or ring-type, alkynyl represents the group of the carbon number 2~6 of straight-chain or branched, and hydroxy alkyl represents above-mentioned C1~C6Alkyl has the group of 1 hydroxyl substitution, and the group of the carbon number 1~6 of alcoxyl basis representation straight-chain, branched or ring-type, alkoxyalkyl represents above-mentioned C1~C6Alkyl has 1 above-mentioned C1~C6The group of alkoxy substitution, carboxyalkyl represents above-mentioned C1~C6Alkyl has the group of 1 carboxyl substitution, and acyl group represents aroyl or the above-mentioned C such as alkanoyl (including formoxyl), benzoyl or the naphthoyl of carbon number 1~61~C6Alkanoyl has foregoing C6~C14The aromatic yl silane terephthalamide yl of aryl substitution, N- alkyl-carbamoyls represent above-mentioned C1~C6The carbamoyl that alkyl replaces on nitrogen-atoms, N, N- dialkyl carbamoyls represent 2 above-mentioned C1~C6The carbamoyl that alkyl replaces on nitrogen-atoms, alkoxy carbonyl is represented by above-mentioned C1~C6Alkoxy and the group of carbonyl formation, alkoxy carbonyl alkyl represent above-mentioned C1~C6Alkyl has 1 above-mentioned C1~C6The group of alkoxy carbonyl substitution, haloalkyl represents above-mentioned C1~C6Alkyl has the group of 1~3 halogen atom substitution.In described above, the position of substitution is not particularly limited.
Following radicals
[in base, R5、R6、R7、R8As it was previously stated, 1~6 numeral represents position], wherein, R5And R6Respective independence, preferably hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl.R5And R6More preferably hydrogen atom or alkyl, when being alkyl, preferably methyl.R7And R8A preferably side is hydrogen atom, and the opposing party is the situation of hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein, especially desirable situation is that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom preferably fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The preferable example for the specific group that above formula is represented can enumerate chlorostyrene base, fluorostyryl, bromstyrol base, acetylenylbenzene vinyl etc., the position of substitution of halogen atom in these groups, alkyl or alkynyl is not particularly limited, but particularly desirably 4 in above-mentioned formula, specific preferably example can enumerate 4- chlorostyrenes base, 4- fluorostyryls, 4- bromstyrols base, 4- acetylenylbenzene vinyl etc..
Following radicals
Figure G2003801097466D00131
[in base, R9And R10As it was previously stated, 1~6 numeral represents position], wherein, R9And R10Respective independence, preferably hydrogen atom, halogen atom, alkyl or alkynyl.Preferably R9For hydrogen atom, R10For hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom preferably fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The preferable example for the specific group that above formula is represented can enumerate chlorobenzene acetenyl, fluorophenylethynyl, bromobenzene acetenyl, acetylenylbenzene acetenyl etc., the position of substitution of halogen atom in these groups, alkyl or alkynyl is not particularly limited, but particularly desirably 4 in above-mentioned formula, specific preferably example can enumerate 4- Chlorophenylethynyls, 4- fluorophenylethynyls, 4- bromophenyls acetenyl, 4- ethynyl phenyl acetenyls etc..
Following radicals
[in base, R11、R12And R13As it was previously stated, 1~8 numeral represents position], wherein, R11、R12And R13Respective independence, preferably hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl.R11More preferably hydrogen atom, alkyl, halogen atom and hydroxyl, particularly preferably hydrogen atom.R12And R13Preferable situation be that a side is hydrogen atom, the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom preferably fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.Above-mentioned naphthyl, 2- naphthyls more preferably, when being 2- naphthyls, are not particularly limited than 1- naphthyl to the position of substitution of halogen atom, alkyl or alkynyl, but 6 in preferably above-mentioned formula or 7, most preferably 6.Preferably chlorine atom, fluorine atom, bromine atoms, alkynyl etc. these naphthyls are replaced after group, it is special it is good be group after chlorine atom, fluorine atom, bromine atoms, alkynyl etc. are replaced.Specific preferably example can enumerate the chloro- 2- naphthyls of 6-, the fluoro- 2- naphthyls of 6-, the bromo- 2- naphthyls of 6-, 6- acetenyl -2- naphthyls, the chloro- 2- naphthyls of 7-, the fluoro- 2- naphthyls of 7-, the bromo- 2- naphthyls of 7-, 7- acetenyl -2- naphthyls etc..
Following radicals
Figure G2003801097466D00141
[in base, X1、R14、R15And R16As it was previously stated, 4~7 numeral represents position], wherein, X1Preferably NH, NOH, N, O and S, more preferably NH, O and S.R14Preferably hydrogen atom, halogen atom, acyl group, N- alkyl-carbamoyls, N, N- dialkyl carbamoyls, alkyl, R15And R16Respective independence, preferably hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl.R15And R16Preferable situation be a side be hydrogen atom or halogen atom, preferably fluorine atom or chlorine atom, the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be the opposing party for hydrogen atom, halogen atom, alkyl or alkynyl situation.In this case halogen atom preferably fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The position of substitution of halogen atom, alkyl or alkynyl is not particularly limited, 4,5 or 6 in preferably above-mentioned formula.The preferable example for the specific group that above-mentioned formula is represented can enumerate 5- chloro-indole bases, 5- fluoro indole bases, 5- bromo indole bases, 5- Ethynylindole bases, 5- methyl indol bases, the chloro- 4- fluoro indoles bases of 5-, the chloro- 3- fluoro indoles bases of 5-, the fluoro- 3- chloro-indoles bases of 5-, 5- acetenyl -3- fluoro indole bases, the chloro- 3- of 5- (N, N- formyl-dimethylamino) indyl, the fluoro- 3- of 5- (N, N- formyl-dimethylamino) indyl, the chloro- 3- formyl indoles bases of 5-, the fluoro- 3- formyl indoles bases of 5-, 6- chloro-indole bases, 6- fluoro indole bases, 6- bromo indole bases, 6- Ethynylindole bases, 6- methyl indol bases, 5- chloro thiophene bases, 5- fluorobenzothiophen bases, 5- bromobenzothiophene bases, 5- acetenyl benzothienyls, 5- methyl benzothiophene bases, the chloro- 4- fluorobenzothiophens bases of 5-, 6- chloro thiophene bases, 6- fluorobenzothiophen bases, 6- bromobenzothiophene bases, 6- acetenyl benzothienyls, 6- methyl benzothiophene bases, 5- chlorobenzofur bases, 5- Fluorobenzofur bases, 5- bromobenzofuran bases, 5- acetenyl benzofuranyls, 5- methyl-benzofuranyls, the chloro- 4- Fluorobenzofurs bases of 5-, 6- chlorobenzofur bases, 6- Fluorobenzofur bases, 6- bromobenzofuran bases, 6- acetenyl benzofuranyls, 6- methyl-benzofuranyls etc..To these substituents and T1Binding site be not particularly limited,But the two or three-digit in preferably above-mentioned formula (d),5- chloro-indole -2- bases can specifically be enumerated,5- fluoro indole -2- bases,5- bromo indole -2- bases,5- Ethynylindole -2- bases,5- methyl indol -2- bases,The chloro- 4- fluoro indoles -2- bases of 5-,The chloro- 3- fluoro indoles -2- bases of 5-,The bromo- 5- chloro-indoles -2- bases of 3-,The chloro- 5- fluoro indoles -2- bases of 3-,The bromo- 5- fluoro indoles -2- bases of 3-,The bromo- 3- chloro-indoles -2- bases of 5-,The bromo- 3- fluoro indoles -2- bases of 5-,The chloro- 3- formyl indoles -2- bases of 5-,The fluoro- 3- formyl indoles -2- bases of 5-,The bromo- 3- formyl indoles -2- bases of 5-,5- acetenyl -3- formyl indole -2- bases,Chloro- 3- (the N of 5-,N- formyl-dimethylaminos) indoles -2- bases,Fluoro- 3- (the N of 5-,N- formyl-dimethylaminos) indoles -2- bases,Bromo- 3- (the N of 5-,N- formyl-dimethylaminos) indoles -2- bases,5- acetenyl -3- (N,N- formyl-dimethylaminos) indoles -2- bases,6- chloro-indole -2- bases,6- fluoro indole -2- bases,6- bromo indole -2- bases,6- Ethynylindole -2- bases,6- methyl indol -2- bases,5- chloro-indole -3- bases,5- fluoro indole -3- bases,5- bromo indole -3- bases,5- Ethynylindole -3- bases,5- methyl indol -3- bases,The chloro- 4- fluoro indoles -3- bases of 5-,6- chloro-indole -3- bases,6- fluoro indole -3- bases,6- bromo indole -3- bases,6- Ethynylindole -3- bases,6- methyl indol -3- bases,5- chloro thiophene -2- bases,5- fluorobenzothiophen -2- bases,5- bromobenzothiophene -2- bases,5- acetylenylbenzene bithiophene -2- bases,5- methyl benzothiophene -2- bases,The chloro- 4- fluorobenzothiophens -2- bases of 5-,6- chloro thiophene -2- bases,6- fluorobenzothiophen -2- bases,6- bromobenzothiophene -2- bases,6- acetylenylbenzene bithiophene -2- bases,6- methyl benzothiophene -2- bases,5- chloro thiophene -3- bases,5- fluorobenzothiophen -3- bases,5- bromobenzothiophene -3- bases,5- acetylenylbenzene bithiophene -3- bases,5- methyl benzothiophene -3- bases,The chloro- 4- fluorobenzothiophens -3- bases of 5-,6- chloro thiophene -3- bases,6- fluorobenzothiophen -3- bases,6- bromobenzothiophene -3- bases,6- acetylenylbenzene bithiophene -3- bases,6- methyl benzothiophene -3- bases,5- chlorobenzofur -2- bases,5- Fluorobenzofur -2- bases,5- bromobenzofuran -2- bases,5- acetenyl benzofuran -2- bases,5- methyl benzofuran -2- bases,The chloro- 4- Fluorobenzofurs -2- bases of 5-,6- chlorobenzofur -2- bases,6- Fluorobenzofur -2- bases,6- bromobenzofuran -2- bases,6- acetenyl benzofuran -2- bases,6- methyl benzofuran -2- bases,5- chlorobenzofur -3- bases,5- Fluorobenzofur -3- bases,5- bromobenzofuran -3- bases,5- acetenyl benzofuran -3- bases,5- methyl benzofuran -3- bases,The chloro- 4- Fluorobenzofurs -3- bases of 5-,6- chlorobenzofur -3- bases,6- Fluorobenzofur -3- bases,6- bromobenzofuran -3- bases,6- acetenyl benzofuran -3- bases,6- methyl benzofuran -3- bases etc.；It is special it is good be 5- chloro-indole -2- bases,5- fluoro indole -2- bases,5- bromo indole -2- bases,5- Ethynylindole -2- bases,5- methyl indol -2- bases,The chloro- 4- fluoro indoles -2- bases of 5-,6- chloro-indole -2- bases,6- fluoro indole -2- bases,6- bromo indole -2- bases,6- Ethynylindole -2- bases,6- methyl indol -2- bases,The chloro- 3- fluoro indoles -2- bases of 5-,The bromo- 5- chloro-indoles -2- bases of 3-,The chloro- 5- fluoro indoles -2- bases of 3-,The bromo- 5- fluoro indoles -2- bases of 3-,The bromo- 3- chloro-indoles -2- bases of 5-,The bromo- 3- fluoro indoles -2- bases of 5-,The chloro- 3- formyl indoles -2- bases of 5-,The fluoro- 3- formyl indoles -2- bases of 5-,The bromo- 3- formyl indoles -2- bases of 5-,5- acetenyl -3- formyl indole -2- bases,Chloro- 3- (the N of 5-,N- formyl-dimethylaminos) indoles -2- bases,Fluoro- 3- (the N of 5-,N- formyl-dimethylaminos) indoles -2- bases,Bromo- 3- (the N of 5-,N- formyl-dimethylaminos) indoles -2- bases,5- acetenyl -3- (N,N- formyl-dimethylaminos) indoles -2- bases,5- chloro thiophene -2- bases,5- fluorobenzothiophen -2- bases,5- bromobenzothiophene -2- bases,5- acetylenylbenzene bithiophene -2- bases,5- methyl benzothiophene -2- bases,The chloro- 4- fluorobenzothiophens -2- bases of 5-,6- chloro thiophene -2- bases,6- fluorobenzothiophen -2- bases,6- bromobenzothiophene -2- bases,6- acetylenylbenzene bithiophene -2- bases,6- methyl benzothiophene -2- bases,5- chlorobenzofur -2- bases,5- Fluorobenzofur -2- bases,5- bromobenzofuran -2- bases,5- acetenyl benzofuran -2- bases,5- methyl benzofuran -2- bases,The chloro- 4- Fluorobenzofurs -2- bases of 5-,6- chlorobenzofur -2- bases,6- Fluorobenzofur -2- bases,6- bromobenzofuran -2- bases,6- acetenyl benzofuran -2- bases,6- methyl benzofuran -2- bases.
Following radicals
[in base, X2、X3、X4、R17And R18As it was previously stated, 4~7 numeral represents position], wherein, X2Preferably NH, O or S, X3And X4Either one preferably CH or C, it is special it is good be that a side is C.R17And R18Respective independence, preferably hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl.R17And R18A preferably side is hydrogen atom, and the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom preferably fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The position of substitution of halogen atom, alkyl or alkynyl is not particularly limited, 5 in preferably above-mentioned formula or 6.The preferable example for the specific group that above-mentioned formula is represented can enumerate 5- chlorine indazolyls, 5- fluorine indazolyls, 5- bromo-indazole bases, 5- acetenyl indazolyls, 6- chlorine indazolyls, 6- fluorine indazolyls, 6- bromo-indazole bases, 6- acetenyl indazolyls, 5- chloro benzimidazole bases, 5- fluorobenzimidazole bases, 5- bromine benzimidazolyls, 5- acetenyl benzimidazolyls, 6- chloro benzimidazole bases, 6- fluorobenzimidazole bases, 6- bromine benzimidazolyls, 6- acetenyl benzimidazolyls, 5- chloro benzothiazole bases, 5- fluoro benzothiazole bases, 5- bromo benzothiazole bases, 5- acetylenylbenzene benzothiazolyls, 6- chloro benzothiazole bases, 6- fluoro benzothiazole bases, 6- bromo benzothiazole bases, 6- acetylenylbenzene benzothiazolyls, 5- Lv benzoxazolyls, 5- Fu benzoxazolyls, 5- bromoxynil oxazoline bases, 5- acetenyl benzoxazolyls, 6- Lv benzoxazolyls, 6- Fu benzoxazolyls, 6- bromoxynil oxazoline bases, 6- acetenyl benzoxazolyls, 5- chlorobenzenes and isothiazolyl, 5- fluorobenzene and isothiazolyl, 5- bromobenzenes and isothiazolyl, 5- acetenyl benzo isothiazolyls, 6- chlorobenzenes and isothiazolyl, 6- fluorobenzene and isothiazolyl, 6- bromobenzenes and isothiazolyl, 6- acetenyl benzo isothiazolyls, 5- Lv benzoisoxazole bases, 5- fluorobenzene Bing isoxazolyls, 5- bromobenzene Bing isoxazolyls, 5- acetenyl benzo isoxazolyls, 6- Lv benzoisoxazole bases, 6- fluorobenzene Bing isoxazolyls, 6- bromobenzene Bing isoxazolyls, 6- acetenyl benzo isoxazolyls etc., to these substituents and T1Binding site be not particularly limited,But preferably 5- chlorine indazole -3- bases,5- fluorine indazole -3- bases,5- bromo-indazole -3- bases,5- acetenyl indazole -3- bases,6- chlorine indazole -3- bases,6- fluorine indazole -3- bases,6- bromo-indazole -3- bases,6- acetenyl indazole -3- bases,5- chloro benzimidazole -2- bases,5- fluorobenzimidazole -2- bases,5- bromine benzimidazole -2- bases,5- acetenyl benzimidazole -2- bases,6- chloro benzimidazole -2- bases,6- fluorobenzimidazole -2- bases,6- bromine benzimidazole -2- bases,6- acetenyl benzimidazole -2- bases,5- chloro benzothiazole -2- bases,5- fluoro benzothiazole -2- bases,5- bromo benzothiazole -2- bases,5- acetenyl benzo thiazol-2-yls,6- chloro benzothiazole -2- bases,6- fluoro benzothiazole -2- bases,6- bromo benzothiazole -2- bases,6- acetenyl benzo thiazol-2-yls,5- Lv benzoxazole -2- bases,5- Fu benzoxazole -2- bases,5- bromoxynil oxazoline -2- bases,5- acetenyl benzoxazole -2- bases,6- Lv benzoxazole -2- bases,6- Fu benzoxazole -2- bases,6- bromoxynil oxazoline -2- bases,6- acetenyl benzoxazole -2- bases,5- chlorine benzisothiazole -3- bases,5- fluorine benzisothiazole -3- bases,5- bromine benzisothiazole -3- bases,5- acetenyl benzisothiazole -3- bases,6- chlorine benzisothiazole -3- bases,6- fluorine benzisothiazole -3- bases,6- bromine benzisothiazole -3- bases,6- acetenyl benzisothiazole -3- bases,5- Lv benzoisoxazole -3- bases,5- fluorobenzene Bing isoxazole -3-bases,5- bromobenzene Bing isoxazole -3-bases,5- acetenyl benzo isoxazole -3-bases,6- Lv benzoisoxazole -3- bases,6- fluorobenzene Bing isoxazole -3-bases,6- bromobenzene Bing isoxazole -3-bases,6- acetenyl benzo isoxazole -3-bases,It is special it is good be 5- chloro benzimidazole -2- bases,5- fluorobenzimidazole -2- bases,5- bromine benzimidazole -2- bases,5- acetenyl benzimidazole -2- bases,6- chloro benzimidazole -2- bases,6- fluorobenzimidazole -2- bases,6- bromine benzimidazole -2- bases,6- acetenyl benzimidazole -2- bases,5- chloro benzothiazole -2- bases,5- fluoro benzothiazole -2- bases,5- bromo benzothiazole -2- bases,5- acetenyl benzo thiazol-2-yls,6- chloro benzothiazole -2- bases,6- fluoro benzothiazole -2- bases,6- bromo benzothiazole -2- bases,6- acetenyl benzo thiazol-2-yls,5- Lv benzoxazole -2- bases,5- Fu benzoxazole -2- bases,5- bromoxynil oxazoline -2- bases,5- acetenyl benzoxazole -2- bases,6- Lv benzoxazole -2- bases,6- Fu benzoxazole -2- bases,6- bromoxynil oxazoline -2- bases,6- acetenyl benzoxazole -2- bases,Most preferably 5- chloro benzimidazoles -2- bases,5- fluorobenzimidazole -2- bases,5- bromine benzimidazole -2- bases,5- acetenyl benzimidazole -2- bases.
Following radicals
Figure G2003801097466D00171
[in base, N represents R191 of the carbon atom of substituted ring or 2 is replaced by nitrogen-atoms, R19、R20And R21As it was previously stated, 5~8 numeral represents position], wherein, R19、R20And R21Respective independence, preferably hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl.R19Particularly preferably hydrogen atom, R20And R21A preferably side is hydrogen atom, and the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom is fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The position of substitution of halogen atom, alkyl or alkynyl is not particularly limited, 6 in preferably above-mentioned formula or 7.The specific group that above-mentioned formula is represented can enumerate quinolyl, isoquinolyl, cinnolines base, preferably 6- chloroquinolines base, 6- fluorine quinolyl, 6- bromoquinolines base, 6- acetenyls quinolyl, 6- chlorine isoquinolyl, 6- fluorine isoquinolyl, 6- bromo-isoquinolines base, 6- acetenyls isoquinolyl, 7- chlorine cinnolines base, 7- fluorine cinnolines base, 7- bromine cinnolines base, 7- acetenyl cinnolines bases etc..It is particularly preferred that 6- chloroquinoline -2- bases, 6- fluorine quinoline -2- bases, 6- bromoquinoline -2- bases, 6- acetenyl quinoline -2- bases, 6- chloroquinoline -3- bases, 6- fluorine quinoline -3- bases, 6- bromoquinoline -3- bases, 6- acetenyl quinoline -3- bases, 7- chloroquinoline -2- bases, 7- fluorine quinoline -2- bases, 7- bromoquinoline -2- bases, 7- acetenyl quinoline -2- bases, 7- chloroquinoline -3- bases, 7- fluorine quinoline -3- bases, 7- bromoquinoline -3- bases, 7- acetenyl quinoline -3- bases, 6- chlorine isoquinolin -3- bases, 6- fluorine isoquinolin -3- bases, 6- bromo-isoquinoline -3- bases, 6- acetenyl isoquinolin -3- bases, 7- chlorine isoquinolin -3- bases, 7- fluorine isoquinolin -3- bases, 7- bromo-isoquinoline -3- bases, 7- acetenyl isoquinolin -3- bases, 7- chlorine cinnolines -3- bases, 7- fluorine cinnolines -3- bases, 7- bromine cinnolines -3- bases, 7- acetenyl cinnolines -3- bases etc..Wherein most preferably 6- chloroquinolines -2- bases, 6- fluorine quinoline -2- bases, 6- bromoquinoline -2- bases, 6- acetenyl quinoline -2- bases, 7- chloroquinoline -3- bases, 7- fluorine quinoline -3- bases, 7- bromoquinoline -3- bases, 7- acetenyl quinoline -3- bases, 7- chlorine isoquinolin -3- bases, 7- fluorine isoquinolin -3- bases, 7- bromo-isoquinoline -3- bases, 7- acetenyl isoquinolin -3- bases, 7- chlorine cinnolines -3- bases, 7- fluorine cinnolines -3- bases, 7- bromine cinnolines -3- bases, 7- acetenyl cinnolines -3- bases.
Following radicals
[in base, 5~8 numeral represents position, X5Represent CH2, CH, N or NH, Z1 represents N, NH or O, Z2Represent CH2, CH, C or N, Z3Represent CH2、CH、S、SO2Or C=O, X5-Z2Represent X5And Z2Combined with singly-bound or double bond, R22、R23And R24As previously described], wherein, R22And R23Respective independence, preferably hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl.R22And R23A preferably side is hydrogen atom, and the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom is fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The position of substitution of halogen atom, alkyl or alkynyl is not particularly limited, 6 in preferably above-mentioned formula or 7.R24Preferably hydrogen atom or alkyl, alkyl preferably methyl.R24Particularly preferably hydrogen atom.The specific group that above-mentioned formula is represented can enumerate 4- oxo-dihydros quinolyl, tetrahydric quinoline group, 4- oxo-dihydro quinazoline -2- bases, 4- oxo tetrahydrochysene cinnolines base, 4- oxochromens base, 4- oxo benzothiadiazines base, 1,1- titanium dioxide -4- oxo benzothiadiazines base, Ben Bing oxadiazine bases etc..More specifically group can enumerate the chloro- 4- oxo-dihydros quinolyls of 6-,6- fluorin-4-oxygens are for EEDQ base,The bromo- 4- oxo-dihydros quinolyls of 6-,6- acetenyl -4- oxo-dihydro quinolyls,The chloro- 4- oxo-dihydros quinolyls of 7-,7- fluorin-4-oxygens are for EEDQ base,The bromo- 4- oxo-dihydros quinolyls of 7-,7- acetenyl -4- oxo-dihydro quinolyls,The chloro- 4- oxos -1 of 6-,4- dihydroquinazoline bases,6- fluorin-4-oxygens generation -1,4- dihydroquinazoline bases,The bromo- 4- oxos -1 of 6-,4- dihydroquinazoline bases,6- acetenyl -4- oxos -1,4- dihydroquinazoline bases,The chloro- 4- oxos -1 of 7-,4- dihydroquinazoline bases,7- fluorin-4-oxygens generation -1,4- dihydroquinazoline bases,The bromo- 4- oxos -1 of 7-,4- dihydroquinazoline bases,7- acetenyl -4- oxos -1,4- dihydroquinazoline bases,6- chloro- 1,2,3,4- tetrahydric quinoline groups,6- fluoro- 1,2,3,4- tetrahydric quinoline groups,6- bromo- 1,2,3,4- tetrahydric quinoline groups,6- acetenyls -1,2,3,4- tetrahydric quinoline groups,7- chloro- 1,2,3,4- tetrahydric quinoline groups,7- fluoro- 1,2,3,4- tetrahydric quinoline groups,7- bromo- 1,2,3,4- tetrahydric quinoline groups,7- acetenyls -1,2,3,4- tetrahydric quinoline groups,6- chloro- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines bases,6- fluoro- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines bases,6- bromo- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines bases,6- acetenyls -1,2,3,4- tetrahydrochysene -4- oxo cinnolines bases,7- chloro- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines bases,7- fluoro- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines bases,7- bromo- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines bases,7- acetenyls -1,2,3,4- tetrahydrochysene -4- oxo cinnolines bases,The chloro- 4H-4- oxochromens bases of 6-,The fluoro- 4H-4- oxochromens bases of 6-,The bromo- 4H-4- oxochromens bases of 6-,6- acetenyl -4H-4- oxochromen bases,The chloro- 4H-4- oxochromens bases of 7-,The fluoro- 4H-4- oxochromens bases of 7-,The bromo- 4H-4- oxochromens bases of 7-,7- acetenyl -4H-4- oxochromen bases,6- chloro- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,6- fluoro- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,6- bromo- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,6- acetenyls -1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,7- chloro- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,7- fluoro- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,7- bromo- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,7- acetenyls -1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,The chloro- 2H-1 of 6-,2,4- Ben Bing oxadiazine bases,The fluoro- 2H-1 of 6-,2,4- Ben Bing oxadiazine bases,The bromo- 2H-1 of 6-,2,4- Ben Bing oxadiazine bases,6- acetenyls -2H-1,2,4- Ben Bing oxadiazine bases,The chloro- 2H-1 of 7-,2,4- Ben Bing oxadiazine bases,The fluoro- 2H-1 of 7-,2,4- Ben Bing oxadiazine bases,The bromo- 2H-1 of 7-,2,4- Ben Bing oxadiazine bases,7- acetenyls -2H-1,2,4- Ben Bing oxadiazine bases etc..It is special it is good be the chloro- 4- oxos -1 of 6-,4- EEDQ -2- bases,6- fluorin-4-oxygens generation -1,4- EEDQ -2- bases,The bromo- 4- oxos -1 of 6-,4- EEDQ -2- bases,6- acetenyl -4- oxos -1,4- EEDQ -2- bases,The chloro- 4- oxos -1 of 7-,4- EEDQ -2- bases,7- fluorin-4-oxygens generation -1,4- EEDQ -2- bases,The bromo- 4- oxos -1 of 7-,4- EEDQ -2- bases,7- acetenyl -4- oxos -1,4- EEDQ -2- bases,The chloro- 4- oxos -1 of 6-,4- dihydroquinazoline -2- bases,6- fluorin-4-oxygens generation -1,4- dihydroquinazoline -2- bases,The bromo- 4- oxos -1 of 6-,4- dihydroquinazoline -2- bases,6- acetenyl -4- oxos -1,4- dihydroquinazoline -2- bases,The chloro- 4- oxos -1 of 7-,4- dihydroquinazoline -2- bases,7- fluorin-4-oxygens generation -1,4- dihydroquinazoline -2- bases,The bromo- 4- oxos -1 of 7-,4- dihydroquinazoline -2- bases,7- acetenyl -4- oxos -1,4- dihydroquinazoline -2- bases,6- chloro- 1,2,3,4- tetrahydroquinoline -2- bases,6- fluoro- 1,2,3,4- tetrahydroquinoline -2- bases,6- bromo- 1,2,3,4- tetrahydroquinoline -2- bases,6- acetenyls -1,2,3,4- tetrahydroquinoline -2- bases,6- chloro- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines -2- bases,6- fluoro- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines -2- bases,6- bromo- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines -2- bases,6- acetenyls -1,2,3,4- tetrahydrochysene -4- oxo cinnolines -2- bases,7- chloro- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines -2- bases,7- fluoro- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines -2- bases,7- bromo- 1,2,3,4- tetrahydrochysene -4- oxo cinnolines -2- bases,7- acetenyls -1,2,3,4- tetrahydrochysene -4- oxo cinnolines -2- bases,The chloro- 4H-4- oxochromens -2- bases of 6-,The fluoro- 4H-4- oxochromens -2- bases of 6-,The bromo- 4H-4- oxochromens -2- bases of 6-,6- acetenyl -4H-4- oxochromen -2- bases,The chloro- 4H-4- oxochromens -2- bases of 7-,The fluoro- 4H-4- oxochromens -2- bases of 7-,The bromo- 4H-4- oxochromens -2- bases of 7-,7- acetenyl -4H-4- oxochromen -2- bases,6- chloro- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine -3- bases,6- fluoro- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine -3- bases,6- bromo- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine -3- bases,6- acetenyls -1,1- titanium dioxides -2H-1,2,4- benzothiadiazine -3- bases,7- chloro- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine -3- bases,7- fluoro- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine -3- bases,7- bromo- 1,1- titanium dioxides -2H-1,2,4- benzothiadiazine -3- bases,7- acetenyls -1,1- titanium dioxides -2H-1,2,4- benzothiadiazine -3- bases,The chloro- 2H-1 of 6-,2,4- Ben Bing oxadiazine -3- bases,The fluoro- 2H-1 of 6-,2,4- Ben Bing oxadiazine -3- bases,The bromo- 2H-1 of 6-,2,4- Ben Bing oxadiazine -3- bases,6- acetenyls -2H-1,2,4- Ben Bing oxadiazine -3- bases,The chloro- 2H-1 of 7-,2,4- Ben Bing oxadiazine -3- bases,The fluoro- 2H-1 of 7-,2,4- Ben Bing oxadiazine -3- bases,The bromo- 2H-1 of 7-,2,4- Ben Bing oxadiazine -3- bases,7- acetenyls -2H-1,2,4- Ben Bing oxadiazine -3- bases etc..The chloro- 4- oxos -1 of wherein most preferably 6-, 4- EEDQ -2- bases, 6- fluorin-4-oxygens generation -1,4- EEDQ -2- bases, the bromo- 4- oxos -1 of 6-, 4- EEDQ -2- bases, 6- acetenyl -4- oxos -1, the chloro- 4- oxos-Isosorbide-5-Nitrae-dihydroquinazoline -2- bases of 4- EEDQ -2- bases, 6-, 6- fluorin-4-oxygens generation-Isosorbide-5-Nitrae-dihydroquinazoline -2- bases, the bromo- 4- oxos -1 of 6-, 4- dihydroquinazoline -2- bases, 6- acetenyls -4- oxo-Isosorbide-5-Nitrae-dihydroquinazoline -2- bases.
Following radicals
[in base, X6Represent O or S, R25And R26As it was previously stated, 5~8 numeral represents position], wherein, X6Preferably O, R25And R26Respective independence, preferably hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl.R25And R26A preferably side is hydrogen atom, and the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom is fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The position of substitution of halogen atom, alkyl or alkynyl is not particularly limited, 6 in preferably above-mentioned formula or 7.Specific group can enumerate the chloro- 2H- chromenes -3- bases of 6-, the fluoro- 2H- chromenes -3- bases of 6-, the bromo- 2H- chromenes -3- bases of 6-, 6- acetenyl -2H- chromene -3- bases, the chloro- 2H- chromenes -3- bases of 7-, the fluoro- 2H- chromenes -3- bases of 7-, the bromo- 2H- chromenes -3- bases of 7-, 7- acetenyl -2H- chromene -3- bases.It is special it is good be the chloro- 2H- chromenes -3- bases of 7-, the fluoro- 2H- chromenes -3- bases of 7-, the bromo- 2H- chromenes -3- bases of 7-, 7- acetenyl -2H- chromene -3- bases.
Following radicals
Figure G2003801097466D00202
[in base, R27And R28As it was previously stated, 1~6 numeral represents position], wherein, R27And R28A preferably side is hydrogen atom or halogen atom; the opposing party is hydrogen atom, cyano group, nitro, amino, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl or N; N- dialkyl carbamoyls, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom is fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The preferable example for the specific group that above-mentioned formula is represented can enumerate phenyl, chlorphenyl, fluorophenyl, bromophenyl, ethynyl phenyl, chlorofluorobenzene base etc., the position of substitution of halogen atom in these groups, alkyl or alkynyl is not particularly limited, when substituent is 1, spy is 3 and 4 in above-mentioned formula well, when substituent is 2, spy is the combination of 4 in above-mentioned formula and two or three-digit well.Specific example can enumerate phenyl, 4- chlorphenyls, 4- fluorophenyls, 4- bromophenyls, 4- ethynyl phenyls, 3- chlorphenyls, 3- fluorophenyls, 3- bromophenyls, 3- ethynyl phenyls, the chloro- 4- fluorophenyls of 3-, the chloro- 3- fluorophenyls of 4-, the chloro- 2- fluorophenyls of 4-, the chloro- 4- fluorophenyls of 2-, the bromo- 2- fluorophenyls of 4-, the bromo- 4- fluorophenyls of 2-, 2, 4- dichlorophenyls, 2, 4- difluorophenyls, 2, 4- dibromo phenyls, the chloro- 3- aminomethyl phenyls of 4-, the fluoro- 3- aminomethyl phenyls of 4-, the bromo- 3- aminomethyl phenyls of 4-, 4- chloro-2-methyl phenyl, 4- fluoro-2-methylbenzene bases, the bromo- 2- aminomethyl phenyls of 4-, 3, 4- dichlorophenyls, 3, 4- difluorophenyls, 3, 4- dibromo phenyls.
Following radicals
Figure G2003801097466D00211
[in base, E1、E2、R29And R30As it was previously stated, 1~6 numeral represents position], wherein, R29And R30A preferably side is hydrogen atom or halogen atom, and the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom is fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The specific group that above-mentioned formula is represented can enumerate pyridine radicals, pyrimidine radicals, pyridazinyl etc., and the position of substitution of the halogen atom in these groups, alkyl or alkynyl is not particularly limited, with group T12 in above-mentioned formula of combination when, particularly preferably 4 in above-mentioned formula and 5.Specific preferably example can enumerate 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 4- chloro-2-pyridyls, the fluoro- 2- pyridine radicals of 4-, 4- bromo-2-pyridyl bases, 4- acetenyl -2- pyridine radicals, 4- chloro-3-pyridyl bases, 4- fluoro-3-pyridine bases, the bromo- 3- pyridine radicals of 4-, 4- acetenyl -3- pyridine radicals, 5- chloro-2-pyridyls, the fluoro- 2- pyridine radicals of 5-, 5- bromo-2-pyridyl bases, 5- acetenyl -2- pyridine radicals, the fluoro- 2- pyridine radicals of the chloro- 5- of 4-, the fluoro- 2- pyridine radicals of the chloro- 4- of 5-, 5- chloro-3-pyridyl bases, 5- fluoro-3-pyridine bases, the bromo- 3- pyridine radicals of 5-, 5- acetenyl -3- pyridine radicals, the chloro- 2- pyrimidine radicals of 5-, the fluoro- 2- pyrimidine radicals of 5-, the bromo- 2- pyrimidine radicals of 5-, 5- acetenyl -2- pyrimidine radicals, the chloro- 3- pyridazinyls of 4-, the fluoro- 3- pyridazinyls of 4-, the bromo- 3- pyridazinyls of 4-, 4- acetenyl -3- pyridazinyls, the chloro- 3- pyridazinyls of 6-, the fluoro- 3- pyridazinyls of 6-, the bromo- 3- pyridazinyls of 6-, 6- acetenyl -3- pyridazinyls etc..It is special it is good be 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 4- chloro-2-pyridyls, the fluoro- 2- pyridine radicals of 4-, 4- bromo-2-pyridyl bases, 4- acetenyl -2- pyridine radicals, 4- chloro-3-pyridyl bases, 4- fluoro-3-pyridine bases, the bromo- 3- pyridine radicals of 4-, 4- acetenyl -3- pyridine radicals, 5- chloro-2-pyridyls, the fluoro- 2- pyridine radicals of 5-, 5- bromo-2-pyridyl bases, 5- acetenyl -2- pyridine radicals, the fluoro- 2- pyridine radicals of the chloro- 5- of 4-, the fluoro- 2- pyridine radicals of the chloro- 4- of 5-, 5- chloro-3-pyridyl bases, 5- fluoro-3-pyridine bases, the bromo- 3- pyridine radicals of 5-, 5- acetenyl -3- pyridine radicals, the chloro- 3- pyridazinyls of 6-, the fluoro- 3- pyridazinyls of 6-, the bromo- 3- pyridazinyls of 6-, 6- acetenyl -3- pyridazinyls, the chloro- 3- pyridazinyls of 4-, the fluoro- 3- pyridazinyls of 4-, the bromo- 3- pyridazinyls of 4-, 4- acetenyl -3- pyridazinyls.The wherein most preferably fluoro- 2- pyridine radicals of 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 5- chloro-2-pyridyls, 5-, 5- bromo-2-pyridyls base, 5- acetenyl -2- pyridine radicals, the fluoro- 2- pyridine radicals of the chloro- 4- of 5-, the fluoro- 2- pyridine radicals of the chloro- 5- of 4-, the chloro- 3- pyridazinyls of 4-, the fluoro- 3- pyridazinyls of 4-, the bromo- 3- pyridazinyls of 4-, 4- acetenyl -3- pyridazinyls.
In addition, following radicals
[in base, Y1、Y2、R31And R32As it was previously stated, 1~5 numeral represents position], wherein, R31And R32A preferably side is hydrogen atom or halogen atom, and the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.In this case halogen atom is fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.The specific group that above-mentioned formula is represented can enumerate thienyl, pyrrole radicals, furyl, oxazolyls, thiazolyl etc., and the position of substitution of the halogen atom in these groups, alkyl or alkynyl is not particularly limited, particularly preferably 4 in above-mentioned formula and 5.The chloro- 2- thienyls of 4- can specifically be enumerated, the fluoro- 2- thienyls of 4-, the bromo- 2- thienyls of 4-, 4- acetenyl -2- thienyls, the chloro- 2- pyrrole radicals of 4-, the fluoro- 2- pyrrole radicals of 4-, the bromo- 2- pyrrole radicals of 4-, 4- acetenyl -2- pyrrole radicals, the chloro- 2- furyls of 4-, the fluoro- 2- furyls of 4-, the bromo- 2- furyls of 4-, 4- acetenyl -2- furyls, the chloro- 2- thienyls of 5-, the fluoro- 2- thienyls of 5-, the bromo- 2- thienyls of 5-, 5- acetenyl -2- thienyls, the chloro- 2- thiazolyls of 5-, the fluoro- 2- thiazolyls of 5-, the bromo- 2- thiazolyls of 5-, 5- acetenyl -2- thiazolyls, the chloro- 2- oxazolyls of 5-, the fluoro- 2- oxazolyls of 5-, the bromo- 2- oxazolyls of 5-, 5- acetenyl -2- oxazolyls etc..It is special it is good be the chloro- 2- thiazolyls of 5-, the fluoro- 2- thiazolyls of 5-, the bromo- 2- thiazolyls of 5-, 5- acetenyl -2- thiazolyls.
Following radicals
[in base, 1~8 numeral represents position, and each N represents that any one and 5~8 any one of carbon atom of 1~4 carbon atom are replaced by 1 nitrogen-atoms respectively, R34~R36As previously described], wherein, the position of each nitrogen-atoms can be arbitrary position, R34Preferably hydrogen atom or halogen atom, R35And R36A preferably side is hydrogen atom or halogen atom, and the opposing party is hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, wherein it is special it is good be that the opposing party is hydrogen atom, halogen atom, alkyl or alkynyl.Halogen atom preferably fluorine atom, chlorine atom and bromine atoms, alkyl preferably methyl, alkynyl preferably acetenyl.To halogen atom,The position of substitution of alkyl or alkynyl is not particularly limited,The specific group that above-mentioned formula is represented can enumerate 6- chloro- 1,5- naphthyridines -2- bases,6- fluoro- 1,5- naphthyridines -2- bases,6- bromo- 1,5- naphthyridines -2- bases,6- acetenyls -1,5- naphthyridines -2- bases,7- chloro- 1,5- naphthyridines -2- bases,7- fluoro- 1,5- naphthyridines -2- bases,7- bromo- 1,5- naphthyridines -2- bases,7- acetenyls -1,5- naphthyridines -2- bases,6- chloro- 1,5- naphthyridines -3- bases,6- fluoro- 1,5- naphthyridines -3- bases,6- bromo- 1,5- naphthyridines -3- bases,6- acetenyls -1,5- naphthyridines -3- bases,7- chloro- 1,5- naphthyridines -3- bases,7- fluoro- 1,5- naphthyridines -3- bases,7- bromo- 1,5- naphthyridines -3- bases,7- acetenyls -1,5- naphthyridines -3- bases,6- chloro- 1,7- naphthyridines -2- bases,6- fluoro- 1,7- naphthyridines -2- bases,6- bromo- 1,7- naphthyridines -2- bases,6- acetenyls -1,7- naphthyridines -2- bases,6- chloro- 1,7- naphthyridines -3- bases,6- fluoro- 1,7- naphthyridines -3- bases,6- bromo- 1,7- naphthyridines -3- bases,6- acetenyls -1,7- naphthyridines -3- bases,6- chloro- 1,8- naphthyridines -2- bases,6- fluoro- 1,8- naphthyridines -2- bases,6- bromo- 1,8- naphthyridines -2- bases,6- acetenyls -1,8- naphthyridines -2- bases,7- chloro- 1,8- naphthyridines -2- bases,7- fluoro- 1,8- naphthyridines -2- bases,7- bromo- 1,8- naphthyridines -2- bases,7- acetenyls -1,8- naphthyridines -2- bases,6- chloro- 1,8- naphthyridines -3- bases,6- fluoro- 1,8- naphthyridines -3- bases,6- bromo- 1,8- naphthyridines -3- bases,6- acetenyls -1,8- naphthyridines -3- bases,7- chloro- 1,8- naphthyridines -3- bases,7- fluoro- 1,8- naphthyridines -3- bases,7- bromo- 1,8- naphthyridines -3- bases,7- acetenyls -1,8- naphthyridines -3- bases,6- chloro- 2,5- naphthyridines -3- bases,6- fluoro- 2,5- naphthyridines -3- bases,6- bromo- 2,5- naphthyridines -3- bases,6- acetenyls -2,5- naphthyridines -3- bases,7- chloro- 2,5- naphthyridines -3- bases,7- fluoro- 2,5- naphthyridines -3- bases,7- bromo- 2,5- naphthyridines -3- bases,7- acetenyls -2,5- naphthyridines -3- bases,7- chloro- 2,6- naphthyridines -3- bases,7- fluoro- 2,6- naphthyridines -3- bases,7- bromo- 2,6- naphthyridines -3- bases,7- acetenyls -2,6- naphthyridines -3- bases,6- chloro- 2,8- naphthyridines -3- bases,6- fluoro- 2,8- naphthyridines -3- bases,6- bromo- 2,8- naphthyridines -3- bases,6- acetenyls -2,8- naphthyridines -3- bases,7- chloro- 2,8- naphthyridines -3- bases,7- fluoro- 2,8- naphthyridines -3- bases,7- bromo- 2,8- naphthyridines -3- bases,7- acetenyls -2,8- naphthyridines -3- bases etc..It is special it is good be chloro- 2, the 5- naphthyridines -3- bases of 7-, fluoro- 2, the 5- naphthyridines -3- bases of 7-, bromo- 2, the 5- naphthyridines -3- bases of 7-, 7- acetenyl -2,5- naphthyridines -3- bases etc..
In addition to 12 kinds of groups of above-mentioned (a)~(1), can preferably have the Thienopyrroles base of substituent.There can be 1~3 substituent; the substituent can enumerate hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, carbamoyl, N- alkyl-carbamoyls, N; N- dialkyl carbamoyls, alkoxy carbonyl, amidino groups and alkoxy carbonyl alkyl; wherein, preferably cyano group, halogen atom, alkyl, alkenyl, alkynyl and haloalkyl.Specific preferably example can enumerate 2- chlorothiophenes simultaneously [2,3-b] pyrroles -5- bases, 2- fluorine thieno [2,3-b] pyrroles -5- bases, 2- bromothiophenes simultaneously [2,3-b] pyrroles -5- bases or 2- thiophene acetylenes simultaneously [2,3-b] pyrroles -5- bases etc..
[on group Q1]
In the present invention, Q1The saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups can with substituent are represented, can have the saturation or undersaturated 5~7 circle heterocycles base of substituent, can have the saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings.
Above-mentioned saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups can enumerate cyclopenta, cyclopentenyl, cyclohexyl, cyclopentenyl, phenyl etc., preferably cyclopenta, cyclohexyl and phenyl, preferably phenyl.
Saturation or undersaturated 5~7 circle heterocycles basis representation have 1 valency group of the heteroatomic heterocycle formation of at least one selected from oxygen atom, sulphur atom and nitrogen-atoms, can enumerate furyl, pyrrole radicals, thienyl, pyrazolyl, imidazole radicals, pyrazolinyl, oxazolyl, oxazolinyls, thiazolyl, thiazolinyl, thiadiazolyl group, furazanyl, pyranose, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrrolidinyl, piperazinyl, piperidyl, oxazinyl, oxadiazines base, morpholinyl, thiazinyl, thiadiazine base, thio-morpholinyl, tetrazole radical, triazolyl, triazine radical, azepine
Figure G2003801097466D00241
Base, diaza
Figure G2003801097466D00242
Base and three azepinesBase etc..Wherein, preferably thienyl, pyrazolyl, imidazole radicals, oxazolyls, thiazolyl, thiadiazolyl group, furazanyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, thiadiazine base and triazolyl.Preferably thienyl, thiazolyl, pyrazolyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrrolidinyl, piperazinyl and piperidyl.In addition, in these heterocyclic radicals, nitrogen heterocycle can be formed as N- oxides.
The fusion alkyl of saturation or undersaturated 2 ring or 3 rings and the Q of formula (1)4Explanation described in saturation or undersaturated 2 ring or 3 rings fusion alkyl implication it is identical, specific example can enumerate indenyl, indanyl, naphthyl, tetralyl, anthryl, phenanthryl etc., preferably indenyl, indanyl, naphthyl and tetralyl.
The annelated heterocycles base of saturation or undersaturated 2 ring or 3 rings and the Q of formula (1)4Explanation described in saturation or undersaturated 2 ring or 3 rings annelated heterocycles base implication it is identical,Specific example can enumerate benzofuranyl,Isobenzofuran-base,Benzothienyl,Indyl,Indolinyl,Isoindolyl,Isoindoline base,Indazolyl,Quinolyl,EEDQ base,4- oxo-dihydros quinolyl (EEDQ -4- ketone),Tetrahydric quinoline group,Isoquinolyl,Tetrahydro isoquinolyl,Chromene base,Chromanyl,Isochroman base,4H-4- oxochromen bases,3,4- dihydro -4H-4- oxochromen bases,4H- quinolizine bases,Quinazolyl,Dihydroquinazoline base,Tetrahydro quinazoline base,Quinoxalinyl,Tetrahydroquinoxaline base,Cinnolines base,Tetrahydrochysene cinnolines base,Indolizine base,Indolizine base,Benzothiazolyl,Tetrahydro benzothiazol base,Benzoxazolyl,Benzisothia oxazolyl,Benzoisoxazole base,Benzimidazolyl,Naphthyridines base,Naphthane piperidinyl,Thienopyridine base,Tetrahydrothieno pyridines base,Thiazolopyridinyl,Tetrahydro-thiazoles and pyridine radicals,Thiazole and pyridazinyl,Tetrahydro-thiazoles and pyridazinyl,Pyrrolopyridinyl,Pyrrolin and pyridine radicals,Nafoxidine and pyridine radicals,Pyrrolo-pyrimidine radicals,Pyrrolin and pyrimidine radicals,Pyrido quinazolyl,Dihydro pyrido quinazolyl,Pyridopyrimidine base,Tetrahydropyridine and pyrimidine radicals,Pyrans benzothiazolyl,Dihydropyran benzothiazolyl,Furopyridyl,Tetrahydrofuran and pyridine radicals,Oxazole and pyridine radicals,Si Qing oxazoles and pyridine radicals,Oxazole and pyridazinyl,Si Qing oxazoles and pyridazinyl,Pyrroles's benzothiazolyl,Pyrrolin benzothiazolyl,Bi Ka Bing oxazolyls,Pyrrolin Bing oxazolyls,Thienopyrroles base,Thiazolopyrimidinyl,Thiazoline and pyrimidine radicals,4- oxo tetrahydrochysene cinnolines bases,1,2,4- benzothiadiazine bases,1,1- titanium dioxides -2H-1,2,4- benzothiadiazine bases,1,2,4- Ben Bing oxadiazine bases,Cyclopenta pyranose,Thienofuran base,Furans and pyranose,Bi Ding Bing oxazinyls,Bi Zuo Bing oxazolyls,Imidazothiazole base,Imidazopyridyl,Imidazolidine and pyridine radicals,Pyrazine and pyridazinyl,Benzisoquinoline base,Furans and cinnolines base,Pyrazolo thiazole and pyridazinyl,Tetrahydro-pyrazole and thiazole and pyridazinyl,Hexahydro thiazole and pyridazine and pyridazinyl,Imidazo-triazine base,Oxazole and pyridine radicals,Benzo oxa-
Figure G2003801097466D00244
Base, benzo-aza
Figure G2003801097466D00245
Base, tetrahydro benzo azepine
Figure G2003801097466D00246
Base, benzodiazepineBase, the azepine of benzo threeBase, thieno azepine
Figure G2003801097466D00249
Base, thiophane and azepine
Figure G2003801097466D002410
Base, thieno diazaBase, the azepine of thieno threeBase, thiazole and azepineBase, tetrahydro-thiazoles and azepineBase, 4,5,6,7- tetrahydrochysene -5,6- tetramethylene thiazoles and pyridazinyl, 5,6- trimethylenes -4,5,6,7- tetrahydro-thiazoles and pyridazinyl etc..Wherein, preferably benzothiazolyl, tetrahydro benzothiazol base, thienopyridine base, tetrahydrothieno pyridines base, Thienopyrroles base, thiazolopyridinyl, tetrahydro-thiazoles and pyridine radicals, thiazole and pyridazinyl, tetrahydro-thiazoles and pyridazinyl, pyrrolo-pyrimidine radicals, pyrrolin and pyrimidine radicals, pyrans benzothiazolyl, dihydropyran benzothiazolyl, furopyridyl, tetrahydrofuran and pyridine radicals, oxazole and pyridine radicals, Si Qing oxazoles and pyridine radicals, pyrrolopyridinyl, pyrrolin and pyridine radicals, nafoxidine and pyridine radicals, oxazole and pyridazinyl, Si Qing oxazoles and pyridazinyl, pyrroles's benzothiazolyl, pyrrolin benzothiazolyl, Bi Ka Bing oxazolyls, pyrrolin Bing oxazolyls, thiazole and phonetic piperazine base, thiazoline and phonetic piperazine base, benzo-azaBase, tetrahydro benzo azepine
Figure G2003801097466D00252
Base, thiazole and azepine
Figure G2003801097466D00253
Base, tetrahydro-thiazoles and azepine
Figure G2003801097466D00254
Base, thieno azepineBase, thiophane and azepineBase, 4,5,6,7- tetrahydrochysene -5,6- tetramethylene thiazoles and pyridazinyl, 5,6- trimethylenes -4,5,6,7- tetrahydro-thiazoles and pyridazinyl.It is particularly preferred that tetrahydro benzothiazol base, tetrahydrothieno pyridines base, tetrahydro-thiazoles and pyridine radicals, tetrahydro-thiazoles and pyridazinyl, pyrrolin and pyrimidine radicals, dihydropyran benzothiazolyl, Si Qing oxazoles and pyridine radicals, pyrrolin benzothiazolyl, 4,5,6,7- tetrahydrochysenes -5,6- tetramethylenes thiazole and pyridazinyl, 5,6- trimethylenes -4,5,6,7- tetrahydro-thiazoles and pyridazinyl.
Fusion form to above-mentioned annelated heterocycles base is not particularly limited, such as thienopyridine, can be thieno [2,3-b] pyridine, thieno [2,3-c] pyridine, thieno [3,2-b] pyridine, thieno [3,2-c] pyridine, thieno [3,4-b] pyridine, thieno [3, any of 4-c] pyridine, preferably thieno [2,3-c] pyridine and thieno [3,2-c] pyridine.Thienopyrroles, can be any of thieno [2,3-b] pyrroles, thieno [3,2-b] pyrroles.Thiazolopyridin, it can be thiazole simultaneously [4,5-b] pyridine, thiazole simultaneously [4,5-c] pyridine, thiazole simultaneously [5,4-b] pyridine, thiazole simultaneously [5,4-c] pyridine, thiazole simultaneously [3,4-a] pyridine, thiazole simultaneously any of [3,2-a] pyridine, preferably thiazole simultaneously [4,5-c] pyridine and thiazole simultaneously [5,4-c] pyridine.Thiazole and pyridazine, can be thiazole simultaneously [4,5-c] pyridazine, thiazole simultaneously [4,5-d] pyridazine, thiazole simultaneously [5,4-c] pyridazine, thiazole simultaneously any of [3,2-b] pyridazines, preferably thiazole simultaneously [4,5-d] pyridazine.Pyrrolopyridine, it can be pyrrolo- [2,3-b] pyridine, pyrrolo- [2,3-c] pyridine, pyrrolo- [3,2-b] pyridine, pyrrolo- [3,2-c] pyridine, pyrrolo- [3,4-b] pyridine, any of pyrrolo- [3,4-c] pyridine, preferably pyrrolo- [2,3-c] pyridine and pyrrolo- [3,2-c] pyridine.Pyrrolopyrimidine, can be any of pyrrolo- [3,4-d] pyrimidine, pyrrolo- [3,2-d] pyrimidine, pyrrolo- [2,3-d] pyrimidine, preferably pyrrolo- [3,4-d] pyrimidine.Pyridopyrimidine, it can be pyrido [2,3-d] pyrimidine, pyrido [3,2-d] pyrimidine, pyrido [3,4-d] pyrimidine, pyrido [4,3-d] pyrimidine, pyrido [1,2-c] pyrimidine, any of pyrido [1,2-a] pyrimidine, preferably pyrido [3,4-d] pyrimidine and pyrido [4,3-d] pyrimidine.Pyrans and thiazole, can be pyrans simultaneously [2,3-d] thiazole, pyrans simultaneously [4,3-d] thiazole, pyrans simultaneously [3,4-d] thiazole, pyrans simultaneously any of [3,2-d] thiazole, preferably pyrans simultaneously [4,3-d] thiazole, pyrans simultaneously [3,4-d] thiazole.Furopyridine, it can be furans simultaneously [2,3-b] pyridine, furans simultaneously [2,3-c] pyridine, furans simultaneously [3,2-b] pyridine, furans simultaneously [3,2-c] pyridine, furans simultaneously [3,4-b] pyridine, furans simultaneously any of [3,4-c] pyridine, preferably furans simultaneously [2,3-c] pyridine and furans simultaneously [3,2-c] pyridine.Oxazole and pyridine, Ke Yi Shi oxazoles simultaneously [4,5-b] pyridine, oxazoles simultaneously [4,5-c] pyridine, oxazoles simultaneously [5,4-b] pyridine, oxazoles simultaneously [5,4-c] pyridine, oxazoles simultaneously [3,4-a] pyridine, oxazoles simultaneously any of [3,2-a] pyridine, the Hao Wei oxazoles of compare simultaneously [4,5-c] pyridine is Ji oxazole simultaneously [5,4-c] pyridine.Oxazole and pyridazine, Ke Yi Shi oxazoles simultaneously [4,5-c] pyridazine, oxazoles simultaneously [4,5-d] pyridazine, oxazoles simultaneously [5,4-c] pyridazine, oxazoles simultaneously any of [3,4-b] pyridazine, the Hao Wei oxazoles of compare simultaneously [4,5-d] pyridazine.Pyrrolo- thiazole, can be pyrrolo- [2,1-b] thiazole, pyrrolo- [1,2-c] thiazole, pyrrolo- [2,3-d] thiazole, pyrrolo- [3,2-d] thiazole, pyrrolo- [3,4-d] any of thiazole, preferably pyrrolo- [3,4-d] thiazole.Bi Ka Bing oxazoles, can be pyrrolo- [2,1-b] oxazoles, pyrrolo-es [1,2-c] oxazoles, pyrrolo- [2,3-d] oxazoles, pyrrolo- [3,2-d] oxazoles, pyrrolo- [3, any of 4-d] oxazoles, preferably pyrrolo- [3,4-d] oxazoles.Benzo-azaCan be 1H-1- benzo-azas1H-2- benzo-azas
Figure G2003801097466D00263
1H-3- benzo-azas
Figure G2003801097466D00264
Any of, preferably 1H-3- benzo-azas
Figure G2003801097466D00265
Thiazole simultaneously [4,5-c] azepineIt can be 4H- thiazoles simultaneously [4,5-c] azepine
Figure G2003801097466D00267
4H- thiazoles simultaneously [4,5-d] azepine4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D00269
Any of, preferably 4H- thiazoles simultaneously [4,5-d] azepineThieno [2,3-c] azepine
Figure G2003801097466D002611
It can be 4H- thienos [2,3-d] azepine
Figure G2003801097466D002612
4H- thienos [3,2-c] azepine
Figure G2003801097466D002613
Any of, preferably 4H- thienos [2,3-d] azepine
Figure G2003801097466D002614
In these heterocyclic radicals, nitrogen heterocycle is formed as N- oxides.To above-mentioned substituent and Q2Binding site be not particularly limited.
The annelated heterocycles base of the fusion alkyl or saturation or undersaturated 2 ring or 3 rings of above-mentioned saturation or unsaturated 5~6 yuan of cyclic hydrocarbon groups, saturation or unsaturated 5~7 circle heterocycles bases, saturation or unsaturated 2 ring or 3 rings can have 1~3 substituent respectively, the substituent can enumerate hydroxyl, the halogen atoms such as fluorine atom, chlorine atom, bromine atoms and iodine atom, the haloalkyl of 1~3 halogen atom substitution, amino, cyano group, amidino groups, hydroxyl amidino groups, straight-chain, alkyl (the hereinafter referred to as C of the carbon number 1~6 of branched or ring-type1~C6Alkyl, represents the alkyl of straight-chain, branched and ring-type, the C of straight or branched such as methyl, ethyl, isopropyl, the tert-butyl group1~C6The C such as alkyl, cyclopropyl, cyclobutyl, cyclopenta, 1- methylcyclopropyl groups3~C6Cycloalkyl), C3~C6Cycloalkyl C1~C6Alkyl (for example, Cvclopropvlmethvl etc.), hydroxyl C1~C6Alkyl (for example, hydroxyethyl, 1,1- dimethyl -2- hydroxyethyls etc.), C1~C6Alkoxy (for example, methoxyl group, ethyoxyl etc.), C1~C6Alkoxy C1~C6Alkyl, carboxyl, C2~C6Carboxyalkyl (for example, carboxymethyl group etc.), C2~C6Alkoxy carbonyl C1~C6Alkyl (for example, Methoxycarbonylmethyl, tert-Butoxycarbonyl-methyl etc.), C2~C6The amidino groups of alkoxy carbonyl substitution, C2~C6Alkenyl (for example, vinyl, pi-allyl etc.), C2~C6Alkynyl (for example, acetenyl, propinyl etc.), C2~C6Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl etc.), amino C1~C6Alkyl (for example, amino methyl, amino-ethyl etc.), C1~C6Alkyl amino C1~C6Alkyl (for example, N- Methylaminomethyls, N- ethylaminomethyls etc.), two (C1~C6Alkyl) amino C1~C6Alkyl (for example, N, N- dimethylaminomethyl, N, N- diethylaminos methyl, N- ethyl-N-methylamino ethyls etc.), C2~C6Alkoxycarbonyl amino C1~C6Alkyl (for example, methyloxycarbonylamino ethyl, tertbutyloxycarbonylamino ethyl etc.), C1~C6Alkanoyl (for example, formoxyl, acetyl group, methylpropionyl, Cyclopentanecarbonyl etc.), C1~C6Alkanoylamino C1~C6Alkyl (for example, acetylaminomethyl etc.), C1~C6Alkyl sulphonyl (for example, mesyl etc.), C1~C6Alkyl sulfonyl-amino C1~C6Alkyl (for example, methane sulfonylamino methyl etc.), carbamoyl, C1~C6Alkyl-carbamoyl (for example, methylcarbamoyl, ethylaminocarbonyl, isopropylcarbamoyl, t-Butylcarbamoyl etc.), the N, (C of N- bis-1~C6Alkyl) carbamoyl (for example, formyl-dimethylamino, diethylamino formoxyl, methylethylamine formoxyl etc.), C1~C6Alkyl amino (for example, N- methylaminos, N- ethylaminos etc.), two (C1~C6Alkyl) amino is (for example; N; N- dimethylaminos, N; N- diethylaminos, N- ethyl-N-methylaminos etc.), amino-sulfonyl, aryl sulfonyl is (for example; phenyl sulfonyl etc.); can be by the substituted aryl carbonyl such as halogen atom (for example, benzoyl, 4- fluoro benzoyls etc.), C2~C6Alkoxy carbonyl (C1~C6Alkyl) amino C1~C6Alkyl (for example, methoxycarbonyl (methyl) amino methyl, tert-butoxycarbonyl (methyl) amino methyl etc.), C1~C6Alkyl sulphonyl C1~C6Alkyl is (for example; sulfonyloxy methyl ylmethyl etc.); 5~6 circle heterocycles bases containing 2 nitrogen of 1 or of the same race or not of the same race, oxygen or sulphur atom are (for example; pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyridine radicals, pyrimidine radicals, THP trtrahydropyranyl etc.), above-mentioned 5~6 circle heterocycles base-C1~C4Alkyl (for example, morpholinyl methyl etc.), above-mentioned 5~6 circle heterocycles base-carbonyl (for example, pyrrolidinylcarbonyl etc.), above-mentioned 5~6 circle heterocycles base-amino-C1~C4Alkyl is (for example, N- (oxazole -2- bases) amino methyl etc.), above-mentioned 5~6 circle heterocycles base-amino is (for example, pyridinylamino etc.), above-mentioned 5~6 circle heterocycles base-epoxide is (for example, 4- pyridines epoxide, (1- methyl-iminos piperidin-4-yl) epoxide etc.), 3~6 circle heterocycles bases-carbonyl-C1~C4Alkyl (for example, (4,4- dioxothiomorpholin -1- bases) carbonvlmethyl etc.), and above-mentioned 5~6 circle heterocycles base (C1~C6Alkyl) amino-C1~C4Alkyl (for example, N- (4,5- dihydro -1,3- oxazole -2- bases)-N- Methylaminomethyls etc.) etc..
Q1Specific example can enumerate the cyclic hydrocarbon group of 5~6 yuan of 2- aminosulfonvlphenyls etc.,5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases,4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases,5- cyclopropyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases,5- carboxymethyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases,5- butyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases,5- (4- pyridine radicals) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases,5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-c] pyridine -2- bases,6- methyl -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine -2- bases,5- methyl -4,5,6,7- tetra- Qing oxazoles simultaneously [5,4-c] pyridine -2- bases,5- methyl -4,6- dihydro -5H- pyrrolo-es [3,4-d] thiazol-2-yl,5,7- dihydro -6- methylpyrroles simultaneously [3,4-d] pyrimidine -2-base,5,6- dimethyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-d] pyridazine -2- bases,5,6- dimethyl -4,5,6,7- tetra- Qing oxazoles simultaneously [4,5-d] pyridazine -2- bases,5- dimethylaminos -4,5,6,7- tetrahydro benzos [d] thiazol-2-yl,5- (4- pyridine radicals) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases,6,7- dihydro -4H- pyrans simultaneously [4,3-d] the 2 ring heterocyclic radicals such as thiazol-2-yl,4- pyridine radicals,The pyridine radicals such as 2- pyridine radicals,4,The dihydro-oxazole bases such as 5- dihydro-oxazole -2- bases,4-[N-(4,5- dihydro-oxazole -2- bases)-N- Methylaminomethyls] thiophene -2- bases,4-[N-(4,5- dihydro-oxazole -2- bases)-N- Methylaminomethyls] -3- chlorothiophene -2- bases,5- (N- Methylaminomethyls) thiazol-2-yl,5- (N- Methylaminomethyls) thiophene -2- bases,5-(N,N- dimethylaminomethyls) thiazol-2-yl,5-(N,N- dimethylaminomethyls) thiophene -2- bases,5-(N,N- dimethylaminomethyls) 5~6 yuan of pyridine -2- bases etc. heterocyclic radical.But, these examples do not limit Q1。
[on group Q2]
Group Q2Represent singly-bound, the alkylidene of the carbon number 1~6 of straight-chain or branched, the alkenylene of the carbon number 2~6 of straight-chain or branched, the alkynylene of the carbon number 2~6 of straight-chain or branched, can have the divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups of substituent, can have the divalent saturation or undersaturated 5~7 circle heterocycles base of substituent, can have the divalent saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the divalent saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings.
Group Q2In, the alkylidene of the carbon number 1~6 of straight-chain or branched can enumerate methylene, ethylidene, trimethylene, propylidene, tetramethylene, pentamethylene, hexa-methylene etc..
The alkenylene of the carbon number 2~6 of straight-chain or branched can enumerate ethenylidene, allylidene, butenylidene, inferior pentenyl etc..In addition, being not particularly limited to the position of double bond.
The alkynylene of the carbon number 2~6 of straight-chain or branched can enumerate ethynylene, sub- propinyl, butynelene, sub- pentynyl, sub- hexin base etc..The binding site of three keys is not particularly limited.
Divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups are the Q in formula (1)4Explanation described in saturation or undersaturated 5~6 yuan of cyclic hydrocarbon divalent group, specific example can enumerate cyclohexylidene, cyclohexadienylidene, phenylene etc., preferably cyclohexylidene and phenylene.
Divalent saturation or undersaturated 5~7 yuan of heterocyclic radical are the Q in formula (1)4Explanation described in saturation or undersaturated 5~7 circle heterocycles divalent group.Specific example can enumerate furans, pyrroles, thiophene, pyrazoles, imidazoles, oxazole, oxazolidines, thiazole, thiadiazoles, furazan, pyrans, pyridine, pyrimidine, pyridazine, pyrrolidines, piperazine, piperidines, oxazine, oxadiazines, morpholine, thiazine, thiadiazine, thiomorpholine, tetrazolium, triazole, triazine, azepineDiazaThree azepinesDeng divalent group, wherein, preferable example can enumerate pyrazoles, imidazoles, oxazoles, thiazole, thiadiazoles, furazan, pyridine, pyrimidine, pyridazine, pyrrolidines, piperazine, piperidines, triazole, triazine, azepineDiazaThree azepinesDivalent group.
The fusion alkyl of divalent saturation or undersaturated 2 ring or 3 rings is the Q in formula (1)4Explanation described in saturation or undersaturated 2 ring or 3 rings fusion hydrocarbon divalent group, its specific example can enumerate the divalent group of indenes, indane, naphthalene, naphthane, anthracene, phenanthrene etc., and preferable example can enumerate the divalent group of indane and naphthalene.
The annelated heterocycles base of divalent saturation or undersaturated 2 ring or 3 rings is the Q in formula (1)4Explanation described in saturation or undersaturated 2 ring or 3 rings annelated heterocycles divalent group, specific example can enumerate benzofuran, benzothiophene, indoles, iso-indoles, indazole, quinoline, tetrahydroquinoline, isoquinolin, tetrahydroisoquinoline, quinazoline, dihydroquinazoline, tetrahydro quinazoline, quinoxaline, tetrahydroquinoxaline, cinnolines, tetrahydrochysene cinnolines, indolizine, indolizine, benzothiazole, tetrahydro benzothiazol, naphthyridines, Tetrahydronaphthyridderivates, thienopyridine, tetrahydrothieno pyridines, thiazolopyridin, tetrahydro-thiazoles and pyridine, thiazole and pyridazine, tetrahydro-thiazoles and pyridazine, pyrrolopyridine, pyrrolin and pyridine, nafoxidine and pyridine, pyrrolopyrimidine, pyrrolin and pyrimidine, dihydro pyrido quinazoline, pyrans and thiazole, dihydropyran and thiazole, furopyridine, tetrahydrofuran and pyridine, oxazole and pyridine, Si Qing oxazoles and pyridine, oxazole and pyridazine, Si Qing oxazoles and pyridazine, pyrrolo- thiazole, pyrrolin and thiazole, Bi Ka Bing oxazoles, pyrrolin Bing oxazoles, benzo-aza
Figure G2003801097466D00287
Deng divalent group, preferable example can enumerate the divalent group of benzofuran, benzothiophene, indoles, indazole, quinoline, isoquinolin, tetrahydroisoquinoline, benzothiazole, naphthyridines, thienopyridine, thiazolopyridin, tetrahydro-thiazoles and pyridine, thiazole and pyridazine, pyrrolopyridine, nafoxidine and pyridine, Pyridopyrimidine, pyrans and thiazole, dihydropyran and thiazole, furopyridine, oxazoles and pyridine, oxazoles and pyridazine, pyrrolo- thiazole, pyrrolin and thiazole, Bi Ka Bing oxazoles and pyrrolin Bing oxazoles.Fusion form in above-mentioned annelated heterocycles base is not particularly limited,For example,Naphthyridines,Can be 1,5-,1,6-,1,7-,1,8-,2,6- or 2,Any of 7- naphthyridines,Thienopyridine,It can be thieno [2,3-b] pyridine,Thieno [2,3-c] pyridine,Thieno [3,2-b] pyridine,Thieno [3,2-c] pyridine,Thieno [3,4-b] pyridine,Thieno [3,Any of 4-c] pyridine,Thiazolopyridin,It can be thiazole simultaneously [4,5-b] pyridine,Thiazole simultaneously [4,5-c] pyridine,Thiazole simultaneously [5,4-b] pyridine,Thiazole simultaneously [5,4-c] pyridine,Thiazole simultaneously [3,4-a] pyridine,Thiazole simultaneously [3,Any of 2-a] pyridine,Thiazole and pyridazine,It can be thiazole simultaneously [4,5-c] pyridazine,Thiazole simultaneously [4,5-d] pyridazine,Thiazole simultaneously [5,4-c] pyridazine,Thiazole simultaneously [3,Any of 2-b] pyridazine,Pyrrolopyridine,It can be pyrrolo- [2,3-b] pyridine,Pyrrolo- [2,3-c] pyridine,Pyrrolo- [3,2-b] pyridine,Pyrrolo- [3,2-c] pyridine,Pyrrolo- [3,4-b] pyridine,Pyrrolo- [3,Any of 4-c] pyridine,Pyrrolopyrimidine,It can be pyrrolo- [3,4-d] pyrimidine,Pyrrolo- [3,2-d] pyrimidine,Pyrrolo- [2,Any of 3-d] pyrimidine,Pyridopyrimidine,It can be pyrido [2,3-d] pyrimidine,Pyrido [3,2-d] pyrimidine,Pyrido [3,Any of 4-d] pyrimidine,Pyrans and thiazole,It can be pyrans simultaneously [2,3-d] thiazole,Pyrans simultaneously [4,3-d] thiazole,Pyrans simultaneously [3,4-d] thiazole,Pyrans simultaneously [3,Any of 2-d] thiazole,Furopyridine,It can be furans simultaneously [2,3-b] pyridine,Furans simultaneously [2,3-c] pyridine,Furans simultaneously [3,2-b] pyridine,Furans simultaneously [3,2-c] pyridine,Furans simultaneously [3,4-b] pyridine,Furans simultaneously [3,Any of 4-c] pyridine,Oxazole and pyridine,Ke Yi Shi oxazoles simultaneously [4,5-b] pyridine radicals,Oxazole simultaneously [4,5-c] pyridine,Oxazole simultaneously [5,4-b] pyridine,Oxazole simultaneously [5,4-c] pyridine,Oxazole simultaneously [3,4-a] pyridine,Oxazole simultaneously [3,Any of 2-a] pyridine,Oxazole and pyridazine,Ke Yi Shi oxazoles simultaneously [4,5-c] pyridazine,Oxazole simultaneously [4,5-d] pyridazine,Oxazole simultaneously [5,4-c] pyridazine,Oxazole simultaneously [3,Any of 4-b] pyridazine,Pyrrolo- thiazole,It can be pyrrolo- [2,1-b] thiazole,Pyrrolo- [1,2-c] thiazole,Pyrrolo- [3,2-d] thiazole,Pyrrolo- [3,Any of 4-d] thiazole,Bi Ka Bing oxazoles,It can be pyrrolo- [2,1-b] oxazoles,Pyrrolo- [1,2-c] oxazoles,Pyrrolo- [2,3-d] oxazoles,Pyrrolo- [3,2-d] oxazoles,Pyrrolo- [3,Any of 4-d] oxazoles.In addition it is also possible to be the form beyond these fusion forms.
Above-mentioned divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups, divalent saturation or undersaturated 5~7 circle heterocycles base, the annelated heterocycles base of the fusion alkyl and divalent saturation or undersaturated 2 ring or 3 rings of divalent saturation or undersaturated 2 ring or 3 rings can have 1~3 substituent respectively, and the substituent can enumerate hydroxyl, fluorine atom, chlorine atom, the halogen atom such as bromine atoms and iodine atom, the haloalkyl of 1~3 halogen atom substitution, amino, cyano group, aminoalkyl, amidino groups, hydroxyl amidino groups, straight-chain, the alkyl of the carbon number 1~6 of branched or ring-type is (for example, methyl, ethyl etc.), straight-chain, the alkoxy of the carbon number 1~6 of branched or ring-type is (for example, methoxyl group, ethyoxyl etc.), straight-chain, the amidino groups of the alkoxy carbonyl substitution of the carbon number 2~7 of branched or ring-type is (for example, methoxycarbonyl amidino groups, ethoxy carbonyl amidino groups etc.), straight-chain, the alkenyl of the carbon number 2~6 of branched or ring-type is (for example, vinyl, pi-allyl etc.), the alkynyl of the carbon number 2~6 of straight-chain or branched is (for example, acetenyl, propinyl etc.), straight-chain, the alkoxy carbonyl of the carbon number 2~6 of branched or ring-type is (for example, methoxycarbonyl, ethoxy carbonyl etc.) and carbamoyl etc..
Above-mentioned Q2In, preferably singly-bound, can have substituent divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups, can have substituent divalent saturation or undersaturated 5~7 circle heterocycles base and can have substituent divalent saturation or undersaturated 2 ring or 3 rings annelated heterocycles base, wherein preferably singly-bound, divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups, divalent saturation or undersaturated 5~7 circle heterocycles base.
Group Q1For can have the fusion alkyl of the saturation of substituent or undersaturated 2 ring or 3 rings or can have substituent saturation or undersaturated 2 ring or 3 rings annelated heterocycles base when, group Q2Preferably singly-bound.In combinations thereof, Q2During for singly-bound, formula (1)
Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4(1)
[in formula, R1、R2、Q1、Q2、Q3、Q4、T0And T1As previously described]
For following formulas (1 ') Suo Shi.
Q1-T0-N(R1)-Q3-N(R2)-T1-Q4(1′)
[in formula, Q1Represent the fusion alkyl or the annelated heterocycles base of 2 rings or 3 rings of above-mentioned 2 ring or 3 rings, R1、R2、Q3、Q4、T0And T1As previously described]
Preferably group Q1For that can have the thienopyridine base of substituent, there can be the tetrahydrothieno pyridines base of substituent, there can be the thiazolopyridinyl of substituent, can have the tetrahydro-thiazoles and pyridine radicals of substituent, can have the thiazole and pyridazinyl of substituent, can have the tetrahydro-thiazoles and pyridazinyl of substituent, there can be the pyrans benzothiazolyl of substituent, there can be the dihydropyran benzothiazolyl of substituent, there can be the furopyridyl of substituent, can have the tetrahydrofuran and pyridine radicals of substituent, can have substituent oxazoles and pyridine radicals, can have the Si Qing oxazoles and pyridine radicals of substituent, there can be the pyrrolopyridinyl of substituent, can have the pyrrolin and pyridine radicals of substituent, can have the nafoxidine and pyridine radicals of substituent, there can be the pyrrolo-pyrimidine radicals of substituent, can have the pyrrolin and pyrimidine radicals of substituent, can have substituent oxazoles and pyridazinyl, can have the Si Qing oxazoles and pyridazinyl of substituent, there can be pyrroles's benzothiazolyl of substituent, there can be the pyrrolin benzothiazolyl of substituent, there can be the Bi Ka Bing oxazolyls of substituent, there can be the pyrrolin Bing oxazolyls of substituent, there can be the benzothiazolyl of substituent, there can be the tetrahydro benzothiazol base of substituent, there can be the thiazolopyrimidinyl of substituent, can have the thiazoline and pyrimidine radicals of substituent, there can be the benzo-aza of substituent
Figure G2003801097466D00301
Base, the tetrahydro benzo azepine can with substituent
Figure G2003801097466D00302
Base, the thiazole and azepine can with substituent
Figure G2003801097466D00303
Base, the tetrahydro-thiazoles and azepine can with substituentBase, the thieno azepine can with substituentBase, the thiophane and azepine can with substituentBase, 4,5,6,7- tetrahydrochysene -5,6- tetramethylene thiazoles and pyridazinyl can with substituent or 5, the 6- trimethylenes -4,5 can with substituent, 6,7- tetrahydro-thiazoles and pyridazinyl, group Q2For singly-bound.
Group Q1During for that can have the saturation of substituent or unsaturated 5~6 yuan of cyclic hydrocarbon groups or can have the saturation of substituent or unsaturated 5~7 circle heterocycles base, group Q2Can preferably have the divalent saturation or unsaturated 5~6 yuan of cyclic hydrocarbon groups or the divalent saturation or undersaturated 5~7 circle heterocycles base can with substituent of substituent, be used as group Q1-Q2-,Preferable example can enumerate 4- (4- pyridine radicals) phenyl,4- (2- pyridine radicals) phenyl,5- (4- pyridine radicals) thiazolyl,1- (4- pyridine radicals) piperidyl,4- (4- pyridine radicals) piperidyl,4- hydroxyls -1- (4- pyridine radicals) piperidin-4-yl,Xenyl,4- (2- aminosulfonvlphenyls) phenyl,4- (2- carbamimido-phenyls) phenyl,4- (2- methylsulfonyl phenyls) phenyl,4- (2- aminomethyl phenyls) phenyl,4- (2- Carbamoylphenyls) phenyl,4- (2- imidazole radicals) phenyl,4- (1- methyl -2- imidazole radicals) phenyl,4-(2,3,4,5- tetrahydropyrimidine -2- bases) phenyl,4- (1- methyl -2,3,4,5- tetrahydropyrimidine -2- bases) phenyl,4- (5- tetrazole radicals) phenyl,1- (4- pyridine radicals) piperidin-4-yl,3- (4- piperidyl) isoxazoline -5- bases,3- (4- carbamimido-phenyl) isoxazoline -5- bases,3- (4- piperidyl) isoxazole alkyl -5- bases,3- (4- carbamimido-phenyl) isoxazole alkyl -5- bases,2- (4- piperidyls) -1,3,4- thiadiazoles -5- bases,2- (4- aminophenyls) -1,3,4- oxadiazole -5- bases,4- (4- piperidyls) piperidin-1-yl,4- (4- piperidyls) piperazine -1- bases,4- (4- piperazinyls) piperazine -1- bases,1- (4- pyrimidine radicals) piperidin-1-yl,1- (2- methylpyrimidine -4- bases) piperidin-4-yl,1- (4- pyrimidine radicals) pyrrolidin-3-yl,1- (4- methylpyrimidine -6- bases) piperazine -4- bases,1- (2- methylpyrimidine -4- bases) pyrrolidines -4- bases,1- (6- chlorine pyrimidine-4-yl) piperidin-4-yl,5- (4- chlorphenyls) thiophene -2- bases,2- (4- chlorphenyls) thiazole-4-yl,3- (4- chlorphenyls) -1H- pyrroles's -2- bases,4- (4- pyrimidine radicals) phenyl,4- (4- imidazole radicals) phenyl,5- (pyridin-4-yl) pyrimidine -2-base,2 '-[(dimethylamino) methyl] [1,1 '-biphenyl] -4- bases,4- [2- (hydroxymethyl) pyridin-4-yl] phenyl,4- [2- (amino methyl) pyridin-4-yl] phenyl,2 '-(amino-sulfonyl) [1,1 '-xenyl] -4- bases,4- (3- oxomorpholin -4- bases) phenyl etc..
[on group Q3]
Group Q3By following radicals
Figure G2003801097466D00311
Represent, in group, Q5Represent alkylidene, the alkenylene of carbon number 2~8 or the base-(CH of carbon number 1~82)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH-, 1 and 2 represents position)；
R3And R4Containing Q5Ring on carbon atom,Replaced on nitrogen-atoms or sulphur atom,It is each independent,Represent hydrogen atom,Hydroxyl,Alkyl,Alkenyl,Alkynyl,Halogen atom,Haloalkyl,Cyano group,Cyanoalkyl,Amino,Aminoalkyl,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,Acyl,There can be the acyl amino of substituent,Alkoximino,Oxyimino,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Carboxyalkyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxy carbonyl alkyl amino,Carboxyalkylamino,Alkoxycarbonyl amino,Alkoxycarbonylamino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkoxycarbamoyl alkyl,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,Carbamoylalkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Carbamoyloxy alkyl,N- alkyl carbamoyloxy base alkyl,N,N- dialkylcarbamoyloxy alkyl,There can be 3~6 circle heterocycles carbonylic alkyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,Aryl,Aralkyl,There can be 3~6 circle heterocycles bases of substituent,There can be 3~6 circle heterocycles alkyl of substituent,Alkylsulfonyloxy,Arenesulfonyl amino,Alkyl sulfonyl amino alkyl,Arenesulfonyl amino alkyl,Alkylsulphonylaminocarbonyl,Arenesulfonyl amino carbonyl,Alkylsulphonylaminocarbonyl alkyl,Arenesulfonyl amino carbonylic alkyl,Oxo base,Carbamoyloxy,Aralkoxy,Carboxyalkoxy,Alkoxycarbonylalkoxy,Acyloxy,Acyloxyallcyl,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Alkoxyalkoxycarbonyl,Hydroxyl acyl group,Alkoxyacyl,Halogenacyl,Carboxyacyl,Aminoacyl,Acyloxy acyl group,Acyloxyallcyl sulfonyl,Hydroxy alkyl sulfonyl,Alkoxyalkyl sulfonyl,There can be 3~6 circle heterocycles sulfonyls of substituent,There can be 3~6 circle heterocycles epoxides of substituent,N- alkylaminoacyls,N,N- dialkyl amido acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl sulphonyls,Alkyl sulphonyl acyl group,N- aryl-amino-carbonyls,The circle heterocycles carbamoyl of N-3~6,N- alkyl-N-arylamino formoxyls,The circle heterocycles carbamoyl of N- alkyl-N-3~6,N- aryl-amino-carbonyl alkyl,The circle heterocycles carbamoylalkyl of N-3~6,N- alkyl-N-arylamino carbamoylalkyls,The circle heterocycles carbamoylalkyl of N- alkyl-N-3~6,Aminothio formoxyl,N- alkyl amino thioformyls,N,The thio sulfonyl of N- dialkyl amidos,Alkoxyalkyl (thiocarbonyl),Alkylthio alkyl or N- acyl group-N- alkylaminoalkyl groups or R3And R4Alkylidene, the alkenylene of carbon number 2~5, the alkylenedioxy group or carbonyldioxy of carbon number 1~5 of carbon number 1~5 are represented together.
Following radicals are described in detail.
Figure G2003801097466D00321
[in base, Q5、R3And R4As it was previously stated, 1 and 2 tables not position]
Containing above-mentioned group Q5Cyclic structure part can to have the cyclic hydrocarbon group of 3~10 yuan of divalent of 1 double bond or with 1~2 heteroatomic 5~12 yuan of divalent heterocyclic radical, the heterocyclic radical of the cyclic hydrocarbon group of preferably 3~8 yuan of divalent or 5~8 yuan of divalent heterocyclic radical, the cyclic hydrocarbon group of more preferably 5~7 yuan of divalent or 5~7 yuan of divalent.Wherein, Q5The preferably alkylidene of carbon number 3~6 or base-(CH2)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, and expression 0 or 1, A are as previously described), Q5Particularly preferably the alkylidene of carbon number 4.
It is preferably cis when being 5 yuan in addition, the cyclic hydrocarbon group or heterocyclic radical can obtain cis and transconfiguration in the relation of 1 and 2, at 6~7 yuan, it may be preferable to be it is cis can also be trans.
To above-mentioned substituent R3And R4It is described in detail.Halogen atom represents fluorine atom, chlorine atom, bromine atoms or iodine atom.Alkyl can enumerate the C of straight-chain, branched or ring-type1~C6Alkyl (for example, methyl, cyclopropyl, isobutyl group etc.), haloalkyl, which can enumerate abovementioned alkyl, the group (for example, chloromethyl, 1- bromoethyls, trifluoromethyl etc.) of 1~3 halogen atom substitution.Cyanoalkyl can enumerate above-mentioned C1~C6Alkyl has the group (for example, cyano methyl, 1- cyano ethyls etc.) of 1 cyano group substitution.Alkenyl can enumerate the group (for example, vinyl, pi-allyl etc.) of the carbon number 2~6 of straight-chain or branched with 1 double bond.Alkynyl can enumerate the group (for example, acetenyl, propinyl etc.) of the carbon number 2~6 of straight-chain or branched with 1 three key.Acyl group can enumerate the C such as alkanoyl (for example, formoxyl, acetyl group etc.), benzoyl or the naphthoyl of carbon number 1~67~C15Aroyl or above-mentioned C1~C6Alkanoyl has 1 C6~C14The aromatic yl silane terephthalamide yl (for example, phenylacetyl group etc.) of aryl substitution.Acyl can enumerate above-mentioned C1~C6Alkyl has the group (for example, acetylmethyl etc.) of 1 above-mentioned acyl group substitution.Alkoxy can enumerate the C of straight-chain, branched or ring-type1~C6Alkoxy (for example, methoxyl group, ring propoxyl group, isopropoxy etc.).Alkoxyalkyl can enumerate above-mentioned C1~C6Alkyl has 1 above-mentioned C1~C6The group (for example, methoxy, ethoxyl methyl etc.) of alkoxy substitution.Hydroxy alkyl can enumerate above-mentioned C1~C6Alkyl has the group (for example, hydroxymethyl, 1- hydroxyethyls etc.) of 1 hydroxyl substitution.Carboxyalkyl can enumerate above-mentioned C1~C6Alkyl has the group (for example, carboxymethyl, 1- carboxyethyls etc.) of 1 carboxyl substitution.Alkoxy carbonyl can enumerate above-mentioned C1~C6The group (for example, methoxycarbonyl, ethoxy carbonyl etc.) that alkoxy and carbonyl are constituted.Alkoxy carbonyl alkyl can enumerate above-mentioned C1~C6Alkyl has the group (for example, dion e, ethoxycarbonylethyl group etc.) of 1 above-mentioned alkoxy carbonyl substitution.Carbamoylalkyl can enumerate above-mentioned C1~C6Alkyl has the group (for example, carbamo, lmethyl, carbamoylethyl) that carbamoyl replaces.
Can have substituent 3~6 circle heterocycles basis representations can the saturation containing 1~3 hetero atom (nitrogen-atoms, oxygen atom, sulphur atom etc.) or undersaturated 3~6 circle heterocycles base, heterocyclic radical can have hydroxyl, halogen atom, amino, C1~C6The substituents such as alkyl, oxo base, haloalkyl, 3~6 yuan of heterocyclic radical is pyrrole radicals, thienyl, pyrazolyl, imidazole radicals, pyrazolinyl, oxazolyl, oxazolinyl, oxadiazolyl, oxazole alkyl, thiazolyl, thiazolinyl, thiadiazolyl group, furazanyl, pyranose, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrrolidinyl, piperazinyl, piperidyl, oxazinyl, oxadiazine base, morpholinyl, thiazinyl, thiadiazine base, thio-morpholinyl, tetrazole radical, triazolyl and triazine radical etc..Thiazolyl can specifically be enumerated, 4, 5- dihydro-thiazolyls, oxazolyl, 4, 5- dihydro-oxazole bases, 5- Jia Ji oxazolyls, imidazole radicals, pyrrolidinyl, 3- hydroxypyrrole alkyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1, 1- dioxothiomorpholinyls, THP trtrahydropyranyl, pyridine radicals, 1, 2, 4- oxadiazolyls, 3- methyl isophthalic acids, 2, 4- oxadiazolyls, 5- methyl isophthalic acids, 2, 4- oxadiazolyls, 1, 3, 4- oxadiazolyls, 5- methyl isophthalic acids, 3, 4- oxadiazolyls, 5- (trifluoromethyl) -1, 3, 4- oxadiazolyls, 1, 3- oxazolyls, 1, 3, 4- thiadiazolyl groups, 5- methyl isophthalic acids, 3, 4- thiadiazolyl groups, 1, 3- oxazole alkyl etc..Can have 3~6 circle heterocycles alkyl of substituent to enumerate alkyl has the group of 1 above-mentioned 3~6 circle heterocycles bases substitution with substituent (for example, benzothiazolylmethyl, 4,5- thiazolines ylmethyl, morpholinyl methyl, 1,1- dioxothiomorpholinyl methyl etc.).Aryl can enumerate the group of the carbon numbers such as phenyl, naphthyl 6~14, and aryl can be selected from above-mentioned C1~C6Alkyl, above-mentioned C1~C6Alkanoyl, hydroxyl, nitro, cyano group, halogen atom, above-mentioned C2~C6Alkenyl, above-mentioned C2~C6Alkynyl, above-mentioned C1~C6Haloalkyl, above-mentioned C1~C6Alkoxy, carboxyl, carbamoyl, above-mentioned C1~C61~3 substituent group of alkoxy carbonyl etc..Aralkyl can enumerate above-mentioned C1~C6Alkyl has 1 above-mentioned C6~C14The group (for example, benzyl, phenethyl etc.) of aryl substitution.In described above, the position of substitution is not particularly limited.As the acyl amino can with substituent, above-mentioned C can be enumerated1~C6Have 1 on the group (for example, Formylamino, acetyl-amino etc.) of acyl group substituted-amino, acyl group~several halogen atoms, hydroxyl, C1~C6Alkoxy, acyl group, N-C1~C6Alkyl amino, N, the C of N- bis-1~C6Alkyl amino, carboxyl, C2~C6The substituted acyl group such as alkoxy carbonyl (for example, 2- methoxyacetylaminos, 3- aminopropionyl amino etc.).Acylaminoalkyl can enumerate above-mentioned C1~C6Acyl amino replaces above-mentioned C1~C6The group (for example, Formylamino methyl, acetylaminomethyl etc.) of alkyl.Aminoalkyl can enumerate above-mentioned C1~C6Alkyl has the group (for example, amino methyl, 1- amino-ethyls etc.) of 1 amino substitution.N- alkylaminoalkyl groups can enumerate amino-C1~C6There is 1 C on the nitrogen-atoms of alkyl1~C6Alkyl-substituted group (for example, N- Methylaminomethyls, N- methylaminoethyls etc.), N, N- dialkyl aminoalkyls can enumerate amino-C1~C6There are 2 C on the nitrogen-atoms of alkyl1~C6Alkyl-substituted group (for example, N, N- dimethylaminomethyl, N- ethyl-N-methylamino methyl etc.).N- alkenyl aminos formoxyl can enumerate the C of straight-chain or branched2~C6The group (for example, allyl amino formoxyl etc.) of alkenyl substituted-amino formoxyl.N- alkenyl aminos carbamoylalkyl can enumerate above-mentioned N-C2~C6Alkenyl amino formoxyl replaces C1~C6The group (for example, allyl amino formylethyl etc.) of alkyl.N- alkenyl-N- alkyl-carbamoyls can enumerate above-mentioned N-C2~C6There is the C of straight-chain or branched on the nitrogen-atoms of alkenyl amino carbamoylalkyl1~C6Alkyl-substituted group (for example, N- pi-allyl-N- methylcarbamoylmethyls etc.).N- alkenyl-N- alkylcarbamoylalkyls can enumerate above-mentioned N-C2~C6There is the C of straight-chain or branched on the nitrogen-atoms of alkenyl amino formoxyl1~C6Alkyl-substituted group (for example, N- pi-allyl-N- methylcarbamoyls etc.).N- alkoxycarbamoyls can enumerate the C of straight-chain or branched1~C6The group (for example, methoxyformamido base etc.) of alkoxy substituted-amino formoxyl.N- alkoxycarbamoyls alkyl can enumerate above-mentioned N-C1~C6C of the alkoxycarbamoyl in straight-chain or branched1~C6The group (for example, methoxyformamido ylmethyl etc.) replaced on alkyl.N- alkyl-N- alkoxycarbamoyls can enumerate the C of straight-chain or branched1~C6Alkoxy and C1~C6The group (for example, N- ethyl-N- methoxyformamido bases etc.) that alkyl replaces on carbamoyl.N- alkyl-N- alkoxycarbamoyls alkyl can enumerate above-mentioned N-C1~C6Alkyl-N-C1~C6C of the alkoxycarbamoyl in straight-chain or branched1~C6The group (for example, N- ethyl-N- methoxyformamido ylmethyls etc.) replaced on alkyl.The C by 1~3 straight-chain or branched can be enumerated by 1~3 alkyl-substituted carbazyl, in addition to carbazyl1~C6Alkyl-substituted carbazyl (for example, 1- methyl carbazoles base, 1,2- Dimethylcarbazole bases etc.).Alkyl sulphonyl can enumerate the C of straight-chain, branched or ring-type1~C6Alkyl sulphonyl (for example, mesyl etc.).Alkylsulfonylalkyl can enumerate above-mentioned C1~C6The C of alkyl sulphonyl substituted straight chain shape or branched1~C6The group (for example, mesylmethyl etc.) of alkyl.Alkoximino can enumerate C1~C6Alkoximino (for example, methoxyimino, ethoxy imino etc.).Alkoxy carbonyl alkyl amino, which can enumerate amino, 1 above-mentioned C1~C6The group (for example, Methoxycarbonylmethylamino, ethoxycarbonyl propyl amino etc.) of alkoxy carbonyl alkyl substitution.Carboxyalkylamino, which can enumerate amino, 1 above-mentioned carboxyl C1~C6Alkyl-substituted group (for example, carboxymethylamino, carboxyethylamino group etc.).Alkoxycarbonyl amino, which can enumerate amino, 1 above-mentioned C1~C6The group (for example, methyloxycarbonylamino, tertbutyloxycarbonylamino etc.) of alkoxy carbonyl substitution.Alkoxycarbonylamino, which can enumerate abovementioned alkyl, 1 above-mentioned C1~C6The group (for example, methyloxycarbonylamino methyl, tertbutyloxycarbonylamino ethyl etc.) of alkane ethylcarbonylamino substitution.The C of straight-chain, branched or ring-type can with substituent can be represented on alkyl with the N- alkyl-carbamoyls of substituent1~C6Alkyl-substituted carbamoyl, the substituent can enumerate hydroxyl, amino, N-C1~C6Alkyl amino, amidino groups, halogen atom, carboxyl, cyano group, carbamoyl, C1~C6Alkoxy, C1~C6Alkanoyl, C1~C6Alkanoylamino, C1~C6Alkyl sulfonyl-amino etc., its specific example can enumerate N- methylcarbamoyls, N- ethylaminocarbonyls, N- isopropylcarbamoyls, N- cyclopropylcarbamoyls, N- (2- hydroxyethyls) carbamoyl, N- (2- fluoro ethyls) carbamoyl, N- (2- cyano ethyls) carbamoyl, N- (2- methoxy ethyls) carbamoyl, N- carboxymethyl groups carbamoyl, N- (2- amino-ethyls) carbamoyl, N- (2- amidinoethyls) carbamoyl etc..There can be the N of substituent on alkyl, N- dialkyl carbamoyls are represented by the C of 2 straight-chains, branched or ring-type can with substituent1~C6Alkyl-substituted carbamoyl, the substituent can enumerate hydroxyl, amino, N-C1~C6Alkyl amino, amidino groups, halogen atom, carboxyl, cyano group, carbamoyl, C1~C6Alkoxy, C1~C6Alkanoyl, C1~C6Alkanoylamino, C1~C6Alkyl sulfonyl-amino etc., its specific example can enumerate N, N- formyl-dimethylaminos, N, N- diethylamino formoxyls, N- ethyl-N-methylamino formoxyls, N- isopropyl-N- methylcarbamoyls, N- (2- hydroxyethyls)-N- methylcarbamoyls, N, double (2- hydroxyethyls) carbamoyls of N-, N, double (2- fluoro ethyls) carbamoyls of N-, N- (2- cyano ethyls)-N- methylcarbamoyls, N- (2- methoxy ethyls)-N- methylcarbamoyls, N- carboxymethyl group-N- methylcarbamoyls, N, double (2- amino-ethyls) carbamoyls of N- etc..The N- alkylcarbamoylalkyls that can have substituent on alkyl can enumerate above-mentioned C1~C6Can have the N- alkyl-carbamoyl substituted straight chain shapes of substituent or the C of branched on alkyl1~C6The group (for example, N- methylcarbamoylmethyls, N- (2- hydroxyethyls) carbamo, lmethyl etc.) of alkyl.There can be the N of substituent on alkyl, N- dialkyl carbamoyls alkyl can enumerate above-mentioned C1~C6Can have the N of substituent, N- dialkyl carbamoyl substituted straight chain shapes or branched C on alkyl1~C6The group (for example, N, N- Dimethylcarbamoylmethyl, N- (2- hydroxyethyls)-N- methylcarbamoylmethyls etc.) of alkyl.Can have substituent 3~6 circle heterocycles carbonyls can enumerate above-mentioned 3~6 circle heterocycles bases with substituent and carbonyl composition group (for example, aziridine base carbonyl, azetidinyl carbonyl, 3- hydroxy azetidine base carbonyls, 3- methoxyl group azetidinyl carbonyls, pyrrolidinylcarbonyl, 3- hydroxypyrrole alkyl carbonyls, 3- fluoropyrrolidine base carbonyls, piperidino carbonyl, piperazinyl carbonyl, morpholinyl carbonyl, thiomorpholinyl carbonyl, 1, 1- dioxothiomorpholinyl carbonyls, THP trtrahydropyranyl carbonyl, PYRIDYLCARBONYL, furanylcarbonyl, thiophenecarbonyl groups etc.).3~6 circle heterocycles carbonylic alkyls can with substituent are that 1 above-mentioned 3~6 circle heterocycles carbonyl with substituent replaces above-mentioned C1~C6The group (for example, azetidinyl carbonyl methyl, pyrrolidinylcarbonyl ethyl etc.) of alkyl.3~6 circle heterocycles carbonyl epoxide alkyl can with substituent can enumerate the above-mentioned C of 3~6 circle heterocycles carbonyl epoxides substitution that 1 above-mentioned 3~6 circle heterocycles carbonyls and oxygen atom with substituent are constituted1~C6The group (for example, piperidino carbonyl epoxide ethyl, morpholinyl carbonyl epoxide methyl etc.) of alkyl.Carbamoyloxy alkyl can enumerate the above-mentioned C of carbamoyloxy substitution that 1 carbamoyl and oxygen atom are constituted1~C6The group (for example, carbamoyloxy methyl, carbamoyloxy ethyl etc.) of alkyl.N- alkyl carbamoyloxy base alkyl can enumerate 1 above-mentioned C1~C6The N- alkyl carbamoyloxies base that can have the N- alkyl-carbamoyls and oxygen atom of substituent to constitute on alkyl replaces above-mentioned C1~C6The group (for example, N- methylcarbamoyl epoxides methyl, N- methylcarbamoyl epoxide ethyls etc.) of alkyl.N, N- dialkylcarbamoyloxy alkyl can enumerate 1 above-mentioned C1~C6There can be the N of substituent on alkyl, the N that N- dialkyl carbamoyls and oxygen atom are constituted, N- dialkylcarbamoyloxies replace above-mentioned C1~C6The group (for example, N, N- dimethyl carbamoyl epoxide methyl, N- ethyl-N-methylamino formyloxy ethyls etc.) of alkyl.Alkyl sulfonyl-amino, which can enumerate 1, has above-mentioned C1~C6The group (for example, sulfonyloxy methyl amino, isopropyl ylsulfonylamino etc.) of the alkyl sulphonyl substituted-amino of alkyl.Arenesulfonyl amino can enumerate the group (for example, phenylsulfonyl-amido, naphthyl sulfonamido etc.) of 1 above-mentioned aryl sulfonyl substituted-amino with aryl.Alkyl sulfonyl amino alkyl can enumerate 1 above-mentioned C1~C6Alkyl sulfonyl amino replaces above-mentioned C1~C6The group (for example, sulfonyloxy methyl amino methyl, methanesulfonylaminoethyl etc.) of alkyl.Arenesulfonyl amino alkyl can enumerate above-mentioned C1~C6Alkyl has the group (for example, phenylsulfonyl-amido methyl, naphthyl sulfonamido ethyl etc.) of 1 above-mentioned Arenesulfonyl amino substitution.Alkylsulphonylaminocarbonyl can enumerate above-mentioned C1~C6The group (for example, sulfonyloxy methyl amino carbonyl, isopropyl sulfonyl-amino-carbnyl etc.) that alkyl sulfonyl amino and carbonyl are constituted.Arenesulfonyl amino carbonyl can enumerate the group (for example, phenylsulfonyl-amido carbonyl, naphthyl sulfonyl-amino-carbnyl etc.) that above-mentioned Arenesulfonyl amino and carbonyl are constituted.Alkylsulphonylaminocarbonyl alkyl can enumerate above-mentioned C1~C6Alkylsulphonylaminocarbonyl replaces above-mentioned C1~C6The group (for example, sulfonyloxy methyl amino carbonvlmethyl, isopropyl sulfonyl-amino-carbnyl methyl etc.) of alkyl.Arenesulfonyl amino carbonylic alkyl can enumerate above-mentioned Arenesulfonyl amino carbonyl and replace above-mentioned C1~C6The group (for example, phenylsulfonyl-amido carbonvlmethyl, naphthyl sulfonyl-amino-carbnyl methyl etc.) of alkyl.Alkoxycarbonylalkoxy can enumerate above-mentioned alkoxy carbonyl and replace above-mentioned C1~C6The group (for example, formyloxy, acetoxyl group etc.) that group (for example, methoxyvarbonyllnethoxy etc.), the above-mentioned acyl group of acyl-oxygen basis representation and the oxygen atom of alkoxy are constituted.Acyloxyallcyl can enumerate above-mentioned acyloxy and replace above-mentioned C1~C6The group (for example, formyloxymethyl, acetoxy-methyl etc.) of alkyl.Aralkoxy can enumerate above-mentioned aryl and replace above-mentioned C1~C6The group (for example, benzyloxy, naphthylmethoxy etc.) of alkoxy.Carboxyalkoxy can enumerate the group (for example, Carboxvmethoxv, Carboxyethoxy etc.) that carboxyl replaces above-mentioned alkoxy.
Aryl sulfonyl can enumerate C6~C14Aryl sulfonyl (for example, phenyl sulfonyl, Naphthylsulfonyl etc.).Alkoxy carbonyl alkyl sulfonyl can enumerate above-mentioned C1~C6The group (for example, dion e sulfonyl, ethoxycarbonylethyl group sulfonyl etc.) that alkoxy carbonyl alkyl and sulfonyl are constituted.Carboxyalkyl sulfonyl can enumerate the group (for example, carboxymethyl group sulfonyl, carboxy ethyl sulfonyl etc.) that above-mentioned carboxyalkyl and sulfonyl are constituted.Alkoxy carbonyl acyl group can enumerate the group (for example, Methoxycarbonylmethyl carbonyl, ethoxy carbonyl methyl carbonyl etc.) that above-mentioned alkoxy carbonyl alkyl and carbonyl are constituted.Alkoxyalkoxycarbonyl can enumerate 1 above-mentioned C1~C6Alkoxy replaces the group (for example, methoxymethoxy carbonyl, methoxyethoxycarbonyl etc.) of above-mentioned alkoxy carbonyl.Hydroxyl acyl group can enumerate 1 hydroxyl and replace above-mentioned acyl group (including C1~C6Alkanoyl and aroyl) group (for example, glycolyl, propyl alcohol acyl group, benziloyl etc.).Alkoxyacyl can enumerate 1 above-mentioned C1~C6Alkoxy replaces the group (for example, Methoxyacetyl, Ethoxyacetyl base etc.) of above-mentioned acyl group.Halogenacyl can enumerate the group (for example, chloromethyl carbonyl, Trifluoromethylcarbonyl etc.) that above-mentioned haloalkyl and carbonyl are constituted.Carboxyacyl can enumerate the group (for example, carboxyacetyl, 2- carboxypropanoyls etc.) that 1 carboxyl replaces above-mentioned acyl group.Aminoacyl can enumerate 1 amino and replace above-mentioned acyl group (including C1~C6Alkanoyl and aroyl) group (for example, aminomethylcarbonyl, 1- aminoethylcarbonyls etc.).Acyloxy acyl group can enumerate the group (for example, formyloxymethyl carbonyl, acetyloxymethylcarbonyl etc.) that above-mentioned acyloxyallcyl and carbonyl are constituted.Acyloxyallcyl sulfonyl can enumerate the group (for example, formyloxymethyl sulfonyl, acetoxy-methyl sulfonyl etc.) that above-mentioned acyloxyallcyl and sulfonyl are constituted.Hydroxy alkyl sulfonyl can enumerate above-mentioned C1~C6The group (for example, hydroxymethyl sulfonyl, 1- hydroxyethyl sulfonyls etc.) that hydroxy alkyl and sulfonyl are constituted.Alkoxyalkyl sulfonyl can enumerate above-mentioned C1~C6The group (for example, methoxy sulfonyl, ethoxyethyl group sulfonyl etc.) that alkoxyalkyl and sulfonyl are constituted.3~6 circle heterocycles sulfonyls can with substituent can enumerate the group (for example, aziridine base sulfonyl, azetidinyl sulfonyl, pyrrolidinyl sulfonyl, piperidinylsulfonyl, piperazinylsulfonyl, morpholinosulfonyl, THP trtrahydropyranyl sulfonyl etc.) that can have 3~6 circle heterocycles and sulfonyl of above-mentioned substituent to constitute.3~6 circle heterocycles epoxides can with substituent can enumerate the group (for example, tetrahydrofuran epoxide etc.) that above-mentioned 3~6 circle heterocycles and oxygen atom with substituent are constituted.N- alkylaminoacyls, which can be enumerated, 1 above-mentioned C on the nitrogen-atoms of above-mentioned aminoacyl1~C6Alkyl-substituted group (for example, N- methylaminos acetyl group, N- ethylamino acetyl group etc.).N, N- dialkyl amido acyl group, which can be enumerated, 2 above-mentioned C on the nitrogen-atoms of above-mentioned aminoacyl1~C6Alkyl-substituted group (for example, N, N- Dimethyl Glycyl, N- ethyl-N-methylamino acetyl group etc.).There can be the N of substituent on alkyl, N- dialkyl carbamoyls acyl group can enumerate above-mentioned C1~C6There can be the N of substituent on alkyl, N- dialkyl carbamoyls replace the group (for example, N, N- formyl-dimethylamino acetyl group, N, N- diethylamino formoxyls acetyl group, N- ethyl-N-methylamino diformylamino bases etc.) of above-mentioned acyl group.There can be the N of substituent on alkyl, N- dialkyl carbamoyls alkyl sulphonyl can enumerate above-mentioned C1~C6Can have the N of substituent, the group (for example, N, N- Dimethylcarbamoylmethyl sulfonyl, N- (2- hydroxyethyls)-N- methylcarbamoylmethyl sulfonyls etc.) that N- dialkyl carbamoyls and sulfonyl are constituted on alkyl.Alkyl sulphonyl acyl group, which can enumerate 1, has above-mentioned C1~C6The group (for example, methyl sulphonyl acetyl group, isopropelsulfonyl acetyl group etc.) of the alkyl sulphonyl substituted acyl of alkyl.
N- aryl-amino-carbonyls can enumerate the group (for example, phenylcarbamoyl, naphthyl-amino formoxyl etc.) of above-mentioned aryl substituted-amino formoxyl.The circle heterocycles carbamoyl of N-3~6 can enumerate the group (for example, pyridinylamino formoxyl, thienyl carbamoyl etc.) of above-mentioned 3~6 circle heterocycles base substituted-amino formoxyls with substituent.N- alkyl-N-arylaminos formoxyl can enumerate the C for having straight-chain or branched on the nitrogen-atoms of above-mentioned N- aryl-amino-carbonyls1~C6Alkyl-substituted group (for example, N- methyl-N-phenyl formoxyls etc.).The circle heterocycles carbamoyl of N- alkyl-N-3~6 can enumerate the C for having straight-chain or branched on the nitrogen-atoms of the circle heterocycles carbamoyl of above-mentioned N-3~61~C6Alkyl-substituted group (for example, N- methyl-N- thienyl carbamoyls etc.).N- aryl-amino-carbonyls alkyl can enumerate above-mentioned N- aryl-amino-carbonyls substituted straight chain shape or the C of branched1~C6The group (for example, phenylcarbamoylmethyl etc.) of alkyl.The circle heterocycles carbamoylalkyl of N-3~6 can enumerate the heterocyclic amino group formoxyl substituted straight chain shape of above-mentioned N-3~6 yuan or the C of branched1~C6The group (for example, pyridinylamino carbamoylmethyl etc.) of alkyl.N- alkyl-N-arylaminos carbamoylalkyl can enumerate the C for having straight-chain or branched on the nitrogen-atoms of above-mentioned N- aryl-amino-carbonyls alkyl1~C6Alkyl-substituted group (for example, N- methyl-N-phenyl carbamoylmethyls etc.).The circle heterocycles carbamoylalkyl of N- alkyl-N-3~6 can enumerate the C for having straight-chain or branched on the nitrogen-atoms of the circle heterocycles carbamoylalkyl of above-mentioned N-3~61~C6Alkyl-substituted group (for example, N- methyl-N- thienyl carbamo, lmethyls etc.).
Aminothiocarbonyl is-C (=S)-NH2The group of expression, N- thio-alkyl amino-carbonyls are represented by 1 alkyl-substituted aminothiocarbonyl, can enumerate (methylamino) thiocarbonyl, (ethylamino) thiocarbonyl etc..N, N- dialkylaminothiocarbonyl are represented by 2 alkyl-substituted aminothiocarbonyls, can enumerate (dimethylamino) thiocarbonyl, (diethylamino) thiocarbonyl, (ethylmethylamino) thiocarbonyl etc..Alkoxyalkyl (thiocarbonyl), alkyl-thio-alkyl can enumerate the C of straight-chain, branched or ring-type1~C6The C of alkylthio group substituted straight chain shape, branched or ring-type1~C6The group (for example, methylthiomethyl, 1- methylmercaptoethyls etc.) of alkyl.N- acyl group-N- alkylaminoalkyl groups can enumerate amino-C1~C6There is C on the nitrogen-atoms of alkyl1~C6Alkyl and the group (for example, N- acetyl group-N- Methylaminomethyls etc.) of acyl group substitution.The group that above-mentioned alkoxyalkyl and thiocarbonyl are constituted is represented, 2- ethyoxyl ethanethioyls etc. can be enumerated.
The straight-chain of alkylene basis representation carbon number 1~5 or the alkylidene of branched, can enumerate methylene, ethylidene, propylidene etc..Alkenylene is the alkenylene of the carbon number 2~5 with 1 double bond, can enumerate ethenylidene, allylidene etc..Alkylene dioxo base can enumerate the group of the carbon numbers 1~5 such as methylene-dioxy, ethylenedioxy, sub- the third two epoxide.Carbonyldioxy is the group that-O-C (=O)-O- is represented.In described above, the position of substitution is not particularly limited.
R3And R4In the substituent of expression,Preferably hydrogen atom,Hydroxyl,Alkyl,Alkenyl,Alkynyl,Halogen atom,Haloalkyl,Amino,Oxyimino,Alkoximino,Aminoalkyl,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,Acyl,There can be the acyl amino of substituent,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Carboxyalkyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxycarbonyl amino,Alkoxycarbonylamino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkoxycarbamoyl alkyl,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,There can be 3~6 circle heterocycles bases of substituent,Carbamoylalkyl,Carbamoyloxy alkyl,N- alkyl carbamoyloxy base alkyl,N,N- dialkylcarbamoyloxy alkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Alkyl sulfonyl-amino,Alkylsulfonylaminoalkyl,Oxo base,Acyloxy,Acyloxyallcyl,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Carboxyacyl,Alkoxyalkoxycarbonyl,Halogenacyl,N,N- dialkyl amido acyl groups,Acyloxy acyl group,Alkoxyacyl,Alkoxyalkyl sulfonyl,N,N- dialkyl carbamoyl acyl groups,N,N- dialkyl carbamoyl alkyl sulphonyls,Alkyl sulphonyl acyl group,Aminothio formoxyl,N- alkyl amino thioformyls,N,N- dialkyl amidos thioformyl or alkoxyalkyl (thiocarbonyl) etc.,In addition,Preferably R3And R4Alkylidene, alkenylene, alkylene dioxo base, carbonyldioxy etc. are represented together.
Preferable situation is R3And R4In R3For hydrogen atom, R4For the above-mentioned substituent enumerated as preferable group.At this moment as R4More preferable group can enumerate hydrogen atom,Hydroxyl,Alkyl,Halogen atom,Oxyimino,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,There can be the acyl amino of substituent,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxycarbonyl amino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,There can be 3~6 circle heterocycles alkyl of substituent,Carbamoylalkyl,N,N- dialkylcarbamoyloxy alkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Alkyl sulfonyl-amino,Alkylsulfonylaminoalkyl,Acyloxy,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Carboxyacyl,Alkoxyalkoxycarbonyl,Halogenacyl,N,N- dialkyl amido acyl groups,Acyloxy acyl group,Hydroxyl acyl group,Alkoxyacyl,Alkoxyalkyl sulfonyl,N,N- dialkyl carbamoyl acyl groups,N,N- dialkyl carbamoyl alkyl sulphonyls,Alkyl sulphonyl acyl group,Aminothio formoxyl,N- alkyl amino thioformyls,N,N- dialkyl amidos thioformyl or alkoxyalkyl (thiocarbonyl) etc..
In these groups, R is used as4Especially desirable group can enumerate hydrogen atom, hydroxyl, alkyl, N, N- dialkyl aminoalkyl, there can be the acyl amino of substituent, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxy alkyl, alkoxy carbonyl, alkoxycarbonyl amino, carbamoyl, there can be the N- alkyl-carbamoyls of substituent on alkyl, can have the N of substituent, N- dialkyl carbamoyls on alkyl, N- alkenyl amino formoxyls, N- alkenyl amino carbamoylalkyls, N- alkenyl-N- alkyl-carbamoyls, N- alkenyl-N- alkylcarbamoylalkyls, N- alkyl-N- alkoxycarbamoyls, can be by 1~3 alkyl-substituted carbazyl, alkyl sulphonyl, Alkylsulfonylalkyl, there can be 3~6 circle heterocycles carbonyls of substituent, there can be 3~6 circle heterocycles bases of substituent, N, N- dialkylcarbamoyloxy alkyl, there can be the N- alkylcarbamoylalkyls of substituent on alkyl, can have the N of substituent, N- dialkyl carbamoyl alkyl on alkyl, alkyl sulfonyl-amino, alkylsulfonylaminoalkyl, acyloxy, acyl group, alkoxyalkoxycarbonyl, halogenacyl, N, N- dialkyl amido acyl group, hydroxyl acyl group, alkoxyacyl, aminothio formoxyl, N- alkyl amino thioformyls, N, N- dialkyl amido thioformyl or alkoxyalkyl (thiocarbonyl) etc..
R3And R4The example of preferable specific substituent can enumerate hydrogen atom,Hydroxyl,Methyl,Ethyl,Isopropyl,N,N- dimethylaminomethyls,N,N- dimethyl aminoethyls,N,N- diethylamino methyl,Acetyl-amino,Methoxyacetylamino,Acetylaminomethyl,Acetaminoethyl,Methoxyl group,Ethyoxyl,Methoxy,Methoxy ethyl,Hydroxymethyl,2- hydroxyethyls,1- hydroxyl -1- Methylethyls,Methoxycarbonyl,Ethoxy carbonyl,Methyloxycarbonylamino,Ethoxycarbonylamino group,N- allyl amino formoxyls,N- allyl amino carbamoylmethyls,N- pi-allyl-N- methylcarbamoyls,N- pi-allyl-N- methylcarbamoylmethyls,N- methoxy-. N-methyl carbamoyls,N,N- Dimethylcarbazole bases,N,N,N '-trimethyl carbazyl,Methane sulfonyl,Methansulfonvlmethvl,Ethanesulfonyl ylmethyl,N- methylcarbamoyls,N- ethylaminocarbonyls,N- propvlcarbamovls,N- isopropylcarbamoyls,N- t-Butylcarbamoyls,N- cyclopropylcarbamoyls,N- Cyclopropyl-methyl-amino formoxyls,N- (1- ethoxy carbonyls cyclopropyl) carbamoyl,N- (2- hydroxyethyls) carbamoyl,N- (2- fluoro ethyls) carbamoyl,N- (2- methoxy ethyls) carbamoyl,N- (carboxymethyl group) carbamoyl,N- (2- amino-ethyls) carbamoyl,N- (2- amidinoethyls) carbamoyl,N,N- formyl-dimethylaminos,N,N- diethylamino formoxyls,N- ethyl-N-methylamino formoxyls,N- isopropyl-N- methylcarbamoyls,N- methyl-N-propylamino formoxyls,N- (2- hydroxyethyls)-N- methylcarbamoyls,N- (2- fluoro ethyls)-N- methylcarbamoyls,N,Double (2- hydroxyethyls) carbamoyls of N-,N,Double (2- fluoro ethyls) carbamoyls of N-,N- (2- methoxy ethyls)-N- methylcarbamoyls,N- carboxymethyl group-N- methylcarbamoyls,N,Double (2- amino-ethyls) carbamoyls of N-,Azetidinyl carbonyl,3- methoxyl group azetidinyl carbonyls,3- hydroxy azetidine base carbonyls,Pyrrolidinylcarbonyl,3- hydroxypyrrole alkyl carbonyls,3- fluoropyrrolidine base carbonyls,3,4- dimethoxy pyrrolidinylcarbonyls,Piperidino carbonyl,Piperazinyl carbonyl,Morpholinyl carbonyl,(tetrahydropyran -4-base) carbonyl,Benzoyl,PYRIDYLCARBONYL,Thiazolyl,4,5- dihydro-thiazolyls,Oxazolyl,4,5- dihydro-oxazole bases,5- Jia Ji oxazolyls,Imidazole radicals,Pyrrolidinyl,3- hydroxypyrrole alkyl,Piperidyl,Piperazinyl,Morpholinyl,Thio-morpholinyl,1,1- dioxothiomorpholinyls,THP trtrahydropyranyl,Pyridine radicals,1,2,4- oxadiazolyls,3- methyl isophthalic acids,2,4- oxadiazolyls,5- methyl isophthalic acids,2,4- oxadiazolyls,1,3,4- oxadiazolyls,5- methyl isophthalic acids,3,4- oxadiazolyls,5- (trifluoromethyl) -1,3,4- oxadiazolyls,1,3- oxazolyls,1,3,4- thiadiazolyl groups,5- methyl isophthalic acids,3,4- thiadiazolyl groups,1,3- oxazole alkyl,N- methylcarbamoylmethyls,N- methylcarbamoyl ethyls,N- ethylaminocarbonyl methyl,N- (2- fluoro ethyls) carbamo, lmethyl,N- (2- methoxy ethyls) carbamo, lmethyl,N,N- Dimethylcarbamoylmethyls,N,N- formyl-dimethylamino ethyls,N- (2- fluoro ethyls)-N- methylcarbamoylmethyls,N- (2- methoxy ethyls)-N- methylcarbamoylmethyls,N,N- dimethyl carbamoyl epoxide methyl,2- (N- ethyl-N-methylaminos formyloxy) ethyl,Methylsulfonylamino,Ethylsulphsulphonylamino,Methylsulfonylamino methyl,Methylsulfonylamino ethyl,Acetyl group,Propiono,Isobutyryl,2- methoxyethoxycarbonyls,Trifluoroacetyl group,N,N- Dimethyl Glycyls,N- ethyl-N-methylamino acetyl group,Hydroxyacetyl,1,1- dimethyl -2- hydroxyethyl carbonyls,Methoxyacetyl,1,1- dimethyl -2- methoxy ethyl carbonyls,Aminothio formoxyl,(dimethylamino) thioformyl,2- methoxyl group ethanethioyls etc..
As it was previously stated, R3And R4Preferable situation be R3For hydrogen atom, R4For above-mentioned specific substituent etc..It is particularly preferred that there can be the N of substituent on alkyl, N- dialkyl carbamoyls, wherein, more preferably N, N- formyl-dimethylaminos.R3And R4It is not limited to these specific substituents.
[on group T0]
Group T0Represent carbonyl or thiocarbonyl, but more preferably carbonyl.
[on group T1]
Group T1Represent carbonyl, sulfonyl, base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-, base-C (=S)-C (=S)-N (R ')-(R ' in group represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-A1- N (R ")-(A in group1Represent can there is the alkylidene of the carbon number 1~5 of substituent, R " represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-, base-C (=S)-NH-, base-C (=O)-NH-NH-, base-C (=O)-A2- C (=O)-(the A in group2Represent the alkylidene of singly-bound or carbon number 1~5), base-C (=O)-A3- the C (=O)-NH- (A in group3Represent carbon number 1~5 alkylidene), base-C (=O)-C (=NORa)-N(Rb)-, base-C (=S)-C (=NORa)-N(RbR in)-(groupaRepresent hydrogen atom, alkyl or alkanoyl, RbRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-N=N-, base-C (=S)-N=N-, base-C (=NORc)-C (=O)-N (RdR in)-(groupcRepresent hydrogen atom, alkyl, alkanoyl, aryl or aralkyl, RdRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=N-N- (Re)(Rf))-C (=O)-N (RgR in)-(groupeAnd RfIt is each independent, represent hydrogen atom, alkyl, alkanoyl, alkyl (thiocarbonyl), RgRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-C (=O)-, base-C (=S)-NH-C (=O)-, base-C (=O)-NH-C (=S)-, base-C (=S)-NHC (=S)-, base-C (=O)-NH-SO2-, base-SO2- NH-, base-C (=NCN)-NH-C (=O)-, base-C (=S)-C (=O)-or thiocarbonyl.
In above-mentioned group, A1、A2And A3In the straight-chain of alkylene basis representation carbon number 1~5 of carbon number 1~5, the alkylidene of branched or ring-type, can for example enumerate methylene, ethylidene, propylidene, cyclopropylidene, 1,3- cyclopentylenes etc..R’、R”、Ra、Rb、Rc、Rd、Re、RfAnd RgIn alkyl be the straight-chain of carbon number 1~6, the alkyl of branched or ring-type, methyl, ethyl etc. can be enumerated.Alkoxy can enumerate the alkoxy of the straight-chain, branched or ring-type of carbon number 1~6, can enumerate methoxyl group, ethyoxyl etc..
Ra、Rc、ReAnd RfIn alkanoyl represent straight-chain, branched or ring-type carbon number 1~6 alkyl and carbonyl constitute group, acetyl group, propiono etc. can be enumerated.
RcIn aryl represent the group of carbon number 6~14, phenyl, naphthyl etc. can be enumerated.The aryl of aralkyl basis representation carbon number 6~14 replaces the group of the alkyl of the straight-chain, branched or ring-type of carbon number 1~6, can enumerate benzyl, phenethyl etc..
Group T1More preferably carbonyl, base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-, base-C (=S)-C (=S)-N (R ')-and base-C (=O)-CH2- N (R ")-, particularly preferably carbonyl, base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-, base-C (=S)-C (=S)-N (R ')-.
[on group R1And R2]
R1And R2It is each independent, represent hydrogen atom, hydroxyl, alkyl or alkoxy, but preferably hydrogen atom or alkyl, more preferably hydrogen atom.
R1And R2In, alkyl is the alkyl of the straight-chain, branched or ring-type of carbon number 1~6, can enumerate methyl, ethyl etc..Alkoxy is the alkoxy of the straight-chain, branched or ring-type of carbon number 1~6, can enumerate methoxyl group, ethyoxyl etc..R1And R2It is preferably each independent, the situation of hydrogen atom or alkyl is represented, is more preferably both hydrogen atom.
T1For carbonyl or sulfonyl, group Q3In Q5During the alkenylene of alkylidene or carbon number 2~8 for carbon number 1~8, Q4(in group (f), N represents R to (b), (f), (g), (h), (i), (j), (k) and (l) in preferably foregoing 12 kinds of groups192 carbon atoms on substituted ring are replaced by nitrogen-atoms).
In addition, T1For carbonyl or sulfonyl, group Q3In Q5During the alkenylene of alkylidene or carbon number 2~8 for carbon number 1~8, Q5On substituent preferably N- alkyl-carbamoyls or N, N- dialkyl carbamoyl.
T1For base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-or base-C (=S)-C (=S)-N (R ')-, group Q3In Q5During the alkenylene of alkylidene or carbon number 2~8 for carbon number 1~8, Q4(i), (j) and (k) in preferably foregoing 12 kinds of groups.
In addition, T1For base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-or base-C (=S)-C (=S)-N (R ')-, group Q3In Q5During the alkenylene of alkylidene or carbon number 2~8 for carbon number 1~8, Q5On substituent preferably N- alkyl-carbamoyls or N, N- dialkyl carbamoyl.
Compound, its salt, its solvate or its N- oxide that the formula (1) of the present invention is represented are in group T1With group Q3Combination in possess feature, substantially following 2 kinds of situations ((I) and (II)).
(I)T1Represent carbonyl, sulfonyl, base-C (=O)-NH-C (=O)-, base-C (=S)-NH-C (=O)-, base-C (=O)-NH-C (=S)-, base-C (=S)-NHC (=S)-, base-C (=O)-NH-SO2-, base-SO2- NH-, base-C (=NCN)-NH-C (=O)-, base-C (=S)-C (=O)-or thiocarbonyl, Q3Represent following radicals,
Figure G2003801097466D00431
In base, Q5Represent base-(CH2)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH-) situation.
(II)T1Represent base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-, base-C (=S)-C (=S)-N (R ')-(R ' in group represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-A1- N (R ")-(A in group1Represent can there is the alkylidene of the carbon number 1~5 of substituent, R " represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-, base-C (=S)-NH-, base-C (=O)-NH-NH-, base-C (=O)-A2- C (=O)-(the A in group2Represent the alkylidene of singly-bound or carbon number 1~5), base-C (=O)-A3- (=O)-NH- (the A in group3Represent carbon number 1~5 alkylidene), base-C (=O)-C (=NORa)-N(Rb)-, base-C (=S)-C (=NORa)-N(RbR in)-(groupaRepresent hydrogen atom, alkyl or alkanoyl, RbRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-N=N-, base-C (=S)-N=N-, base-C (=NORc)-C (=O)-N (RdR in)-(groupcRepresent hydrogen atom, alkyl, alkanoyl, aryl or aralkyl, RdRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=N-N- (Re)(Rf))-C (=O)-N (RgR in)-(groupeAnd RfIt is each independent, represent hydrogen atom, alkyl, alkanoyl, alkyl (thiocarbonyl), RgRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-C (=O)-, base-C (=S)-NH-C (=O)-, base-C (=O)-NH-C (=S)-, base-C (=S)-NHC (=S)-, base-C (=O)-NH-SO2-, base-SO2- NH-, base-C (=NCN)-NH-C (=O)-, base-C (=S)-C (=O)-or thiocarbonyl, Q3Represent following radicals,
Figure G2003801097466D00432
In base, Q5Represent alkylidene, the alkenylene of carbon number 2~8 or the base-(CH of carbon number 1~82)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH-) situation.
In above-mentioned (I) and (II), following (i) and (ii) can be enumerated as preferable example.
(i) group R1And group R2It is each independent, it is hydrogen atom or alkyl, group Q1For that can have the fusion alkyl of the saturation or undersaturated 2 ring of substituent or 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings, group Q2For singly-bound, group Q3In Q5For base-(CH2)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, and expression 0 or 1, A are as previously described), group Q4To be selected from (a)~(h) and (1) this 9 kinds group, group T in foregoing 12 kinds0For carbonyl or thiocarbonyl, group T1For carbonyl or sulfonyl.
(ii) in formula (1), group R1And group R2It is each independent, it is hydrogen atom or alkyl, group Q1For that can have the fusion alkyl of the saturation or undersaturated 2 ring of substituent or 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings, group Q2For singly-bound, group Q3In Q5Alkylidene or base for carbon number 3~6-(CH2)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, and expression 0 or 1, A are as previously described), group Q4To be selected from (i), (j) and (k) this 3 kinds group, group T in foregoing 12 kinds0For carbonyl or thiocarbonyl, group T1For base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-or base-C (=S)-C (=S)-N (R ')-.
Stereoisomer or the optical isomer from asymmetric carbon atom is may be present in the compound that the formula (1) of the present invention is represented, these stereoisomers, optical isomer and their mixture are included within the scope of the invention.
The formula (1) of the present invention as long as the salt that allows in the salt medicine of the compound represented, it is not particularly limited, the inorganic acid salt such as hydrochloride, hydrobromate, hydriodate, phosphate, nitrate and sulfate can specifically be enumerated, the organic sulfonic acid salts such as benzoate, mesylate, 2- isethionates and tosilate, and the organic carboxyl acid salt such as acetate, propionate, oxalates, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and amygdalate etc..In addition, when the compound that formula (1) is represented has acidic-group, also can be with alkali metal ion or alkaline-earth metal ion forming salt.As long as allowing in solvate medicine, it is not particularly limited, can specifically enumerates hydrate, ethanolates etc..In addition, can also form N- oxide bulks in the presence of having nitrogen-atoms in formula (1).
The compound of the present invention is particularly preferably salt and following compounds, its salt of compound, compound shown in aftermentioned embodiment etc..
1) chloro- the N- ((1S of 3-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) [1,6] naphthyridines -7- formamides (carboxamide)
2) chloro- the N- ((1S of 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -4- fluorine cinnolines -3- formamides
3) chloro- the N- ((1S of 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -4a, 8a- dihydros -4H-1,2,4- Ben Bing oxadiazine -3- formamides
4) N- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -6- fluorin-4-oxygens generation-Isosorbide-5-Nitrae-EEDQ -2- formamides
5) chloro- the N- ((1S of 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -5- oxos -4,5- dihydros -1H-1, the azepine of 3,4- benzo three
Figure G2003801097466D00441
- 2- formamides
6) chloro- the N- ((1S of 6-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -4- oxos -3,4- dihydros -2 (1H) -1,2,4- cinnolinecarboxamides
7) chloro- the N- ((1S of 6-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -1,2,3,4- tetrahydroquinoline -2- formamides
8) N- { (1R, 2S, 5S) -2- { [3- (3- chlorphenyls) -2- propionos] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
9) N- { (1R, 2S, 5S) -2- [(4- chlorobenzene formacyls) amino] -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
10) N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -6- methyl -5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [4,5-d] azepine- 2- formamides
11) chloro- the N- [(1S of 5-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- ({ [5- (3- pyrroles's alkoxy) thiazol-2-yl] carbonyl } amino) cyclohexyl] indole 2-carboxamides
12)N1- (4- chlorphenyls)-N2- ((1S, 2R) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
13)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
14)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R) -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide
15)N1- (4- chlorphenyls)-N2- ((1S, 2R) -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide
16)N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R) -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclopenta) oxalamide
17)N1- (4- chlorphenyls)-N2- ((1R, 2R) -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclopenta) oxalamide
18)N1- (4- chlorphenyls)-N2- ((1R, 2R) -2- [[(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } suberyl) oxalamide
19)N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } suberyl) oxalamide
20)N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R) -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } suberyl) oxalamide
21)N1- (4- chlorphenyls)-N2- ((1R, 2R) -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } suberyl) oxalamide
22)N1- (the chloro- 6- picolines -2- bases of 5-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
23)N1- (the chloro- 3- picolines -2- bases of 5-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
24)N1- (the chloro- 4- picolines -2- bases of 5-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
25)N1- (4- chloro-3-hydroxyls phenyl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
26)N1- (4- chlorine-2-hydroxyls phenyl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
27)N1- [4- chloro- 2- (methyl fluoride) phenyl]-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
28)N1- [4- chloro- 2- (methoxy) phenyl]-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
29) N- { (1R, 2S, 5S) -2- ({ [1- (4- chloroanilinos) cyclopropyl) carbonyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
30)N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R, 4R) -4- (hydroxymethyl) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclopenta) oxalamide
31)N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R, 4S) -4- (hydroxymethyl) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclopenta) oxalamide
32)N1- ((3R, 4S) -1- acetyl group -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidyl -4- bases)-N2- (5- chloropyridine -2- bases) oxalamide
33)N1- (5- chloropyridine -2- bases)-N2- ((3R, 4S) -1- (methyl sulphonyl) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidyl -4- bases) oxalamide
34)N1- { (1S, 2R, 4S) -2- { [(3- chloro thiophene -2- bases) carbonyl] amino } -4- [(dimethylamino) carbonyl] cyclohexyl }-N2- (5- chloropyridine -2- bases) oxalamide
35)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) thiocarbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
36)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) thiocarbonyl] amino } cyclohexyl) oxalamide
37)N1- (5- chloropyridine -2- bases)-N2- ((3R, 4S) -1- (2- methoxyl groups ethanethioyl) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide
38)N1- (5- chloropyridine -2- bases)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) thiocarbonyl] amino } piperidin-4-yl) oxalamide
39) N- [(3R; 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
40) N- [(3R; 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- ethanethioyls } amino) -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
41)N1- (4- chlorphenyls)-N2- ((3R, 4S) -1- (2- methoxyl groups ethanethioyl) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide
42)N1- (4- chlorphenyls)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) thiocarbonyl] amino } piperidin-4-yl) oxalamide
43) N- [(3R; 4S) -4- { [2- (4- chloroanilinos) -2- oxos ethanethioyl] amino } -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
44) N- [(3R; 4S) -4- ({ 2- [(4- chlorphenyls) amino] -2- ethanethioyls } amino) -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
45)N1- ((1S, 2R, 4S) -4- (1- azetidinyl carbonyls) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (5- chloropyridine -2- bases) oxalamide
46)N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1- pyrrolidinylcarbonyls) cyclohexyl] oxalamide
47)N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1- piperidino carbonyls) cyclohexyl] oxalamide
48)N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (4- morpholinyl carbonyls) cyclohexyl] oxalamide
49)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(methylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
50) N- { (1R; 2S; 5S) -2- ({ 2- [(6- chlorine pyridazine -3- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
51)N1- (4- bromophenyls)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide
52)N1- (5- chloropyridine -2- bases)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [4- (pyridin-4-yl) benzoyl] amino } piperidin-4-yl) oxalamide
53)N1- (5- chloropyridine -2- bases)-N2- [(3R, 4S) -1- (2- Methoxyacetyls) -3- ({ [2- (pyridin-4-yl) pyrimidine -5- bases] carbonyl } amino) piperidin-4-yl] oxalamide
54)N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- ([2- (pyridin-4-yl) pyrimidine -5- bases] carbonyl] and amino) cyclohexyl] oxalamide
55) N- { (1R, 2S, 5S) -2- { [2- (4- chloroanilinos) -2- oxoethanaminiums (methoxyl group) imino group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
56) N- { (1R; 2S; 5S) -2- { [2- (4- chloroanilinos) -2- (methoxyimino) acetyl group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
57)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(4,4,5- trimethyls -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide
58)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(4,4- ethylidene -5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide
59) N- { (1R; 2S; 5S) -2- ({ [(E) -2- (4- chlorphenyls) vinyl] sulfonyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
60) N- { (1R, 2S, 5S) -2- { [(4- chlorobenzyls) sulfonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
61) N- { (1R; 2S; 5S) -2- [(2- { [(4- chlorphenyls) sulfonyl] amino } acetyl group) amino] -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
62) N- { (1R; 2S; 5S) -2- ({ 2- [(5- chlorine pyrimidine -2-base) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
63) N- { (1R; 2S; 5S) -2- ({ 2- [(5- chloropyrazine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
64) N- [(1R; 2S; 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(the fluoro- 2- thienyls of 5-) amino] -2- oxos ethanethioyl } amino) cyclohexyl] -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
65) N- { (1R; 2S; 5S) -2- { [2- (3- amino -4- chloroanilinos) -2- oxos ethanethioyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
66)N1- (4- chlorine thiazol-2-yl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
67)N1- ((1S, 2R, 4S) -5- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (3- fluorophenyls) oxalamide
68)N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- phenyl oxalamide
69)N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (pyridine -2- bases) oxalamide
70)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5,6,6- trimethyls -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide
71)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(4,4,5,6,6- pentamethyls -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide
72)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [2- methyl -2,3- thiazoline simultaneously [5,4-d] isoxazole -5-bases) carbonyl] amino } cyclohexyl) oxalamide
73)N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(2- methyl -2,3- thiazoline simultaneously [4,5-d] isoxazole -5-bases) carbonyl] amino } cyclohexyl) oxalamide
74)N1- (the chloro- 2- furyls of 5-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
75)N1- (5- Lv oxazole -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
76)N1- (the chloro- 1H- imidazoles -2- bases of 5-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
77) N- { (1R, 2S, 5S) -2- { [2- (4- chloroanilinos) -1- ethoxy imino -2- oxoethyls] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
78) N- { (1R, 2S, 5S) -2- { [2- (4- chloroanilinos) -1- phenoxy group imino group -2- oxoethyls] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
79) N- { (1R, 2S, 5S) -2- { [1- benzyloxy imino groups -2- (4- chloroanilinos) -2- oxoethyls] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
80) N- { (1R, 2S, 5S) -2- ({ 2- (4- chloroanilinos) -1- hydrazono- -2- oxoethyls] amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
81) N- { (1R, 2S, 5S) -2- ({ 2- (4- chloroanilinos) -1- (2- methylhydrazonos) -2- oxoethyls] amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
82) N- { (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -1- (2,2- dimethyl hydrazono-) -2- oxoethyls } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
83) N- { (1R, 2S, 5S) -2- { [2- (4- chloroanilinos) -1- methyl-imino -2- oxoethyls] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
84) N- { (1R; 2S; 5S) -2- { [1- (2- acetyl group hydrazono-) -2- (4- chloroanilinos) -2- oxoethyls] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
85) N- { (1R; 2S; 5S) -2- ({ 2- (4- chloroanilinos) -1- [(2- ethanethioyls hydrazono-) -2- oxoethyls] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
86) N- { (1R; 2S; 5S) -2- { [(E) -3- (5- chloropyridine -2- bases) -2- acryloyl groups] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Hereinafter, the preparation method to the diamine derivative (1) of the present invention is illustrated.
[preparation method 1]
Compound, its salt, their solvate or their the N- oxides that formula (1) is represented can for example be prepared in accordance with the following methods.
[in formula, Q1、Q2、Q3、Q4、R1And R2As it was previously stated, T1For carbonyl]
Carboxylic acid (3) is derivative for mixed acid anhydride, etheride or active ester etc., it is set to be reacted with diamines (2) and compound (4) is made, gained compound (4) is reacted with carboxylic acid (5) under identical condition, result in the compound (1) of the present invention.In the reaction of above steps, as long as using the reaction reagent and condition that are normally used for peptide symthesis.Above-mentioned mixed acid anhydride for example in the presence of a base, makes the chloro-carbonic acid such as ethyl chloroformate, isobutyl chlorocarbonate esters and carboxylic acid (3) react and can be made.Etheride can be handled carboxylic acid (3) and is made by etherides such as thionyl chloride, oxalyl chlorides.Active ester can use various esters, for example with N, the condensing agent such as N '-dicyclohexyl carbodiimide or 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride, the phenols such as p-nitrophenol, N- hydroxybenzotriazoles or n-hydroxysuccinimide etc. is reacted with carboxylic acid (3) can be made.In addition, pass through the reaction of carboxylic acid (3) and trifluoroacetic acid pentafluorophenyl esters etc., the reaction of carboxylic acid (3) and 1- BTA epoxide tripyrrole Wan Ji Phosphonium hexafluorophosphates, the reaction of carboxylic acid (3) and diethyl phosphorocyanidate (salt enters method), carboxylic acid (3) and triphenyl phasphine and 2, reaction (Xiang Shanfa) of the sulphur of 2 '-bipyridyl two etc., can also be made active ester.In the presence of appropriate alkali, in atent solvent, react mixed acid anhydride, etheride or the active ester and diamines (2) of carboxylic acid (3) achieved above in -78 DEG C~150 DEG C, compound (4) can be made.Under identical condition, react gained compound (4) and the mixed acid anhydride, etheride or active ester of carboxylic acid (5), the compound (1) of the present invention can be made.Reagent and reaction condition in the reaction of compound (4) and carboxylic acid (5) is identical with the reagent and reaction condition in the reaction of diamines (2) and carboxylic acid (3).
Specific alkali used can enumerate sodium carbonate in above steps, potassium carbonate, caustic alcohol, butanol potassium, sodium hydroxide, potassium hydroxide, sodium hydride, the carbonate of the alkali metal such as hydrofining or alkaline-earth metal, alkali metal alcoholates, alkali metal hydroxide or hydride, or with lithium alkylides such as n-BuLis, the lithium dialkyl amides such as lithium diisopropyl amido are the organic metal alkali of representative, the organic metal alkali of the bis-silyl amine such as double (trimethyl silyl) amido lithiums, or pyridine, 2, 6- lutidines, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, organic bases such as diazabicyclo [5.4.0] hendecene -7 (DBU) etc..
Atent solvent for this reaction can enumerate the haloalkyl series solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1, the ether series solvents such as 2- dimethoxy-ethane, dioxanes, the fragrant family solvent such as benzene, toluene, DMF, N, the acid amides series solvents such as N- dimethyl acetamides, NMP, in addition, it is also possible to use the sulfoxide series solvent such as dimethyl sulfoxide, sulfolane according to different situations, ketone series solvent such as acetone, methyl ethyl ketone etc..
[preparation method 2]
The compound (1) of the present invention can also be made by the following method.
[in formula, Q1、Q2、Q3、Q4、R1And R2As it was previously stated, T1For carbonyl, Boc is tert-butoxycarbonyl, and Boc-ON is 2- (tert-butoxycarbonyl oxyimino group) -2- phenylacetonitriles]
As described above; diamines (2) is handled with Boc-ON (6); the compound (7) that one of 2 amino of preparation is protected by tert-butoxycarbonyl; gained (7) is set to be reacted with carboxylic acid (5); compound (8) is made; then processing is carried out with acid and obtains compound (9), then (9) is reacted with carboxylic acid (3), the compound (1) of the present invention is made.Compound (7) can be reacted and be made by dichloromethane equal solvent, in the presence of triethylamine at -10 DEG C~40 DEG C.Compound (7) and mixed acid anhydride, etheride or the active ester of carboxylic acid (5) is reacted under the reagent and reaction condition described in preparation method 1, compound (8) can be made.Amine (9) can be made in -20 DEG C~70 DEG C of processing by trifluoroacetic acid etc. in gained compound (8).In the reaction of gained amine (9) and carboxylic acid (3), it can use and reagent and reaction condition same described in preparation method 1.
But, the tert-butoxycarbonyl of compound (7) can be substituted with other amino protecting groups.In this case, reagent (6) is also substituted with other reagents, it is necessary to using reaction condition correspondingly etc..Other amino protecting groups can enumerate the alkanoyls such as acetyl group; the alkoxy carbonyls such as methoxycarbonyl, ethoxy carbonyl; benzyloxycarbonyl, to methoxybenzyloxycarbonyl, to Arylmethoxycarbonyl groups such as (or adjacent) nitrobenzyloxycarbonyls; the aryl methyls such as benzyl, trityl; the aroyls such as benzoyl; or the aryl sulfonyl such as 2,4- dinitrobenzenesulfonyl, ortho-nitrophenyl sulfonyl.These protection groups can correspond to property of compound of protection amino etc. and carry out choice selection, when these protection groups are cut off, and the reagent and reaction condition corresponding to the protection group also may be selected.
[preparation method 3]
The compound (1) of the present invention can be condensed and be made by making after diamines (2) and sulfuryl halide (10) reaction with carboxylic acid (5).
Figure G2003801097466D00521
[in formula, Q1、Q2、Q3、Q4、R1And R2As it was previously stated, T1For sulfonyl, X is halogen atom]
In atent solvent, in the presence of the alkali such as triethylamine, make diamines (2) and sulfuryl halide (10) in -10 DEG C~30 DEG C reactions, compound (4) can be made.Atent solvent and alkali can be selected suitably using the solvent and alkali described in preparation method 1.Gained (4) is condensed with carboxylic acid (5) using the reagent and reaction condition described in preparation method 1, the compounds of this invention (1) can be made.In addition, sulfuryl halide (10) can be synthesized in the presence of appropriate alkali by known method (WO 96/10022, WO 00/09480) or as the method for benchmark.
[preparation method 4]
The compounds of this invention (1) can also be prepared by following method.
[in formula, Q1、Q2、Q3、Q4、R1、R2And X is as it was previously stated, T1For sulfonyl]
That is, in atent solvent, in the presence of a base, amine (9) and sulfuryl halide (10) is reacted at -10 DEG C~30 DEG C, compound (1) can be made.Atent solvent and alkali can suitably select to use from solvent and alkali described in preparation method 1.
[preparation method 5]
The Q of the compound (1) of the present invention3Part be following radicals when,
Figure G2003801097466D00523
[in group, R3、R4And Q5As it was previously stated, 1 and 2 numeral represents position]
Trans and cis geometric isomer may be present in the relation of 1 and 2.Hereinafter, the preparation method to the cis and trans compound (1) is illustrated.
[preparation method of trans body]
[in formula, Q5、R3And R4As previously described]
As the preparation example that trans diol (12a) is obtained by ring-type alkene (11), such as known to have from cyclohexene conversion be trans cvclohexvl glycol (Organic Synthesis, nineteen fifty-five, III volumes, page 217) etc..In addition, as the preparation example that trans diamines (2a) is converted into by trans diol (12a), being had been reported that to being converted into trans ring pentanediamine (WO 98/30574) etc. by trans ring pentanediol.According to these reports, trans diamines (2a) can be obtained by ring-type alkene (11).
Trans compound (1) can be obtained by the method for above-mentioned preparation method 1~4 by trans diamines (2a) made from the above method again.
[preparation method of cis body]
[in formula, Q5、R3And R4As previously described]
As the preparation example that c/s-diol (12b) is obtained by ring-type alkene (11), such as known to have from cyclohexene conversion be cis cyclohexanediol (J.Org.Chem, 1998, volume 63, page 6094) etc..In addition, as the preparation example that cis diamines (2b) is converted into by c/s-diol (12b), being had been reported that to being converted into cis ring pentanediamine (WO 98/30574) etc. by cis ring pentanediol.According to these reports, cis diamines (2b) can be made.
Cis compound (1) can be obtained by the method for above-mentioned preparation method 1~4 by cis diamines (2b) made from the above method again.
[preparation method 6]
As described above, the Q of the compound (1) of the present invention3Part occasionally there are trans and cis, there is geometric isomer, in addition, can also be respectively present optical isomer.Hereinafter, the preparation method to optically active body is illustrated.
[in formula, Q5、R1、R2、R3And R4As it was previously stated, R50For the protection group of amino]
On optically active body 1, the preparation method of 2- trans amino alcohols derivative (15), it is for example known to obtain optically active body 1 from cyclopentene oxide, the preparation method of the trans -2- amino cyclopentyls alcohol of 2- obtains optically active body 1, the preparation method (Tetrahedron of the trans -2- aminocyclohexanols of 2- from cyclohexene oxide：Asymmetry, 1996, volume 7, page 843；J.Org.Chem., 1985, volume 50, page 4154；J.Med.Chem., 1998, volume 41, page 38).Make the amino and appropriate protection reagent reacting by optically active body aminoalcohol derivative (15) made from the known method or application this method, compound (16) can be made.With the R in compound (16)50The alkoxy carbonyls such as methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl in the preferably common acyl group type protection group of suitable protection group; benzyloxycarbonyl, to methoxybenzyloxycarbonyl, to Arylmethoxycarbonyl groups such as (or adjacent) nitrobenzyloxycarbonyls; the aryl sulfonyls such as 2,4- dinitrobenzenesulfonyls, ortho-nitrophenyl sulfonyl.For example, when being protected by tert-butoxycarbonyl, in atent solvent, in -78 DEG C~50 DEG C, making aminoalcohol derivative (15) be reacted with di-tert-butyl dicarbonate, compound (16) being made.Atent solvent can suitably select to use from the solvent described in preparation method 1.
In atent solvent, in the presence of a base, react compound (16) and mesyl chloride in -78 DEG C~50 DEG C, compound (17) can be made.Atent solvent can suitably select to use from the solvent described in preparation method 1.Alkali preferably organic base such as pyridine, 2,6- lutidines, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] hendecene -7 (DBU) etc..
In appropriate solvent, in -10 DEG C~150 DEG C, make compound (17) and reaction of sodium azide, compound (18) can be made.It is used as solvent preferably N, dinethylformamide, N, the acid amides series solvents such as N- dimethyl acetamides, NMP, the alcohol series solvents such as methanol, ethanol, the ether series solvent such as tetrahydrofuran, 1,2- dimethoxy-ethane, dioxanes, the benzene series solvent such as toluene, mixed solvent of the halohydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, acetone, dimethyl sulfoxide and these solvents and water etc..
The method that azido derivant (18) is converted into compound (7a) has the method being hydrogenated with using palladium series catalyst, Raney nickel catalyst or platinum catalyst, using the reaction of the reducing agents such as lithium aluminium hydride reduction, sodium borohydride, zinc borohydride, the reaction of zinc is used in the presence of nickel chloride or cobalt chloride, the various methods such as the reaction using triphenyl phasphine, can select appropriate reaction condition according to the property of compound.For example, in appropriate solvent, using 1~20% palladium carbon as catalyst, being hydrogenated with a temperature of -10 DEG C~70 DEG C, compound (7a) can be obtained by azido compound (18).Hydrogen pressure can be risen to more than atmospheric pressure.It is used as the solvent preferably alcohol series solvent such as methanol, ethanol, tetrahydrofuran, 1, the ether series solvents such as 2- dimethoxy-ethane, dioxanes, N, dinethylformamide, N, the acid amides series solvents such as N- dimethyl acetamides, NMP, the ester series solvent, acetic acid such as ethyl acetate, mixed solvent of hydrochloric acid, water or these solvents etc..
, can the optically active amines as made from by the above method (7a) acquisition optical activation type compound (1) according to above-mentioned preparation method 2.It is also possible to use the enantiomer (1) of optically active body (1) is made by optically active amines (7a) for same method.
In addition, optical activation type compound (1) can also be separated by the pillar formed by optical activity carrier and is made to racemic modification (1).The intermediate (2), (4), (7), (8) or (9) of racemic modification (1) is prepared using the pillar separation of optical activity carrier formation, again to being isolated with optically active (2), (4), (7), (8) or (9), then it can be also made with optically active compound (1) according to preparation method 1~4.It is used as the isolation process with optically active (1), (2), (4), (7), (8) or (9), it can be pair method that fractional crystallization is carried out with the salt with optically active carboxylic acid, or on the contrary, pair method that fractional crystallization is carried out with the salt with optically active alkali.
[preparation method 7]
Hereinafter, to the Q in the compound (1) of the present invention3In be described in detail containing the preparation method of heteroatomic compound (1c).
Compound, its salt, their solvate or their the N- oxides that formula (1c) is represented can for example be prepared in accordance with the following methods.
Figure G2003801097466D00551
[in formula, Q1、Q2、Q4、R3、R4, A, m and n be as it was previously stated, T1Represent carbonyl]
Carboxylic acid (3) is derivative for mixed acid anhydride, etheride or active ester etc., it is set to be reacted with compound (2c) and compound (4c) is made, gained compound (4c) is reacted with carboxylic acid (5) under identical condition, result in the compound (1c) of the present invention.
In the reaction of above steps, as long as using the reaction reagent and condition that are normally used for peptide symthesis.Above-mentioned mixed acid anhydride for example in the presence of a base, makes the chloro-carbonic acid such as ethyl chloroformate, isobutyl chlorocarbonate esters and carboxylic acid (3) react and can be made.Etheride can be handled carboxylic acid (3) and is made by etherides such as thionyl chloride, oxalyl chlorides.Active ester can use various esters, for example with N, the condensing agent such as N '-dicyclohexyl carbodiimide (DCC) or 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride, the phenols such as its p-nitrophenol, N- hydroxybenzotriazoles or n-hydroxysuccinimide etc. is reacted with carboxylic acid (3) can be made.In addition, pass through the reaction of carboxylic acid (3) and trifluoroacetic acid pentafluorophenyl esters etc., the reaction of carboxylic acid (3) and 1- BTA epoxide tripyrrole Wan Ji Phosphonium hexafluorophosphates, the reaction of carboxylic acid (3) and diethyl phosphorocyanidate (salt enters method), carboxylic acid (3) and triphenyl phasphine and 2, reaction (Xiang Shanfa) of the sulphur of 2 '-bipyridyl two etc., can also be made active ester.In the presence of appropriate alkali, in atent solvent, under cooling~heating under, make mixed acid anhydride, etheride or the active ester of carboxylic acid (3) achieved above and compound (2c) reaction, compound (4c) can be made.Under identical condition, react gained compound (4c) and the mixed acid anhydride, etheride or active ester of carboxylic acid (5), the compound (1c) of the present invention can be made.Reagent and reaction condition in the reaction of compound (4c) and carboxylic acid (5) is identical with the reagent and reaction condition in the reaction of compound (2c) and carboxylic acid (3).
Specific alkali used can enumerate sodium carbonate in above steps, the carbonate of the alkali metal such as potassium carbonate or alkaline-earth metal, caustic alcohol, the alkali metal alcoholates such as butanol potassium, sodium hydroxide, the alkali metal hydroxides such as potassium hydroxide, sodium hydride, hydrofining etc. or alkali metal hydride, or with lithium alkylides such as n-BuLis, the lithium dialkyl amides such as lithium diisopropyl amido are the organic metal alkali of representative, the organic metal alkali of the bis-silyl amine such as double (trimethyl silyl) amido lithiums, or pyridine, 2, 6- lutidines, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, organic bases such as diazabicyclo [5.4.0] hendecene -7 (DBU) etc..
Atent solvent for this reaction can enumerate the haloalkyl series solvent such as dichloromethane, chloroform, the ether series solvent such as tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-, the aromatic solvent such as benzene, toluene, the acid amides series solvent such as DMF.In addition, it is also possible to use the sulfoxide series solvent such as dimethyl sulfoxide according to different situations, ketone series solvent such as acetone etc..
In above-mentioned preparation process, the compound (1c) of the present invention can be made by adding the operation of the addition and removing of appropriate protection group or the conversion of functional group.
The protection group of amino can be using the protection group commonly used in the peptide symthesis in the synthesis of organic compound as amino protecting group; the alkoxy carbonyls such as tert-butoxycarbonyl, methoxycarbonyl, ethoxy carbonyl can specifically be enumerated; benzyloxycarbonyl, to methoxybenzyloxycarbonyl, to Arylmethoxycarbonyl groups such as (or adjacent) nitrobenzyloxycarbonyls; the aryl methyls such as benzyl, 4- methoxy-benzyls, trityl; the alkanoyls such as formoxyl, acetyl group; the aroyls such as benzoyl; or the aryl sulfonyl such as 2,4- dinitrobenzenesulfonyl, ortho-nitrophenyl sulfonyl etc..
It is used as the protection group of hydroxyl; the protection group of the hydroxyl for the synthesis for being generally used for organic compound can be used; the alkoxy methyls such as methoxy can specifically be enumerated; the aryl methyls such as benzyl, 4- methoxy-benzyls, trityl; the alkanoyls such as acetyl group; the aroyls such as benzoyl, t-butyidiphenylsilyl epoxide etc..Carboxyl can be by being protected with the aryl methyl such as alkyl or benzyl such as methyl, ethyl, tert-butyl group formation ester.The addition and removing of above-mentioned protection group can be carried out according to well-established law.
Compound in the compound (1c) of the present invention can form various derivatives by converting the functional group of the compound.For example; common organic chemistry procedures; mixed acid anhydride, etheride or active ester etc. is used A is formed amide compound for the compound acylation of unsubstituted nitrogen-atoms; make its with sulfuryl halide etc. reaction and sulfonamide compounds is made; it is set to be reacted with alkyl halide and N- alkyl compounds are made; make the reaction such as aryl halide that N- aryl compounds are made, carbamate compounds are made by making method that isocyanates reacts etc..A is the compound of unsubstituted nitrogen-atoms, for example, compound (1c) can be made according to preparation method 7 by the diamines (2c) protected by A by tert-butoxycarbonyl, carry out acid treatment to the compound (1c) and be made.
The compounds of this invention produced above can be isolated and refined such as extraction, precipitation, differential chromatography, fractional crystallization, recrystallization by known method.In addition, the compounds of this invention can form desired salt by common salt-forming reaction.
In addition, due to there is optical isomer with chiral carbon in the compounds of this invention.These optical isomers are in addition to the method by being prepared with optically active diamines (2c), can also be by racemic modification with having optically active amine or sour forming salt, then the method for fractional crystallization, or be made using the method that chromatographic column with optically active carrier etc. is separated.
In addition, in the reaction of compound (2c) and carboxylic acid (3), substituting carboxylic acid (3) with sulfuryl halide (10), T being made1For the compound (1c) of sulfonyl.
[preparation method 8]
The compound (1c) of the present invention can also be made in accordance with the following methods.
Figure G2003801097466D00581
[in formula, Q1、Q2、Q4、R3、R4, A, m and n be as it was previously stated, T1Represent carbonyl, R51And R61Represent the protection group of amino]
By the protection group R for removing the compound (19) that the amido protecting of compound (2c) is got up and obtained61, compound (21) can be made.Here, as R51And R61As long as the protection group of the amino of illustration is typically used for the group of the protection of amino, it is not particularly limited, its typical example can enumerate the protection group of the amino described in preparation method 7.In this case, R51And R61Must be can distinct methods or under the conditions of the protection group that removes.R can for example be enumerated51For tert-butoxycarbonyl, R61Combination for benzyloxycarbonyl etc. is the example of representative.These protection groups can carry out choice selection according to property of compound of protection amino etc., when removing these protection groups, and the reagent and reaction condition corresponding to the protection group also may be selected.
In addition, the hydroxyl of amino alcohol body (20) is transformed into amino can also be made compound (21).As the preparation example of amino alcohol body (20), for example it is known have 3- hydroxyl -4- amino thiapyrans -1,1- dioxide (Tetrahedron Lett., volume 37, page 7457,1996 years) etc. is converted to by methionine.
The method for being converted to amino as the hydroxyl by amino alcohol body (20), can enumerate makes after the reaction such as amino alcohol body (20) and mesyl chloride, paratoluensulfonyl chloride, trifluoromethanesulfanhydride anhydride, make itself and ammonia, benzylamine, 4-Methoxybenzylamine, 2, the primary aralkyl amine such as 4- dimethoxybenzylamines, the secondary aralkyl amine, N- benzyl hydroxylamines such as dibenzylamine, N, azanol class such as O- dibenzyl hydroxylamines etc. is reacted, and benzyl etc. is removed if necessary, the method that diamines (21) is made.In addition, reaction (Xiang Shanfa) that amino alcohol body (20) is handled by using triphenyl phasphine and ethyl azodicaboxylate etc., after phthalimide or succinimide reaction, handled with hydrazine or N- methyl hydrazines etc., result in diamines (21).In addition, the A in formula is SO2During n=0, make after the reaction such as amino alcohol body (20) and mesyl chloride, paratoluensulfonyl chloride, trifluoromethanesulfanhydride anhydride, handled or amino alcohol body (20) is handled with triphenyl phasphine and ethyl azodicaboxylate with appropriate alkali directly, make the α of generation again, β-unsaturated cyclic sulfone and ammoniacal liquor, benzylamine, 4-Methoxybenzylamine, 2, the primary aralkyl amine such as 4- dimethoxybenzylamines, the secondary aralkyl amine such as dibenzylamine, N- benzyl hydroxylamines, N, azanol class such as O- dibenzyl hydroxylamines etc. carries out addition, then removes benzyl etc., and diamines (21) can be made.
Gained diamine compound (21) and carboxylic acid (3) is carried out reaction prepare compound (22), then remove protection group R51, obtain after compound (4c), then compound (4c) and carboxylic acid (5) are reacted, the compound (1c) of the present invention can be made.In the reaction of compound (21) and carboxylic acid (3) and the reaction of compound (4c) and carboxylic acid (5), using with reagent and reaction condition same described in preparation method 7.
Equally, in the reaction of compound (21) and carboxylic acid (3), carboxylic acid (3) is substituted with sulfuryl halide (10), T can be made1For the compound (1c) of sulfonyl.
[preparation method 9]
The representational preparation method for preparing intermediate (2c) described in preparation method 7 is illustrated.
[in formula, R3、R4, A, m and n as previously described]
It is used as the preparation example of glycol body (23), it is for example known to have by 1,2,3,6- tetrahydropyridines are converted to the cis- dihydroxy pyrrolidine (Japanese Patent Laid-Open 7-138264) of 1- benzyloxycarbonyls -3,4-, and (R is converted to by L-TARTARIC ACID, R)-erythritan or (R, R)-N- benzyl-pyrrole alkane glycol (Tetrahedron：Asymmetry, volume 8, page 1861,1997) etc..Using these known methods or this method is applied, protection group is removed as needed or functional group's conversion is carried out, glycol body (23) can be prepared.
In atent solvent, in the presence of a base, under cooling~at room temperature, reacted glycol body (23) and mesyl chloride, compound (24) can be made.Atent solvent can suitably select to use from the solvent described in preparation method 7, be particularly preferred that the haloalkyl series solvent such as dichloromethane, chloroform, the ether series solvent such as tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-.It is used as alkali, preferably organic base such as pyridine, 2,6- lutidines, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] hendecene -7 (DBU) etc..
In appropriate solvent, under under cooling~heating, compound (24) and sodium azide are reacted, nitrine body (25) can be made.It is used as solvent, preferably N, the acid amides series solvents such as dinethylformamide, NMP, the alcohol series solvents such as methanol, ethanol, the ether series solvent such as tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-, the fragrant family solvent such as benzene, toluene, the haloalkyl series solvent such as dichloromethane, chloroform, dimethyl sulfoxide, acetone etc..Also can be using above-mentioned common solvent and the mixture of water.
The method for being converted to compound (2c) by nitrine body (25) has the method being hydrogenated with using palladium series catalyst, Raney nickel catalyst or platinum catalyst, using the reaction of the reducing agents such as lithium aluminium hydride reduction, sodium borohydride, the reaction of zinc is used in the presence of nickel chloride or cobalt chloride, the various methods such as the reaction using triphenyl phasphine, can select appropriate reagent and reaction condition according to the property of compound.Hydrogen pressure can be risen to more than atmospheric pressure.It is used as the solvent preferably ether series solvent, N such as the alcohol series solvent such as methanol, ethanol, tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-, the acid amides series solvents such as dinethylformamide, NMP, the ester series solvent, acetic acid such as ethyl acetate, mixed solvent of hydrochloric acid, water or these solvents etc..Using diamines body (2c) made from the above method, the compounds of this invention (1c) can be made according to above-mentioned preparation method 7.
There is optically active body when being trans- 3,4- dihydroxytetrahydrofandns or trans- 1- substitution -3,4- dihydroxy pyrrolidines etc. in glycol body (23).By these there is optically active glycol body (23) can obtain with optically active diamines body (2c), can be obtained with optically active the compounds of this invention (1c) according still further to preparation method 7.
[preparation method 10]
The representative preparation method with optically active compound (30), (31) and (32) included in the compound (19) recorded to preparation method 8 is illustrated.The configuration of chiral carbon shown in following preparation paths is used as 1 expression.
[in formula, m, n, R3、R51And R61As it was previously stated, R71Represent the protection group of carboxyl]
Document (J.Org.Chem., volume 61, page 581,1996 can be used with optically active alpha, beta-unsaturated esters body (26)；J.Org.Chem., volume 57, page 6279,1992 etc.) record method or application this method be made.In appropriate solvent, under under cooling~heating, make, with optically active alpha, beta-unsaturated esters body (26) and amine reaction, diastereoisomer (27a) and (27b) can be made.Amine can suitably select to use from the amine described in above-mentioned preparation method 8.It can be used and the nonreactive organic solvent such as matrix, product or reagent, particularly preferably the alcohol series solvent such as methanol, ethanol, the ether series solvent such as tetrahydrofuran, 1,2- dimethoxy-ethanes, the dioxane of Isosorbide-5-Nitrae-as solvent.In addition, using document (J.Org.Chem., volume 63, page 7263,1998) record method, organic metal alkali such as alpha, beta-unsaturated esters body (26) and N- benzyls (trimethyl silyl) amido lithium etc. is reacted, diastereoisomer (27a) and (27b) can be also made.By separating the diastereoisomer, for example, (27a) can be used for reaction thereafter.
In appropriate solvent, under under cooling~heating, acid treatment is carried out to compound (27a), compound (28) can be made.Acid used can enumerate the lewis acids such as hydrochloric acid, sulfuric acid, boron trifluoride, trifluoroacetic acid, p-methyl benzenesulfonic acid etc..For the solvent of reaction, water, the alcohol series solvent such as methanol and ethanol etc. can be used.Also can be using above-mentioned solvent and the mixture of water.In addition, there is the protection group R of amino in this reaction61Cut-off situation.In this case, it can be reacted as needed with appropriate amido protecting agent.
In a solvent, under under cooling~heating, acid treatment is carried out to compound (28), can be made with optically active compound (30).Acid used can be used in appropriate selection from foregoing acid, it is special it is good be the lewis acids such as boron trifluoride and p-methyl benzenesulfonic acid etc.., can be using the ether series solvent such as the dioxane of Isosorbide-5-Nitrae-, tetrahydrofuran as the solvent for reaction, the fragrant family solvent such as benzene, toluene.In addition, compound (30) can be also made by nitrine body (29).It is used as the preparation example with optically active nitrine body (29), for example it is known have (R is converted to by L-Aspartic acid, R)-(3S, 4S) -3- amino -4- azidos -5- oxo-tetrahydrofurans (Can, J.Chem., volume 71, page 1407,1993) etc..Using the known method or this method is applied, remove protection group as needed or carry out the conversion of functional group, can be made with optically active nitrine body (29).The azido of nitrine body (29) is reduced, is formed as after amino, is reacted with appropriate amido protecting agent, compound (30) can be made.The reduction of azido can use and nitrine body (25) is converted to reaction condition and reagent same described in compound (2c) method with preparation method 9.
The hydroxylic moiety of compound (28) is converted to after amino, compound (31) can be made using alkali progress processing.As the method that the hydroxyl of compound (28) is converted into amino, for example, it can be carried out according to above-mentioned preparation method 8.Or, alcohol body (28) is handled with oxidant, then by gained aldehyde body reductive amination, compound (31) can be also made.Specific example preferably Pyridinium chlorochromate on silica gel (PCC), Pyridinium dichromate (PDC), sulfur trioxide pyridine complex salt of oxidant used etc. in above-mentioned reaction.As amine, the Primary alkyl amines such as ammoniacal liquor, methylamine, ethamine can be enumerated, primary aralkyl amine such as benzylamine, 4-Methoxybenzylamine, 2,4- dimethoxybenzylamines etc..Restoring method has the method being hydrogenated with using palladium series catalyst, Raney nickel catalyst or platinum catalyst, reaction using reducing agents such as sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydrides etc., can accept or reject selective reagent and condition according to property of compound etc..In addition, the alkali for above-mentioned steps can suitably select to use from the alkali described in preparation method 7.Using above-claimed cpd (30) and amine, document (Tetrahedron, Lett., 41 volume, page 1141,2000 years are utilized；Heterocycles, volume 53, page 173,2000) record method or apply this method, compound (31) can be made.Amine used can enumerate the primary alkylamine class such as ammonia, methylamine, ethamine, the primary aralkyl amine such as benzylamine, 4-Methoxybenzylamine, aniline etc..
In a solvent, under under cooling~heating, processing is carried out to above-claimed cpd (31) with reducing agent can be made compound (32).As reducing agent, the reducing agents such as borine tetrahydrofuran complex, borine Dimethyl sulfide complex compound, lithium aluminium hydride reduction can be enumerated, selective reagent and reaction condition can be accepted or rejected according to the property of compound., can be using the organic solvent that will not be reacted with matrix, product or reagent etc., particularly preferably tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-etc. as solvent.
Using compound made from the above method (30), (31) and (32), the optically active body (1c) of the compounds of this invention can be made according to above-mentioned preparation method 8.
Above-mentioned preparation process is the illustration of a kind of progress to optically active body, for the different optically active body of spatial configuration, as long as using the different initial substance of spatial configuration, can be made by same step.
[preparation method 11]
T1It can be made for the compound (1) of-CO-CO-N (R ')-base (R ' in group is as previously described) according to following step.
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CO-CO-N (R ')-base (R ' in group is as previously described)]
I.e., carboxylic acid (33) is derivative for etheride or active ester etc., it is set to be reacted with diamines (2) and compound (4) is made, gained compound (4) is reacted with carboxylic acid (5) under identical condition, result in the compound (1) of the present invention.In the reaction of above steps, as long as using the reaction reagent and condition that are normally used for peptide symthesis.Above-mentioned etheride can be handled carboxylic acid (33) and is made by etherides such as thionyl chloride, oxalyl chlorides.Active ester can use various esters, for example with N, the condensing agent such as N '-dicyclohexyl carbodiimide or 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride, the phenols such as p-nitrophenol, N- hydroxybenzotriazoles or n-hydroxysuccinimide etc. is reacted with carboxylic acid (33) can be made.In addition, pass through the reaction of carboxylic acid (33) and trifluoroacetic acid pentafluorophenyl esters etc., the reaction of carboxylic acid (33) and 1- BTA epoxide tripyrrole Wan Ji Phosphonium hexafluorophosphates, the reaction of carboxylic acid (33) and diethyl phosphorocyanidate (salt enters method), carboxylic acid (33) and triphenyl phasphine and 2, reaction (Xiang Shanfa) of the sulphur of 2 '-bipyridyl two etc., can also be made active ester.In the presence of appropriate alkali, in atent solvent, react mixed acid anhydride, etheride or the active ester and diamines (2) of carboxylic acid (33) achieved above in -78 DEG C~150 DEG C, compound (4) can be made.Under identical condition, react gained compound (4) and the mixed acid anhydride, etheride or active ester of carboxylic acid (5), the compound (1) of the present invention can be made.Reagent and reaction condition in the reaction of compound (4) and carboxylic acid (5) is identical with the reagent and reaction condition in the reaction of diamines (2) and carboxylic acid (3 osmium).Alkali and solvent for above steps can suitably select the alkali and solvent described in preparation method 1.
In addition, preparing Q3For following radicals,
[in group, R3、R4And Q5As it was previously stated, 1 and 2 numeral represents position] relation of 1 and 2 when being trans and cis compound (1), can use the diamines (2a) or (2b) of the record of preparation method 5.
In addition, preparing Q5In containing heteroatomic compound (1) such as nitrogen-atoms, oxygen atom or sulphur atom when, in the compound (2c) and the reaction of carboxylic acid (3) that preparation method 7 is recorded, carboxylic acid (3) can be substituted with carboxylic acid (33).That is, Q can be prepared by following step5In (1) containing heteroatomic compound, i.e. compound (1c).
Figure G2003801097466D00632
[in formula, Q1、Q2、Q4、R3、R4, R ', A, m and n be as it was previously stated, T1For-CO-CO-N (R ')-base (R ' in group is as previously described)]
[preparation method 12]
T1Compound (1) for-CO-CO-N (R ')-base (R ' in group is as previously described) can also be prepared by following steps.
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CO-CO-N (R ')-base (R ' in group is as previously described)]
In the reaction of amine (9) and carboxylic acid (33), it can use and reagent and reaction condition same described in preparation method 1.
, for example can also be by being made the step of preparation process as following amine (41) except being prepared the step of being recorded by preparation method 2 used herein of amine (9).
[in formula, R3、R4、Q1、Q2And Q5As it was previously stated, R52Represent the protection group of amino]
In dichloromethane equal solvent, cyclenes is handled and epoxidation with benzylhydroperoxide or derivatives thereof Dengs, the compound (34) in above-mentioned preparation process can be made.The reaction condition can be used the epoxidised normal condition of alkene.In addition, compound (34) also can be by J.Org.Chem., volume 61, method or be made as the method for benchmark that 8687-8691 is recorded for (1996).
Conventionally, catalysis reduction is carried out with sodium azide etc. to compound (34) after the nitrine body (35) of processing acquisition, protects amino, compound (36) can be made.At this moment the protection group of amino can enumerate the protection group described in preparation method 2.It is same with the method that preparation method 5 is recorded to operate, formed by compound (36) after azide (38), except the protection group deaminized, compound (39) can be made.Compound (39) and carboxylic acid (5) are reacted, is formed after compound (40), compound (41) can be made by being catalyzed reduction.
[preparation method 13]
The reaction of compound (9) and carboxylic acid (3) in the step of preparation method 2 is recorded is changed to the reaction of compound (9) and carboxylic acid (33), and T can be also made1For the compound (1) of-CO-CO-N (R ')-base (R ' in group is as previously described).
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CO-CO-N (R ')-base (R ' in group is as previously described)]
The condition that reaction condition can be recorded using preparation method 2.
In addition, preparing Q3For following radicals,
[in group, R3、R4And Q5As it was previously stated, 1 and 2 numeral represents position]
Q5In containing heteroatomic compound (1) such as nitrogen-atoms, oxygen atom or sulphur atom when, in the compound (21) and the reaction of carboxylic acid (3) that preparation method 8 is recorded, carboxylic acid (3) can be substituted with carboxylic acid (33).That is, Q can be prepared by following step5In (1) containing heteroatomic compound, i.e. compound (1c).
Figure G2003801097466D00651
[in formula, Q1、Q2、Q4、R3、R4, R ', A, m and n be as it was previously stated, T1For-CO-CO-N (R ')-base (R ' in group is as previously described), R51Represent the protection group of amino]
[preparation method 14]
In atent solvent, using condensing agent, compound (9) and Q that preparation method 2 is recorded are made in -50~50 DEG C4-N(R”)-A1-CO2H (42) reacts, and T can be made1For-CO-A1(in formula, R " represents hydrogen atom, hydroxyl, alkyl or alkoxy, A to-N (R ")-base1Represent can have substituent carbon number 1~5 alkylidene) compound (1).As condensing agent, N, N '-dicyclohexyl carbodiimide or 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride etc. can be enumerated.As atent solvent, the haloalkyl series solvent such as dichloromethane, chloroform, carbon tetrachloride can be enumerated, the ether series solvent such as tetrahydrofuran, 1,2- dimethoxy-ethane, dioxanes, the fragrant family solvent such as benzene, toluene, the acid amides series solvent such as DMF etc..
[in formula, Q1、Q2、Q3、Q4、R1、R2And R " is as it was previously stated, T1For-CO-A1(in formula, R " represents hydrogen atom, hydroxyl, alkyl or alkoxy, A to-N (R ")-base1Represent can there is the alkylidene of the carbon atom acid 1~5 of substituent)]
For example, in acetonitrile or N, in dinethylformamide equal solvent, in the presence of the alkali such as potassium carbonate, make in 40~120 DEG C after the ester reaction of the arylamine such as 4- chloroanilines and bromine alkanoic acid, ester is hydrolyzed with alkali such as lithium hydroxide, potassium hydroxide, sodium hydroxides the compound (42) that can be made described in above-mentioned preparation method.Sylvite of compound 42 etc. can be directly used for reaction.
[preparation method 15]
In atent solvent, compound (9) and isocyanates (Q that preparation method 2 is recorded are made in -20~50 DEG C4- N=C=O) or isothiocyanates (Q4- N=C=S) reaction, T can be made1For the compound (1) of-C (=O)-NH- bases or-C (=S)-NH- bases.As atent solvent, the solvent of the record of preparation method 14 can be enumerated as representative examples.During the unavailable commercially available product of isocyanates or isothiocyanates used, it can pass through and be prepared as the common method of isocyanates or the preparation method of isothiocyanates.
[in formula, Q1、Q2、Q3、Q4、R1And R2As it was previously stated, T1For-C (=O)-NH- bases or-C (=S)-NH- bases]
[preparation method 16]
In atent solvent, as needed in the presence of a base, make the compound (9) and Q of the record of preparation method 2 in room temperature~150 DEG C4-NH-NH-CO2Ph (43) reacts, and T can be made1For the compound (1) of-CO-NH-NH- bases.As atent solvent, in addition to acetonitrile or DMF, the solvent of the record of preparation method 14 can be enumerated as representative examples.As alkali, pyridine, 2,6- lutidines, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] hendecene -7 (DBU) can be enumerated.
[in formula, Q1、Q2、Q3、Q4、R1And R2As it was previously stated, T1For-CO-NH-NH- bases, Ph is phenyl]
For example, in acetonitrile, N, dinethylformamide, dichloromethane, chloroform, tetrahydrofuran, 1, in 2- dimethoxy-ethane, dioxanes, benzene, toluene equal solvent, in making the aryl hydrazines such as 4- chlorophenyl hydrazines and diphenyl carbonate reaction at room temperature~120 DEG C, the compound (43) described in above-mentioned preparation method can be made.
[preparation method 17]
In atent solvent, using condensing agent, compound (9) and Q that preparation method 2 is recorded are made in -50~50 DEG C4-CO-A2-CO2H (44) reacts, and T can be made1For-CO-A2- CO- bases (in formula, A2For singly-bound or the alkylidene of carbon number 1~5) compound (1).As condensing agent, N, N '-dicyclohexyl carbodiimide or 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride etc. can be enumerated.As solvent, solvent described in preparation method 16 etc. can be enumerated.
[in formula, Q1、Q2、Q3、Q4、R1And R2As it was previously stated, T1For-CO-A2- CO- bases (in formula, A2For singly-bound or the alkylidene of carbon number 1~5)]
In A2During for singly-bound, the alkali such as can use lithium hydroxide, potassium hydroxide, sodium hydroxide, to by the fragrant race's heterocycle of the aromatic hydrocarbons such as chlorobenzene or thiophene and other aromatic and chlorine ethyl (for example, ClCO-CO2Et Knut Fridell)-obtained compound of Kerafyrm thatch reaction is (for example, Q4-CO-CO2Et) it is hydrolyzed, the compound (44) described in above-mentioned preparation method can be made.
In addition, A2During for methylene, such as in the presence of magnesium chloride and triethylamine, the heteroaryl formyl chlorides such as the aryl formyl chloride class such as 4- chlorobenzoyl chlorides and thiophene chloride are made to be reacted with the ester monocarboxylic acid sylvite of malonic acid one and obtain keto ester derivative (for example, Q4-CO-CH2-CO2Et), then the derivative is hydrolyzed with alkali such as lithium hydroxide, potassium hydroxide, sodium hydroxides, compound (44) can be made.The carboxylic acid that the carbonyl of above-mentioned keto ester derivative hydrolyzes acquisition after ethylene ketal can also be used for and the reaction of compound (9).In addition, A2For carbon number more than 2 alkylidene when, the alkali such as with lithium hydroxide, potassium hydroxide, sodium hydroxide, obtained keto ester derivative is reacted (for example, Q to Knut Fridell-Kerafyrm thatch by the aromatic hydrocarbons such as benzene or the fragrant race's heterocycle of thiophene and other aromatic and the acyl chlorides of one ester of alkylene dicarboxylic acids one4-CO-A2-CO2Et) it is hydrolyzed, can prepare compound (44).
[preparation method 18]
In atent solvent, using condensing agent, compound (9) and Q that preparation method 2 is recorded are made in -50~50 DEG C4-NH-CO-A3-CO2H (45) reacts, and T can be made1For-CO-A3- CO-NH- bases (in formula, A3For the alkylidene of carbon number 1~5) compound (1).As condensing agent, N, N '-dicyclohexyl carbodiimide or 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride etc. can be enumerated.As atent solvent, the haloalkyl series solvent such as dichloromethane, chloroform, carbon tetrachloride can be enumerated, the ether series solvent such as tetrahydrofuran, 1,2- dimethoxy-ethane, dioxanes, the fragrant family solvent such as benzene, toluene, the acid amides series solvent such as DMF etc..
[in formula, Q1、Q2、Q3、Q4、R1And R2As it was previously stated, T1For-CO-A3- CO- bases (in formula, A3For the alkylidene of carbon number 1~5)]
In atent solvent, using condensing agent, make in -50~50 DEG C equivalent to Q4-NH2The heteroaryl such as the arylamine or aminopyridine amine such as 4- chloroanilines and the reaction of the ester monocarboxylic acid sylvite of alkylene dicarboxylic acids one, compound is made (for example, Q4-NH-CO-A3-CO2Et), then with alkali such as lithium hydroxide, potassium hydroxide, sodium hydroxides the compound is hydrolyzed, compound (45) can be made.
[preparation method 19]
T1Compound (1) for-CS-CO-N (R ')-base (in base, R ' is as previously described) can be prepared according to following steps.
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CS-CO-N (R ')-base (in base, R ' is as previously described)]
That is, sodium thiosulfate (46) and compound (9) are dissolved or is suspended in solvent and heats, the compound (1) of the present invention can be made.Preferably 80~200 DEG C of reaction temperature, particularly preferably 150 DEG C or so.Solvent for the reaction can enumerate water, the alcohols such as methanol, ethanol, the basic solvent such as pyridine, N-methylmorpholine, the haloalkyl series solvent such as dichloromethane, chloroform, the ether series solvent such as tetrahydrofuran, 1,2- dimethoxy-ethane, dioxanes, acid amides series solvents such as DMF etc..These solvents can be suitably used in mixed way, and as the example of mixed solvent, can enumerate mixed solvent of methanol and dichloromethane etc..In addition, in the reaction, being not necessarily to make solvent refluxing, for example, in the mixed solvent using methanol and dichloromethane, reaction solution (or reactant mixture) is heated into outer 150 DEG C of temperature, boil off after solvent, residue is heated in mutually synthermal continuation.
[preparation method 20]
T1Compound (1) for-CO-CS-N (R ')-base (in base, R ' is as previously described) can be prepared according to following steps.
Figure G2003801097466D00682
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CO-CS-N (R ')-base (in base, R ' is as previously described)]
I.e., in the presence of a base, react compound (9) and chloracetyl chloride, obtain after compound (47), compound (47) and sodium thiosulfate are heated in a solvent, thiosulfuric acid sodio-derivative (48) can be made.To (48) achieved above and amine, i.e. NH (R ')-Q4Heated, the compounds of this invention (1) can be made.
Reaction condition and solvent from compound (9) prepare compound (47) etc. can be using the reaction conditions and solvent commonly used in amine and acyl chloride reaction.From compound (47) prepare compound (48) when, it can be made to be heated to reflux with sodium thiosulfate in ethanol equal solvent about 1 hour.When compound (47) is the salt of hydrochloric acid etc., it can be reacted in the presence of the alkali such as sodium acid carbonate.The preparation condition of compound (48) is not limited to the content of this record, and temperature, the species of solvent, the species of alkali can suitably change.Compound (48) and NH (R ')-Q4Reaction condition it is identical with described in preparation method 19.
[preparation method 21]
T0It can be made for the compound (1) of thiocarbonyl (- CS- bases) by following steps.
[in formula, Q1、Q2、Q3、Q4And R2As it was previously stated, T1For-SO2- base ,-CO- bases ,-CO-NH- bases ,-CS-NH- bases ,-CO-NH-NH- bases ,-CO-CO-N (R ')-base are (in base, R ' is as previously described) ,-CO-CS-N (R ')-base is (in base, R ' is as previously described) ,-CS-CO-N (R ')-base is (in base, R ' is as previously described) ,-CS-CS-N (R ')-base (in base, R ' is as previously described) ,-CO-A1- N (R ")-base (in base, A1And R " is as previously described) ,-CO-A2- CO- bases (in base, A2As previously described) ,-CO-A3- CO-NH- bases (in base, A3As previously described) ,-CO-A3- CO- bases (in base, A3As previously described)]
I.e., in the presence of the acid catalysts such as p-methyl benzenesulfonic acid, compound (49) and amine (50) is set to carry out dehydration, obtain after compound (51), in ethanol/methylene mixed liquor equal solvent, itself and sulphur powder are heated together, the compound (1) of the present invention can be made.Can be using the condition commonly used when being typically prepared schiff bases by the condition of compound (49) and amine (50) prepare compound (51).Specifically, under conditions of water is removed from reaction system, in presence of an acid catalyst, compound can be made to be heated to reflux in benzene or toluene using Dean and Stark apparatus etc..In addition, in the case where removing water from reaction system, can also use molecular sieve.
[preparation method 22]
T1Compound (1) for-CS-CO-N (R ')-base (in base, R ' is as previously described) can be prepared according to following steps.
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CS-CO-N (R ')-base (in base, R ' is as previously described)]
In the basic solvent such as the atent solvents such as DMF or pyridine, make in -78 DEG C~150 DEG C equivalent to HN (R ') Q4The heteroaryl such as the arylamine or aminopyridine amine such as 4- chloroanilines and dichloroacetyl chloride reaction, compound (52) can be made.In addition, making dichloroacetic acid and equivalent to HN (R ') Q with the conditions of in the reagent described in preparation method 14Amine reaction, compound (52) can be also made.
Compound (52) and sulphur powder is suspended in solvent, add the alkali such as diisopropylethylamine or triethylamine and diamines (9), in being reacted them under 0 DEG C~200 DEG C of reaction temperature, compound (1) can be more effectively made.Amount preferably 1N for the sulphur powder of reaction.Preferably 60 DEG C~160 DEG C of reaction temperature, particularly preferably 90 DEG C~140 DEG C.Solvent for the reaction can enumerate the acid amides series solvents such as DMF, the basic solvent such as N-methylmorpholine, pyridine, the ether series solvent such as alcohols , dioxanes such as ethanol, butanol, acetonitrile, water etc..
[preparation method 23]
T1Compound (1) for-CS-CO-N (R ')-base (in base, R ' is as previously described) can be prepared according to following steps.
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CS-CO-N (R ')-base (in base, R ' is as previously described)]
In the basic solvent such as the atent solvents such as DMF or pyridine, make in -78 DEG C~150 DEG C equivalent to HN (R ') Q4The heteroaryl such as the arylamine or aminopyridine amine such as 4- chloroanilines and chloracetyl chloride reaction, compound (53) can be made.In addition, making chloroacetic acid and equivalent to HN (R ') Q with the conditions of in the reagent described in preparation method 14Amine reaction, compound (53) can be also made.
Compound (53) and sulphur powder is suspended in solvent, add the alkali such as diisopropylethylamine or triethylamine, after stirring 5 minutes~8 hours, add diamines (9) and condensing agent, carry out reaction, compound (1) can be made.Amount preferably more than 2N for the sulphur powder of reaction.Preferably 0 DEG C~80 DEG C of reaction temperature.As condensing agent, 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochlorides or N, N can be enumerated '-dicyclohexyl carbodiimide etc..Solvent for the reaction can enumerate the acid amides series solvents such as DMF, the basic solvent such as N-methylmorpholine, pyridine, the ether series solvent such as haloalkyl series solvent , dioxanes such as dichloromethane, chloroform, acetonitrile etc..In addition, the reaction can also carry out that compound (1) is made under conditions of without condensing agent.Now, in addition to aforementioned solvents, the alcohols such as methanol, ethanol and water etc. be it is also possible to use.
[preparation method 24]
T1Compound (1) for-CS-CO-N (R ')-base (in base, R ' is as previously described) also can be by via T1It is prepared by the following steps for the compound (4) of-CS-CO-N (R ')-base (in base, R ' is as previously described).
Figure G2003801097466D00711
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CS-CO-N (R ')-base (in base, R ' is as previously described)]
I.e.; in a solvent; in the presence of a base; make after dichloro acetamide body (52) or chloroacetamide body (53), sulphur powder and amine (7) reaction; slough protection group; compound (4) is made, gained compound (4) is condensed with carboxylic acid (5), the compound (1) of the present invention can be made.Compound (52) and sulphur powder is suspended in solvent, add the alkali such as diisopropylethylamine or triethylamine and amine (7), carry out reaction in 0~200 DEG C of reaction temperature, compound (54) can be more effectively made.Amount preferably 1N for the sulphur powder of reaction.Preferably 60 DEG C~160 DEG C of reaction temperature, particularly preferably 90 DEG C~140 DEG C.Solvent for the reaction can enumerate the acid amides series solvents such as DMF, the basic solvent such as N-methylmorpholine, pyridine, the ether series solvent, acetonitrile and water etc. such as alcohols , dioxanes such as ethanol, butanol.In addition, making compound (53) and sulphur powder be suspended in solvent, the alkali such as diisopropylethylamine or triethylamine is added, after stirring 5 minutes~5 hours, amine (7) and condensing agent reaction is added, compound (54) can be also made.Amount preferably more than 2N for the sulphur powder of reaction.Preferably 0 DEG C~80 DEG C of reaction temperature.As condensing agent, 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochlorides or N, N can be enumerated '-dicyclohexyl carbodiimide etc..Solvent for the reaction can enumerate the acid amides series solvents such as DMF, the basic solvent such as N-methylmorpholine, pyridine, the ether series solvent such as haloalkyl series solvent , dioxanes such as dichloromethane, chloroform, acetonitrile etc..In addition, the reaction can also carry out that compound (54) is made under conditions of without condensing agent.Now, in addition to aforementioned solvents, the alcohols such as methanol, ethanol and water etc. be it is also possible to use.In addition, using the reaction condition described in preparation method 19, being reacted thiosulfuric acid sodium salt (46) and amine (7), compound (54) being also made.At -20 DEG C~70 DEG C, compound (54) is handled with trifluoroacetic acid etc., compound (4) can be made.
Using the method described in preparation method 1, make T produced above1Reacted for the compound (4) and carboxylic acid (5) of-CS-CO-N (R ')-base (in base, R ' is as previously described), the compound (1) of the present invention can be made.
Other amino protecting groups that the tert-butoxycarbonyl of compound (7) can be recorded with preparation method 2 are substituted.The species for selecting protection group can be accepted or rejected according to compound property etc., also can be according to the protection group selective reagent and reaction condition in tripping protection base.
[preparation method 25]
T1Compound (1) for-CO-N (R ')-CO- bases (in base, R ' is as previously described) can be prepared according to following steps.
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-CO-N (R ')-CO- bases (in base, R ' is as previously described)]
That is, make equivalent to NH (R ') COQ4(55) heteroaryl amide such as the aryl amides such as 4- chlorobenzamides or picoline acid amides reacts via acyl isocyanate intermediate and amine (7); compound (54) is made; then; the compound (54) is deprotected; gained compound (4) is condensed with carboxylic acid (5) again, the compound (1) of the present invention can be made.
For example, in atent solvent, under 20 DEG C~100 DEG C of reaction temperature; acid amides (55) and oxalyl chloride are reacted, acyl isocyanate derivative is made, under 0 DEG C~100 DEG C of reaction temperature; the derivative is reacted with amine (7), compound (54) can be made.Atent solvent for this reaction can enumerate the haloalkyl series solvent such as dichloromethane, chloroform, dichloroethanes, the ether series solvent such as tetrahydrofuran, dioxanes, the fragrant family solvent such as benzene, toluene, N, the acid amides series solvents such as dinethylformamide, DMA, acetonitrile etc..
At -20 DEG C~70 DEG C, processing is carried out to compound (54) with trifluoroacetic acid etc. can be made compound (4).
The method recorded using preparation method 1, makes T produced above1Reacted for the compound (4) and carboxylic acid (5) of-CO-N (R ')-CO- bases (in base, R ' is as previously described), the compound (1) of the present invention can be made.
Other amino protecting groups that the tert-butoxycarbonyl of compound (7) can be recorded with preparation method 2 are substituted.The species for selecting protection group can be accepted or rejected according to compound property etc., also can be according to the protection group selective reagent and reaction condition in tripping protection base.
[preparation method 26]
T1For-SO2- N (R ')-base (in base, R ' is as previously described) compound (1) can be prepared according to following steps.
Figure G2003801097466D00722
[in formula, Q1、Q2、Q3、Q4、R1、R2And R ' is as it was previously stated, T1For-SO2- N (R ')-base (in base, R ' is as previously described)]
In atent solvent, under -78 DEG C~30 DEG C of reaction temperature, make equivalent to HN (R ') Q4The amine such as 4- chloroanilines and chlorosulfonic acid reaction, sulfamic acid derivatives can be made, are made after the derivative activates, to react itself and amine (9), compound (1) can be made with reagent as phosphorus pentachloride., for example also can be using condensing agents such as 1,1- carbonyl dimidazoles in addition to the halide reagents such as phosphorus pentachloride, phosphorus oxychloride as the reagent for activating sulfamic acid derivatives.In this reaction, when being activated using halide reagents such as phosphorus pentachloride, phosphorus oxychlorides, most it is better than 50 DEG C~120 DEG C and is heated.Atent solvent for this reaction can enumerate the haloalkyl series solvent such as dichloromethane, chloroform, dichloroethanes, the ether series solvent such as tetrahydrofuran, dioxanes, the fragrant family solvent such as benzene, toluene, N, the acid amides series solvents such as dinethylformamide, DMA, acetonitrile etc..
Hereinafter, the important intermediate described in the preparation method 1~21 of the compound (1) of the present invention is illustrated.
1) compound that following formulas (4) described in above-mentioned preparation method 1,3 and 11 are represented is that the important of compound (1) of the invention prepares intermediate.
HN(R1)-Q3-N(R2)-T1-Q4(4)
[in formula, R1、R2、Q3And Q4As it was previously stated, T1For carbonyl, sulfonyl or-CO-CO-N (R ')-base (in base, R ' is as previously described)]
In above-mentioned intermediate, preferably T1For the T in the compound and above-mentioned formula of-C (=O)-C (=O)-N (R ')-(in base, R ' is hydrogen atom, hydroxyl, alkyl or alkoxy)1For carbonyl, Q3For following radicals
(in base, R3And R4As it was previously stated, Q5Represent base-(CH2)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH-) compound.
2) compound that following formulas (9) described in preparation method 2,4 and 12 are represented is the important intermediate of the compound (1) of the present invention.
Q1-Q2- C (=O)-N (R1)-Q3-NHR2(9)
[in formula, R1、R2、Q1、Q2And Q3As previously described]
In above-mentioned intermediate, preferably Q3For following radicals
Figure G2003801097466D00741
(in base, R3And R4As it was previously stated, Q5Represent base-(CH2)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH-) compound.
3) following compounds (4c) described in preparation method 7,11 and 13 prepare intermediate for the important of compound (1) of the present invention.
[in formula, Q4、R3、R4, A, m and n be as it was previously stated, T1For carbonyl, sulfonyl or-CO-CO-N (R ')-base (in base, R ' is as previously described)]
In above-mentioned intermediate, the T in preferably above-mentioned formula1For the compound of-CO-CO-N (R ')-base (in base, R ' is as previously described), and T1For carbonyl, A is oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH- compound.
4) following compounds (22) described in preparation method 8 and 13 are that the important of compound (1) of the invention prepares intermediate.
Figure G2003801097466D00743
[in formula, Q4、R3、R4, A, m and n be as it was previously stated, T1For carbonyl, sulfonyl or-CO-CO-N (R ')-base (in base, R ' is as previously described), R51For the protection group of amino]
In above-mentioned intermediate, the T in preferably above-mentioned formula1For the compound of-CO-CO-N (R ')-base (in base, R ' is as previously described), and T1For carbonyl, A is oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH- compound.
5) described in preparation method 6 there is the important of compound (1) of optically active following compounds (7a) for the present invention to prepare intermediate.
[in formula, Q5、R1、R2、R3And R4As it was previously stated, R50For the protection group of amino]
In above-mentioned intermediate, the Q in preferably above-mentioned formula5Represent base-(CH2)m-CH2-A-CH2-(CH2)n- (in base, m and n are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH-) compound.
6) following compounds (21) described in preparation method 8 are that the important of the compound (1) of the present invention prepares intermediate.
Figure G2003801097466D00752
[in formula, R3、R4, A, m and n be as it was previously stated, R51For the protection group of amino]
In above-mentioned intermediate, the A in preferably above-mentioned formula is oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH- compound.
7) following compounds described in preparation method 10 are that the important of the compound (1) of the present invention prepares intermediate.
That is, with optically active following trans-compounds (30), (31) and (32),
[in formula, R3, m and n be as it was previously stated, R51And R61For the protection group of amino]
The enantiomer (30a), (31a) and (32a) of same obtained above-claimed cpd,
Figure G2003801097466D00761
[in formula, R3, m and n be as it was previously stated, R51And R61For the protection group of amino]
Cis-compound (30b), (31b), (32b),
Figure G2003801097466D00762
[in formula, R3, m and n be as it was previously stated, R51And R61For the protection group of amino]
And their enantiomer (30c), (31c), (32c),
Figure G2003801097466D00763
[in formula, R3, m and n be as it was previously stated, R51And R61For the protection group of amino] as the present invention compound (1) to prepare intermediate extremely important.
The inhibitory action of activated form factor X of the diamine derivative of the present invention due to showing strength, so being used as mammiferous pharmaceuticals including people, particularly activated form factor X inhibitor, Coagulative inhibitors agent, the prevention of thrombus or embolism and/or therapeutic agent, the prevention of thrombotic diseases and/or therapeutic agent, cerebral infarction, cerebral embolism, miocardial infarction, angina pectoris, lung blocks, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve/joint replacement, blood flow build again after thrombosis and inaccessible again, systemic inflammatory reaction syndrome (SIRS), MODS (MODS), the prevention of blood clotting when thrombosis during extracorporal circulatory system or blood sampling and/or therapeutic agent are useful.
The compounds of this invention 1 day 1mg~1g, preferably 10mg~300mg in use, dosage is grown up as human body pharmaceuticals.Animal is different according to administration purpose (treatment or prevention), the species for the animal that need to be disposed and size, the species of the pathogen of infection and degree with dosage, the dosage of 1 day corresponds generally to every 1kg the weight of animals for 0.1mg~200mg, preferably 0.5mg~100mg.The amount of 1 day can 1 day 1 time or point 2~4 administrations.In addition, the dosage of 1 day can also exceed above-mentioned amount as needed.
Medical composition containing the compounds of this invention can select appropriate preparation according to medication, can be modulated by the modulation method of conventional various preparations.Formulation using the compounds of this invention as the medical composition of host can enumerate the tablet as oral formulations, powder, granule, suspending agent of capsule and solution, syrup, elixir, oiliness~aqueous etc..
As injection, stabilizer, preservative and cosolvent can be used in the formulation, and the solution containing these auxiliary agents is loaded after container, the preparation further modulated when forming the use as solid pharmaceutical preparation by freeze-drying etc..In addition, 1 dosage can be fitted into a container, multiple dosing amount can be also fitted into a container.
Can exemplary solutions agent, suspending agent, emulsion, ointment, gel, creme, lotion, spray, patch etc. as external preparation.
, can also be then formulation such as can select mixed filler class, extender class, adhesive class, disintegrant class, chaotropic agent class, wetting agent class, lubricant as needed containing the additive allowed in pharmacy in solid pharmaceutical preparation in addition to the compounds of this invention.
Solution, suspending agent, emulsion etc. can be enumerated as liquid preparation, can contain suspending agent, emulsifying agent etc. as additive.
As the example of the compounds of this invention, following compound (A)~(E) can be enumerated.
(A) formula (1)
Q1- C (=O)-N (R1)-Q2-N(R2)-T1-Q3(1)
The compound of expression, its salt, their solvate or their N- oxides；
In formula, R1And R2It is each independent, represent hydrogen atom, hydroxyl, alkyl or alkoxy；
Q1The saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups can with substituent are represented, can have the saturation or undersaturated 5~6 circle heterocycles base of substituent, can have the saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q2Represent following radicals,
Figure G2003801097466D00771
Q in the group4For the alkylidene of carbon number 1~8, the alkenylene of carbon number 2~8 or base-(CH2)m-CH2-A-CH2-(CH2)n- (m and n in group are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2- NH-, 1 and 2 represents position)；
R3And R4Containing Q4Ring on carbon atom,Replaced on nitrogen-atoms or sulphur atom,It is each independent,Represent hydrogen atom,Hydroxyl,Alkyl,Alkenyl,Alkynyl,Halogen atom,Haloalkyl,Cyano group,Cyanoalkyl,Amino,Aminoalkyl,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,Acyl,There can be the acyl amino of substituent,Alkoximino,Oxyimino,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Carboxyalkyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxy carbonyl alkyl amino,Carboxyalkylamino,Alkoxycarbonyl amino,Alkoxycarbonylamino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkoxycarbamoyl alkyl,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,Carbamoylalkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Carbamoyloxy alkyl,N- alkyl carbamoyloxy base alkyl,N,N- dialkylcarbamoyloxy alkyl,There can be 3~6 circle heterocycles carbonylic alkyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,Aryl,Aralkyl,Heteroaryl,Heteroaryl alkyl,Alkyl sulfonyl amino,Arenesulfonyl amino,Alkyl sulfonyl amino alkyl,Arenesulfonyl amino alkyl,Alkylsulphonylaminocarbonyl,Arenesulfonyl amino carbonyl,Alkylsulphonylaminocarbonyl alkyl,Arenesulfonyl amino carbonylic alkyl,Oxo base,Carbamoyloxy,Aralkoxy,Carboxyalkoxy,Acyloxy,Acyloxyallcyl,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Alkoxyalkoxycarbonyl,Hydroxyl acyl group,Alkoxyacyl,Halogenacyl,Carboxyacyl,Aminoacyl,Acyloxy acyl group,Acyloxyallcyl sulfonyl,Hydroxy alkyl sulfonyl,Alkoxyalkyl sulfonyl,There can be 3~6 circle heterocycles sulfonyls of substituent,N- alkylaminoacyls,N,N- dialkyl amido acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl sulphonyls,Alkyl sulphonyl acyl group etc. or R3And R4Alkylidene, the alkenylene of carbon number 2~5, the alkylene dioxo base or carbonyldioxy of carbon number 1~5 of carbon number 1~5 are represented together；
Q3Represent the fusion alkyl of the aryl can with substituent, the heteroaryl that there can be the aromatic yl alkenyl of substituent, there can be substituent, the heteroarylalkenyl groups can with substituent, the saturation or unsaturated 2 ring can with substituent or 3 rings, can have the saturation of substituent or the annelated heterocycles base of unsaturated 2 ring or 3 rings；T1Represent carbonyl or sulfonyl.
(B) formula (1)
Q1-Q2- C (=O)-N (R1)-Q3-N(R2)-T1-Q4(1)
The compound of expression, its salt, their solvate or their N- oxides；
In formula, R1And R2It is each independent, represent hydrogen atom, hydroxyl, alkyl or alkoxy；
Q1The saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups can with substituent are represented, can have the saturation or undersaturated 5~6 circle heterocycles base of substituent, can have the saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q2Singly-bound, the divalent saturation or undersaturated 5~6 ring heterocyclic radical that can have the divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups of substituent, there can be substituent are represented, can have the divalent saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the divalent saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q3Represent following radicals,
Q in the group5For the alkylidene of carbon number 1~8, the alkenylene of carbon number 2~8 or base-(CH2)m-CH2-A-CH2-(CH2)n- (m and n in group are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2-NH-)；
R3And R4Containing Q5Ring on carbon atom,Replaced on nitrogen-atoms or sulphur atom,It is each independent,Represent hydrogen atom,Hydroxyl,Alkyl,Alkenyl,Alkynyl,Halogen atom,Haloalkyl,Cyano group,Cyanoalkyl,Amino,Aminoalkyl,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,Acyl,There can be the acyl amino of substituent,Alkoximino,Oxyimino,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Carboxyalkyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxy carbonyl alkyl amino,Carboxyalkylamino,Alkoxycarbonyl amino,Alkoxycarbonylamino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkoxycarbamoyl alkyl,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,Carbamoylalkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Carbamoyloxy alkyl,N- alkyl carbamoyloxy base alkyl,N,N- dialkylcarbamoyloxy alkyl,There can be 3~6 circle heterocycles carbonylic alkyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,Aryl,Aralkyl,Heteroaryl,Heteroaryl alkyl,Alkyl sulfonyl amino,Arenesulfonyl amino,Alkyl sulfonyl amino alkyl,Arenesulfonyl amino alkyl,Alkylsulphonylaminocarbonyl,Arenesulfonyl amino carbonyl,Alkylsulphonylaminocarbonyl alkyl,Arenesulfonyl amino carbonylic alkyl,Oxo base,Carbamoyloxy,Aralkoxy,Carboxyalkoxy,Acyloxy,Acyloxyallcyl,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Alkoxyalkoxycarbonyl,Hydroxyl acyl group,Alkoxyacyl,Halogenacyl,Carboxyacyl,Aminoacyl,Acyloxy acyl group,Acyloxyallcyl sulfonyl,Hydroxy alkyl sulfonyl,Alkoxyalkyl sulfonyl,There can be 3~6 circle heterocycles sulfonyls of substituent,N- alkylaminoacyls,N,N- dialkyl amido acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl sulphonyls,Alkyl sulphonyl acyl group etc. or R3And R4Alkylidene, the alkenylene of carbon number 2~5, the alkylene dioxo base or carbonyldioxy of carbon number 1~5 of carbon number 1~5 are represented together；
Q4Represent the fusion alkyl of the aryl can with substituent, the heteroaryl that there can be the aromatic yl alkenyl of substituent, there can be substituent, the heteroarylalkenyl groups can with substituent, the saturation or unsaturated 2 ring can with substituent or 3 rings, can have the saturation of substituent or the annelated heterocycles base of unsaturated 2 ring or 3 rings；
T1Represent carbonyl, sulfonyl or base-C (=O)-C- (=O)-N (R ')-(R ' in group represents hydrogen atom, hydroxyl, alkyl or alkoxy).
(C) formula (1)
Q1-Q2- C (=O)-N (R1)-Q3-N(R2)-T1-Q4(1)
The compound of expression, its salt, their solvate or their N- oxides；
In formula, R1And R2It is each independent, represent hydrogen atom, hydroxyl, alkyl or alkoxy；
Q1The saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups can with substituent are represented, can have the saturation or undersaturated 5~7 circle heterocycles base of substituent, can have the saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q2Singly-bound, the divalent saturation or undersaturated 5~7 ring heterocyclic radical that can have the divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups of substituent, there can be substituent are represented, can have the divalent saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the divalent saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q3Represent following radicals,
Figure G2003801097466D00801
Q in the group5For the alkylidene of carbon number 1~8, the alkenylene of carbon number 2~8 or base-(CH2)m-CH2-A-CH2-(CH2)n- (m and n in group are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2-NH-)；
R3And R4Containing Q5Ring on carbon atom,Replaced on nitrogen-atoms or sulphur atom,It is each independent,Represent hydrogen atom,Hydroxyl,Alkyl,Alkenyl,Alkynyl,Halogen atom,Haloalkyl,Cyano group,Cyanoalkyl,Amino,Aminoalkyl,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,Acyl,There can be the acyl amino of substituent,Alkoximino,Oxyimino,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Carboxyalkyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxy carbonyl alkyl amino,Carboxyalkylamino,Alkoxycarbonyl amino,Alkoxycarbonylamino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkoxycarbamoyl alkyl,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,Carbamoylalkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Carbamoyloxy alkyl,N- alkyl carbamoyloxy base alkyl,N,N- dialkylcarbamoyloxy alkyl,There can be 3~6 circle heterocycles carbonylic alkyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,Aryl,Aralkyl,Heteroaryl,Heteroaryl alkyl,Alkyl sulfonyl amino,Arenesulfonyl amino,Alkyl sulfonyl amino alkyl,Arenesulfonyl amino alkyl,Alkylsulphonylaminocarbonyl,Arenesulfonyl amino carbonyl,Alkylsulphonylaminocarbonyl alkyl,Arenesulfonyl amino carbonylic alkyl,Oxo base,Carbamoyloxy,Aralkoxy,Carboxyalkoxy,Acyloxy,Acyloxyallcyl,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Alkoxyalkoxycarbonyl,Hydroxyl acyl group,Alkoxyacyl,Halogenacyl,Carboxyacyl,Aminoacyl,Acyloxy acyl group,Acyloxyallcyl sulfonyl,Hydroxy alkyl sulfonyl,Alkoxyalkyl sulfonyl,There can be 3~6 circle heterocycles sulfonyls of substituent,N- alkylaminoacyls,N,N- dialkyl amido acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyls alkyl sulphonyl or alkyl sulphonyl acyl group etc. or R3And R4Alkylidene, the alkenylene of carbon number 2~5, the alkylene dioxo base or carbonyldioxy of carbon number 1~5 of carbon number 1~5 are represented together；
Q4Represent the fusion alkyl of the aryl can with substituent, the aromatic yl polysulfide yl that there can be the aromatic yl alkenyl of substituent, there can be substituent, the heteroarylalkenyl groups that there can be the heteroaryl of substituent, there can be substituent, the saturation or unsaturated 2 ring can with substituent or 3 rings, can have the saturation of substituent or the annelated heterocycles base of unsaturated 2 ring or 3 rings；
T1Represent carbonyl, sulfonyl, base-C (=O)-C- (=O)-N (R ')-(R ' in group represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-A1- N (R ")-(A in group1Represent can there is the alkylidene of the carbon number 1~5 of substituent, R " represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-, base-C (=S)-NH-, base-C (=O)-NH-NH-, base-C (=O)-A2- C (=O)-(the A in group2Represent the alkylidene of singly-bound or carbon number 1~5), base-C (=O)-A3- the C (=O)-NH- (A in group3Represent the alkylidene of carbon number 1~5) or thiocarbonyl.
(D) formula
Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4(1)
The compound of expression, its salt, their solvate or their N- oxides；
In formula, R1And R2It is each independent, represent hydrogen atom, hydroxyl, alkyl or alkoxy；
Q1The saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups can with substituent are represented, can have the saturation or undersaturated 5~7 circle heterocycles base of substituent, can have the saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q2Singly-bound, the divalent saturation or undersaturated 5~7 ring heterocyclic radical that can have the divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups of substituent, there can be substituent are represented, can have the divalent saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the divalent saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q3Represent following radicals,
Q in the group5For the alkylidene of carbon number 1~8, the alkenylene of carbon number 2~8 or base-(CH2)m-CH2-A-CH2-(CH2)n- (m and n in group are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2-NH-)；
R3And R4Containing Q5Ring on carbon atom,Replaced on nitrogen-atoms or sulphur atom,It is each independent,Represent hydrogen atom,Hydroxyl,Alkyl,Alkenyl,Alkynyl,Halogen atom,Haloalkyl,Cyano group,Cyanoalkyl,Amino,Aminoalkyl,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,Acyl,There can be the acyl amino of substituent,Alkoximino,Oxyimino,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Carboxyalkyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxy carbonyl alkyl amino,Carboxyalkylamino,Alkoxycarbonyl amino,Alkoxycarbonylamino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkoxycarbamoyl alkyl,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,Carbamoylalkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Carbamoyloxy alkyl,N- alkyl carbamoyloxy base alkyl,N,N- dialkylcarbamoyloxy alkyl,There can be 3~6 circle heterocycles carbonylic alkyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,Aryl,Aralkyl,Heteroaryl,Heteroaryl alkyl,Alkyl sulfonyl amino,Arenesulfonyl amino,Alkyl sulfonyl amino alkyl,Arenesulfonyl amino alkyl,Alkylsulphonylaminocarbonyl,Arenesulfonyl amino carbonyl,Alkylsulphonylaminocarbonyl alkyl,Arenesulfonyl amino carbonylic alkyl,Oxo base,Carbamoyloxy,Aralkoxy,Carboxyalkoxy,Acyloxy,Acyloxyallcyl,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Alkoxyalkoxycarbonyl,Hydroxyl acyl group,Alkoxyacyl,Halogenacyl,Carboxyacyl,Aminoacyl,Acyloxy acyl group,Acyloxyallcyl sulfonyl,Hydroxy alkyl sulfonyl,Alkoxyalkyl sulfonyl,There can be 3~6 circle heterocycles sulfonyls of substituent,N- alkylaminoacyls,N,N- dialkyl amido acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyls alkyl sulphonyl or alkyl sulphonyl acyl group etc. or R3And R4Alkylidene, the alkenylene of carbon number 2~5, the alkylene dioxo base or carbonyldioxy of carbon number 1~5 of carbon number 1~5 are represented together；
Q4Represent the fusion alkyl of the aryl can with substituent, the aromatic yl polysulfide yl that there can be the aromatic yl alkenyl of substituent, there can be substituent, the heteroarylalkenyl groups that there can be the heteroaryl of substituent, there can be substituent, the saturation or unsaturated 2 ring can with substituent or 3 rings, can have the saturation of substituent or the annelated heterocycles base of unsaturated 2 ring or 3 rings；
T0Represent carbonyl or thiocarbonyl；
T1Represent carbonyl, sulfonyl, base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C- (=O)-N (R ')-, base-C (=O)-C- (=S)-N (R ')-, base-C (=S)-C- (=S)-N (R ')-(R ' in group represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-A1- N (R ")-(A in group1Represent can there is the alkylidene of the carbon number 1~5 of substituent, R " represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-, base-C (=S)-NH-, base-C (=O)-NH-NH-, base-C (=O)-A2- C (=O)-(the A in group2Represent the alkylidene of singly-bound or carbon number 1~5), base-C (=O)-A3- (=O)-NH- (the A in group3Represent carbon number 1~5 alkylidene), base-C (=O)-C (=NORa)-N(Rb)-, base-C (=S)-C (=NORa)-N(RbR in)-(groupaRepresent hydrogen atom, alkyl or alkanoyl, RbRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-N=N-, base-C (=S)-N=N- or thiocarbonyl.
(E) formula (1)
Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4(1)
The compound of expression, its salt, their solvate or their N- oxides；
In formula, R1And R2It is each independent, represent hydrogen atom, hydroxyl, alkyl or alkoxy；
Q1The saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups can with substituent are represented, can have the saturation or undersaturated 5~7 circle heterocycles base of substituent, can have the saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q2Singly-bound, the divalent saturation or undersaturated 5~7 ring heterocyclic radical that can have the divalent saturation or undersaturated 5~6 yuan of cyclic hydrocarbon groups of substituent, there can be substituent are represented, can have the divalent saturation or undersaturated 2 ring of substituent or the fusion alkyl of 3 rings or can have the divalent saturation of substituent or the annelated heterocycles base of undersaturated 2 ring or 3 rings；
Q3Represent following radicals,
Figure G2003801097466D00841
Q in the group5For the alkylidene of carbon number 1~8, the alkenylene of carbon number 2~8 or base-(CH2)m-CH2-A-CH2-(CH2)n- (m and n in group are each independent, represent 0,1~3 integer, and A represents oxygen atom, nitrogen-atoms, sulphur atom ,-SO- ,-SO2- ,-NH- ,-O-NH- ,-NH-NH- ,-S-NH- ,-SO-NH- or-SO2-NH-)；
R3And R4Containing Q5Ring on carbon atom,Replaced on nitrogen-atoms or sulphur atom,It is each independent,Represent hydrogen atom,Hydroxyl,Alkyl,Alkenyl,Alkynyl,Halogen atom,Haloalkyl,Cyano group,Cyanoalkyl,Amino,Aminoalkyl,N- alkylaminoalkyl groups,N,N- dialkyl aminoalkyls,Acyl group,Acyl,There can be the acyl amino of substituent,Alkoximino,Oxyimino,Acylaminoalkyl,Alkoxy,Alkoxyalkyl,Hydroxy alkyl,Carboxyl,Carboxyalkyl,Alkoxy carbonyl,Alkoxy carbonyl alkyl,Alkoxy carbonyl alkyl amino,Carboxyalkylamino,Alkoxycarbonyl amino,Alkoxycarbonylamino,Carbamoyl,There can be the N- alkyl-carbamoyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyls,N- alkenyl amino formoxyls,N- alkenyl amino carbamoylalkyls,N- alkenyl-N- alkyl-carbamoyls,N- alkenyl-N- alkylcarbamoylalkyls,N- alkoxycarbamoyls,N- alkyl-N- alkoxycarbamoyls,N- alkoxycarbamoyl alkyl,N- alkyl-N- alkoxycarbamoyl alkyl,Can be by 1~3 alkyl-substituted carbazyl,Alkyl sulphonyl,Alkylsulfonylalkyl,There can be 3~6 circle heterocycles carbonyls of substituent,Carbamoylalkyl,There can be the N- alkylcarbamoylalkyls of substituent on alkyl,There can be the N of substituent on alkyl,N- dialkyl carbamoyl alkyl,Carbamoyloxy alkyl,N- alkyl carbamoyloxy base alkyl,N,N- dialkylcarbamoyloxy alkyl,There can be 3~6 circle heterocycles carbonylic alkyls of substituent,There can be 3~6 circle heterocycles carbonyl epoxide alkyl of substituent,Aryl,Aralkyl,Heteroaryl,Heteroaryl alkyl,Alkyl sulfonyl amino,Arenesulfonyl amino,Alkyl sulfonyl amino alkyl,Arenesulfonyl amino alkyl,Alkylsulphonylaminocarbonyl,Arenesulfonyl amino carbonyl,Alkylsulphonylaminocarbonyl alkyl,Arenesulfonyl amino carbonylic alkyl,Oxo base,Carbamoyloxy,Aralkoxy,Carboxyalkoxy,Acyloxy,Acyloxyallcyl,Aryl sulfonyl,Alkoxy carbonyl alkyl sulfonyl,Carboxyalkyl sulfonyl,Alkoxy carbonyl acyl group,Alkoxyalkoxycarbonyl,Hydroxyl acyl group,Alkoxyacyl,Halogenacyl,Carboxyacyl,Aminoacyl,Acyloxy acyl group,Acyloxyallcyl sulfonyl,Hydroxy alkyl sulfonyl,Alkoxyalkyl sulfonyl,There can be 3~6 circle heterocycles sulfonyls of substituent,N- alkylaminoacyls,N,N- dialkyl amido acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyl acyl groups,There can be the N of substituent on alkyl,N- dialkyl carbamoyls alkyl sulphonyl or alkyl sulphonyl acyl group etc. or R3And R4Alkylidene, the alkenylene of carbon number 2~5, the alkylene dioxo base or carbonyldioxy of carbon number 1~5 of carbon number 1~5 are represented together；
Q4Represent the fusion alkyl of the aryl can with substituent, the aromatic yl polysulfide yl that there can be the aromatic yl alkenyl of substituent, there can be substituent, the heteroarylalkenyl groups that there can be the heteroaryl of substituent, there can be substituent, the saturation or unsaturated 2 ring can with substituent or 3 rings, can have the saturation of substituent or the annelated heterocycles base of unsaturated 2 ring or 3 rings；
T0Represent carbonyl or thiocarbonyl；
T1Represent carbonyl, sulfonyl, base-C (=O)-C- (=O)-N (R ')-, base-C (=S)-C- (=O)-N (R ')-, base-C (=O)-C- (=S)-N (R ')-, base-C (=S)-C- (=S)-N (R ')-(R ' in group represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-A1- N (R ")-(A in group1Represent can there is the alkylidene of the carbon number 1~5 of substituent, R " represents hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-NH-, base-C (=S)-NH-, base-C (=O)-NH-NH-, base-C (=O)-A2- C (=O)-(the A in group2Represent the alkylidene of singly-bound or carbon number 1~5), base-C (=O)-A3- the C (=O)-NH- (A in group3Represent carbon number 1~5 alkylidene), base-C (=O)-C (=NORa)-N(Rb)-, base-C (=S)-C (=NORa)-N(RbR in)-(groupaRepresent hydrogen atom, alkyl or alkanoyl, RbRepresent hydrogen atom, hydroxyl, alkyl or alkoxy), base-C (=O)-N=N-, base-C (=S)-N=N- or thiocarbonyl.
Embodiment
Hereinafter, enumerate embodiment the present invention will be described
[reference example 1] pyridin-4-yl t-butyl carbamate
4-aminopyridine (10g) is dissolved in tetrahydrofuran (500ml), di-tert-butyl dicarbonate (25.5g) is added, stirred 10 minutes at room temperature.Reaction solution is concentrated under reduced pressure, the solid separated out is washed with hexane, title compound (16.9g) is obtained.
1H-NMR(CDCl3)δ：1.53 (9H, s), 6.86 (1H, br.s), 7.30 (2H, dd, J=1.5,4.9Hz), 8.44 (2H, dd, J=1.5,4.9Hz)
MS(FAB)m/z：195(M+H)+.
[reference example 2] 3- mercaptopyridine -4- carbamates
The compound (61.6g) that reference example 1 is obtained is dissolved in tetrahydrofuran (2000ml), is stirred 10 minutes in -78 DEG C.N-BuLi (1.59N hexane solution, 500ml) is instilled in reaction solution, after stirring 10 minutes, is stirred 2 hours under ice-cooling.Reaction solution is cooled to after -78 DEG C, adds Sulfur powder (12.2g), is warming up to after room temperature and is stirred 1 hour.Add water (1000ml) point liquid in reaction solution.After pH is adjusted to 3~4 by the hydrochloric acid that water layer adds 3N, dichloromethane point liquid is added.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression.Residue (dichloromethane: methanol=50: 1) is refined with silica gel column chromatography, obtains title compound (33.2g).
1H-NMR(DMSO-d6)δ：1.52 (9H, s), 7.89 (1H, d, J=6.4Hz), 7.99 (1H, d, J=6.4Hz), 8.20 (1H, s), 9.91 (1H, br.s)
MS(FAB)m/z：227(M+H)+.
[reference example 3] thiazole simultaneously [5,4-c] pyridine
Figure G2003801097466D00861
The compound (33.2g) that reference example 2 is obtained is dissolved in formic acid (250ml), is heated to reflux 3 days.The lower concentration of reaction solution of decompression, the potassium hydroxide aqueous solution (100ml) and ether that 5N is added in residue carries out a point liquid.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: methanol=25: 1) is refined with silica gel column chromatography, obtains title compound (9.03g).
1H-NMR(CDCl3)δ：8.05 (1H, d, J=5.4Hz), 8.70 (1H, d, J=5.4Hz), 9.23 (1H, s), 9.34 (1H, s)
MS(FAB)m/z：137(M+H)+.
[reference example 4] 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine
The compound (1.61g) for obtaining reference example 3 was dissolved in DMF (50ml), adds after methyl iodide (1.50ml), in 80 DEG C of heating stirrings 4 hours.The lower concentration of reaction solution of decompression, residue is dissolved in methanol (100ml), sodium borohydride (1.53g) is added, stirred 1 hour at room temperature.The lower concentration of reaction solution of decompression, unsaturated carbonate aqueous solutions of potassium is added in residue and ether carries out a point liquid.Boiled off under organic layer anhydrous sodium sulfate drying, decompression after solvent, residue (dichloromethane: methanol=25: 1) is refined with silica gel column chromatography, obtains title compound (1.28g).
1H-NMR(CDCl3)δ：2.52 (3H, s), 2.83 (2H, t, J=5.9Hz), 2.98 (2H, t, J=5.9Hz), 3.70 (2H, s), 8.63 (1H, s)
MS(FAB)m/z：155(M+H)+.
[reference example 5] 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids lithium salts
Figure G2003801097466D00863
The compound (6.43g) that reference example 4 is obtained is dissolved in anhydrous tetrahydro furan (200ml), and instilling n-BuLi (1.47N hexane solution, 34.0ml) in -78 DEG C stirs 40 minutes.After introducing carbon dioxide gas, room temperature is warming up in reaction solution in -78 DEG C, the lower concentration of reaction solution of decompression obtains title compound (9.42g).
1H-NMR(DMSO-d6)δ：2.37 (3H, s), 2.64-2.77 (4H, m), 3.54 (2H, s)
MS(FAB)m/z：199(M+H)+.
[reference example 6] 2- amino -6,7- thiazoline simultaneously [5,4-c] pyridine -5 [4H]-carboxylic acid tert-butyl ester
1- tert-butoxycarbonyl -4- piperidones (40.0g) is dissolved in hexamethylene (80ml), the hydrate of p-methyl benzenesulfonic acid 1 (191mg) and pyrrolidines (17.6ml) are added, is heated to reflux while dehydration with Dean and Stark apparatus 2 hours.After the lower concentration of reaction solution of decompression, residue is dissolved in methanol (60ml), Sulfur powder (6.42g) is added.Cyanamide (8.44g) methanol solution (10ml) is slowly instilled under ice cooling, is stirred 5 hours at room temperature.The solid that leaching is separated out, obtains title compound (31.0g).
1H-NMR(DMSO-d6)δ：1.41 (9H, s), 2.44 (2H, t, J=5.6Hz), 3.57 (2H, t, J=5.6Hz), 4.29 (2H, s), 6.79 (2H, s)
MS(EI)m/z：255(M+).
Bromo- 6, the 7- thiazolines of [reference example 7] 2- simultaneously [5,4-c] pyridine -5 [4H]-carboxylic acid tert-butyl ester
Copper bromide (1.05g) is suspended in N, in dinethylformamide (20ml), added under ice cooling after the compound (1.00g) that nitrite tert-butyl (0.696ml) and reference example 6 are obtained, in 40 DEG C of heating stirring reaction solutions 30 minutes.The lower concentration of reaction solution of decompression, residue (ethyl acetate: hexane=1: 5) is refined with silica gel column chromatography, obtains title compound (568mg).
1H-NMR(CDCl3)δ：1.48 (9H, s), 2.85 (2H, br.s), 3.72 (2H, br.s), 4.56 (2H, br.s)
MS(FAB)m/z：319(M+H)+.
[reference example 8] 2- bromo- 4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine trifluoroacetate
The compound (890mg) that reference example 7 is obtained is dissolved in dichloromethane (2ml), is added trifluoroacetic acid (15ml) and is stirred at room temperature 30 seconds.The lower concentration of reaction solution of decompression, adds ether in residue, and the solid that leaching is separated out obtains title compound (867mg).
1H-NMR(DMSO-d6)δ：2.98 (2H, t, J=6.1Hz), 3.45 (2H, t, J=6.1Hz), 4.35 (2H, s), 9.53 (2H, br.s)
MS(FAB)m/z：219(M+H)+.
The bromo- 5- methyl -4,5 of [reference example 9] 2-, 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine
The compound (422mg) that reference example 8 is obtained is suspended in dichloromethane (10ml), add after triethylamine (0.356ml) dissolving, sequentially add acetic acid (0.216ml), formalin (35% solution, 0.202ml), sodium triacetoxy borohydride (428mg), is stirred 1 hour at room temperature.Saturated sodium bicarbonate aqueous solution (100ml), dichloromethane (100ml) and 3N sodium hydrate aqueous solution (3ml) are added in reaction solution, a point liquid operation is carried out.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtains title compound (286mg).
1H-NMR(CDCl3)δ：2.49 (3H, s), 2.79 (2H, t, J=5.7Hz), 2.85-2.93 (2H, m), 3.58 (2H, t, J=1.8Hz)
MS(FAB)m/z：233(M+H)+.
[reference example 10] 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids lithium salts
The compound (531mg) that reference example 9 is obtained is dissolved in absolute ether (20ml), is instilled under n-BuLi (1.54N hexane solution, 1.63ml), ice cooling and is stirred 30 minutes in -78 DEG C.In -78 DEG C after introducing carbon dioxide gas 10 minutes, room temperature is warming up in reaction solution.The lower concentration of reaction solution of decompression, obtains title compound (523mg).
1H-NMR(DMSO-d6)δ：2.37 (3H, s), 2.64-2.85 (4H, m), 3.54 (2H, s)
[reference example 11] 2- [(E) -2- phenyl vinyl] oxazole -4- carboxylic acid, ethyl esters
Figure G2003801097466D00891
Synthesized according to Panek etc. report (J.Org.Chem., 1996, volume 61, page 6496).Sodium acid carbonate (22.8g) and ethyl bromide acetone (10.5ml) are added in cinnamamide (10.0g) tetrahydrofuran (250ml) solution at room temperature, is heated to reflux 48 hours.Reaction mixture is naturally cooled to after room temperature, is filtered with diatomite, and the lower concentration of decompression obtains residue.TFAA (30ml) is added in 0 DEG C of tetrahydrofuran (30ml) solution in the residue, room temperature is slowly ramped to.After stirring 63 hours, saturated sodium bicarbonate aqueous solution (500ml) is added in reaction mixture and ethyl acetate (150ml) carries out a point liquid, aqueous layer with ethyl acetate (150ml) extraction.After merging organic layer is washed with saturated aqueous common salt (150ml), with anhydrous sodium sulfate drying, decompression is lower to be concentrated, and residue (hexane: ethyl acetate=5: 1 → 3: 1) is refined with silica gel column chromatography, obtains title compound (10.9g).
1H-NMR(CDCl3)δ：1.41 (3H, t, J=7.0Hz), 4.42 (2H, q, J=7.0Hz), 6.96 (1H, d, J=16.6Hz), 7.30-7.40 (3H, m), 7.53 (2H, d, J=6.8Hz), 7.63 (1H, d, J=16.6Hz), 8.20 (1H, s)
[reference example 12] 2- [(E) -2- phenyl vinyl] oxazole -4- formaldehyde
Figure G2003801097466D00892
Diisobutylaluminium hydride (1.0N hexane solution, 66ml) is added dropwise in dichloromethane (80ml) solution for the compound (8.57g) that reference example 11 is obtained in -78 DEG C.After stirring 15 minutes, methanol (11ml) is added dropwise, room temperature was warming up to 1 hour.After reaction mixture is filtered with diatomite, gained pastel is dissolved in ethyl acetate (200ml) and saturated aqueous ammonium chloride (200ml), water layer is extracted with dichloromethane (2 × 100ml) after point liquid.Merge organic layer, washed with saturated sodium bicarbonate aqueous solution (100ml) and saturated aqueous common salt (100ml), merge filtrate during diatomite filtering, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: ethyl acetate=5: 1 → dichloromethane: methanol=10: 1) is refined with silica gel column chromatography, obtains title compound (5.86g).
1H-NMR(CDCl3)δ：6.96 (1H, d, J=16.6Hz), 7.35-7.45 (3H, m), 7.56 (2H, d, J=6.4Hz), 7.67 (1H, d, J=16.6Hz), 8.26 (1H, s), 9.98 (1H, s)
MS(FAB)m/z：200(M+H)+.
[reference example 13] 2- [(E) -2- phenyl vinyls] -4- Yi Xi Ji oxazoles
N-BuLi (1.54N hexane solution, 14.2ml) is added dropwise in tetrahydrofuran (80ml) solution of bromination (methyl) triphenyl phosphonium (8.16g) in 0 DEG C, stirs 30 minutes at room temperature.Reaction mixture is cooled to 0 DEG C again, tetrahydrofuran (20ml) solution for the compound (3.64g) that reference example 12 is obtained is added, is warming up to room temperature.After stirring 2 hours, add water (200ml) and ethyl acetate (100ml) divides liquid, aqueous layer with ethyl acetate (50ml) extraction afterwards.Merge organic layer, washed with saturated aqueous common salt (100ml), after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=4: 1 → 3: 1) is refined with silica gel column chromatography, obtains title compound (2.84g).
1H-NMR(CDCl3)δ：5.33 (1H, dd, J=1.5,10.7Hz), 5.98 (1H, dd, J=1.5,17.6Hz), 6.56 (1H, dd, J=10.7,17.6Hz), 6.95 (1H, d, J=16.6Hz), 7.31-7.42 (3H, m), 7.49-7.56 (4H, m)
MS(FAB)m/z：198(M+H)+.
[reference example 14] 2- { 2- [(E) -2- phenyl vinyl] oxazole -4- bases } -1- ethanol
Figure G2003801097466D00902
9- borabi cyclos [3.3.1] nonane (0.5N tetrahydrofuran solution, 158ml) is added in tetrahydrofuran (500ml) solution for the compound (13.0g) that reference example 13 is obtained in 0 DEG C, is stirred 15 hours at room temperature.Drip water (10ml), 3N sodium hydrate aqueous solution (80ml) and aqueous hydrogen peroxide solution (80ml) in reaction mixture successively in 0 DEG C, stirs 6 hours at room temperature.Water (600ml) is added in reaction mixture and ethyl acetate (200ml) is carried out after point liquid, aqueous layer with ethyl acetate (200ml) extraction.Merge organic layer to be washed with saturated aqueous common salt (200ml), then with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue with silica gel column chromatography (hexane: ethyl acetate=2: 1 → only use ethyl acetate) it is refined, obtain title compound (14.1g).
1H-NMR(CDCl3)δ：2.69 (1H, br.s), 2.80 (2H, t, J=5.6Hz), 3.90-3.97 (2H, m), 6.91 (1H, d, J=16.6Hz), 7.30-7.42 (4H, m), 7.43-7.56 (3H, m)
MS(FAB)m/z：216(M+H)+.
[reference example 15] 2- (2- { 2- [(E) -2- phenyl vinyl] oxazole -4- bases } ethyl) -1H- iso-indoles -1,3 (2H)-diketone
Figure G2003801097466D00911
At room temperature, phthalimide (200mg), triphenyl phasphine (357mg) and diethylazodicarboxylate (0.214ml) are added in tetrahydrofuran (15ml) solution for the compound (292mg) that reference example 14 is obtained, is stirred 4 hours.The solvent of reaction mixture is boiled off under decompression.Residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography, obtains title compound (447mg).
1H-NMR(CDCl3)δ：2.98 (2H, t, J=7.2Hz), 4.03 (2H, t, J=7.2Hz), 6.88 (1H, d, J=16.6Hz), 7.28-7.45 (5H, m), 7.48 (2H, d, J=7.3Hz), 7.71 (2H, dd, J=2.9,5.4Hz), 7.84 (2H, dd, J=2.9,5.4Hz)
MS(FAB)m/z：345(M+H)+.
[reference example 16] 2- { 2- [(E) -2- phenyl vinyl] oxazole -4- bases } ethylcarbamate
Figure G2003801097466D00912
At room temperature, the hydrate of hydrazine 1 (1.50ml) is added in ethanol (150ml) solution for the compound (6.40g) that reference example 15 is obtained, after stirring 1 hour, the hydrate of hydrazine 1 (0.500ml) is added in room temperature again, is stirred 2 hours.Then, dichloromethane (150ml), saturated sodium bicarbonate aqueous solution (150ml) and di-tert-butyl dicarbonate (13.4g) are added in reaction mixture in room temperature.Stirring divides liquid after 30 minutes, water layer is extracted with dichloromethane (50ml).Merge after organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=2: 1 → 1: 1) is refined with silica gel column chromatography, obtains title compound (5.06g).
1H-NMR(CDCl3)δ：1.45 (9H, s), 2.75 (2H, t, J=6.6Hz), 3.46 (2H, dt, J=5.9,6.6Hz), 4.92 (1H, br.s), 6.91 (1H, d, J=16.6Hz), and 7.29-7.45 (4H, m), 7.48 (1H, d, J=16.6Hz), 7.52 (2H, d, J=7.3Hz)
MS(FAB)m/z：315 (M+H)+, 259 (M-isobutene+H)+, 315 (M-Boc+H)+.
[reference example 17] 2- [(E) -2- phenyl vinyls] -6,7- dihydro-oxazoles simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester
Figure G2003801097466D00921
At room temperature, paraformaldehyde (54.5mg) and p-methyl benzenesulfonic acid (7.2mg) are added in toluene (15ml) solution for the compound (190mg) that reference example 16 is obtained.Natural cooling after 1 hour is heated to reflux, ethyl acetate (15ml) is added in reaction mixture and saturated sodium bicarbonate aqueous solution (15ml) carries out a point liquid.After aqueous layer with ethyl acetate (10ml) extraction, merge organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=3: 1 → 2: 1) is refined with silica gel column chromatography, obtains title compound (153mg).
1H-NMR(CDCl3)δ：1.50 (9H, s), 2.67 (2H, br.s), 3.73 (2H, br.s), 4.55 (2H, s), 6.90 (1H, d, J=16.1Hz), 7.29-7.42 (3H, m), 7.46 (1H, d, J=16.1Hz), 7.52 (2H, d, J=7.3Hz)
MS(FAB)m/z：327 (M+H)+, 271 (M-isobutene+H)+, 227 (M-Boc+H)+.
[reference example 18] 2- formoxyls -6,7- dihydro-oxazole simultaneously [5,4-c] pyridine -5 (4H)-carboxylic acid tert-butyl ester
Figure G2003801097466D00922
At room temperature, acetone (8.0ml), water (4.0ml), N- oxidations-N-methylmorpholine (577mg) and 0.039 mole of osmium tetroxide aqueous solution (3.20ml) are added in tetrahydrofuran (16ml) solution for the compound (803mg) that reference example 17 is obtained, is stirred all night.Ethyl acetate (50ml) is added in reaction mixture and 10% sodium thiosulfate solution (50ml) is carried out after point liquid, aqueous layer with ethyl acetate (30ml) extraction.Merge after organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.At room temperature, methanol (8.0ml), water (8.0ml) and sodium metaperiodate (790mg) are added in tetrahydrofuran (16ml) solution of residue.After stirring 3 hours, ethyl acetate (30ml) is added in reaction mixture and water (50ml) carries out a point liquid, aqueous layer with ethyl acetate (20ml) extraction.Washed after merging organic layer with saturated sodium bicarbonate aqueous solution (50ml), then with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=4: 1 → 2: 1) is refined with silica gel column chromatography, obtains title compound (234mg).The aldehyde is unstable, so being immediately used to reaction thereafter.
1H-NMR(CDCl3)δ：1.49 (9H, s), 2.77 (2H, br.s), 3.77 (2H, br.s), 4.62 (2H, s), 9.70 (1H, s)
[reference example 19] 6,7- dihydro-oxazoles simultaneously [5,4-c] pyridine -2,5 (4H)-dicarboxylic acids 5- (tert-butyl ester) 2- methyl esters
At room temperature, Cymag (220mg) and manganese dioxide (780mg) are added in methanol (9.0ml) solution for the compound (225mg) that reference example 18 is obtained, after stirring 30 minutes, filtered with ethyl acetate through diatomite.After filtrate water (50ml) and saturated aqueous common salt (50ml) washing, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=3: 2 → 1: 1) is refined with silica gel column chromatography, obtains title compound (120mg).
1H-NMR(CDCl3)δ：1.49 (9H, s), 2.73 (2H, br.s), 3.74 (2H, br.s), 4.01 (3H, s), 4.59 (2H, s)
MS(FAB)m/z：283(M+H)+.
[reference example 20] 5- methyl -4,5,6,7- tetra- Qing oxazoles simultaneously [5,4-c] pyridine-2-carboxylic acids methyl esters
Figure G2003801097466D00932
At room temperature, trifluoroacetic acid (15ml) is added in dichloromethane (15ml) solution for the compound (500mg) that reference example 19 is obtained, is stirred 10 minutes.The lower concentration reaction mixture of decompression, at room temperature in residue obtained middle addition dichloromethane (20ml), triethylamine (0.495ml), acetic acid (205ml), formalin (0.230ml) and sodium triacetoxy borohydride (570mg).After stirring 15 minutes, dichloromethane (20ml) is added in reaction mixture and saturated sodium bicarbonate aqueous solution (50ml) is carried out after point liquid, water layer is extracted with dichloromethane (3 × 20ml).Merge after organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (chloroform: methanol=20: 1 → 10: 1) is refined with silica gel column chromatography, obtains title compound (257mg).
1H-NMR(CDCl3)δ：2.52 (3H, s), 2.72-2.78 (2H, m), 2.78-2.83 (2H, m), 3.61 (2H, t, J=1.7Hz), 4.00 (3H, s)
MS(FAB)m/z：197(M+H)+, 165 (M-OCH3)+.
[reference example 21] 5- methyl -4,5,6,7- tetra- Qing oxazoles simultaneously [5,4-c] pyridine-2-carboxylic acids lithium salts
At room temperature, water (6.0ml) and lithium hydroxide (99.7mg) are added in tetrahydrofuran (24ml) solution for the compound (800mg) that reference example 20 is obtained, is stirred 10 minutes.The lower concentration reaction mixture of decompression, obtains title compound (825mg).
1H-NMR(DMSO-d6)δ：2.37 (3H, s), 2.47 (2H, t, J=5.6Hz), 2.64 (2H, t, J=5.6Hz), 3.43 (2H, s)
The chloro- 6- fluoro indoles -2- carboxylate methyl esters of [reference example 22] 5-
Figure G2003801097466D00941
Under backflow, after the mixture of 4- fluoro-alphas-nitrine methyl cinnamate (Japanese Patent Laid-Open 7-149723 publications) (1.85g) chloro- to 3- and dimethylbenzene (140ml) is heated 1 hour, solvent is boiled off.Residue is refined with silica gel column chromatography (dichloromethane), obtains title compound (491mg).
1H-NMR(CDCl3)δ：3.95 (3H, s), 7.13-7.15 (1H, m), 7.20 (1H, dd, J=9.3,0.49Hz), 7.71 (1H, d, J=7.3Hz), 8.93 (1H, br.s)
MS(FAB)m/z：227(M+).
The chloro- 6- fluoro indoles -2- carboxylic acids of [reference example 23] 5-
The compound (461mg) for obtaining reference example 22 is dissolved in the in the mixed solvent of tetrahydrofuran (15ml), methanol (10ml) and water (10m1), and lithium hydroxide (283mg) is added at room temperature and is stirred 4 hours.Solvent is boiled off under decompression, 1N hydrochloric acid is added in residue, is adjusted to after faintly acid, powder obtained by leaching is dried, and obtains title compound (422mg).
1H-NMR(CDCl3)δ：7.08-7.10 (1H, m), 7.34 (1H, d, J=9.5Hz), 7.88 (1H, d, J=7.6Hz), 12.04 (1H, s), 13.16 (1H, s)
MS(FAB)m/z：213(M+).
[reference example 24] 5- (pyridin-4-yl) 4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine
1) under ice cooling, phosphorus pentasulfide (500g) is made to be suspended in formamide (3000ml), the evening of stirring one.Water is added in reaction solution and ether carries out a point liquid operation.Organic layer is dried with anhydrous magnesium sulfate, boils off solvent, obtains grease.It is dissolved in n-butanol (350ml), add method (Tetrahedron, nineteen eighty-three, volume 39 recorded according to document, page 3767) synthesis the chloro- 4- oxos -1- piperidine carboxylates (150g) of 3- after, in 100 DEG C stir 2.5 hours.Use after diatomite filtering reacting liquid, filtrate wash respectively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, use anhydrous sodium sulfate drying.Solvent is boiled off, residue (dichloromethane~ethyl acetate: hexane=1: 2) is refined with silica gel column chromatography, obtains 6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-carboxylic acid, ethyl ester (79.0g).
1H-NMR(CDCl3)δ：1.30 (3H, t, J=7.3Hz), 2.96 (2H, br.s), 3.82 (2H, br.s), 4.19 (2H, q, J=7.3Hz), 4.73 (2H, br.s) 8.68 (1H, s)
MS(FAB)m/z：213(M+H)+.
2) 3.5N sodium hydrate aqueous solution (250ml) is added in above-mentioned product (33.5g), an evening is heated to reflux.Reaction solution is cooled to after room temperature, di-tert-butyl dicarbonate (103g) is added under ice cooling, an evening is stirred at room temperature.3N hydrochloric acid is added in reaction solution, after pH is adjusted into 1~2, dichloromethane is added and carries out a point liquid operation.After organic layer is washed successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, anhydrous sodium sulfate drying is used.After the lower concentration of decompression, residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 2) refines, obtains 6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-carboxylic acid tert-butyl ester (21.1g).
1H-NMR(CDCl3)δ：1.49 (9H, s), 2.94 (2H, br.s), 3.76 (2H, br.s), 4.68 (2H, s), 8.67 (1H, s)
MS(FAB)m/z：241(M+H)+.
3) at room temperature, trifluoroacetic acid (25ml) is added in dichloromethane (25ml) solution of the above-mentioned compound (5.00g) 2) obtained.After stirring 10 minutes, the lower concentration of reaction solution of decompression.4- bromopyridines (5.20g), DMF (30ml) and triethylamine (15.5ml) are added in residue in room temperature, after 150 DEG C are stirred 2 days, room temperature is naturally cooled to.Filter off after the colourless precipitate of generation, the lower concentration filtrate of decompression, add dichloromethane (50ml) and saturated sodium bicarbonate aqueous solution (100ml), make water layer saturation with salt.Water layer after liquid is divided to be extracted with dichloromethane (5 × 30ml).Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: methanol=20: 1 → 8: 1) is refined with silica gel column chromatography, obtains title compound (2.97g).
1H-NMR(CDCl3)δ：3.07 (2H, t, J=5.9Hz), 3.81 (2H, t, J=5.9Hz), 4.61 (2H, s), 6.74 (2H, t, J=6.5Hz), 8.30 (2H, t, J=6.5Hz), 8.70 (1H, s)
MS(ESI)m/z：218(M+H)+.
Chloro- 6, the 7- dihydros -4H- pyrans of [reference example 25] 2- simultaneously [4,3-d] thiazole
Figure G2003801097466D00951
1) tetrahydrochysene -4H- pyrans -4- ketone (5.0g) is dissolved in hexamethylene (20ml), pyrrolidines (4.35ml), the hydrate of p-methyl benzenesulfonic acid 1 (48mg) are added, is heated to reflux 70 minutes while removing water with Dean and Stark apparatus.Reaction solution is cooled to after room temperature, point is taken and to be concentrated it under supernatant, decompression.Residue is dissolved under methanol (15ml), water cooling and adds Sulfur powder (1.60g), with the methanol solution (10ml) that cyanamide (2.10g) is added dropwise for 20 minutes after 15 minutes, is stirred 3 days.Solvent is boiled off under decompression, residue (dichloromethane: methanol=20: 1 → 10: 1 → 4: 1) is separated with silica gel column chromatography, obtains 6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazol-2-yl amine (3.97g).
1H-NMR(CDCl3)δ：2.66-2.70 (2H, m), 3.97 (2H, t, J=5.6Hz), 4.63 (2H, s), 4.94 (2H, br.s)
MS(FAB)m/z：157(M+H)+.
2) copper chloride (4.10g) is dissolved in acetonitrile (50ml), under water cooling, once adds nitrite tert-butyl (3.93g).After 10 minutes, the compound (3.97g) that above-mentioned reaction is obtained was added with about 1 hour, is stirred 1 hour at room temperature.Then, reaction solution is heated to 65 DEG C, continues to stir 2 hours.Added in reaction solution after silica gel (20g), solvent is boiled off under decompression, residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography, obtains title compound (1.78g).
1H-NMR(CDCl3)δ：2.85-2.89 (2H, m), 4.02 (2H, t, J=5.6Hz), 4.73 (2H, s)
MS(FAB)m/z：175(M+H)+.
[reference example 26] 6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazole -2- carboxylic acid lithium salts
1) compound (1.78g) obtained reference example 25 is dissolved in methanol (30ml), adds 10% palladium carbon (300mg) and sodium acetate (830mg), is stirred 5 days under the hydrogen stream of 5 air pressure.Concentrated solvent after catalyst is filtered off, residue (hexane: ethyl acetate=2: 1) is refined with silica gel column chromatography, obtains 6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazole (1.14g).
1H-NMR(CDCl3)δ：2.97-3.01 (2H, m), 4.04 (2H, t, J=5.6Hz), 4.87 (2H, s), 8.69 (1H, s)
MS(FAB)m/z：142(M+H)+.
2) above-mentioned product (1.14g) is dissolved in ether (30ml), be cooled to after -78 DEG C, the butyl lithium (6.6ml) for adding 1.6N is stirred.After 20 minutes, with 15 minutes introducing carbon dioxide gas.The temperature of reaction solution is returned back to after room temperature, and decompression is lower to be concentrated, and obtains title compound (1.65g).
1H-NMR(DMSO-d6)δ：2.83 (2H, t, J=5.6Hz), 3.92 (2H, t, J=5.6Hz), 4.73 (2H, s)
[reference example 27] thiazole simultaneously [4,5-c] pyridine
3- (tertbutyloxycarbonylamino) -4- mercaptopyridines (Japanese Patent Laid-Open 4-321691 publications) (9.20g) are dissolved in formic acid (60ml), are heated to reflux 4 hours.The lower concentration of reaction solution of decompression, the potassium hydroxide aqueous solution (100ml) and ether that 5N is added in residue carries out a point liquid.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.Ether is added in residue, the solid that leaching is separated out obtains title compound (3.97g).
1H-NMR(CDCl3)δ：7.93 (1H, d, J=5.4Hz), 8.60 (1H, d, J=5.4Hz), 9.07 (1H, s), 9.46 (1H, s)
[reference example 28] 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-c] pyridine
Figure G2003801097466D00971
Using the method same with reference example 4, title compound is made in the compound obtained by reference example 27.
1H-NMR(CDCl3)δ：2.52 (3H, s), 2.77 (2H, t, J=5.4Hz), 2.92-3.00 (2H, m), 3.69 (2H, t, J=2.0Hz), 8.61 (1H, s)
MS(FAB)m/z：155(M+H)+.
[reference example 29] 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-c] pyridine-2-carboxylic acids lithium salts
Using the method same with reference example 5, title compound is made in the compound obtained by reference example 28.
1H-NMR(DMSO-d6)δ：2.38 (3H, s), 2.64 (2H, br.s), 2.80 (2H, br.s), 3.44 (2H, br.s)
[reference example 30] chloro- N of 2-, N- dimethyl -4,5,6,7- tetrahydrochysene-benzothiazole -6- amine
Figure G2003801097466D00973
By 2- chloro- 4,7- dihydros -1, (5H) -one of 3- benzothiazoles -6 (Helv.Cim.Acta., 1994, volume 77, page 1256) (2.0g) is dissolved in methanol (100ml), and ammonium acetate (8.2g) and sodium cyanoborohydride (4.0g) are added, is heated to reflux 20 hours.Hydrochloric acid is added in reaction solution and decomposes superfluous sodium cyanoborohydride, decompression is lower to remove solvent, after making reaction solution in alkalescence with 1N sodium hydroxide solution, is extracted with dichloromethane.Organic layer is dried with anhydrous magnesium sulfate, and solvent is boiled off under decompression, obtains flaxen grease.The grease is dissolved in methanol (50ml), formalin (4.29g), sodium cyanoborohydride (3.49g) are added at room temperature, is stirred 12 hours.Solvent is boiled off under decompression, dichloromethane is added, is washed with saturated sodium bicarbonate solution, organic layer is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (dichloromethane: methanol=10: 1) is refined with silica gel column chromatography, obtains title compound (740mg).
1H-NMR(CDCl3)δ：1.71-1.78 (1H, m), 2.10-2.19 (1H, m), 2.35 (6H, s), 2.66-2.94 (5H, m)
MS(FAB)m/z：217(M+H)+.
[reference example 31] 6- (dimethylamino) -4,5,6,7- tetrahydro benzothiazol -2- carboxylic acid lithium salts
The compound (750mg) that reference example 30 is obtained is dissolved in ether (15ml), the tert-butyl lithium (3.5ml) that 1.5N is added after -78 DEG C is cooled to, after stirring 20 minutes, with about 15 minutes introducing carbon dioxide gas.Reacting liquid temperature is returned back to after room temperature, and decompression is lower to be concentrated, and obtains title compound.
1H-NMR(DMSO-d6)δ：1.75-1.78 (1H, m), 1.98-2.07 (1H, m), 2.50 (6H, s), 2.64-2.88 (5H, m)
[reference example 32] 2- amino -4,6- dihydro -5H- pyrrolo-es [3,4-d] thiazole-5-carboxylic acid tert-butyl ester
1- tert-butoxycarbonyl -3- pyrrolidones (1.58g) is dissolved in hexamethylene (10ml), the hydrate of p-methyl benzenesulfonic acid 1 (8.12mg) and pyrrolidines (607mg) are added, is heated to reflux while dehydration with Dean and Stark apparatus 1.5 hours.Divide and take supernatant, after the lower concentration of decompression, residue is dissolved in methanol (5ml), stirring 15 minutes under Sulfur powder (274mg), ice cooling are added.Cyanamide (377mg) methanol solution (2ml) is slowly instilled in reaction solution, is stirred all night at room temperature.Then, it is heated to reflux 2 hours, after concentration of reaction solution, adds dichloromethane and saturated sodium bicarbonate aqueous solution, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 39) is refined with silica gel column chromatography, obtains title compound (248mg).
1H-NMR(CDCl3) δ 1.50 (9H, s), 4.34-4.37 (1H, m), 4.40-4.45 (1H, m), 4.49-4.55 (2H, m), 4.99 (2H, m)
Bromo- 4,6- dihydros -5H- pyrrolo-es [3,4-d] the thiazole-5-carboxylic acid tert-butyl esters of [reference example 33] 2-
Figure G2003801097466D00983
Copper bromide (445mg) is suspended in DMF, nitrite tert-butyl (256mg) is instilled at room temperature.Under ice cooling, after the DMF solution (1ml) for adding the compound (400mg) that reference example 32 is obtained, reaction solution is stirred 1.5 hours in 60 DEG C.Ether and saturated aqueous common salt are added in reaction solution, organic layer is dried with anhydrous magnesium sulfate.Decompression is lower to be concentrated, and residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, obtains title compound (174mg).
1H-NMR(CDCl3)δ：1.51 (9H, s), 4.52-4.55 (1H, m), 4.57-4.67 (3H, m)
MS(FAB)m/z：305(M+H)+.
[reference example 34] 5- (tert-butoxycarbonyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids lithium salts
Using the method same with reference example 10, the compound obtained by reference example 7 prepares title compound.
1H-NMR(DMSO-d6)δ：1.42 (9H, s), 2.69-2.77 (2H, m), 3.60-3.68 (2H, m), 4.51-4.58 (2H, m)
The bromo- 4- of [reference example 35] 2- (2- methoxyl group -2- oxoethyls) thiazole-5-carboxylic acid methyl esters
Figure G2003801097466D00992
Under ice cooling, copper bromide (26.8g) is once added in nitrite tert-butyl (15.5g) acetonitrile (500ml) solution.2- amino -5- methoxycarbonyl -4- thiazolyl acetic acid methyl esters (pharmaceutical journals were instilled in the reaction solution with 45 minutes, 1966, volume 86, page 300) acetonitrile solution (500ml) of (23.0g), stir 1 hour, be then stirred at room temperature 30 minutes under ice cooling.Concentration of reaction solution, adds 10% hydrochloric acid and ether in residue, separates organic layer, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, obtains title compound (25.9g).
1H-NMR(CDCl3)δ：3.73 (3H, s), 3.87 (3H, s), 4.21 (2H, s)
[reference example 36] 2- [5- (hydroxymethyl) thiazole-4-yl] -1- ethanol
Figure G2003801097466D00993
Under ice cooling, with tetrahydrofuran (500ml) solution for instilling the compound (23.4g) that reference example 35 is obtained for 1 hour in lithium aluminium hydride reduction (9.03g) tetrahydrofuran (500ml) suspension.After stirring 1 hour under ice-cooling, water (9ml), 35% sodium hydrate aqueous solution (9ml) and water (27ml) are sequentially added, is stirred 1 hour at room temperature.After anhydrous magnesium sulfate is added in reaction solution and is stirred, insoluble matter is filtered to remove by diatomite, filtrate is concentrated.Residue (methanol: dichloromethane=7: 93) is refined with silica gel column chromatography, obtains title compound (8.64g).
1H-NMR(CDCl3)δ：3.01 (2H, t, J=5.5Hz), 3.30 (1H, br.s), 3.57 (1H, br.s), 3.90 (2H, br.s), 4.75 (2H, br.s), 8.66 (1H, s)
MS(ESI)m/z：160(M+H)+.
[reference example 37] methanesulfonic acid 2- (5- { [(methyl sulphonyl) epoxide] methyl } thiazole-4-yl) ethyl ester
The compound (8.64g) and triethylamine (45.4ml) that reference example 36 is obtained are dissolved in dichloromethane (500ml), instill the dichloromethane solution of mesyl chloride (12.6ml) in this solution with 20 minutes in -78 DEG C.Stirred 15 minutes in -78 DEG C, added water after being stirred 1 hour in 0 DEG C, separate organic layer, use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, title compound (13.4g) is obtained.
1H-NMR(CDCl3)δ：2.93 (3H, s), 3.03 (3H, s), 3.28 (2H, t, J=6.3Hz), 4.61 (2H, t, J=6.3Hz), 5.44 (2H, s), 8.84 (1H, s)
[reference example 38] 5- (1- methylcyclopropyl groups) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine
Under ice cooling, 1- methyl cyclopropylamines hydrochloride (J.Org.Chem., 1989, volume 54 are added in the dichloromethane (20ml) of the compound (4.46g) obtained containing reference example 37, page 1815) (1.89g), stir all night at room temperature.Then, additional 1- methyl cyclopropylamine hydrochlorides (1.89g), stir 20 hours at room temperature, are then heated to reflux stirring 5 hours.Dichloromethane and water are added in reaction solution, organic layer is separated, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 49) is refined with silica gel column chromatography, obtains title compound (944mg).
1H-NMR(CDCl3)δ：0.40-0.50 (2H, m), 0.68-0.73 (2H, m), 1.16 (3H, s), 2.88-2.94 (2H, m), 3.03 (2H, t, J=5.7Hz), 3.89 (2H, br.s), 8.60 (1H, s)
MS(ESI)m/z：195(M+H)+.
[reference example 39] 5- (1- methylcyclopropyl groups) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids lithium salts
Figure G2003801097466D01011
Using the method same with reference example 5, the compound obtained by reference example 38 prepares title compound.
1H-NMR(DMSO-d6)δ：(2H, the br.s) of 0.39 (2H, br.s), 0.56 (2H, br.s), 1.10 (3H, br.s), 2.66 (2H, br.s), 2.89 (2H, br.s), 3.75
[reference example 40] 2- [6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-yl] -2- methyl isophthalic acids-propyl alcohol
By the method same with reference example 38, the compound obtained by reference example 37 and 2-amino-2-methyl-1-propanol obtain title compound.
1H-NMR(CDCl3)δ：1.15 (6H, s), 2.91 (4H, s), 3.45 (2H, s), 3.87 (2H, s), 8.63 (1H, s)
[reference example 41] 5- (2- { [tert-butyl group (diphenyl) silicyl] epoxide } -1,1- dimethyl ethyls) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine
At room temperature, tertiary butyl chloride diphenyl silane (1.93g) and imidazoles (994mg) are added in DMF (5ml) solution for the compound (1.24g) that reference example 40 is obtained, is stirred all night.Water and ether are added in reaction solution, organic layer is separated, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=1: 2) is refined with silica gel column chromatography, obtains title compound (2.46g).
1H-NMR(CDCl3)δ：1.07 (9H, s), 1.15 (6H, s), 2.83-2.90 (2H, m), 2.93-3.00 (2H, m), 3.63 (2H, s), 3.97 (2H, s), 7.35-7.48 (6H, m), 7.63-7.70 (4H, m), 8.58 (1H, s)
MS(ESI)m/z：451(M+H)+.
[reference example 42] 5- (2- { [tert-butyl group (diphenyl) silicyl] epoxide } -1,1- dimethyl ethyls) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids lithium salts
Figure G2003801097466D01021
Using the method same with reference example 5, the compound obtained by reference example 41 prepares title compound.
1H-NMR(DMSO-d6)δ：1.01 (9H, s), 1.11 (6H, s), 2.55-2.65 (2H, m), 2.80-2.90 (2H, m), 3.57 (2H, s), 3.80 (2H, br.s), 7.40-7.52 (6H, m), 7.60-7.65 (4H, m)
[reference example 43] 4,7,8,10- tetrahydrochysene -6H- pyrazolos [1,2-a] thiazole simultaneously [4,5-d] pyridazine
1) 4,5- dimethylthiazoles (5.00g), N- bromines succinimide (15.7g) and α, α at room temperature, are made '-azodiisobutyronitrile (362mg) is dissolved in dichloroethanes (500ml), it is heated to reflux 1 hour.Solvent is boiled off, residue (hexane: ether=1: 4) is refined with silica gel column chromatography, obtains double (bromomethyl) thiazoles (5.24g) of 4,5-.
1H-NMR(CDCl3)δ：4.64 (2H, s), 4.74 (2H, s), 8.75 (1H, s)
2) under ice cooling, make 4, double (bromomethyl) thiazoles (1.37g) of 5- and 1,2- trimethylene hydrazine hydrochloride (WO9532965) (732mg) are suspended in ethanol (15ml), and triethylamine (2.82ml) is instilled in 5 minutes.Solvent is boiled off after stirring 2 hours at room temperature, dichloromethane (50ml) and saturated sodium bicarbonate aqueous solution are added in residue, organic layer is separated, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: dichloromethane=3: 47) is refined with silica gel column chromatography, obtains title compound (358mg).
1H-NMR(CDCl3)δ：2.10-2.25 (2H, m), 3.01 (4H, br.s), 3.95 (2H, s), 3.99 (2H, br.s), 8.64 (1H, s) .MS (FAB) m/z：182(M+H)+.
[reference example 44] 4,7,8,10- tetrahydrochysene -6H- pyrazolos [1,2-a] thiazole simultaneously [4,5-d] pyridazine -2- carboxylic acid lithium salts
Using the method same with reference example 5, the compound obtained by reference example 43 prepares title compound.
1H-NMR(DMSO-d6)δ：1.90-2.10 (2H, m), 2.60-3.10 (4H, br.s), 3.65-4.00 (4H, m)
[reference example 45] 4,6,7,8,9,11- hexahydro-pyridazine simultaneously [1,2-a] thiazole simultaneously [4,5-d] pyridazine
Using the method same with reference example 43, title compound is obtained by double (bromomethyl) thiazoles (2.20g) of 4, the 5- 1) obtained of reference example 43 and 1,2- tetramethylene hydrazine hydrochloride (US5726126).
1H-NMR(CDCl3)δ：1.77 (4H, br.s), 2.20-3.50 (4H, br), 3.92 (4H, br.s), 8.65 (1H, s)
MS(FAB)m/z：196(M+H)+.
[reference example 46] 4,6,7,8,9,11- hexahydro-pyridazine simultaneously [1,2-a] thiazole simultaneously [4,5-d] pyridazine -2- carboxylic acid lithium salts
Using the method same with reference example 5, the compound obtained by reference example 45 prepares title compound.
[reference example 47] 2- (methyl mercapto) -5,7- dihydro -6H- pyrrolo-es [3,4-d] pyridazine -6- carboxylic acid tert-butyl esters
At room temperature, 1- (tert-butoxycarbonyl) -3- pyrrolidones (4.57g) and DMF dimethyl acetal (30ml) are added, is heated 1 hour in 140 DEG C.Reaction solution is cooled to after room temperature, and decompression is lower to be concentrated.Hexane is added in residue, the yellow powder that leaching is separated out makes it be dissolved in ethanol (100ml), adds methyl-isourea (9.24g) and caustic alcohol (4.52g) in the solution at room temperature, be heated to reflux 24 hours.Saturated aqueous common salt is added in reaction solution and ether carries out a point liquid, organic layer anhydrous sodium sulfate drying.Decompression is lower to be concentrated, and residue (methanol: dichloromethane=1: 99) is refined with silica gel column chromatography, obtains title compound (1.10g).
1H-NMR(CDCl3)δ：1.51 (9H, s), 2.57 (3H, m), 4.15-4.45 (4H, m), 8.39 (1/2H, s), 8.43 (1/2H, s)
MS(FAB)m/z：268(M+H)+.
[reference example 48] 2- (methyl sulphonyl) -5,7- dihydro -6H- pyrrolo-es [3,4-d] pyrimidine -6- carboxylic acid tert-butyl esters
Under ice cooling, metachloroperbenzoic acid (1.99g) is added in the dichloromethane solution (20ml) for the compound (1.08g) that reference example 47 is obtained, is stirred 5 hours.Add the saturated sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and dichloromethane in reaction solution to carry out after point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, hexane is added in residue, the powder that leaching is separated out obtains title compound (1.09g).
1H-NMR(CDCl3)δ：1.53 (9H, s), 3.36 (3H, m), 4.77-4.90 (4H, m), 8.77 (1/2H, s), 8.81 (1/2H, s)
MS(FAB)m/z：300(M+H)+.
[reference example 49] 2- cyano group -5,7- dihydro -6H- pyrrolo-es [3,4-d] pyrimidine -6- carboxylic acid tert-butyl esters
Figure G2003801097466D01042
At room temperature, tetrabutylammonium cyanide (1.04g) is added in dichloromethane (30ml) solution for the compound (1.05g) that reference example 48 is obtained, is stirred 1 hour at room temperature.1N sodium hydroxide is added in reaction solution, organic layer is separated, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: acetone=20: 1) is refined with silica gel column chromatography, obtains title compound (776mg).
1H-NMR(CDCl3)δ：1.52 (9H, s), 4.70-4.85 (4H, m), 8.68-8.77 (1H, m)
MS(FAB)m/z：247(M+H)+.
[reference example 50] 5,7- dihydro -6H- pyrrolo-es [3,4-d] pyrimidine -2,6- dicarboxylic acids 6- (tert-butyl ester) 2- methyl esters
Figure G2003801097466D01043
At room temperature, concentrated hydrochloric acid (5ml) is added in methanol (10ml) solution for the compound (776mg) that reference example 49 is obtained, is stirred 1 hour in 100 DEG C.After natural cooling, residue is dissolved in methanol (10ml), triethylamine (2.20ml) and di-tert-butyl dicarbonate (1.37g) is added at room temperature, stirred 1 hour by the lower concentration of reaction solution of decompression.Decompression is lower to be concentrated, and adds dichloromethane and saturated aqueous common salt is carried out after point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off, residue (methanol: dichloromethane=3: 97) is refined with silica gel column chromatography, obtains title compound (317mg).
1H-NMR(CDCl3)δ：1.53 (9H, s), 4.09 (3H, s), 4.75-4.85 (4H, m), 8.81 (1/2H, s), 8.85 (1/2H, s)
MS(FAB)m/z：280(M+H)+.
[reference example 51] 5,6- dimethyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-d] pyridazine -2- carboxylic acid lithium salts
1) by 1) obtain the 4 of reference example 43, double (bromomethyl) thiazoles (600mg) of 5- are dissolved in ethanol (20ml), 1 is added under ice cooling, after 2- dimethylhydrazines hydrochloride (294mg), triethylamine (1.23ml) is once added, stirs 30 minutes and is stirred 30 minutes after 50 DEG C at room temperature.Boil off solvent, residue with silica gel column chromatography (methanol: dichloromethane=1: 19) refine, obtain 5,6- dimethyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-d] pyridazine (90mg).
1H-NMR(CDCl3)δ：2.43 (3H, s), 2.56 (3H, s), 3.92 (2H, s), 4.06 (2H, br.s), 8.68 (1H, s) .MS (FAB) m/z：170(M+H)+.
2) method same with reference example 5 is used, by 5,6- dimethyl -4,5, simultaneously [4,5-d] pyridazine obtains title compound to 6,7- tetrahydro-thiazoles.
1H-NMR(DMSO-d6)δ：2.28 (3H, s), 2.39 (3H, s), 3.66 (2H, br.s), 3.88 (2H, br.s)
[reference example 52] 5- chloro-indole -2- carboxylic acid 4- nitro phenyl esters
Figure G2003801097466D01052
5- chloro-indole -2- carboxylic acids (20g) are suspended in dichloromethane (1500ml), added after DMF (2ml), thionyl chloride (11ml) is added dropwise at room temperature.Reaction solution is heated to reflux after an evening, decompression is lower to be concentrated.Residue is dissolved under dichloromethane (1000ml), ice cooling and added after triethylamine (8.47ml), p-nitrophenol (14.2g) is added, stirred 1 hour at room temperature.The lower concentration of reaction solution of decompression, the hydrochloric acid that ethyl acetate and 0.2N are added in residue carries out a point liquid operation.After organic layer is washed successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, with anhydrous sodium sulfate drying, solvent is boiled off under decompression, title compound (29.9g) is obtained.
1H-NMR(CDCl3)δ：7.35 (1H, dd, J=9.0,1.7Hz), 7.39-7.42 (2H, m), 7.45 (2H, dd, J=7.3,1.7Hz), 7.73 (1H, d, J=1.0Hz), 8.35 (2H, dd, J=7.3,1.7Hz), 9.09 (1H, br.s)
MS(FD)m/z：316(M+).
The chloro- 2- quinolinecarbonitriles of [reference example 53] 6-
Figure G2003801097466D01061
6- chloroquinolines (2.50g) are dissolved under dichloromethane (25ml), ice cooling and add metachloroperbenzoic acid (3.71g), are stirred 1 hour at room temperature.After dchloromethane, washed with sodium thiosulfate solution and sodium hydrate aqueous solution, then use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue is dissolved in dichloromethane (40ml), trimethylsilyl cyanide monosilane (2.0ml), N is added, N- dimethylcarbamyl chlorides (1.50ml) are heated to reflux 9 hours.Then, trimethylsilyl cyanide monosilane (1.0ml) and N, N- dimethylcarbamyl chloride (0.80ml) are added, is heated to reflux after 16 hours, with dchloromethane, 10% wet chemical (40ml) is added, stirs 30 minutes.Organic layer is separated, after anhydrous sodium sulfate drying, decompression boils off solvent.Dichloromethane is added in residue, the crystallization that leaching is separated out obtains title compound (1.77g).Then, concentrated mother liquor, it is refined with silica gel column chromatography (dichloromethane), obtain title compound (0.80g).
1H-NMR(DMSO-d6)δ：(1H, d, the J=8.5Hz) of 7.94 (1H, dd, J=9.0,2.2Hz), 8.09 (1H, d, J=8.5Hz), 8.15 (1H, d, J=9.0Hz), 8.29 (1H, d, J=2.2Hz), 8.63
MS(FAB)m/z：189(M+H)+.
The chloro- 2- quinoline carboxylic acids of [reference example 54] 6-
The compound (1.73g) that reference example 53 is obtained is dissolved in concentrated hydrochloric acid (40ml), is heated to reflux 19 hours.Cool the temperature to after room temperature, leaching precipitate, wash, obtain title compound (1.81g).
1H-NMR(DMSO-d6)δ：7.87 (1H, dd, J=9.0,2.4Hz), 8.10-8.20 (2H, m), 8.24 (1H, d, J=2.2Hz), 8.52 (1H, d, J=8.5Hz)
MS(FAB)m/z：208(M+H)+.
[reference example 55] 3- (4- chlorphenyls) -2- (Formylamino) methyl propionate
(±)-(4- chlorphenyls) alanine methyl ester hydrochloride (2.00g) is dissolved in dichloromethane (20ml), add 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (1.60g), the hydrate of I-hydroxybenzotriazole 1 (1.23g), N-methylmorpholine (1.90ml) and formic acid (0.30ml), stirring 15 minutes, then, formic acid (0.30ml) is added to stir 15 minutes, this operation is repeated after 3 times, dchloromethane reaction solution is used.After organic layer washing, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: methanol=40: 1) is refined with silica gel column chromatography, obtains title compound (1.21g).
1H-NMR(CDCl3)δ：3.10 (1H, dd, J=13.9,5.6Hz), 3.18 (1H, dd, J=13.9,5.9Hz), 3.75 (3H, s), 4.95 (1H, m), 6.07 (1H, br), 7.05 (2H, d, J=8.3Hz), 7.27 (2H, d, J=8.3Hz), 8.18 (1H, s)
MS(FAB)m/z：242(M+H)+.
The chloro- 3- isoquinolinecarboxylic acids methyl esters of [reference example 56] 7-
Figure G2003801097466D01071
The compound (1.45g) that reference example 55 is obtained is dissolved in dichloromethane (40ml), instills oxalyl chloride (0.57ml).After stirring 30 minutes at room temperature, Wen Yue -10 DEG C of Wai add iron chloride (1.17g), stir 4 days at room temperature.1N hydrochloric acid is added, with organic layer is separated after dchloromethane, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue is dissolved in methanol (38ml), the concentrated sulfuric acid (2ml) is added and is heated to reflux 20 hours.Sodium bicarbonate aqueous solution is added, is extracted with dichloromethane, uses anhydrous sodium sulfate drying.Decompression boils off solvent, and residue is refined with silica gel column chromatography (hexane: ethyl acetate=2: 1 → ethyl acetate), obtains title compound (0.25g).
1H-NMR(CDCl3)δ：4.07 (3H, s), 7.74 (1H, dd, J=8.8,2.0Hz), 7.94 (1H, d, J=8.8Hz), 8.06 (1H, d, J=2.0Hz), 8.59 (1H, s), 9.28 (1H, s)
The chloro- 3- isoquinolinecarboxylic acids hydrochlorides of [reference example 57] 7-
The compound (0.23g) that reference example 56 is obtained is dissolved in concentrated hydrochloric acid (10ml), is heated to reflux 18 hours.Reacting liquid temperature is down to after room temperature, leaching precipitate, washed, obtain title compound (0.21g).
1H-NMR(DMSO-d6)δ：7.96 (1H, m), 8.29 (1H, d, J=8.5Hz), 8.44 (1H, s), 8.72 (1H, s), 9.45 (1H, d, J=6.6Hz)
MS(FAB)m/z：208(M+H)+.
[reference example 58] (3R) -1- benzyls -3- { [tert-butyl group (diphenyl) silicyl] epoxide } pyrrolidines
(3R) -1- benzyl -3- hydroxyl pyrrolidines (500 μ l) and imidazoles (466mg) are dissolved in N, dinethylformamide (15ml), t-butyldiphenylsilyl chlorine (1.57ml) is added under ice cooling, is stirred 9 days at room temperature.Solvent is boiled off under decompression, dichloromethane is added in residue and water is carried out after point liquid operation, organic layer anhydrous sodium sulfate drying boils off solvent under decompression.Residue (hexane: ethyl acetate=3: 1) is refined with silica gel flash column chromatography, obtains title compound (1.27g).
1H-NMR(CDCl3)δ：1.05 (9H, s), 1.70-1.85 (1H, m), 1.90-2.00 (1H, m), 2.45-2.65 (3H, m), 2.70-2.80 (1H, m), 3.50-3.70 (2H, m), 4.35-4.45 (1H, m), 7.20-7.45 (11H, m), 7.60-7.70 (4H, m)
MS(ESI)m/z：416(M+H)+.
[reference example 59] N- [(1R*, 2S*) -2- amino cyclopropyl] -5- chloro-indole -2- formamides
Figure G2003801097466D01081
At room temperature, cis- 1,2- ring propane diamine hydrochlorides (J.Med.Chem., 1998, volume 41,4723-4732 pages) N of (405mg) and 5- chloro-indole -2- carboxylic acids (546mg), the hydrate of I-hydroxybenzotriazole 1 (377mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (642mg) and wopropyl ethyl amine (1.95ml) are added in dinethylformamide (10ml) solution, is stirred 50 hours.After the lower concentration reaction mixture of decompression, dichloromethane (50ml) and saturated sodium bicarbonate aqueous solution (200ml) are added, the colorless solid separated out is filtered off.To filtrate point liquid, water layer is extracted with dichloromethane.Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue is obtained.(dichloromethane: methanol=100: 7 → 10: 1) refined to residue obtained with silica gel flash column chromatography, obtain title compound (110mg).
1H-NMR(DMSO-d6)δ：0.44 (1H, dd, J=10.7,4.4Hz), 1.11 (1H, dd, J=14.0,7.4Hz), and 2.63-2.70 (1H, m), 3.07-3.16 (1H, m), 6.77 (1H, s), 6.97 (1H, br.s), 7.23 (1H, dd, J=8.9,1.8Hz), 7.36 (1H, d, J=8.9Hz), 7.60 (1H, s), 9.32 (1H, s)
MS(FAB)m/z：250(M+H)+.
[reference example 60] N- [(1R*, 2S*) -2- Aminocyclobutyls] -5- chloro-indole -2- formamides
Using the method same with reference example 59, title compound is obtained by cis- 1,2- rings butanediamine hydrochloride (J, Am.Chem.Soc., nineteen forty-two, volume 64,2696-2700 pages).
1H-NMR(DMSO-d6)δ：1.55-2.20 (4H, m), 3.52-3.62 (1H, m), 4.35-4.50 (1H, m), 7.16 (1H, dd, J=8.7,2.1Hz), 7.19 (1H, s), 7.42 (1H, d, J=8.7Hz), 7.70 (1H, d, J=2.1Hz), 8.36 (1H, d, J=7.8Hz), 11.77 (1H, br.s)
MS(ESI)m/z：264(M+H)+.
[reference example 61] (1R*, 2R*) -2- amino cyclopentyl carbamates
By (±)-trans- 1,2- rings pentanediamine (WO 98/30574) (692mg) is dissolved in dichloromethane (10ml), triethylamine (1.1ml), 2- (tert-butoxycarbonyl epoxide imino group) -2- phenylacetonitriles (493mg) are added in 0 DEG C, is stirred 1 hour in 0 DEG C.Then, additional 2- (tert-butoxycarbonyl epoxide imino group) -2- phenylacetonitriles (493mg), are stirred 7 hours at room temperature.Add water a point liquid in reaction solution, organic layer saturated common salt water washing, uses anhydrous sodium sulfate drying.Residue (dichloromethane: methanol=9: 1) is refined with silica gel flash column chromatography, obtains title compound (395mg).
1H-NMR(CDCl3)δ：1.25-1.40 (2H, m), 1.49 (9H, s), 1.59-1.77 (2H, m), 1.92-2.08 (1H, m), 2.10-2.17 (1H, m), 2.98 (1H, q, J=7.2Hz), 3.48-3.53 (1H, m), 4.49 (1H, br.s)
MS(ESI)m/z：201(M+H)+.
[reference example 62] N- [(1R*, 2R*) -2- amino cyclopentyls] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D01101
The compound (175mg) that reference example 61 is obtained is dissolved in N, dinethylformamide (3ml), add 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids lithium salts (purity 90%, 258mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (252mg), the hydrate of I-hydroxybenzotriazole 1 (60mg), are stirred 2 days at room temperature.Depressurized down with pump and boil off solvent, dichloromethane, saturated sodium bicarbonate aqueous solution are added in residue and carries out a point liquid.Organic layer saturated common salt water washing, with anhydrous sodium sulfate drying, is boiled off after solvent under decompression, and residue (dichloromethane: methanol=47: 3) is refined with silica gel flash column chromatography.Gained pale yellow oil is dissolved in acidic alcohol (5ml), after stirring 1 hour at room temperature, ethyl acetate, the lower concentrated solvent of decompression is added.Ethyl acetate is added in residue, the precipitation of leaching generation obtains title compound (120mg).
1H-NMR(DMSO-d6)δ：1.63-1.73 (4H, m), 1.99-2.06 (2H, m), 2.91 (3H, s), 3.09-3.14 (1H, m), 3.25-3.70 (4H, m), 4.27-4.32 (1H, m), 4.42-4.46 (1H, m), 4.68-4.71 (1H, m), 8.20-8.23 (3H, m), 9.09 (1H, d, J=8.3Hz), 11.82-12.01 (1H, m)
MS(ESI)m/z：281(M+H)+.
[reference example 63] N- [(1R*, 2R*) -2- amino cyclopentyls] the chloro- 1H- indole 2-carboxamides hydrochlorides of -5-
Figure G2003801097466D01102
The compound (1.40g) that reference example 61 is obtained is dissolved in N, dinethylformamide (15ml), 5- chloro-indole -2- carboxylic acids (1.64g), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (2.68g) and the hydrate of I-hydroxybenzotriazole 1 (473mg) are added, is stirred 23 hours at room temperature.Solvent is boiled off under decompression, dichloromethane and saturated sodium bicarbonate aqueous solution, leaching sediment are added in residue.With ethyl acetate, dichloromethane and methanol washing precipitate.On the other hand, a point liquid is carried out to filtrate, divides and take organic layer, after being dried with anhydrous sodium sulfate, solvent is boiled off under decompression.Residue (dichloromethane: methanol=19: 1) is refined with silica gel flash column chromatography, obtains faint yellow solid.Merge the faint yellow solid and the precipitation obtained by leaching, they are dissolved in dichloromethane (10ml), add trifluoroacetic acid (10ml), stir 3 hours at room temperature.Solvent is boiled off under decompression, dichloromethane and 1N sodium hydrate aqueous solution, leaching precipitation are added in residue.Divide the organic layer for taking filtrate, use anhydrous sodium sulfate drying.The precipitation of leaching is added in the solution, 4N Yan Suan dioxane solutions (20ml) is added, solvent is boiled off under decompression.Dichloromethane (10ml) and 4N Yan Suan dioxane solutions (10ml) are added in residue, solvent is boiled off under reduced pressure again.Ethyl acetate is added in residue, the precipitation of leaching generation obtains title compound (1.83g).
1H-NMR(DMSO-d6)δ：1.60-1.75 (4H, m), 2.05-2.10 (2H, m), 3.49 (1H, q, J=7.6Hz), 4.27 (4H, quintet, J=7.6Hz), 7.17 (1H, d, J=8.6Hz), 7.19 (1H, s), 7.42 (1H, d, J=8.6Hz), 7.70 (1H, s), 8.24 (3H, br.s), 8.85 (1H, d, J=7.3Hz), 11.91 (1H, s)
MS(ESI)m/z：278(M+H)+.
[reference example 64] (1R*, 2R*) -2- aminocyclohexyl carbamates
Using the method same with reference example 61, title compound is obtained by (±)-trans- 1,2- cyclohexanediamine.
Fusing point：79~81 DEG C
1H-NMR(CDCl3)δ：1.05-1.34 (4H, m), 1.45 (9H, s), 1.68-1.75 (2H, m), 1.92-2.02 (2H, m), 2.32 (1H, dt, J=10.3,3.9Hz), 3.08-3.20 (1H, m), 4.50 (1H, br.s)
MS(FAB)m/z：215(M+H)+.
[reference example 65] N- [(1R*, 2R*) -2- aminocyclohexyls] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide trifluoroacetate (and hydrochloride)
Figure G2003801097466D01112
Using the method same with reference example 62, title compound is made in the compound obtained by reference example 64.
1H-NMR(DMSO-d6)δ：1.10-1.80 (7H, m), 1.95-2.05 (1H, m), 2.97 (3H, s), 3.00-3.20 (3H, m), 3.63 (2H, br.s), 3.72-3.88 (1H, m), 4.61 (2H, br.s), 7.98 (3H, s), 8.89 (1H, d, J=9.2Hz)
MS(FAB)m/z：295(M+H)+.
It is same to obtain hydrochloride.
[reference example 66] (1R*, 2S*) -2- aminocyclohexyl carbamates
Figure G2003801097466D01121
Using the method same with reference example 61, title compound is obtained by cis- 1,2- cyclohexanediamine.
1H-NMR(CDCl3)δ：1.30-1.70 (17H, m), 2.98-3.05 (1H, m), 3.60 (1H, br.s), 4.98 (1H, br.s)
MS(FAB)m/z：215(M+H)+.
[reference example 67] N- [(1R*, 2S*) -2- aminocyclohexyls] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride (and trifluoroacetate)
Using the method same with reference example 62, the compound obtained by reference example 66 prepares title compound.
1H-NMR(DMSO-d6)δ：1.30-1.90 (8H, m), 2.92 (3H, s), 3.05-3.79 (5H, m), 4.23 (1H, br.s), 4.34-4.79 (2H, m), 8.01-8.34 (3H, m), 8.30-8.49 (1H, m), 11.90-12.30 (1H, m)
MS(FAB)m/z：295(M+H)+.
It is same to obtain trifluoroacetate.
[reference example 68] (1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate
At room temperature, 5- chloro-indole -2- carboxylic acids (2.88g), the hydrate of I-hydroxybenzotriazole 1 (2.08g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (2.95g) are added in DMF (10ml) solution for the compound (3.00g) that reference example 64 is obtained.After stirring 3 days, the lower concentration reaction mixture of decompression, in residue obtained middle addition dichloromethane (30ml), saturated sodium bicarbonate aqueous solution (150ml) and water (150ml), after the colourless precipitate of leaching generation, dry, obtain title compound (5.21g).
1H-NMR(DMSO-d6)δ：1.10-1.45 (4H, m), 1.21 (9H, s), 1.68 (2H, d, J=8.1Hz), 1.86 (2H, t, J=16.2Hz), and 3.22-3.42 (1H, m), 3.69 (1H, br.s), 6.66 (1H, d, J=8.5Hz), 7.02 (1H, s), 7.15 (1H, dd, J=8.5,2.0Hz), 7.41 (1H, d, J=8.5Hz), 7.67 (1H, d, J=2.0Hz), 8.15 (1H, d, J=8.1Hz), 11.73 (1H, br.s)
MS(ESI)m/z：392(M+H)+.
[reference example 69] N- [(1R*, 2R*) -2- aminocyclohexyls] -5- chloro-indole -2- carboxamide hydrochlorides
Figure G2003801097466D01132
At room temperature, ethanol solution hydrochloride (100ml) is added in dichloromethane (100ml) solution for the compound (5.18g) that reference example 68 is obtained.After stirring 2 days, the lower concentration reaction mixture of decompression is dried after residue obtained middle addition ether (300ml), the colourless precipitate of leaching generation, obtains title compound (4.30g).
1H-NMR(DMSO-d6)δ：1.20-1.36 (2H, m), 1.36-1.50 (2H, m), 1.60 (2H, br.s), (1.90 1H, d, J=13.0Hz), (2.07 1H, d, J=13.7Hz), 3.06 (1H, br.s), 3.83-3.96 (1H, m), 7.15-7.24 (2H, m), (7.45 1H, d, J=8.6Hz), 7.73 (1H, s), 8.00 (3H, br.s), 8.60 (1H, d, J=8.3Hz), 11.86 (1H, s)
MS(ESI)m/z：292(M+H)+
[reference example 70] (1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate
Using the method same with reference example 68, the compound obtained by reference example 66 prepares title compound.
1H-NMR(DMSO-d6)δ：1.20-1.45 (11H, m), 1.45-1.70 (4H, m), 1.70-1.85 (2H, m), (3.76 1H, br.s), 4.08 (1H, br.s), 6.64 (1H, d, J=7.6Hz), 7.12 (1H, s), 7.16 (1H, dd, J=8.8,2.0Hz), 7.43 (1H, d, J=8.8Hz), 7.69 (1H, d, J=2.0Hz), 7.85 (1H, d, J=6.9Hz), 11.80 (1H, br.s)
MS(ESI)m/z：392(M+H)+.
[reference example 71] N- [(1R*, 2S*) -2- aminocyclohexyls] -5- chloro-indole -2- carboxamide hydrochlorides
Figure G2003801097466D01142
Using the method same with reference example 69, the compound obtained by reference example 70 prepares title compound.
1H-NMR(DMSO-d6)δ：1.30-1.50 (2H, m), 1.55-1.95 (6H, m), 3.41 (1H, br.s), 4.32 (1H, br.s), 7.19 (1H, dd, J=8.7,2.0Hz), 7.33 (1H, s), 7.45 (1H, d, J=8.7Hz), 7.60-7.90 (4H, m), 8.17 (1H, d, J=7.1Hz), 11.91 (1H, s)
MS(FAB)m/z：292(M+H)+.
[reference example 72] (1R*, 2R*) -1,2- cycloheptyl glycol
It is a small amount of every time in 30% aqueous hydrogen peroxide solution (45ml) and 88% formic acid (180ml) to add cycloheptene (3.85g), after 40~50 DEG C are stirred 1 hour, an evening is stirred at room temperature.Solvent is boiled off under decompression, 35% sodium hydrate aqueous solution is added in residue and is adjusted to alkalescence.After 40~50 DEG C are stirred 10 minutes to reaction solution, add ethyl acetate and carry out a point liquid, 4 extracting operations are carried out from water layer with ethyl acetate.Merge organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression, title compound (4.56g) is obtained.
1H-NMR(CDCl3)δ：1.44-1.56 (6H, m), 1.63-1.70 (2H, m), 1.83-1.91 (2H, m), 2.91 (2H, br.s), 3.40-3.44 (2H, m)
MS(FAB)m/z：131(M+H)+.
[reference example 73] (1R*, 2R*) -1,2- cycloheptyl diamine hydrochlorides
The compound (4.56g) that reference example 72 is obtained is dissolved in dichloromethane (35ml), adds triethylamine (29ml), is cooled to -78 DEG C.Mesyl chloride (8.13ml) is instilled wherein.Additional dichloromethane (10ml), after stirring 20 minutes at the same temperature, stirs 1.5 hours in 0 DEG C.Added water a point liquid in reaction solution, and organic layer is washed with saturated sodium bicarbonate aqueous solution, then uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, grease is obtained.The grease is dissolved in DMF (90ml), sodium azide (13.65g) is added, stirred 18 hours in 65 DEG C.Ether is added in reaction solution and water carries out point liquid, ether layer saturated sodium bicarbonate aqueous solution and a saturated common salt water washing, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, grease is obtained.
The grease is dissolved in ethanol (70ml), 10% palladium carbon (containing 50% moisture, 4g) is added, is stirred 4 days in hydrogen (3.5 air pressure) atmosphere.10% palladium carbon is filtered, 1N ethanol solution hydrochloride (70ml) is added in filtrate, solvent is boiled off under decompression.Methanol is dissolved in, ethyl acetate is added, boils off solvent under reduced pressure again.The precipitation of leaching generation, obtains title compound (3.57g).
1H-NMR(DMSO)δ：1.44 (4H, br.s), 1.73-1.81 (6H, m), 3.43 (2H, br.s), 8.63 (6H, br.s) .MS (ESI) m/z：129(M+H)+.
[reference example 74] N- [(1R*, 2R*) -2- aminocycloheptyls] -5- chloro-indole -2- formamides
Using the method same with reference example 59, the compound obtained by reference example 73 prepares title compound.
1H-NMR(DMSO-d6)δ：1.49-1.52 (4H, m), 1.72-1.91 (6H, m), 4.04-4.10 (1H, m), 7.17-7.23 (2H, m), 7.44 (1H, d, J=8.8Hz), 7.72 (1H, d, J=2.0Hz), 7.96 (2H, br.s), 8.75 (1H, d, J=8.5Hz), 11.89 (1H, br.s)
MS(ESI)m/z：306(M+H)+.
[reference example 75] (1R*, 2S*) -1,2- ring ethohexadiol hydrochlorides
Cyclo-octene (4.41g) is dissolved in acetonitrile (45ml) and water (15ml), add N- oxidations-N-methylmorpholine (5.15g) and the osmium tetroxide (1g of microencapsulation, contain 10% osmium tetroxide), stirred 21 hours at 40~50 DEG C.Insoluble microencapsulation osmium tetroxide is filtered off, is washed with acetonitrile.After the lower concentration filtrate of decompression, residue (hexane: ethyl acetate=1: 1) is refined with silica gel flash column chromatography, obtains title compound (4.97g).
1H-NMR(CDCl3)δ：1.48-1.58 (6H, m), 1.64-1.75 (4H, m), 1.86-1.96 (2H, m), 2.28 (2H, d, J=2.9Hz), 3.90 (2H, d, J=8.3Hz)
MS(FAB)m/z：145(M+H)+.
[reference example 76] (1R*, 2S*The nitrine cyclooctane of) -1,2- bis-
Cis- 1,2- rings ethohexadiol (4.82g) is dissolved in dichloromethane (60ml), triethylamine (27.7ml) is added, by the gas displacement in container for after argon gas, -78 DEG C are cooled to, mesyl chloride (7.7ml, 100mmol) is instilled.After amounting to stirring at the same temperature 1 hour, stirred 1 hour in 0 DEG C, added water a point liquid in reaction solution, and organic layer is washed with water, 0.5N aqueous hydrochloric acid solution, water, saturated sodium bicarbonate aqueous solution, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue is dissolved in DMF (80ml), sodium azide (13.0g) is added, stirred 19 hours in 65 DEG C.Ether is added in reaction solution and water carries out point liquid, ether layer saturated sodium bicarbonate aqueous solution and a saturated common salt water washing, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=6: 1) is refined with silica gel flash column chromatography, obtains title compound (4.85g).
1H-NMR(CDCl3)δ：1.49-1.64 (6H, m), 1.67-1.78 (2H, m), 1.81-1.97 (4H, m), 3.74-3.76 (2H, m)
[reference example 77] (1R*, 2S*) -1,2- ring octamethylenediamine hydrochlorides
The compound (4.85g) that reference example 76 is obtained is dissolved in ethanol (55ml), is added 10% palladium carbon (containing 50% moisture, 3.0g), is stirred 21 hours in hydrogen (4.5 air pressure) atmosphere.Catalyst is filtered off, 1N ethanol solution hydrochloride (50ml) is added in filtrate, solvent is boiled off under decompression.Ethyl acetate is added in residue, the precipitation of leaching generation obtains title compound (4.14g).
1H-NMR(DMSO)δ：1.51 (6H, br.s), 1.69 (2H, br.s), 1.79-1.99 (4H, m), 3.68-3.70 (2H, m), 8.66 (6H, br.s)
MS(ESI)m/z：143(M+H)+.
[reference example 78] N- [(1R*, 2S*) -2- aminocyclooctyls] -5- chloro-indole -2- formamides
Figure G2003801097466D01172
Using the method same with reference example 59, the compound obtained by reference example 77 prepares title compound.
MS(ESI)m/z：320(M+H)+.
[reference example 79] (1R*, 2R*) -4- methoxyl group -1,2- rings pentanediol (mixture of the stereoisomer of 4)
Figure G2003801097466D01173
3- cyclopentene -1- alcohol (1.68g) and methyl iodide (1.25ml) are dissolved under tetrahydrofuran (20ml), ice cooling, it is a small amount of every time in the solution to add 60% sodium hydride (800mg), stir all night at room temperature.Water is added in the reaction solution and ether carries out a point liquid, organic layer is dried with anhydrous magnesium sulfate, and solvent is boiled off under being depressurized under ice cooling, obtains rough 4- methoxyl group -1- cyclopentene.
At room temperature, 88% formic acid (90ml) and 30% hydrogen peroxide (3.17ml) are added in the 4- methoxyl group -1- cyclopentene of gained, stirred all night at room temperature.The lower concentration of reaction solution of decompression, adds 35% sodium hydrate aqueous solution in residue, makes reaction solution in alkalescence, is stirred 10 minutes in 50 DEG C.It is cooled to after room temperature, is extracted with ethyl acetate, organic layer is dried with anhydrous magnesium sulfate.Solvent is boiled off, (methanol: dichloromethane=1: 19) is refined with silica gel column chromatography, obtains title compound (1.21g).
1H-NMR(CDCl3)δ：1.65-1.85 (2H, m), 2.15-2.30 (2H, m), 3.28 (3H, s), 3.90-4.00 (2H, m), 4.26 (1H, br.s)
[reference example 80] (1R*, 2R*Nitrine -4- methoxies the cyclopentanes (mixture of the stereoisomer of 4) of) -1,2- bis-
The compound (1.21g) and triethylamine (7.66ml) that reference example 79 is obtained are dissolved in dichloromethane (20ml), and mesyl chloride (2.13ml) was instilled with 20 minutes in -78 DEG C.After completion of dropwise addition, 0 DEG C is warming up to, is stirred 80 minutes, rough (1R is obtained*, 2R*Double (the mesyloxy) -4- methoxy cyclopentanes of) -1,2-.It is dissolved in DMF (20ml), adds sodium azide (3.57g), in 65 DEG C of heating stirring 22 hours.Then, sodium azide (3.57g) is added, is stirred 2 days in 70 DEG C.Natural cooling reaction solution, after water and ether point liquid, organic layer is dried with anhydrous magnesium sulfate.Solvent is boiled off, residue (hexane: ethyl acetate=2: 1) is refined with silica gel column chromatography, obtains title compound (584mg).
1H-NMR(CDCl3)δ：1.65-1.80 (2H, m), 2.05-2.18 (1H, m), 2.25-2.40 (1H, m), 3.21 (3H, s), 3.55-3.65 (1H, m), 3.75-3.90 (2H, m)
[reference example 81] (1R*, 2R*) -4- methoxyl group -1,2- ring pentanediamine hydrochlorides (mixture of the stereoisomer of 4)
The compound (584mg) that reference example 80 is obtained is dissolved in ethanol, adds under 10% palladium carbon (321mg), normal temperature and pressure and is hydrogenated with 2 days.Filter off and concentrated after catalyst, 1N ethanol solution hydrochloride and ethyl acetate is added in residue, title compound (488mg) is obtained after concentration.
1H-NMR(CDCl3)δ：1.72-1.83 (1H, m), 1.91-2.03 (1H, m), 2.07-2.18 (1H, m), 2.37-2.50 (1H, m), 3.19 (3H, s), 3.55-3.75 (2H, br), 3.85-3.95 (1H, m), 8.60-8.90 (6H, br)
MS(ESI)m/z：261(2M+H)+.
[reference example 82] N- [(1R*, 2R*) -2- amino-4-methoxyls cyclopenta] -5- chloro-indole -2- formamides (mixture of the stereoisomer of 4)
Figure G2003801097466D01191
The compound (470mg) that reference example 81 is obtained is suspended in N, dinethylformamide (5ml), triethylamine (0.966ml) and 5- chloro-indole -2- carboxylic acids p-nitrophenyl esters (805mg) are added, is stirred 4 days at room temperature.Solvent is boiled off under decompression, dichloromethane is added and saturated sodium bicarbonate aqueous solution is carried out after point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 9) is refined with silica gel column chromatography, obtains title compound (268mg).
[reference example 83] (1R*, 2R*) -4- [(benzyloxy) methyl] -1,2- rings pentanediol (mixture of the stereoisomer of 4)
By the method same with reference example 79, after making 4- hydroxymethyl -1- cyclopentene (J.Heterocycl.Chem., 1989, volume 26, page 451) Benzylation with benzyl bromide a-bromotoluene, title compound is obtained using formic acid-hydrogen peroxide.
1H-NMR(CDCl3)δ：1.44-1.52 (1H, m), 1.77-1.85 (1H, m), 1.89-1.97 (1H, m), 2.25-2.35 (1H, m), 2.46-2.58 (1H, m), 3.40-3.50 (2H, m), 3.89 (1H, br.s), 4.08 (1H, br.s), 4.54 (2H, s), 7.27-7.39 (5H, m)
MS(FAB)m/z：223(M+H)+.
[reference example 84] (1R*, 2R*) -4- [(benzyloxy) methyl] -1,2- rings pentanediamine (mixture of the stereoisomer of 4)
Using the method same with reference example 80, (1R is made in the compound obtained by reference example 83*, 2R*) bis- nitrine pentamethylene of -4- benzyloxymethyls -1,2-.Without refined, title compound is made using with the same method of reference example 81.
[reference example 85] N- { (1R*, 2R*) -2- amino -4- [(benzyloxy) methyl] cyclopenta -5- chloro-indole -2- formamides (mixture of the stereoisomer of 4)
Figure G2003801097466D01201
Using the method same with reference example 59, title compound is prepared by the compound of reference example 84.
1H-NMR(DMSO-d6)δ：1.07-1.15 (0.5H, m), 1.26-1.35 (0.5H, m), 1.47-1.55 (0.5H, m), 1.61-1.79 (1H, m), 1.83-1.92 (0.5H, m), 1.99-2.10 (0.5H, m), 2.12-2.20 (0.5H, m), 2.27-2.40 (1H, m), 3.10-3.20 (1H, m), 3.33-3.39 (2H, m), 3.81-3.92 (1H, m), 4.48 (2H, s), 7.13-7.20 (2H, m), 7.22-7.39 (5H, m), 7.43 (1H, d, J=8.5Hz), 7.69 (1H, d, J=2.2Hz), 8.34 (1H, t, J=7.1Hz)
MS(FAB)m/z：398(M+H)+.
[reference example 86] (1R*, 3R*, 6S*) -7- oxabicyclos [4.1.0] heptane -3- carboxylic acid, ethyl esters
By (1R*, 4R*, 5R*) iodo- 6- oxabicyclos [3.2.1] octane-7-ketone (J.Org.Chem. of -4-, 1996, volume 61, page 8687) (14.3g) be dissolved in ethanol (130ml), add after 2N sodium hydrate aqueous solution (34.5ml), stir 7 hours at room temperature under ice cooling.Boiled off under decompression after solvent, added water in residue is extracted with dichloromethane, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=83: 17) is refined with silica gel column chromatography, obtains title compound (6.54g).
1H-NMR(CDCl3)δ：1.25 (3H, t, J=7.1Hz), 1.50-1.70 (2H, m), 1.71-1.82 (1H, m), 2.08-2.28 (4H, m), 3.16 (2H, s), 4.12 (2H, q, J=7.1Hz)
[reference example 87] (1R*, 3S*, 4S*) -3- azido -4- hydroxy cyclohexane carboxylic's ethyl esters
The compound (13.6g) that reference example 86 is obtained is dissolved in DMF (100ml), sequentially adds at room temperature after ammonium chloride (6.45g) and sodium azide (7.8g), is stirred 12 hours in 75 DEG C.Solvent concentration is diluted with water and ethyl acetate, stirred 3 minutes to after 1/3 or so.Organic layer water and saturated common salt water washing, are dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression.Residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, obtains title compound (15.8g).
1H-NMR(CDCl3)δ：1.28 (3H, t, J=7.1Hz), 1.37-1.67 (2H, m), 1.86-1.95 (1H, m), 2.04-2.18 (2H, m), 2.32-2.43 (1H, m), 2.68-2.78 (1H, m), 3.40-3.60 (2H, m), 4.17 (2H, q, J=7.1Hz)
[reference example 88] (1R*, 3S*, 4S*) -3- [(tert-butoxycarbonyl) amino] -4- hydroxy cyclohexane carboxylic's ethyl esters
Figure G2003801097466D01212
The compound (100mg) and di-tert-butyl dicarbonate (133mg) that reference example 87 is obtained are dissolved in ethyl acetate (12ml), add 10% palladium carbon of catalytic amount, are stirred at room temperature under hydrogen stream 12 hours.Filter off after insoluble matter, solvent is boiled off under decompression, residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography, obtains title compound (145mg).
1H-NMR(CDCl3)δ：1.28 (3H, t, J=7.1Hz), 1.45 (9H, s), 1.38-1.57 (2H, m), 1.86-1.95 (1H, m), 2.05-2.17 (1H, m), 2.29-2.39 (2H, m), 2.61-2.68 (1H, m), 3.25-3.66 (3H, m), 4.17 (2H, q, J=7.1Hz), 4.53 (1H, br.s)
[reference example 89] (1R*, 3S*, 4R*) -4- azidos -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylates and (1R*, 3S*, 4S*) -4- azidos -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
Figure G2003801097466D01213
The compound (16g) and triethylamine (38ml) that reference example 88 is obtained are dissolved in dichloromethane (150ml), are cooled to after -78 DEG C, and mesyl chloride (13ml) is added dropwise at identical temperature.Then, stir 15 minutes at the same temperature, be warming up to after 0 DEG C and stir 30 minutes, then at stirring 2 hours at room temperature.0.1N hydrochloric acid is added, after dchloromethane, organic layer is separated, after saturated sodium bicarbonate aqueous solution and saturated common salt water washing, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, rough (1R is obtained*, 3S*, 4S*) -3- [(tert-butoxycarbonyl) amino] -4- [(methyl sulphonyl) epoxide] cyclohexanecarboxylate
Above-mentioned product is dissolved in DMF (100ml), sodium azide (18g) is added at room temperature, is warming up to after 75 DEG C and stirs 12 hours.After solvent concentration to 1/3 or so, it is diluted, is stirred 3 minutes with water and ethyl acetate.Organic layer is separated, after saturated common salt water washing, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, obtains title compound [(1R*, 3S*, 4R*) body, 6.74g] and [(1R*, 3S*, 4S*) body, 1.32g].
(1R*, 3S*, 4R*) body：
1H-NMR(CDCl3)δ：1.26 (3H, t, J=7.1Hz), 1.45 (9H, s), 1.38-2.33 (6H, m), 2.57-2.68 (1H, m), 3.77-4.20 (4H, m), 4.63 (1H, br.s)
(1R*, 3S*, 4S*) body：
1H-NMR(CDCl3)δ：1.27 (3H, t, J=7.1Hz), 1.46 (9H, s), 1.53-2.30 (6H, m), 2.50-2.65 (1H, m), 3.42-3.72 (2H, m), 4.15 (2H, q.J=7.1Hz), 4.67 (1H, br.s)
[reference example 90] (1R*, 3S*, 4R*) -4- amino -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
(the 1R that reference example 89 is obtained*, 3S*, 4R*) -4- azidos -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate (5.4g) is dissolved in the in the mixed solvent of ethanol (10ml) and ethyl acetate (10ml), 10% palladium carbon of catalytic amount is added, is stirred at room temperature under hydrogen stream 20 hours.Filter after insoluble matter, solvent is boiled off under decompression, obtain title compound (4.7g).
[reference example 91] (1R*, 3S*, 4R*) -3- [(tert-butoxycarbonyl) amino] -4- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexanecarboxylate
The compound (4.62g) that reference example 90 is obtained is dissolved in dichloromethane (50ml), 5- chloro-indole -2- carboxylic acids (3.63g), the hydrate of I-hydroxybenzotriazole 1 (2.43g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (3.45g) are added at room temperature, are stirred 12 hours.0.1N aqueous hydrochloric acid solution is added in reaction solution, after being extracted with dichloromethane, organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing are dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=2: 3) is refined with silica gel column chromatography, obtains title compound (5.3g).
1H-NMR(CDCl3)δ：1.26 (3H, t, J=7.1Hz), 1.43 (9H, s), 1.35-2.46 (7H, m), 3.91-4.02 (1H, m), 4.10-4.22 (2H, m), 4.79 (1H, br.s), 6.79 (1H, s), 7.18-7.40 (2H, m), 7.59 (1H, s), 8.00 (1H, br.s), 9.13 (1H, br.s)
[reference example 92] (1S, 3S, 6R) -7- oxabicyclos [4.1.0] heptane -3- carboxylic acid, ethyl esters
By (1S, 4S, 5S) iodo- 6- oxabicyclos [3.2.1] octane-7-ketone (J.Org.Chem of -4-, .1996 year, volume 61, page 8687) (89.3g) be suspended in ethanol (810ml), after the sodium hydrate aqueous solution (213ml) for adding 2N, stir 3 hours at room temperature.Solvent is boiled off under decompression, is added water in residue, after being extracted with dichloromethane, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=17: 3) is refined with silica gel column chromatography, obtains title compound (41.3g).
[α]D 25=-58 ° of (c=1.0, chloroform)
[reference example 93] (1S, 3R, 4R) -3- azido -4- hydroxy cyclohexane carboxylic's ethyl esters
The compound (41g) that reference example 92 is obtained is dissolved in DMF (300ml), sequentially adds at room temperature after ammonium chloride (19.3g) and sodium azide (23.5g), is stirred 13 hours in 76 DEG C.Filtering reacting liquid, concentrates filtrate, previous leaching thing is added in residue, is dissolved in water.It is extracted with ethyl acetate, organic layer water and saturated common salt water washing are dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, title compound (51.5g) is obtained.
[α]D 25=+8 ° (c=1.0, chloroform)
[reference example 94] (1S, 3R, 4R) -3- [(tert-butoxycarbonyl) amino] -4- hydroxy cyclohexane carboxylic's ethyl esters
The compound (51.2g) and di-tert-butyl dicarbonate (68.1g) that reference example 93 is obtained are dissolved in ethyl acetate (1000ml), 5% palladium carbon (5.0g) are added, at room temperature with 7kg/cm2Hydrogen pressure stir all night.Filter after insoluble matter, the lower concentrated solvent of decompression, residue (hexane: ethyl acetate=4: 1 → 3: 1) is refined with silica gel column chromatography, adds hexane solidification, obtain title compound (46.9g).
[α]D 25=+25 ° of (c=1.0, chloroform)
[reference example 95] (1S, 3R, 4S) -4- azidos -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylates and (1S, 3R, 4R) -4- azidos -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
The compound (53.5g) and triethylamine (130ml) that reference example 94 is obtained are dissolved in dichloromethane (500ml), under -10~-15 DEG C cool down, and mesyl chloride (42ml) was instilled with 20 minutes.After being stirred 20 minutes at identical temperature, room temperature was warming up to 2 hours.Reaction solution is cooled to 0 DEG C, 0.5N hydrochloric acid (800ml) is instilled, is extracted with dichloromethane.Organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing; dried with anhydrous magnesium sulfate; solvent is boiled off under decompression; obtain rough (1S; 3R, 4R) -3- [(tert-butoxycarbonyl) amino] -4- [(methyl sulphonyl) epoxide] cyclohexanecarboxylate.
Above-mentioned rough compound is dissolved in DMF (335ml), sodium azide (60.5g) is added, stirred 16 hours in 67~75 DEG C.Filtering reacting liquid, concentrates filtrate, boils off 250ml solvent.Merge residue and previous leaching thing, they are dissolved in water, is extracted with ethyl acetate.Organic layer saturated common salt water washing, after being dried with anhydrous magnesium sulfate, solvent is boiled off under decompression.Residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, acquisition is used as (1S, 3R, 4S) body (18.4g) of title compound and the (1S as title compound, 3R, 4R) body (3.3g).(1S, 3R, 4S) body：[α]D 25=+62 ° (c=1.0, chloroform), (1S, 3R, 4R) body：[α]D 25=-19 ° of (c=1.0, chloroform)
[reference example 96] (1S, 3R, 4S) -4- amino -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
The compound (4.0g) that reference example 95 is obtained is dissolved in the in the mixed solvent of ethanol (150m) and ethyl acetate (150ml), adds 5% palladium carbon (0.5g), under a hydrogen atmosphere (5kg/cm2) be stirred at room temperature 17 hours.Filter off after insoluble matter, solvent is boiled off under decompression, obtain title compound (4.2g).
[reference example 97] (1S, 3R, 4S) -3- [(tert-butoxycarbonyl) amino] -4- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexanecarboxylate
Figure G2003801097466D01241
The compound (4.2g) that reference example 96 is obtained is dissolved in dichloromethane (50ml), 5- chloro-indole -2- carboxylic acids (3.33g), the hydrate of I-hydroxybenzotriazole 1 (2.52g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (3.15g) are added at room temperature, are stirred 12 hours.0.1N aqueous hydrochloric acid solution is added in reaction solution, after being extracted with dichloromethane, organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing, dried with anhydrous magnesium sulfate, solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 1) is refined with silica gel column chromatography, obtains title compound (4.36g).
[α]D=-27 ° of (c=1.0, chloroform)
[reference example 98] (1R*, 3S*, 4R*) -3- [(tert-butoxycarbonyl) amino] -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexanecarboxylate
Using the method same with reference example 91, the compound that the compound obtained by reference example 90 and reference example 10 are obtained prepares title compound.
[reference example 99] 3- cyclohexene -1- benzyl carboxylates
(±) -3- cyclohexene -1- carboxylic acids (50g) are dissolved under DMF (550ml), ice cooling and add triethylamine (170ml) and benzyl bromide a-bromotoluene (61ml), are stirred 12 hours at room temperature.Add water, be extracted with ethyl acetate, organic layer is dried with after saturated common salt water washing with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography, obtains title compound (70.8g).
1H-NMR(CDCl3)δ：1.66-1.76 (1H, m), 2.00-2.13 (3H, m), 2.27-2.29 (2H, m), 2.58-2.65 (1H, m), 5.13 (2H, s), 5.66 (2H, br.s), 7.29-7.38 (5H, m)
[reference example 100] (1R*, 3S*, 6S*) -7- oxabicyclos [4.1.0] heptane -3- benzyl carboxylates
Figure G2003801097466D01253
The compound (40g) that reference example 99 is obtained, which is dissolved under dichloromethane (500ml), ice cooling, adds metachloroperbenzoic acid (86g) stirring 2 hours.After adding the stirring of 10% sodium thiosulfate solution 20 minutes, organic layer is separated, after saturated sodium bicarbonate solution and saturated common salt water washing, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 9) is refined with silica gel column chromatography, obtains title compound (23.4g) and (1R*, 3R*, 6S*) -7- oxabicyclos [4.1.0] heptane -3- benzyl carboxylates (12.1g).
1H-NMR(CDCl3)δ：1.39-1.49 (1H, m), 1.75-1.82 (1H, m), 1.90-2.04 (3H, m), 2.30 (1H, dd, J=14.9,4.9Hz), 2.54-2.61 (1H, m), 3.12-3.14 (1H, m), 3.22-3.24 (1H, m), 5.12 (2H, s), 7.30-7.39 (5H, m)
MS(FAB)m/z：233(M+H)+.
[reference example 101] (1R*, 3S*, 4S*) -4- azido -3- hydroxy cyclohexane carboxylic's benzyl esters
The compound (52.3g) that reference example 100 is obtained is dissolved in DMF (1000ml), adds ammonium chloride (21.9g) and sodium azide (18.1g), in 70 DEG C of heating, stirs 24 hours.Solvent is boiled off under decompression, being added water in residue is extracted with ethyl acetate, organic layer is dried with after saturated common salt water washing with anhydrous magnesium sulfate.Solvent is boiled off under decompression, title compound (61.8g) is obtained.
1H-NMR(CDCl3)δ：1.51-1.66 (2H, m), 1.91-1.98 (1H, m), 2.07-2.10 (1H, m), 2.27-2.32 (1H, m), 2.51-2.52 (1H, m), 2.81-2.86 (1H, m), 3.30-3.36 (1H, m), 3.70-3.75 (1H, m), 5.13 (2H, s), 7.30-7.39 (5H, m)
[reference example 102] (1R*, 3S*, 4S*) -4- [(tert-butoxycarbonyl) amino] -3- hydroxy cyclohexane carboxylic's benzyl esters
The compound (5.27g) that reference example 101 is obtained is dissolved in tetrahydrofuran (25ml), adds triphenyl phasphine (5.53g) and water (0.55ml), is stirred 20 hours at room temperature.Di-tert-butyl dicarbonate (4.82g) is added in reaction solution, stirring 2 hours is further continued for.Solvent is boiled off under decompression, (hexane: ethyl acetate=2: 1) is refined with silica gel column chromatography, obtains title compound (6.22g).
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.59-1.66 (2H, m), 1.88-2.00 (2H, m), 2.29-2.32 (1H, m), 2.80-2.85 (1H, m), 3.02 (1H, br.s), 3.42 (1H, br.s), 3.59-3.65 (1H, m), 4.56 (1H, br.s), 5.12 (2H, q, J=12.5Hz), 7.30-7.38 (5H, m)
MS(FAB)m/z：350(M+H)+.
[reference example 103] (1R*, 3S*, 4S*) -4- [(tert-butoxycarbonyl) amino] -3- hydroxy cyclohexane carboxylic's methyl esters
The compound (2.54g) that reference example 102 is obtained is dissolved in ethyl acetate (15ml), adds 10% palladium carbon of catalytic amount, is stirred at room temperature under hydrogen stream 20 hours.Catalyst is filtered off, the lower concentration filtrate of decompression obtains the (1R in colorless oil*, 3S*, 4S*) -4- [(tert-butoxycarbonyl) amino] -3- hydroxy cyclohexane carboxylics.In the mixed solution for being dissolved in methanol (8ml) and toluene (15ml), 2N trimethyl silyl diazomethane hexane solution (10ml) is added under ice cooling, is stirred 30 minutes at room temperature.Solvent is boiled off under decompression, (hexane: ethyl acetate=1: 1) is refined with silica gel column chromatography, obtains title compound (1.82g).
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.36-2.32 (7H, m), 2.74-2.82 (1H, m), 3.04 (1H, br.s), 3.33-3.47 (1H, m), 3.55-3.65 (1H, m), 3.68 (3H, s), 4.56 (1H, br.s)
MS(FAB)m/z：274(M+H)+.
[reference example 104] (1R*, 3R*, 4S*) -3- azidos -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid methyl esters and (1R*, 3S*, 4S*) -3- azidos -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid methyl esters
The compound (1.81g) that reference example 103 is obtained is dissolved in dichloromethane (36ml), adds triethylamine (4.6ml) and mesyl chloride (1.63ml) in -78 DEG C, 0 DEG C is warming up to after 30 minutes, is stirred for 30 minutes.1N hydrochloric acid is added, is extracted with dichloromethane, organic layer is dried with after saturated common salt water washing with anhydrous magnesium sulfate.Solvent is boiled off under decompression, rough (1R is obtained*, 3S*, 4S*) -4- [(tert-butoxycarbonyl) amino] -3- [(methyl sulphonyl) epoxide] cyclohexane-carboxylic acid methyl esters.Above-mentioned crude compound is dissolved in DMF (23ml), sodium azide (1.29g) is added, in 70 DEG C of heating, stirred 12 hours.Add water and be extracted with ethyl acetate in reaction solution, organic layer is dried with after saturated common salt water washing with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=3: 17) is refined with silica gel column chromatography, obtains (1R*, 3S*, 4S*) -3- azidos -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid methyl esters (85mg) and (1R*, 3R*, 4S*) -3- azidos -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid methyl esters (590mg).
(1R*, 3R*, 4S*) body：1H-NMR(CDCl3)δ：1.45 (9H, s), 1.35-2.35 (7H, m), 2.45-2.55 (1H, m), 3.73 (3H, s), 3.67-3.84 (2H, m), 4.70 (1H, br.s)
MS(FAB)m/z：299(M+H)+.
(1R*, 3S*, 4S*) body：1H-NMR(CDCl3)δ：1.45 (9H, s), 1.56-2.25 (7H, m), 2.68-2.80 (1H, m), 3.70 (3H, s), 3.48-3.68 (2H, m), 4.56 (1H, br.s)
MS(FAB)m/z：299(M+H)+.
[reference example 105] (1R*, 3R*, 4S*) -3- amino -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid methyl esters
(the 1R that reference example 104 is obtained*, 3R*, 4S*) compound (230mg) is dissolved in ethyl acetate (8ml), 10% palladium carbon of catalytic amount is added, is stirred 20 hours under hydrogen stream.Insoluble matter is filtered off, the lower concentration filtrate of decompression obtains title compound (220mg).
[reference example 106] (1R*, 3R*, 4S*) -4- [(tert-butoxycarbonyl) amino] -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid methyl esters
Figure G2003801097466D01282
Using the method same with reference example 91, the compound that the compound obtained by reference example 105 and reference example 10 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.53-1.95 (5H, m), 2.17-2.24 (1H, m), 2.50 (3H, s), 2.50-2.53 (1H, m), 2.80-2.96 (4H, m), 3.67 (3H, s), 3.69-3.74 (1H, m), 4.10 (2H, br.s), 4.88 (1H, br.s)
MS(FAB)m/z：453(M+H)+.
[reference example 107] (1R*, 3R*, 4S*) -4- [(tert-butoxycarbonyl) amino] -3- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexane-carboxylic acid methyl esters
Figure G2003801097466D01283
Using the method same with reference example 91, the compound obtained by reference example 105 prepares title compound.
1H-NMR(CDCl3)δ：1.33 (9H, s), 1.42-2.47 (6H, m), 2.78-2.88 (1H, m), 3.70 (3H, s), 3.86-4.15 (2H, m), 4.65-4.75 (1H, m), 6.86 (1H, br.s), 7.18-7.38 (2H, m), 7.57-7.61 (1H, m), 8.32 (1H, br.s) .MS (ESI) m/z：450(M+H)+.
[reference example 108] (1S, 3R, 6R) -7- oxabicyclos [4.1.0] heptane -3- benzyl carboxylates
1) method same with reference example 99 is used, (1R) -3- cyclohexene -1- benzyl carboxylates are obtained by (1R) -3- cyclohexene -1- carboxylic acids (J.Am.Chem.Soc, 1978, volume 100, page 5199).
2) method same with reference example 100 is used, title compound is obtained by above-mentioned product.
MS(FAB)m/z：233(M+H)+.
[reference example 109] (1R, 3S, 4S) -4- [(tert-butoxycarbonyl) amino] -3- hydroxy cyclohexane carboxylic's benzyl esters
1) method same with reference example 101 is used, (1R, 3S, 4S) -4- azido -3- hydroxy cyclohexane carboxylic's benzyl esters are made in the compound obtained by reference example 108.
2) method same with reference example 102 is used, title compound is prepared by above-mentioned product.
MS(FAB)m/z：350(M+H)+.
[reference example 110] (1R, 3R, 4S) -3- azidos -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid benzyl ester
Using the method same with reference example 104, the compound obtained by reference example 109 prepares title compound.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.52-1.66 (2H, m), 1.83-2.01 (3H, m), 2.20-2.28 (1H, m), 2.51-2.54 (1H, m), 3.77 (2H, br.s), 4.70 (1H, br.s), 5.15 (2H, ABq, J=12.2Hz), 7.33-7.38 (5H, m)
MS(FAB)m/z：375(M+H)+.
[reference example 111] (1R, 3R, 4S) -3- azidos -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid methyl esters
Figure G2003801097466D01292
The compound (3.5g) that reference example 110 is obtained is dissolved in tetrahydrofuran (130ml) and water (16ml), lithium hydroxide (291mg) is added under ice cooling, it is room temperature to reply temperature after 10 minutes, is stirred 20 hours.Boil off after solvent and (methanol: dichloromethane=1: 20) residue is refined using silica gel column chromatography under decompression, obtain (the 1R in pale yellow oil, 3R, 4S) -3- azidos -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid (3.34g).It is dissolved in methanol (18ml) and toluene (64ml), 2 moles of trimethyl silyl diazomethane hexane solution (6.1ml) is added under ice cooling, it is room temperature to reply temperature after 10 minutes, is stirred 2 hours.Boiled off under decompression after solvent, residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, obtains title compound (3.35g).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.57-1.63 (2H, m), 1.82-1.85 (1H, m), 1.95-1.99 (2H, m), 2.20-2.28 (1H, m), 2.48-2.51 (1H, m), 3.73 (3H, s), 3.78 (2H, br.s), 4.70-4.72 (1H, m)
MS(FAB)m/z：299(M+H)+.
[reference example 112] (1R, 3R, 4S) -4- [(tert-butoxycarbonyl) amino] -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid methyl esters
1) method same with reference example 105 is used, the compound obtained by reference example 111 prepares (1R, 3R, 4S) -3- amino -4- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid methyl esters.
2) method same with reference example 106 is used, the compound obtained by above-mentioned product and reference example 10 prepares title compound.
MS(FAB)m/z：453(M+H)+.
[reference example 113] (1R*, 2S*, 5S*) -5- amino carbonyls -2- { [(5- chloro-indole -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate
Figure G2003801097466D01302
The compound (590mg) that reference example 91 is obtained is dissolved in the in the mixed solvent of ethanol (3ml) and tetrahydrofuran (6ml), and 1N sodium hydrate aqueous solution (2.5ml) is added at room temperature, stirs 12 hours.Solvent is boiled off, (1R is obtained*, 3S*, 4R*) -3- [(tert-butoxycarbonyl) amino] -4- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexane-carboxylic acid sodium salt.DMF (4ml) is suspended in, di-tert-butyl dicarbonate (654mg) and ammonium hydrogen carbonate (1g) are added at room temperature, is stirred 18 hours.Solvent is boiled off under decompression, adds water and is extracted with chloroform, organic layer is dried with after saturated common salt water washing with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (dichloromethane: methanol=47: 3) is refined with silica gel column chromatography, obtains title compound (82mg).
MS(ESI)m/z：435(M+H)+.
[reference example 114] (1R, 6S) -6- { [(benzyloxy) carbonyl] amino } -3- cyclohexene -1- aminocarbamic acid benzyl esters
Figure G2003801097466D01311
By 4- cyclohexene -1,2- diamine hydrochlorides (4.0g) are dissolved in the mixed solvent of water (20ml) and acetonitrile (20ml), benzyl chloroformate (7.66ml), potassium carbonate (14.9g) are added, is stirred 3 days at room temperature.Water is injected in reaction solution, is extracted with dichloromethane, organic layer saturated common salt water washing.After anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue is refined with silica gel column chromatography (dichloromethane), obtains title compound (8.22g).
1H-NMR(CDCl3)δ：2.03 (2H, m), 2.53 (2H, d, J=17.1Hz), 3.77 (2H, m), 5.03 (2H, q, J=12.3Hz), 5.09 (2H, q, J=12.3Hz), 5.59 (2H, s), 7.32 (10H, m)
MS(ESI)m/z：381(M+H)+.
[reference example 115] (1R*, 2S*) -2- { [(benzyloxy) carbonyl] amino } -5- hydroxy-cyclohexyl benzyq carbamates
The compound (10g) that reference example 114 is obtained is dissolved in anhydrous tetrahydro furan (70ml), and borane dimethyl sulphide complex compound (7.4ml) is added in 0 DEG C, is slowly ramped to stir 14 hours after room temperature.It is on the rocks in reaction solution, superfluous borine is decomposed, 1N sodium hydrate aqueous solution (80ml) and 30% aquae hydrogenii dioxidi (80ml) is added, directly stirred 1 hour.It is extracted with ethyl acetate, organic layer saturated common salt water washing uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=2: 1) is refined with silica gel column chromatography, obtains title compound (9.2g).
1H-NMR(CDCl3)δ：1.98 (1H, m), 2.08 (1H, m), 2.30 (1H, m), 3.43 (2H, m), 3.73 (1H, m), 5.06 (6H, m), 7.32 (10H, s)
MS(ESI)m/z：399(M+H)+.
[reference example 116] (1R*, 2S*) -2- { [(benzyloxy) carbonyl] amino } -5- oxocyclohexyl benzyq carbamates
In under -60 DEG C of cooling and stirrings, in oxalyl chloride (9.9ml) solution of dichloromethane (90ml) has been dissolved add dimethyl sulfoxide (8.2ml), then-it is secondary add reference example 115 obtain compound (9.2g) tetrahydrofuran (90ml) solution.- 40 DEG C are warming up to after 1 hour, triethylamine (26ml) is once added.Directly it is warming up to after room temperature and stirs 3 hours.Reaction solution is injected in water, extracted with dichloromethane, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 1) is refined with silica gel column chromatography, obtains title compound (8.0g).
1H-NMR(CDCl3)δ：2.27-2.43 (4H, m), 2.78 (1H, dd, J=14.4,3.9Hz), 3.86 (2H, m), 5.08 (4H, m), 5.22 (2H, m), 7.32 (10H, m)
MS(ESI)m/z：397(M+H)+.
[reference example 117] (1R*, 2S*) -2- { [(benzyloxy) carbonyl] amino } -5,5- dimethoxycyclohexyl benzyq carbamates
Figure G2003801097466D01322
The compound (3.89g) that reference example 116 is obtained is dissolved in the in the mixed solvent of methanol (15ml) and tetrahydrofuran (15ml), add 2,2- dimethoxy propanes (10.7ml) and p-methyl benzenesulfonic acid (187mg), are stirred 3 hours at room temperature.Concentrate solution, adds saturated sodium bicarbonate aqueous solution, is extracted with ethyl acetate.Organic layer saturated common salt water washing, after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (ethyl acetate: hexane=1: 2) is refined with silica gel column chromatography, obtains title compound (3.54g).
1H-NMR(CDCl3)δ：1.30-1.41 (4H, m), 1.93 (1H, m), 2.38 (1H, m), 3.19 (6H, s), 3.46 (1H, m), 3.59 (1H, m), 5.03 (2H, q, J=12.5Hz), 5.09 (2H, q, J=12.5Hz), 7.32 (10H, s)
[reference example 118] N- [(1R*, 2S*) -2- amino -4,4- dimethoxycyclohexyl] -5- chloro-indole -2- formamides and N- [(1R*, 2S*) -2- amino -5,5- dimethoxycyclohexyl] -5- chloro-indole -2- formamides
Figure G2003801097466D01331
The compound (1.45g) that reference example 117 is obtained is dissolved in methanol (12ml), is added 10% palladium carbon (290mg), is stirred at room temperature in nitrogen atmosphere 20 hours.10% palladium carbon (290mg) and methanol (10ml) are added again, are stirred 8 hours.Use diatomite filtering reacting liquid, after concentrated mother liquor, residue is dissolved in N, dinethylformamide (10ml), 5- chloro-indole -2- carboxylic acids (320mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (377mg), the hydrate of I-hydroxybenzotriazole 1 (301mg) and N-methylmorpholine (360ml) are added, is stirred 14 hours at room temperature.Reaction solution is injected in sodium bicarbonate aqueous solution, is extracted with ethyl acetate, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, with preparation silica gel thin-layer chromatography (dichloromethane: methanol=93: 7) separation and purification, acquisition N- [(1R*, 2S*) -2- amino -4,4- dimethoxycyclohexyl] -5- chloro-indole -2- formamides (or N- [(1R*, 2S*) -2- amino -5,5- dimethoxycyclohexyl] -5- chloro-indole -2- formamides) (98mg) and N- [(1R*, 2S*) -2- amino -5,5- dimethoxycyclohexyl] -5- chloro-indole -2- formamides (or N- [(1R*, 2S*) -2- amino -4,4- dimethoxycyclohexyl] -5- chloro-indole -2- formamides) (105mg).
N-[(1R*, 2S*) -2- amino -4,4- dimethoxycyclohexyl] -5- chloro-indole -2- formamides：
1H-NMR(CDCl3)δ：1.45-1.50 (2H, m), 2.06-2.10 (2H, m), 2.34 (1H, d, J=13.1Hz), 2.78 (1H, dt, J=2.9,13.1Hz), 3.18 (3H, s), 3.23 (3H, s), 3.75-3.77 (1H, m), 6.24 (1H, d, J=8.3Hz), 6.79 (1H, s), 7.23 (1H, dd, J=8.8,2.0Hz), 7.35 (1H, d, J=8.8Hz), 7.60 (1H, d, J=8.8Hz), 9.53 (1H, br.s)
MS(ESI)m/z：352(M+H)+.
N-[(1R*, 2S*) -2- amino -5,5- dimethoxycyclohexyl] -5- chloro-indole -2- formamides：
1H-NMR(CDCl3)δ：1.83-1.87 (1H, m), 1.97-2.01 (1H, m), 2.39 (1H, br, J=13.2Hz), and 2.86-2.90 (1H, m), 3.22-3.28 (10H, m), 4.00-4.02 (1H, m), 6.77 (1H, s), 7.23 (1H, d, J=8.5Hz), 7.37 (1H, d, J=8.5Hz), 7.61 (1H, s), 9.49 (1H, br.s)
MS(ESI)m/z：352(M+H)+.
[reference example 119] (7R*, 8S*) -7- { [(benzyloxy) carbonyl] amino }-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 8- aminocarbamic acid benzyl esters
The compound (4.0g) that reference example 116 is obtained is dissolved in anhydrous tetrahydro furan (30ml), adds ethylene glycol (5.6ml) and p-methyl benzenesulfonic acid (192mg), stirs 17 hours at room temperature.Reaction solution is injected into saturated sodium bicarbonate aqueous solution, is extracted with ethyl acetate, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 1) is refined with silica gel column chromatography, obtains title compound (4.23g).
1H-NMR(CDCl3)δ：1.65-1.71 (4H, m), 2.00 (1H, m), 2.11 (1H, m), 3.49 (1H, m), 3.73 (1H, m), 3.93 (4H, s), 5.03 (2H, q, J=12.2Hz), 5.08 (2H, q, J=12.2Hz), 7.32 (10H, s)
MS(ESI)m/z：441(M+H)+.
[reference example 120] N- [(7R*, 8S*) -7- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 8- yls] -5- chloro-indole -2- formamides and N- [(7R*, 8S*) -8- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 7- yls] -5- chloro-indole -2- formamides
Figure G2003801097466D01342
Using the method same with reference example 118, the compound obtained by reference example 119 obtains N- [(7R*, 8S*) -7- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 8- yls] -5- chloro-indole -2- formamides or (N- [(7R*, 8S*) -8- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 7- yls] -5- chloro-indole -2- formamides) and N- [(7R*, 8S*) -8- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 7- yls] -5- chloro-indole -2- formamides (or N- [(7R*, 8S*) -7- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 8- yls] -5- chloro-indole -2- formamides).
N-[(7R*, 8S*) -8- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 7- yls] -5- chloro-indole -2- formamides (or N- [(7R*, 8S*) -7- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 8- yls] -5- chloro-indole -2- formamides)：
1H-NMR(CDCl3)δ：1.68-1.81 (4H, m), 2.11 (2H, m), 2.87 (1H, td, J=3.9,11.2Hz), 3.77 (1H, m), 3.97 (4H, s), 6.27 (1H, d, J=7.6Hz), 6.80 (1H, s), 7.24 (1H, d, J=9.0Hz), 7.35 (1H, d, J=9.0Hz), 7.61 (1H, s), 9.47 (br.s, 1H)
MS(ESI)m/z：350(M+H)+.
N-[(7R*, 8S*) -8- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 7- yls] -5- chloro-indole -2- formamides (or N- [(7R*, 8S*) -7- amino-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 8- yls] -5- chloro-indole -2- formamides)：
1H-NMR(CDCl3)δ：1.65 (2H, m), 1.88 (1H, m), 1.96 (1H, m), 2.31 (1H, dd, J=12.9,3.2Hz), 2.96 (1H, m), 3.98 (1H, m), 4.02 (4H, s), 4.12 (1H, m), 6.77 (1H, s), 7.06 (1H, br.s), 7.23 (1H, dd, J=8.8,2.0Hz), 7.37 (1H, d, J=8.8Hz), 7.62 (1H, d, J=2.0Hz), 9.49 (1H, br.s)
MS(ESI)m/z：350(M+H)+.
[reference example 121] (1R, 6S) -6- [(tert-butoxycarbonyl) amino] -3- cyclohexene -1- carbamates
Figure G2003801097466D01351
By cis- 4- cyclohexene -1,2- diamine hydrochlorides (4.0g) are dissolved in water (40ml) and acetonitrile (40ml), two tert-butoxy carbonic esters (11.8g) and triethylamine (12ml) are added, is stirred 4.5 hours at room temperature.Reaction solution is injected in water, extracted with dichloromethane, dichloromethane layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, obtains title compound (6.12g).
1H-NMR(CDCl3)δ：1.44 (18H, s), 1.98 (2H, dd, J=9.3,15.9Hz), 2.48 (2H, br.d, J=15.9Hz), 3.66 (2H, br.s), 4.88 (2H, br.s), 5.58 (2H, d, J=2.7Hz)
[reference example 122] (1R*, 2S*) -2- [(tert-butoxycarbonyl) amino] -5- hydroxy cyclohexylphenyls carbamate (mixture of stereoisomer)
Figure G2003801097466D01352
The compound (6.1g) that reference example 121 is obtained is dissolved in anhydrous tetrahydro furan (40ml), and borane-dimethyl sulfide complex compound (2.22ml) is added under ice cooling, is directly slowly ramped to stir 16 hours while room temperature.It is on the rocks in reaction solution, 1N sodium hydrate aqueous solution and 30% aqueous hydrogen peroxide solution (50ml) is added, is directly stirred at room temperature 2 hours.It is extracted with ethyl acetate, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 2 → 2: 1) is refined with silica gel column chromatography, obtains title compound (6.1g).
1H-NMR(CDCl3)δ：1.42 (9H, s), 1.43 (9H, s), 1.83-1.67 (5H, m), 2.15 (1H, m), 2.22 (1H, s), 3.34 (1H, m), 3.78 (1H, m), 4.15 (1H, s), (4.98 1H, q, J=9.0Hz), 5.02 (1H, q, J=9.0Hz)
MS(ESI)m/z：331(M+H)+.
[reference example 123] (1R*, 2S*) -2- [(tert-butoxycarbonyl) amino] -5- oxocyclohex carbamates
Figure G2003801097466D01361
Oxalyl chloride (8.2ml) and dimethyl sulfoxide (6.8ml) are dissolved in dichloromethane (100ml), it is cooled to -60 DEG C, the tetrahydrofuran solution (80ml) for the compound (mixture of stereoisomer) (6.32g) that reference example 122 is obtained once is added, is stirred 1 hour.- 40 DEG C are warming up to, triethylamine (21ml) is added, is warming up to room temperature, is injected after 3 hours in water.Extracted with dichloromethane, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 1) is refined with silica gel column chromatography, obtains title compound (3.8g).
1H-NMR(CDCl3)δ：1.43 (9H, s), 1.44 (9H, s), 2.24-2.36 (3H, m), 2.39-2.44 (2H, m), 2.75 (1H, dd, J=14.6,2.9Hz), 3.66-3.81 (2H, m), 4.95-4.90 (1H, m), 4.97-5.03 (1H, m)
MS(ESI)m/z：329(M+H)+.
[reference example 124] (1R*, 2S*) -2- [(tert-butoxycarbonyl) amino] -5- (methoxyimino) Cyclohexylamino t-butyl formate
The compound (1.5g) that reference example 123 is obtained is dissolved in methanol (30ml), adds O- methyl hydroxylamine hydrochlorides (572mg) and pyridine (737ml), is stirred 17 hours at room temperature.Add water, be extracted with ethyl acetate after concentration of reaction solution, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, obtains title compound (1.52g).
1H-NMR(CDCl3)δ：1.44 (18H, s), 1.64 (1H, m), 2.16 (2H, m), 2.44 (1H, m), 3.45-3.63 (3H, m), 3.82 (3H, s), 4.93 (1H, m)
MS(ESI)m/z：358(M+H)+.
[reference example 125] (1R*, 2S*) -2- [(tert-butoxycarbonyl) amino] -5- { [tert-butyl group (diphenyl) silicyl] epoxide } Cyclohexylamino t-butyl formate (stereoisomer A)
Figure G2003801097466D01371
Using the method same with reference example 58, the compound obtained by reference example 122 (mixture of stereoisomer) obtains sub-titled compound.In addition, reclaiming (1R*, 2S*) -2- [(tert-butoxycarbonyl) amino] -5- hydroxy cyclohexylphenyl carbamates (stereoisomer B).
1H-NMR(CDCl3)δ：1.03 (9H, s), 1.39 (9H, s), 1.40 (9H, s), 1.72 (1H, m), 1.86 (1H, m), 2.13 (1H, m), 3.24 (2H, m), 3.65 (1H, m), 4.83 (1H, m), 7.37 (10H, m)
[reference example 126] (1R*, 2S*) -2- { [(benzyloxy) carbonyl] amino } -5- hydroxy-5-methyl butylcyclohexyl benzyq carbamates
Anhydrous cerium chloride (6.4g) is suspended in tetrahydrofuran (50ml), under argon gas stream, -78 DEG C are cooled to.MethyUithium solution (1.14N diethyl ether solution, 22.5ml) is added in suspension, is stirred 30 minutes in -78 DEG C.The tetrahydrofuran solution (50ml) for the mixture (3.0g) that reference example 116 is obtained is added dropwise in -78 DEG C, stirs 30 minutes.Reaction solution is injected in 3% acetic acid aqueous solution (100ml), ether (50ml) is added, stirred 10 minutes at room temperature.Reaction solution is extracted with ethyl acetate, and organic layer first uses saturated common salt water washing again with saturated sodium bicarbonate aqueous solution, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: chloroform=0: 100~1: 19) is carried out 2 times and refined, obtain title compound (stereoisomer A) (780mg) and title compound (stereoisomer B) (1.1g) with silica gel column chromatography.
Stereoisomer A：
1H-NMR(CDCl3)δ：1.26 (3H, s), 1.27-2.08 (6H, m), 3.48 (1H, br.s), 3.59 (1H, br.s), 5.02-5.09 (5H, m), 5.33 (1H, br.s), 7.30-7.32 (10H, s)
MS(FAB)m/z：413(M+H)+.
Stereoisomer B：
1H-NMR(CDCl3)δ：1.25 (3H, s), 1.29-2.07 (6H, m), 3.39 (1H, br.s), 3.82 (1H, br.s), 5.02-5.23 (6H, m), 7.30 (10H, s)
MS(FAB)m/z：413(M+H)+.
[reference example 127] (3R*, 4S*) -3,4- diaminourea -]-methyl cyclohexanol (stereoisomer A)
Figure G2003801097466D01381
In the methanol solution (100ml) that 10% palladium carbon (350mg) is suspended in the compound (stereoisomer A) (780mg) of the acquisition of reference example 126, stirred 5 hours under hydrogen stream.Filter off catalyst, the lower concentration filtrate of decompression.Residue is dissolved in dichloromethane (100ml), with solvent is boiled off after anhydrous sodium sulfate drying, obtains title compound (stereoisomer A) (190mg).
1H-NMR(CDCl3)δ：1.22 (3H, s), 1.25-2.48 (11H, m), 2.62 (1H, br.s), 2.78 (1H, br.s)
[reference example 128] N- [(1R*, 2S*) -2- amino-4-hydroxy -4- methylcyclohexyls] -5- chloro-indole -2- formamides (stereoisomer A) and N- [(1R*, 2S*) -2- amino -5- hydroxy-5-methyls butylcyclohexyl] and -5- chloro-indole -2- formamides (stereoisomer A) mixture
Figure G2003801097466D01382
Using the method same with reference example 59, the compound (stereoisomer A) obtained by reference example 127 and 5- chloro-indole -2- carboxylic acids obtain title compound.
1H-NMR(CDCl3)δ：1.32 (3H, s), 1.34-2.29 (6H, m), 4.42-4.70 (4H, br), 7.13 (2H, s), 7.50 (2H, s), 8.00 (1H, s), 11.0 (1H, br)
[reference example 129] (1R*, 2R*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (hydroxymethyl) Cyclohexylamino t-butyl formate
1) (the 1R obtained by reference example 89*, 3S*, 4S*) body, using the method same with the method that reference example 90~91 is recorded, obtain (1R*, 3S*, 4S*) -3- [(tert-butoxycarbonyl) amino] -4- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexanecarboxylate.
1H-NMR(CDCl3)δ：1.22-1.72 (6H, m), 2.15-2.28 (2H, m), 2.41-2.49 (1H, m), 2.85 (1H, brs), 3.62-3.75 (1H, m), 3.78-3.92 (1H, m), 4.12-4.28 (2H, m), 4.56-4.63 (1H, m), 6.88 (1H, brs), 7.20 (1H, dd, J=8.8and 2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.52-7.57 (1H, m), 7.59 (1H, d, J=2.0Hz), 9.24 (1H, s)
MS(ESI)m/z：464(M+H)+.
2) above-mentioned product (735mg) is dissolved in dichloromethane (10ml), the 1N of diisobutylaluminium hydride hexane solution (5ml) is added in -78 DEG C, after stirring 3 hours, stirred 30 minutes in 0 DEG C.Saturated aqueous ammonium chloride is added in -78 DEG C, is extracted, after organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing, is dried with anhydrous magnesium sulfate with dichloromethane.Solvent is boiled off under decompression, residue (dichloromethane: methanol=19: 1) is refined with silica gel column chromatography, obtains title compound (480mg).
1H-NMR(CDCl3)δ：1.20-2.30 (7H, m), 3.60-3.86 (4H, m), 4.64 (1H, br.s), 6.87 (1H, s), 7.20-7.48 (3H, m), 9.15 (1H, br.s)
MS(ESI)m/z：422(M+H)+.
[reference example 130] (1R*, 3R*, 6S*) -3- (methoxy) oxabicyclo [4.1.0] heptane
Figure G2003801097466D01392
1) by (1R*, 4R*, 5R*) iodo- 6- oxabicyclos [3.2.1] octane-7-ketones (2.8g) of -4- are dissolved in the in the mixed solvent of tetrahydrofuran (27ml) and water (3ml), concentrated hydrochloric acid (0.1ml) is added, is heated to reflux 1 hour.Solvent is boiled off under decompression, (the 1R in colorless solid is obtained*, 3R*, 4R*) -3- hydroxyl -4- iodocyclohexanes carboxylic acids (3.23g).
2) product (3.22g) obtained above-mentioned reaction, which is dissolved under tetrahydrofuran (50ml), ice cooling, adds borane-dimethyl sulfide complex compound (2 moles of tetrahydrofuran solutions, 47ml), stirs 12 hours at room temperature.Solvent is boiled off under decompression, residue is dissolved in isopropanol (10ml), 1N sodium hydrate aqueous solution (12ml) is added at room temperature, is stirred 12 hours.Solvent concentration, with water and dchloromethane, is stirred 10 minutes to after 1/5 or so.Organic layer is separated, successively with saturated aqueous ammonium chloride and saturated common salt water washing, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 2) is refined with silica gel column chromatography, obtains (the 1R in colorless oil*, 3R*, 6S*) -7- oxabicyclos [4.1.0] hept- 3- bases methanol (1.25g).
3) product (4.63g) that above-mentioned reaction 2) is obtained is dissolved in tetrahydrofuran (50ml), double (trimethyl silyl) amido potassium (0.5N toluene solutions are added in -78 DEG C, 80ml), after being stirred 10 minutes at identical temperature, methyl iodide (2.93ml) is added.It is warming up to after 0 DEG C and stirs 1 hour, adds saturated aqueous ammonium chloride, diluted with ether.Organic layer is separated, saturated common salt water washing is used, anhydrous magnesium sulfate is dried.Solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 4) is refined with silica gel column chromatography, obtains title compound (3.7g).
1H-NMR(CDCl3)δ：0.89-1.63 (5H, m), 1.80-2.05 (2H, m), 1.89-3.06 (4H, m), 3.16 (3H, s)
[reference example 131] (1R*, 2R*, 4S*) -2- azidos -4- (methoxy) cyclohexanol
Using the method same with reference example 87, the compound obtained by reference example 130 prepares title compound.
1H-NMR(CDCl3)δ：1.45-1.70 (5H, m), 1.77-1.95 (2H, m), 1.98-2.08 (1H, m), 3.30 (2H, d, J=6.8Hz), 3.35 (3H, s), 3.45-3.65 (2H, m)
[reference example 132] (1R*, 2R*, 5S*) -2- hydroxyls -5- (methoxy) Cyclohexylamino t-butyl formate
Figure G2003801097466D01402
Using the method same with reference example 88, the compound obtained by reference example 131 prepares title compound.
1H-NMR(CDCl3)δ：1.35-2.01 (16H, m), 3.05 (1H, br.s), 3.32 (2H, d, J=7.1Hz), 3.34 (3H, s), 3.44-3.62 (2H, m), 4.59 (1H, br.s)
[reference example 133] (1R*, 2S*, 5S*) -2- azidos -5- (methoxy) Cyclohexylamino t-butyl formate
Using the method same with reference example 89, the compound obtained by reference example 132 obtains title compound via its methanesulfonates.
1H-NMR(CDCl3)δ：1.31-1.93 (16H, m), 3.27 (2H, d, J=6.4Hz), 3.32 (3H, s), 3.57-3.70 (1H, m), 3.67 (1H, br.s), 3.95 (1H, br.s)
[reference example 134] (1R*, 2S*, 5S*) -2- amino -5- (methoxy) Cyclohexylamino t-butyl formate
Figure G2003801097466D01412
Using the method same with reference example 90, the compound obtained by reference example 133 prepares title compound.
[reference example 135] (1R*, 2S*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (methoxy) Cyclohexylamino t-butyl formate
Figure G2003801097466D01413
Using the method same with reference example 91, the compound obtained by reference example 134 and 5- chloro-indole -2- carboxylic acids obtain title compound.
1H-NMR(CDCl3)δ：1.12-2.31 (16H, m), 3.14-3.30 (2H, m), 3.34 (3H, s), 3.92 (1H, br.s), 4.13 (1H, br.s), 4.88 (1H, br.s), 6.82 (1H, s), 7.21 (1H, br.d, J=8.8Hz), 7.33 (1H, d, J=8.8Hz), 7.60 (1H, s), 8.09 (1H, br.s), 9.42 (1H, br.s)
MS(ESI)m/z：436(M+H)+.
[reference example 136] (1R*, 2S*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (hydroxymethyl) Cyclohexylamino t-butyl formate
Using the method same with reference example 129, the compound obtained by reference example 91 prepares title compound.
1H-NMR(CDCl3)δ：0.78-2.30 (16H, m), 3.41-3.59 (3H, m), 3.86-3.95 (1H, m), 4.12-4.20 (1H, m), 4.82-4.91 (1H, m), 6.81 (1H, s), 7.17-7.40 (2H, m), 7.60 (1H, s), 8.03 (1H, br.s), 9.18 (1H, br.s)
MS(ESI)m/z：422(M+H)+.
[reference example 137] (1R*, 2S*, 5S*) -5- (azido methyl) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate
Figure G2003801097466D01422
Using the method same with reference example 80, the compound obtained by reference example 136 prepares title compound.
[reference example 138] 3- cyclohexene -1- carbamates
3- cyclohexene -1- carboxylic acids (25.3g) are dissolved in the tert-butyl alcohol (250ml), triethylamine (28ml) and diphenylphosphoryl azide (43.0ml) is added, stirs 1 hour, is then stirred 2 days at 90 DEG C at room temperature.Solvent is boiled off under decompression, after residue is refined with silica gel column chromatography (dichloromethane), (hexane: ethyl acetate=20: 1) is re-refined with silica gel column chromatography, obtains title compound (24.9g).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.45-1.60 (1H, m), 1.80-1.90 (2H, m), 2.05-2.20 (2H, m), 2.35-2.45 (1H, m), 3.78 (1H, br), 4.56 (1H, br), 5.55-5.65 (1H, m), 5.65-5.75 (1H, m)
[reference example 139] (3R*, 4S*) -3,4- dihydroxy Cyclohexylamino t-butyl formates
The compound (1.24g) that reference example 138 is obtained is dissolved in the in the mixed solvent of acetonitrile (15ml) and water (5ml), N- oxidations-N-methylmorpholine (0.90g) and 10% osmium tetroxide (1g) of microencapsulation are added, is stirred 1 day in about 80 DEG C.Filter off after insoluble matter, be concentrated under reduced pressure filtrate, residue obtained use silica gel column chromatography (dichloromethane: methanol=20: 1) refines, obtains title compound (1.28g).
1H-NMR(CDCl3)δ：1.15-1.30 (1/2H, m), 1.35-2.00 (15H, m), 2.15-2.30 (3/2H, m), 2.40-2.60 (1H, m), 3.64 (1H, br), 3.75-3.90 (3/2H, m), 4.00 (1/2H, br)
MS(FAB)m/z：232(M+H)+.
[reference example 140] (3R*, 4S*) -3,4- diazido Cyclohexylaminos t-butyl formate (stereoisomer A and stereoisomer B)
Figure G2003801097466D01432
Using the method same with reference example 80, the compound obtained by reference example 139 prepares title compound (stereoisomer A and stereoisomer B)
Stereoisomer A：
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.40-1.55 (1H, m), 1.55-1.80 (3H, m), 1.95-2.15 (2H, m), 3.53 (1H, m), 3.59 (1H, br), 3.80 (1H, m), 4.70 (1H, br)
Stereoisomer B：
1H-NMR(CDCl3)δ：1.27 (1H, m), 1.44 (9H, s), 1.40-1.55 (1H, m), 1.80-2.00 (2H, m), 2.00-2.15 (1H, m), 2.21 (1H, m), 3.48 (1H, m), 3.77 (1H, br), 3.89 (1H, br), 4.34 (1H, br)
[reference example 141] (1R, 3R, 4S) -4- { [(benzyloxy) carbonyl] amino } -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
The compound (3.10g) that reference example 96 is obtained is dissolved in tetrahydrofuran (50ml), adds saturated sodium bicarbonate aqueous solution (50ml).Instill after benzyloxycarbonyl chlorine (1.71ml), stirred 4 days at room temperature in reaction solution under ice cooling.Ethyl acetate (200ml) is added in reaction solution and water (200ml) carries out a point liquid operation.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.The solid that leaching is separated out, obtains title compound (3.24g).
1H-NMR(CDCl3)δ：1.24 (3H, t, J=7.1Hz), 1.29-1.44 (1H, m), 1.44 (9H, s), 1.51-1.64 (1H, m), 1.72-2.10 (4H, m), 2.27-2.43 (1H, m), 3.60-3.73 (1H, m), 4.00-4.18 (3H, m), 4.62 (1H, br.s), 5.01-5.13 (2H, m), 5.26 (1H, br.s), 7.27-7.38 (5H, m)
[reference example 142] (1S, 3R, 4S) -4- { [(benzyloxy) carbonyl] amino } -3- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid
Figure G2003801097466D01442
The compound (620mg) that reference example 141 is obtained is dissolved in tetrahydrofuran (20ml), adds the aqueous solution (10ml) of the hydrate of lithium hydroxide 1 (93mg), stirs 16 hours at room temperature.The additional hydrate of lithium hydroxide 1 (217mg) in reaction solution, after stirring 2 hours at room temperature, the aqueous hydrochloric acid solution for adding 1N is neutralized, and is extracted with dichloromethane.Organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off, title compound (600mg) is obtained.
1H-NMR(CDCl3)δ：1.22-2.20 (6H, m), 1.44 (9H, s), 2.45 (1H, br.s), 3.60-3.80 (1H, br), 4.09 (1H, br.s), 4.66 (1H, br.s), 5.00-5.20 (2H, m), 5.26 (1H, br.s), 7.20-7.40 (5H, m)
MS(ESI)m/z：393(M+H)+.
[reference example 143] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino benzyl formate
The compound (600mg) and dimethylamine hydrochloride (240mg) that reference example 142 is obtained are suspended in after dichloromethane (50ml), add appropriate tetrahydrofuran formation solution.Triethylamine (0.41ml), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (422mg) and the hydrate of I-hydroxybenzotriazole 1 (338mg) are added in the solution, is stirred 1 hour at room temperature.Additional dimethylamine hydrochloride (480mg) and triethylamine (0.82ml), are stirred for 18 hours at room temperature in reaction solution.Reaction solution is injected in water, organic layer is separated, after 1N hydrochloric acid and saturated common salt water washing, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: dichloromethane=3: 47 → 2: 23) is refined with silica gel column chromatography, obtains title compound (620mg).
1H-NMR(CDCl3)δ：1.20-1.50 (2H, m), 1.44 (9H, s), 1.50-2.10 (4H, m), 2.60 (1H, br.t, J=11.6Hz), 2.93 (3H, s), 3.02 (3H, s), 3.70 (1H, br.s), 4.14 (1H, br.s), 4.65 (1H, br.s), 5.00-5.30 (3H, m), 7.26-7.40 (5H, m)
MS (ESI) m/z=420 (M+H)+.
[reference example 144] (1R, 2S, 5S) -2- amino -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
10% palladium carbon (57g) is added in methanol (8000ml) solution for the compound (190g) that reference example 143 is obtained, in the stirring under hydrogen 3 hours of 7 air pressure.Filter off after catalyst, the lower concentration filtrate of decompression.After addition toluene is concentrated under reduced pressure in residue, hexane (2500ml) solidification is added, leaching is dried, and obtains title compound (121g).
1H-NMR(CDCl3)δ：1.20-1.77 (6H, m), 1.45 (9H, s), 2.20-2.35 (1H, br), 2.63-2.74 (1H, m), 2.92 (3H, s), 3.02 (3H, s), 3.02-3.11 (2H, m), 3.74-3.82 (1H, m), 4.88-5.00 (1H, br) MS (ESI) m/z：286(M+H)+.
[reference example 145] (1R, 2S, 5S) -2- { [(6- chloroquinoline -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 91, the compound that the compound obtained by reference example 144 and reference example 54 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.41 (9H, br), 1.50-1.70 (1H, m), 1.75-1.95 (2H, m), 1.95-2.25 (3H, m), 2.65-2.80 (1H, m), 2.96 (3H, s), 3.07 (3H, s), 4.15-4.30 (1H, m), 4.30-4.40 (1H, m), 4.95 (1H, br), 7.66 (1H, d, J=8.8Hz), 7.84 (1H, s), (8.00 1H, d, J=8.8Hz), (8.19 1H, d, J=8.6Hz), 8.30 (1H, d, J=8.6Hz)
MS(FAB)m/z：475(M+H)+.
[reference example 146] (1R, 2S, 5S) -2- { [(7- chloroquinoline -3- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 91, the compound that the compound obtained by reference example 144 and reference example 57 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.30-1.65 (10H, br), 1.75-1.90 (2H, m), 1.90-2.25 (3H, m), 2.65-2.90 (1H, br), 2.96 (3H, s), 3.08 (3H, s), 4.20-4.30 (1H, m), 4.30-4.40 (1H, m), 4.93 (1H, br), 7.68 (1H, m), 7.90 (1H, br), 7.99 (1H, s), 8.35-8.70 (2H, m), 9.01 (1H, br)
MS(FAB)m/z：475(M+H)+.
The bromo- 5- isopropyls -4,5 of [reference example 147] 2-, 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine
Figure G2003801097466D01471
Same with reference example 9, the compound obtained by reference example 8 prepares title compound.
1H-NMR(CDCl3)δ：1.13 (6H, d, J=6.5Hz), 2.86 (4H, s), 2.89-3.00 (1H, m), 3.70 (2H, s)
[reference example 148] 5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids lithium salts
Same with reference example 10, the compound obtained by reference example 147 prepares title compound.
1H-NMR(DMSO-d6)δ：(1.05 6H, d, J=6.4Hz), and 2.68-2.70 (2H, m), 2.75-2.77 (2H, m), 2.87-2.93 (1H, m), 3.66 (2H, s)
[reference example 149] 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids 4- nitro phenyl esters
Figure G2003801097466D01473
Same with reference example 52, the compound and p-nitrophenol obtained by reference example 10 prepares title compound.
1H-NMR(CDCl3)δ：2.55 (3H, s), 2.88 (2H, t, J=5.7Hz), 3.06-3.12 (2H, m), 3.80 (2H, s), 7.46 (2H, d, J=9.3Hz), 8.32 (2H, d, J=9.3Hz)
MS(ESI)m/z：320(M+H+).
[reference example 150] 3- oxo cyclobutane-carboxylic acid benzyl esters
In 3- oxo cyclobutane-carboxylic acids (J.Org.Chem., volume 53,3841-3843 pages, 1981) triethylamine (2.0ml) and benzyl bromide a-bromotoluene (1.2ml) are added in tetrahydrofuran (5.0ml) solution of (995mg), stirring 2 hours at room temperature.Reaction solution is diluted with ethyl acetate, successively with 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, then with after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 6) refines, obtains title compound (886mg).
1H-NMR(CDCl3)δ：3.22-3.33 (3H, m), 3.37-3.48 (2H, m), 5.19 (2H, s), 7.31-7.42 (5H, m) .MS (FAB) m/z：205(M+H+).
[reference example 151] 3- hydroxycyclobutane benzyl carboxylates
0 DEG C, add and stirred 30 minutes at sodium borohydride (76mg), identical temperature in the tetrahydrofuran (10ml) of compound (781mg), the mixed solution of methanol (0.5ml) that reference example 150 is obtained.Reaction solution is diluted with ethyl acetate, successively with saturated sodium bicarbonate aqueous solution and saturated common salt water washing, then with after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 2) refines, obtains title compound (770mg).
1H-NMR(CDCl3)δ：2.13-2.27 (3H, m), 2.55-2.71 (3H, m), 4.14-4.23 (1H, m), 5.12 (2H, s), 7.28-7.39 (5H, m)
MS(FAB)m/z：207(M+H+).
[reference example 152] 3- hydroxycyclobutane carboxylic acids
Figure G2003801097466D01482
10% palladium carbon (108mg) is added in ethanol (10ml) solution for the compound (706mg) that reference example 151 is obtained, is stirred 2 hours in nitrogen atmosphere at room temperature.After diatomite filtration catalytic agent, be concentrated under reduced pressure filtrate, obtains title compound (399mg).
1H-NMR(CD3OD)δ：2.00-2.21 (2H, m), 2.41-2.61 (3H, m), 4.01-4.13 (1H, m)
[reference example 153] 3- methoxyl group cyclobutane-carboxylic acid benzyl esters
Methyl iodide (194 μ l), silver oxide (237mg) are added in DMF (3.0ml) solution for the compound (317mg) that reference example 151 is obtained, is stirred 1 hour in 45 DEG C.Methyl iodide (194 μ l), silver oxide (226mg) are added in reaction solution, is stirred 16 hours in 45 DEG C.Filter off after catalyst, be concentrated under reduced pressure filtrate.Residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 10) refines, obtains title compound (152mg).
1H-NMR(CDCl3)δ：2.14-2.24 (2H, m), 2.44-2.54 (2H, m), 2.59-2.72 (1H, m), 3.21 (3H, s), 3.73-3.81 (1H, m), 5.11 (2H, s), 7.22-7.39 (5H, m)
MS(ESI)m/z：221(M+H+).
[reference example 154] 3- methoxyl group cyclobutane-carboxylic acids
Same with reference example 152, the compound obtained by reference example 153 prepares title compound.
1H-NMR(CDCl3)δ：2.17-2.27 (2H, m), 2.48-2.58 (2H, m), 2.62-2.73 (1H, m), 3.25 (3H, s), 3.76-3.86 (1H, m), 8.60-9.30 (1H, br)
[reference example 155] 3- methoxyl groups -2- (methoxy) methyl propionate
Sodium methoxide (1.21g) is added in methanol (10ml) solution of 2- (bromomethyl) methyl acrylate (1.0ml), is heated to reflux 26 hours.Diluted after reaction solution cooling with ether, filter off sediment, be concentrated under reduced pressure filtrate.Residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 4) refines, obtains title compound (726mg).
1H-NMR(CDCl3)δ：2.90-2.96 (1H, m), 3.34 (6H, s), 3.57 (2H, dd, J=9.3,5.9Hz), 3.64 (2H, dd, J=9.3,6.6Hz), 3.73 (3H, s)
13C-NMR(CDCl3)δ：172.71,70.31,59.91,46.49.
MS(ESI)m/z：163(M+H+).
[reference example 156] tetrahydrochysene -2H- pyrans -4- carboxylic acids
Figure G2003801097466D01493
20% hydrochloric acid (20ml) is added in tetrahydrochysene -4H- pyrans -4,4- dimethyl dicarboxylate (4.04g), is heated to reflux 19 hours.Add water and extracted with ether in reaction solution, after anhydrous sodium sulfate drying, solvent is boiled off under decompression for organic layer saturated common salt water washing.It is residue obtained solidified with hexane after, solid obtained by leaching obtains title compound (2.63g) after washing.
1H-NMR(CDCl3)δ：1.75-1.95 (4H, m), 2.55-2.65 (1H, m), 3.40-3.52 (2H, m), 3.93-4.05 (2H, m)
[reference example 157] 3- { [tert-butyl group (diphenyl) silicyl] epoxide }-PA methyl esters
Figure G2003801097466D01501
It is same with reference example 41, title compound is obtained by 2,2- dimethyl -3- hydroxy methyl propionates.
1H-NMR(CDCl3)δ：1.03 (9H, s), 1.20 (6H, s), 3.64-3.68 (5H, m), 7.38-7.44 (6H, m), 7.63-7.65 (4H, m)
[reference example 158] 3- { [tert-butyl group (diphenyl) silicyl] epoxide }-PA
Under ice cooling, add water (0.24ml) stirring 5 minutes in potassium tert-butoxide (5.32g) and the suspension of ether (100ml) formation.The compound (2.22g) that reference example 157 is obtained is added wherein, and an evening is stirred at room temperature.Added water in reaction solution, make the solution in acidity with 1N aqueous hydrochloric acid solution, extracted 3 times with ether.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 6) refines, obtains title compound (735mg).
1H-NMR(CDCl3)δ：1.04 (9H, d, J=0.7Hz), 1.22 (6H, s), 3.65 (2H, s), 7.36-7.45 (6H, m), 7.64-7.66 (4H, m)
[reference example 159] 3- methoxyl groups-PA methyl esters
Figure G2003801097466D01503
Under ice cooling, 3- hydroxyls -2 are instilled in the suspension for being suspended in 60% sodium hydride (8.32g) of oil and tetrahydrofuran (100ml) formation, tetrahydrofuran (300ml) solution of 2- Dimethyl-propionic acids methyl esters (25.0g), is stirred 1 hour in 60 DEG C.Methyl iodide (53.7g) is added in the reaction solution, is stirred at room temperature 2 hours.Carefully add water, extracted 2 times with dichloromethane, organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression with after saturated common salt water washing.Distillation gained grease, obtains title compound (12.8g).
Boiling point：140~142 DEG C (normal pressure)
1H-NMR(CDCl3)δ：(3H, d, the J=1.0Hz) of 1.19 (6H, d, J=1.0Hz), 3.33 (3H, d, J=1.0Hz), 3.38 (2H, d, J=1.0Hz), 3.69
[reference example 160] 3- methoxyl groups-PA
Handled with the same compound to the acquisition of reference example 159 of reference example 158, obtain title compound.
1H-NMR(CDCl3)δ：(2H, d, the J=0.7Hz) of 1.22 (6H, d, J=0.7Hz), 3.38 (3H, d, J=0.7Hz), 3.40
[reference example 161] 1- (methoxycarbonyl) cyclopropane-carboxylic acid
Figure G2003801097466D01511
1,1- cyclopropane dicarboxylic acids dimethyl ester (25g) is dissolved in methanol (250ml), is cooled with ice.Then, 1N sodium hydrate aqueous solution (158ml) is instilled, temperature is returned back into room temperature, the evening of stirring one.Boil off after methanol, with chloroform, with ice cooling water layer, after pH is adjusted into 2 with concentrated hydrochloric acid aqueous solution, be extracted with ethyl acetate, then with anhydrous sodium sulfate drying, solvent is boiled off under decompression, title compound (16.8g) is obtained.
1H-NMR(CDCl3)δ：1.76-1.80 (2H, m), 1.82-1.88 (2H, m), 3.79 (3H, s), 12.73 (1H, br)
[reference example 162] 1- (hydroxymethyl) methyl cyclopropanecarboxylate
Figure G2003801097466D01512
The compound (9.0g) and triethylamine (9.7ml) that reference example 161 is obtained are dissolved in tetrahydrofuran (180ml), are cooled to -10 DEG C, instill isobutyl chlorocarbonate (9.1ml), stir 1 hour.On the other hand, sodium borohydride (7.1g) is dissolved in tetrahydrofuran (100ml)-water (25ml), with ice cooling.Previous solution is instilled while insoluble matter is filtered off, is stirred 1 hour at the same temperature.Reaction solution is injected in 10% cold aqueous citric acid solution, is extracted with ethyl acetate, after saturated common salt water washing, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 9~2: 1) refines, obtains title compound (4.25g).
1H-NMR(CDCl3)δ：0.87-0.93 (2H, m), 1.28-1.30 (2H, m), 3.63 (2H, s), 3.70 (3H, s)
[reference example 163] 1- (bromomethyl) methyl cyclopropanecarboxylate
In blanket of nitrogen, at room temperature, triphenyl phasphine (10g) and carbon tetrabromide (16g) are added in the dichloromethane solution (168ml) for the compound (4.20g) that reference example 162 is obtained, after 2 minutes, saturated sodium bicarbonate aqueous solution is added.Organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression with after saturated common salt water washing.Residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 19) refines, obtains title compound (2.15g).
1H-NMR(CDCl3)δ：1.00-1.05 (2H, m), 1.52-1.59 (2H, m), 3.61 (2H, s), 3.73 (3H, s)
[reference example 164] (4S) -4- [(E) -3- ethyoxyl -3- oxo -1- acrylic] -2,2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters
Figure G2003801097466D01521
In 100 DEG C to (4R) -4- formoxyls -2; the mixed solution heating stirring of 2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters (11.7g), (carbethoxymethylene) dihalotriphenylphosphoranes (20.7g) and toluene (100ml) formation 18 hours.Concentration of reaction solution, residue obtained use silica gel column chromatography (hexane: ethyl acetate=8: 1) refines, obtains title compound (17g).
1H-NMR(CDCl3)δ：1.29 (3H, t, J=6.6Hz), 1.43-1.56 (15H, m), 3.80 (1H, dd, J=9.0,2.4Hz), 4.09 (1H, dd, J=9.0,6.6Hz), 4.11-4.23 (2H, m), 4.30-4.61 (1H, m), 5.83-6.02 (1H, m), 6.74-6.89 (1H, m)
[reference example 165] (4S) -4- [1- (benzylamino) -3- ethyoxyl -3- oxopropyls] -2,2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters
Figure G2003801097466D01522
The mixed solution of the compound (22.2g), benzylamine (16g) and ethanol (100ml) formation that are obtained to reference example 164 is heated to reflux 2 days.Concentration of reaction solution, residue obtained use silica gel column chromatography (hexane: ethyl acetate=8: 1) refines, obtains title compound (26g).
1H-NMR(CDCl3)δ：1.25 (3H, t, J=6.6Hz), 1.42-1.63 (15H, m), 2.24-2.33 (0.5H, m), 2.40-2.50 (1H, m), 2.63-2.74 (0.5H, m), 3.41-3.52 (1H, m), 3.67-3.80 (1H, m), 3.83 (2H, s), 3.89-4.00 (1H, m), 4.03-4.22 (4H, m), 7.23-7.45 (5H, m)
[reference example 166] (4S) -4- (1- amino -3- ethyoxyl -3- oxopropyls) -2,2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters
10% palladium carbon (10g) is added in ethanol (200ml) solution for the compound (13.6g) that reference example 165 is obtained, is stirred 2 days under a hydrogen atmosphere.It is passed to Celite pad and filters off insoluble matter, the lower concentration filtrate of decompression obtains title compound (10.5g).
1H-NMR(DMSO-d6)δ：1.19 (1.5H, t, J=6.6Hz), 1.20 (1.5H, t, J=6.6Hz), and 1.32-1.50 (15H, m), 2.63-2.81 (2H, m), 3.22-3.34 (2H, m), 3.93 (1H, dd, J=10.0,6.8Hz), 4.08 (2H, q, J=6.6Hz), 4.20-4.30 (1H, m)
[reference example 167] (4S) -4- (1- { [(benzyloxy) carbonyl] amino } -3- ethyoxyl -3- oxopropyls) -2,2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters
Figure G2003801097466D01532
The compound (3.0g) for obtaining reference example 166 is suspended in 9% sodium bicarbonate aqueous solution (56ml), dioxane (12ml) solution of N- (benzyloxycarbonyl epoxide) succinimides (2.3g) is instilled under ice cooling, temperature is stirred 3 hours while being returned to room temperature.Ethyl acetate dilute reaction solution is used, after water, 10% aqueous citric acid solution and saturated common salt water washing, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (chloroform) refines, and obtains title compound (3.8g).
1H-NMR(CDCl3)δ：1.23 (3H, t, J=6.6Hz), 1.48 (9H, s), 1.56 (6H, s), 2.40-2.51 (2H, m), 2.63-2.70 (2H, m), 3.92-4.04 (1H, m), 4.06-4.10 (2H, m), 4.14-4.22 (1H, m), 5.09 (2H, s), 7.30-7.43 (5H, m)
[reference example 168] (3S, 4S) -3- { [(benzyloxy) carbonyl] amino } -4- [(tert-butoxycarbonyl) amino] -5- hydroxypentanoic acids ethyl esters (low polar compound) and (3R, 4S) -3- { [(benzyloxy) carbonyl] amino } -4- [(tert-butoxycarbonyl) amino] -5- hydroxypentanoic acids ethyl ester (highly polar compound)
Figure G2003801097466D01541
The low highly polar compound of polar compound
Under ice cooling, trifluoroacetic acid (100ml) is instilled in dichloromethane (100ml) solution for the compound (30g) that reference example 167 is obtained, is stirred 3 hours while being slowly returned to room temperature.The lower concentration of reaction solution of decompression, dichloromethane (100ml) is dissolved in by residue obtained.Under ice cooling, dichloromethane (100ml) solution of triethylamine (20ml) and di-tert-butyl dicarbonate (19g) is instilled successively in the solution, stirred 4 hours while being slowly returned to room temperature.The lower concentration of reaction solution of decompression, residue obtained use silica gel column chromatography (hexane: ethyl acetate=2: 1) refines, obtains the low polar compound (7.6g) of title and the highly polar compound (10g) of title.
Low polar compound：
1H-NMR(CDCl3)δ：1.24 (3H, t, J=6.6Hz), 1.42 (9H, s), 2.63 (2H, d, J=4.4Hz), 3.30-3.41 (1H, m), 3.50 (1H, t, J=9.7Hz), 3.65 (1H, t, J=9.7Hz), 3.75 (1H, d, J=11.7Hz), 3.90-4.00 (1H, m), 4.03-4.23 (2H, m), 5.12 (2H, s), 5.13-5.25 (1H, m), 5.79-6.02 (1H, m), 7.32-7.41 (5H, m)
Highly polar compound：
1H-NMR(CDCl3)δ：1.22 (3H, t, J=6.6Hz), 1.41 (9H, s), 2.50-2.70 (2H, m), 3.20-3.31 (1H, m), 3.43-3.51 (1H, m), 3.56-3.70 (1H, m), 3.74-3.78 (1H, m), 4.00-4.19 (2H, m), 4.23-4.30 (1H, m), 4.78-4.89 (1H, m), 5.10 (2H, s), 5.56-5.67 (1H, m), 7.31-7.40 (5H, m)
[reference example 169] methanesulfonic acid (3R, 4S) -4- [(methyl sulphonyl) epoxide] tetrahydrochysene -3- furans esters
Figure G2003801097466D01542
Under ice cooling, it is added dropwise under triethylamine (12.0ml) and mesyl chloride (3.6ml), ice cooling and stirs 10 minutes successively in Isosorbide-5-Nitrae-anhydroerythritol (5.0g) dichloromethane (50ml) solution.Reaction solution dchloromethane, with 10% aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, title compound (9.2g) is obtained.
1H-NMR(CDCl3)δ：3.15 (6H, s), 3.99 (2H, dd, J=11.2,2.5Hz), 4.16 (2H, dd, J=11.2,4.6Hz), 5.10-5.20 (2H, m)
[reference example 170] (3R, 3S) -3,4- diazido tetrahydrofurans
The compound (9.2g) that reference example 169 is obtained was dissolved in DMF (50ml), adds sodium azide (18g), in 100 DEG C of heating stirrings 18 hours.Reaction solution ethyl acetate uses water and saturated common salt water washing after diluting.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, title compound (3.8g) is obtained.
1H-NMR(CDCl3)δ：3.83 (2H, dd, J=8.6,2.0Hz), 3.96-4.12 (4H, m)
The hydrochloride of [reference example 171] (3R, 4S)-tetrahydrochysene -3,4- furans diamines 2
The compound (3.8g) that reference example 170 is obtained is dissolved in ethanol (50ml), adds 10% palladium carbon (1.0g), stirs 18 hours under a hydrogen atmosphere.Insoluble matter, the lower concentration filtrate of decompression are filtered off by Celite pad.After residue obtained middle addition 1N ethanol solution hydrochloride formation hydrochloride, recrystallized with the mixed solvent of ethanol and ether, obtain title compound (2.0g).
1H-NMR(CDCl3)δ：3.90 (2H, dd, J=9.0,3.7Hz), 4.01-4.13 (4H, m), 8.84 (6H, s)
[reference example 172] N- [(3R*, 4S*) -4- amino tetrahydrochysene -3- furyls] -5- chloro-indole -2- formamides
Figure G2003801097466D01553
At room temperature, the N of the compound (0.5g) obtained in reference example 171,5- chloro-indole -2- carboxylic acids (0.29g), I-hydroxybenzotriazole (0.2g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (0.6g) are sequentially added in dinethylformamide (10ml) solution, in 50 DEG C of heating stirrings 1 day.Concentration of reaction solution, residue obtained use chloroform: the mixed solvent dilution of methanol (9: 1) formation, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue obtained use silica gel column chromatography (chloroform: methanol=95: 5) refines, obtains title compound (0.2g).
1H-NMR(CDCl3)δ：1.80-1.92 (1H, m), 3.62 (1H, dd, J=9.3,4.2Hz), and 3.68-3.80 (2H, m), 4.06 (1H, dd, J=9.3,5.6Hz), 4.21 (1H, dd, J=9.3,6.8Hz), 4.36-4.52 (2H, m), 6.87 (1H, s), 7.24 (1H, dd, J=8.8,2.0Hz), 7.36 (1H, d, J=8.8Hz), 7.44-7.56 (1H, m), 7.62 (1H, d, J=2.0Hz), 9.41 (1H, s)
[reference example 173] (4R) -4- [(E) -3- ethyoxyl -3- oxo -1- acrylic] -2,2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters
Figure G2003801097466D01561
It is same with reference example 164, title compound is obtained by (4S) -4- formoxyl -2,2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters.
1H-NMR(CDCl3)δ：1.29 (3H, t, J=6.6Hz), 1.40-1.60 (15H, m), 3.80 (1H, dd, J=9.0,2.4Hz), 4.09 (1H, dd, J=9.0,6.6Hz), 4.11-4.21 (2H, m), 4.32-4.64 (1H, m), 5.78-6.01 (1H, m), 6.67-6.89 (1H, m)
[reference example 174] (4R) -4- [1- (benzylamino) -3- ethyoxyl -3- oxopropyls] -2,2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters
Figure G2003801097466D01562
Same with reference example 165, the compound obtained by reference example 173 prepares title compound.
1H-NMR(CDCl3)δ：1.25 (3H, t, J=6.6Hz), 1.40-1.61 (15H, m), 2.21-2.32 (0.5H, m), 2.40-2.51 (1H, m), 2.61-2.72 (0.5H, m), 3.43-3.50 (1H, m), 3.67-3.80 (1H, m), 3.83 (2H, s), 3.90-4.03 (1H, m), 4.04-4.22 (4H, m), 7.20-7.40 (5H, m)
[reference example 175] (4R) -4- (1- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- ethyoxyl -3- oxopropyls) -2,2- dimethyl -1,3- oxazolidine -3- carboxylic acid tert-butyl esters
Same with reference example 166, the compound that catalysis reduction reference example 174 is obtained is removed after benzyl, same with reference example 172, by the condensation with 5- chloro-indole -2- carboxylic acids, obtains title compound.
1H-NMR(CDCl3)δ：1.23 (1.5H, t, J=6.6Hz), 1.25 (1.5H, t, J=6.6Hz), 1.50 (4.5H, s), 1.54 (4.5H, s), 1.62 (6H, s), 2.50-2.70 (1.5H, m), 2.86 (0.5H, dd, J=16.4, 5.5Hz), 3.80-3.90 (0.5H, m), 4.00-4.31 (5H, m), 4.41-4.67 (0.5H, m), 6.85 (0.5H, s), 6.87 (0.5H, s), 7.10-7.20 (1H, m), 7.34 (0.5H, d, J=8.8Hz), 7.38 (0.5H, d, J=8.8Hz), 7.57 (0.5H, s), 7.63 (0.5H, s), 7.88 (0.5H, d, J=7.6Hz), 8.54 (0.5H, d, J=7.6Hz), 9.40 (0.5H, s), 9.54 (0.5H, s)
[reference example 176] (3R, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -6- oxo tetrahydrochysene -2H- pyrans -3- carbamates (low polar compound) and (3R, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -6- oxo tetrahydrochysene -2H- pyrans -3- carbamates (highly polar compound)
The low highly polar compound of polar compound
1N sodium hydrate aqueous solution (4.0ml) is added in ethanol (20ml) solution for the compound (1.0g) that reference example 175 is obtained, is stirred 4 hours.After pH is adjusted to 4.0 by addition citric acid in reaction solution, it is extracted with ethyl acetate.Organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression with after saturated common salt water washing.It is residue obtained to be dissolved in methanol (50ml), add the hydrate of toluenesulfonic acid 1 (0.1g) and stir 18 hours.Reaction solution is diluted with ethyl acetate, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression, residue obtained use silica gel column chromatography (chloroform: methanol=99: 1) refines, obtains the low polar compound (0.3g) and highly polar compound (0.3g) of title.
Low polar compound：
1H-NMR(CDCl3)δ：1.45 (9H, s), 2.70 (1H, dd, J=16.5,4.9Hz), 2.85 (1H, dd, J=16.5,4.6Hz), and 3.50-3.61 (1H, m), 3.71-3.81 (2H, m), 4.30-4.40 (1H, m), 5.30 (1H, d, J=9.5Hz), 6.89 (1H, s), 7.23 (1H, dd, J=8.8,2.0Hz), 7.38 (1H, d, J=8.8Hz), 7.62 (1H, d, J=2.0Hz), 7.93 (1H, d, J=9.5Hz), 9.30 (1H, s)
Highly polar compound：
1H-NMR(CDCl3)δ：1.39 (9H, s), 2.75 (1H, dd, J=16.5,4.9Hz), 2.82 (1H, dd, J=16.5,4.6Hz), and 3.41-3.52 (2H, m), 3.71-3.82 (1H, m), 3.85-3.94 (1H, m), (5.03 1H, d, J=9.3Hz), 6.99 (1H, s), 7.22-7.31 (1H, m), 7.34 (1H, d, J=8.8Hz), 7.61 (1H, d, J=2.0Hz), 7.83 (1H, d, J=9.3Hz), 9.28 (1H, s)
[reference example 177] 1,1,3- trioxy- hexahydro -1- thiapyran -4- carbamates
Tetrahydrofuran (900ml) solution of N- tert-butoxycarbonyls-METHIONINE sulfo methyl ester (60.2g) is cooled to -78 DEG C, instill double (trimethyl silyl) amido potassium (toluene solutions of 0.5M, after 900ml), stir 2 hours, be stirred at room temperature 4 hours half in -78 DEG C.1M aqueous ammonium chloride solutions are added to be stirred.Separate after reaction solution, organic layer water and saturated common salt water washing are dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, the solid of leaching generation obtains title compound (12.4g).2 extractions are carried out to the water layer being previously separated with ethyl acetate, merges organic layer, after water and saturated common salt water washing, is dried with anhydrous magnesium sulfate.Then, merge the water layer for washing, be extracted with ethyl acetate again, use saturated common salt water washing, dried with anhydrous magnesium sulfate.Combined ethyl acetate extract, depressurizes lower concentration, obtains title compound (27.7g) (full dose of title compound after drying：40.1g).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.85-1.96 (1H, m), 2.76-2.78 (1H, m), 3.34-3.46 (2H, m), 4.05 (1H, dd, J=13.5,3.7Hz), 4.14 (1H, d, J=13.5Hz), 4.38-4.44 (1H, m), 5.46 (1H, br)
MS(ESI)m/z：262(M-H)-.
[reference example 178] (3R*, 4R*) -3- hydroxyl -1,1- dioxo hexahydro -1- thiapyran -4- carbamates
Sodium borohydride (2.17g) is added in methanol (200ml) suspension for the compound (10.1g) that reference example 177 is obtained, is stirred 2 hours at room temperature.The lower concentration of reaction solution of decompression.Ethyl acetate and saturated sodium bicarbonate aqueous solution are added in residue, after separation, aqueous layer with ethyl acetate is extracted 2 times.Merge organic layer, after being dried with magnesium sulfate, decompression is lower to be concentrated, and obtains title compound (9.96g).
1H-NMR(CDCl3)δ：1.44 (9H, s), 2.21-2.36 (2H, m), 3.03-3.17 (2H, m), 3.26-3.28 (2H, m), 3.77-3.80 (2H, m), 4.26-4.28 (1H, m), 5.05-5.07 (1H, m)
MS(ESI)m/z：264[(M-H)-].
[reference example 179] (3R*, 4R*) -3- amino -1,1- dioxo hexahydro -1- thiapyran -4- carbamates (low polar compound) and (3R*, 4S*) -3- amino -1,1- dioxo hexahydro -1- thiapyran -4- carbamates (highly polar compound)
The low highly polar compound of polar compound
(racemic modification) (racemic modification)
Diethylazodicarboxylate (6.96g) is added in the compound (9.66g) and tetrahydrofuran (150ml) solution of triphenyl phasphine (10.5g) that reference example 178 is obtained, is stirred 4 hours half at room temperature.After the lower concentration of reaction solution of decompression, ether, the solid of leaching generation are added in residue.The solid of leaching (hexane: ethyl acetate=7: 3) is refined with silica gel column chromatography, obtains dioxo -1,2 containing 1,1- in colorless solid, the mixture (7.25g) of 3,4- tetrahydric thiapyran-4-group t-butyl carbamates.Then, lower concentrated mother liquor is depressurized, residue obtained use silica gel column chromatography (hexane: ethyl acetate=7: 3) is refined, obtain dioxo -1,2 containing 1,1- in colorless solid, mixture (9.18g) (full dose of 3,4- tetrahydric thiapyran-4-group t-butyl carbamates：16.4g).Gained mixture is dissolved in dioxane (60ml), 28% ammoniacal liquor (60ml) is added, stirred 4 hours half in 60 DEG C in tube sealing.After natural cooling, the lower concentration of reaction solution of decompression.After Zheng Qu dioxanes, extracted 5 times with dichloromethane.Merge organic layer, decompression is lower to be concentrated.Residue obtained use silica gel column chromatography (dichloromethane: methanol=96: 4) separation and purification, the low polar compound (2.31g) and highly polar compound (4.31g) of acquisition title.
Low polar compound：
1H-NMR(CDCl3)δ：1.44 (9H, s), 2.14-2.28 (2H, m), 3.01-3.08 (3H, m), 3.23 (1H, dd, J=13.8,3.9Hz), 3.47-3.49 (1H, m), 3.71-3.76 (1H, m), 5.32 (1H, d, J=7.3Hz)
MS(ESI)m/z：265(M+H+).
Highly polar compound：
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.94-2.01 (1H, m), 2.37-2.44 (1H, m), 2.91 (1H, dd, J=11.2,14.1Hz), 3.04-3.07 (2H, m), 3.12-3.19 (1H, m), 3.26-3.30 (1H, m), 3.39-3.42 (1H, m), 4.62 (1H, br)
MS(ESI)m/z：265(M+H+).
Double (the methoxymethoxy)-BDOs of [reference example 180] (2S, 3S) -2,3-
Under ice cooling, chloromethyl methyl ether (4.8ml) is instilled in L-TARTARIC ACID diethylester (8.6g) and the mixed solution of diisopropylethylamine (40ml) and dichloromethane (40ml) formation, is slowly ramped to stir 18 hours while room temperature.Concentration of reaction solution, dilutes residue obtained, with 10% aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing with ethyl acetate.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, tetrahydrofuran is dissolved in by residue obtained.Under ice cooling, instill under above-mentioned solution, ice cooling and stir 2 hours in the tetrahydrofuran suspension of lithium aluminium hydride reduction (2.2g).Under ice cooling, 10% sodium bisulphate solution is carefully added into, after stirring 1 hour, is diluted with saturated aqueous common salt, ethyl acetate is extracted.After gained organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, title compound (3.0g) is obtained.
1H-NMR(CDCl3)δ：1.55-1.64 (2H, m), 3.44 (6H, s), 3.70-3.81 (6H, m), 4.70 (2H, d, J=6.9Hz), 4.76 (2H, d, J=6.9Hz)
Double (methoxymethoxy) tetrahydrofurans of [reference example 181] (3S, 4S) -3,4-
Figure G2003801097466D01602
Diethylazodicarboxylate (2.64ml) is instilled in the compound (3.0g) that reference example 180 is obtained, triphenyl phasphine (4.5g), tetrahydrofuran (10ml) and the mixed solution of toluene (40ml) formation, is stirred 4 days at room temperature.Concentration of reaction solution, in residue obtained middle addition hexane: the mixed solvent (160ml) of ether (1: 1), stirring filters off the insoluble matter of precipitation after 3 hours.Filtrate is concentrated, residue obtained use silica gel column chromatography (hexane: ethyl acetate=4: 1) refines, obtains title compound (1.95g).
1H-NMR(CDCl3)δ：3.38 (6H, s), 3.80 (2H, dd, J=9.2,1.7Hz), 4.00 (2H, dd, J=9.2,4.4Hz), 4.23 (2H, dd, J=4.4,1.7Hz), (4.67 2H, d, J=6.9Hz), 4.71 (2H, d, J=6.9Hz)
[reference example 182] (3S, 4S) tetrahydrochysene -3,4- furans glycol
Concentrated hydrochloric acid (2.1ml) is added in methanol (6.0ml) solution for the compound (1.95g) that reference example 181 is obtained, is stirred 18 hours.Concentration of reaction solution, dilutes residue obtained with chloroform, and after being dried with potassium carbonate, solvent is boiled off under decompression, title compound (0.52g) is obtained.
1H-NMR(CDCl3)δ：1.77 (2H, d, J=4.7Hz), 3.73 (2H, d, J=10.2Hz), 4.08 (2H, dd, J=10.2,3.7Hz), 4.18-4.34 (2H, m)
[reference example 183] (3S, 4S) tetrahydrochysene -3,4- furans diamines
Figure G2003801097466D01612
The compound obtained by reference example 182, using the method same with the method that reference example 169~171 is recorded, obtains title compound.
1H-NMR(CDCl3)δ：1.35-1.46 (4H, m), 3.19 (2H, dd, J=5.6,4.1Hz), 3.50 (2H, dd, J=9.0,4.1Hz), 4.09 (2H, dd, J=9.0,5.6Hz)
Double (the methoxymethoxy)-BDOs of [reference example 184] (2R, 3R) -2,3-
Figure G2003801097466D01613
It is same with reference example 180, title compound is obtained by D- ethyl tartrates.
1H-NMR：It is consistent with as the reference example 180 of enantiomer.
Double (methoxymethoxy) tetrahydrofurans of [reference example 185] (3R, 4R) -3,4-
Same with reference example 181, the compound obtained by reference example 184 obtains title compound.
1H-NMR：It is consistent with as the reference example 181 of enantiomer.
[reference example 186] (3R, 4R) tetrahydrochysene -3,4- furans glycol
Figure G2003801097466D01622
Same with reference example 182, the compound obtained by reference example 185 prepares title compound.
1H-NMR：It is consistent with as the reference example 182 of enantiomer.
[reference example 187] (3R, 4R) tetrahydrochysene -3,4- furans diamines
Figure G2003801097466D01623
Same with reference example 183, the compound obtained by reference example 186 obtains title compound.
1H-NMR：It is consistent with as the reference example 183 of enantiomer.
[reference example 188] (3R, 4R) -1- benzyl -3,4- dihydroxy -2,5- pyrrolidine-diones
Figure G2003801097466D01624
L-TARTARIC ACID (30g) and benzylamine (22ml) are added in dimethylbenzene (150ml), with Dean-Rodney Stark dehydration device, in 150.DEG C it is heated to reflux 3 hours.After the evening of reaction solution natural cooling one, leaching crystallization is washed with acetone.Gained runic ethyl alcohol recrystallization, obtains title compound (23.2g).
1H-NMR(DMSO-d6)δ：4.36-4.40 (2H, m), 4.55 (each 1H, AB type d, J=15Hz), 6.26-6.30 (2H, m), 7.25-7.35 (5H, m)
[reference example 189] (3S, 4S) -1- benzyl -3,4- pyrrolidines glycol
Figure G2003801097466D01631
Under ice cooling, the compound (11g) that reference example 188 is obtained is dissolved in tetrahydrofuran (110ml), a small amount of every time to add lithium aluminium hydride reduction (5.69g).It is warming up to after room temperature and is heated to reflux 1 hour, is further continued for being heated to reflux an evening.It is cooled with ice after natural cooling, sequentially adds water (5.7ml), 15% sodium hydrate aqueous solution (5.7ml) and water (17.1ml), is returned to temperature and is stirred at room temperature 1 hour.Filtered with diatomite after precipitate, concentrated mother liquor, with re-crystallizing in ethyl acetate, obtain title compound (6.35g).
1H-NMR(CDCl3)δ：2.40-2.44 (2H, m), 2.88-2.92 (2H, m), 3.58 (each 1H, AB type d, J=7.8Hz), 4.04 (2H, t, J=4.2Hz), 7.25-7.34 (5H, m)
[reference example 190] methanesulfonic acid (3S, 4S) -1- benzyls -4- [(methyl sulphonyl) epoxide] pyrroles's alkyl ester
Figure G2003801097466D01632
Same with reference example 169, the compound obtained by reference example 189 prepares title compound.
1H-NMR(CDCl3)δ：2.76 (2H, dd, J=11,4.6Hz), 3.08 (6H, s), 3.64 (2H, d, J=2.5Hz), 3.68-3.75 (2H, m), 5.12-5.15 (2H, m), 7.27-7.35 (5H, m)
Double [(methyl sulphonyl) the epoxide] -1- pyrrolidine carboxylic acid's tert-butyl esters of [reference example 191] (3S, 4S) -3,4-
Figure G2003801097466D01633
The compound (1.57g) that reference example 190 is obtained is dissolved in 1,2- dichloroethanes (16ml), and chloro-carbonic acid 1- chloroethenes ester (0.73ml) is added at room temperature, is heated to reflux 4 hours.Boiled off under decompression after solvent; in residue obtained middle addition methanol (16ml); it is heated to reflux 1 hour; concentrated after natural cooling; crystallized with ethyl acetate leaching; obtain double [(methyl sulphonyl) epoxide] pyrrolidine hydrochlorides (1.30g) of (3S, 4S) -3,4- in colourless crystallization.Di-tert-butyl dicarbonate (1.15ml) is added in dichloromethane (26ml) solution of gained hydrochloride and triethylamine (1.40ml), an evening is stirred at room temperature.Diluted after concentration with ethyl acetate, with water and saturated common salt water washing, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (ethyl acetate: hexane=1: 9~1: 1) refines, obtains title compound (1.40g).
1H-NMR(CDCl3)δ：1.47 (9H, s), 3.12 (6H, s), 3.70-3.73 (2H, m), 3.79 (1H, d, J=4.5Hz), 3.82 (1H, d, J=4.5Hz), 5.19 (2H, br)
[reference example 192] (3R, 4R) -3,4- diazido -1- pyrrolidine carboxylic acid's tert-butyl esters
Same with reference example 170, the compound obtained by reference example 191 prepares title compound.
1H-NMR(CDCl3)δ：1.47 (9H, s), 3.37-3.46 (2H, m), 3.64-3.71 (2H, m), 3.96 (2H, t, J=3.2Hz)
[reference example 193] (3R, 4R) -3- amino -4- { [(5- chloro-indole -2- bases) carbonyl] amino } pyrrolidines -1- carboxylic acid tert-butyl esters
Using the method same with the method that reference example 171 and 172 is recorded, the compound obtained by reference example 192 prepares title compound.
1H-NMR(DMSO-d6)δ：1.39 (9H, s), 2.95-3.00 (1H, m), 3.09-3.13 (1H, m), 3.52 (1H, dd, J=10,6.5Hz), 3.68 (1H, dd, J=10,7.8Hz), 4.04-4.09 (2H, m), 7.16 (1H, s), 7.18 (1H, s), 7.42 (1H, d, J=8.5Hz), 7.69 (1H, d, J=1.5Hz), 8.50 (1H, d, J=6.5Hz), 11.77 (1H, br)
[reference example 194] (3S) -5- oxo tetrahydrochysene -3- furans carbamates
Figure G2003801097466D01643
Di-tert-butyl dicarbonate (4.1g) and 10% palladium carbon (0.4g) are added in tetrahydrofuran (20ml) solution of (3S)-(-)-tetrahydrochysene -5- oxo -3- furyls benzyq carbamates (3.3g), is stirred 1 day in nitrogen atmosphere.Insoluble matter is filtered off by Celite pad, the lower concentration filtrate of decompression, residue obtained use silica gel column chromatography (hexane: ethyl acetate=4: 1) refines, obtains title compound (1.5g).
1H-NMR(CDCl3)δ：1.45 (9H, s), 2.45 (1H, dd, J=17.8,2.7Hz), 2.86 (1H, dd, J=17.8,7.3Hz), 4.12-4.23 (1H, m), 4.54-4.62 (2H, m), 4.85-4.95 (1H, m)
[reference example 195] (3S, 4S) -4- azido -5- oxo tetrahydrochysene -3- furans carbamates
Figure G2003801097466D01651
Double (trimethyl silyl) the amido potassium (tetrahydrofuran solution, 8.65ml) of 1M are instilled in tetrahydrofuran (20ml) solution for the compound (0.87g) that reference example 194 is obtained in -78 DEG C, are stirred 30 minutes.Then, tetrahydrofuran (10ml) solution of p-toluene sulfonyt azide (1.02g) is added, stirring adds trim,ethylchlorosilane (1.7ml) after 5 minutes, temperature is stirred 2 hours while being returned to room temperature.Ether dilute reaction solution is used, after 10% aqueous hydrochloric acid solution, 5% saturated sodium bicarbonate aqueous solution and saturated common salt water washing, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (hexane: ethyl acetate=4: 1) refines, obtains title compound (0.62g).
1H-NMR(CDCl3)δ：1.46 (9H, s), 4.09 (1H, dt, J=15.3,7.6Hz), 4.12-4.23 (1H, m), 4.37-4.50 (1H, m), 4.54 (1H, dd, J=9.0,7.6Hz), 4.81-4.90 (1H, m)
[reference example 196] (3S, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- oxo tetrahydrochysene -3- furans carbamates
Using the method same with the method that reference example 90 and 91 is recorded, title compound is prepared by the compound of reference example 195.
1H-NMR(CDCl3)δ：1.44 (9H, s), 4.01-4.13 (1H, m), 4.20-4.36 (1H, m), 4.78-4.93 (2H, m), 6.15 (1H, s), 6.93 (1H, s), 7.03-7.11 (1H, m), 7.20-7.28 (1H, m), 7.30 (1H, d, J=8.8Hz), 7.61 (1H, s), 9.27 (1H, s)
[reference example 197] (3S, 4S) -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -5- oxo tetrahydrochysene -3- furans carbamates
Figure G2003801097466D01661
It is same with reference example 90, the compound obtained by reference example 195 prepares (3S, 4S) after -4- amino-5-oxos tetrahydrochysene -3- furans carbamates, according to the reaction condition of reference example 91, the compound reaction that reference example 10 is obtained is set to prepare title compound.
1H-NMR(CDCl3)δ：1.44 (9H, s), 2.52 (3H, s), 2.83 (2H, t, J=5.9Hz), 2.79-3.02 (2H, m), 3.74 (2H, s), 4.03-4.12 (1H, m), 4.21-4.36 (1H, m), 4.80-4.95 (2H, m), 6.14-6.24 (1H, m), 7.76-7.85 (1H, m)
[reference example 198] 2- [((3S) -3- [(tert-butoxycarbonyl) amino] -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- maloyl groups) amino] ethyl acetate
Compound (0.4g), glycine ethyl ester hydrochloride (1.0g) and triethylamine (1.0ml) that reference example 196 is obtained are added in ethanol (20ml), is heated to reflux in 60 DEG C 18 hours.Reaction solution is diluted with chloroform, with 10% aqueous citric acid solution and saturated common salt water washing.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression, residue obtained use silica gel column chromatography (chloroform: methanol=98: 2) refines, obtains title compound (0.31g).
1H-NMR(DMSO-d6)δ：1.17 (3H, t, J=7.0Hz), 1.34 (6H, s), 1.36 (3H, s), 3.51-3.63 (0.6H, m), 3.72-3.80 (2H, m), 4.06 (2H, q, J=7.0Hz), 4.11-4.23 (1.4H, m), 4.67-4.82 (1H, m), 4.85-4.91 (1H, m), 6.48 (0.4H, d, J=9.5Hz), 6.80 (0.6H, d, J=9.5Hz), 7.10-7.22 (2H, m), 7.42 (1H, d, J=8.8Hz), 7.72 (0.4H, d, J=2.0Hz), 7.73 (0.6H, d, J=2.0Hz), 8.23-8.31 (0.6H, m), 8.34-8.41 (0.4H, m), 8.43-8.50 (1H, m), 11.83 (1H, s)
[reference example 199] 2- ((4R) -4- amino -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -2- oxo-pyrrolidine -1- bases) ethyl acetate hydrochloride
Using the reaction condition recorded with reference example 181, the compound that reference example 198 is obtained is converted into after pyrrolidinone derivatives, same with reference example 69, removes tert-butoxycarbonyl, obtains title compound.
1H-NMR(DMSO-d6)δ：1.17 (2H, t, J=7.0Hz), 1.23 (1H, t, J=7.0Hz), 3.31-3.40 (0.6H, m), 3.57 (0.4H, d, J=11.2Hz), 3.90-4.23 (4H, m), 4.42 (0.6H, dd, J=12.0, 6.1Hz), 4.50-4.60 (0.4H, m), 4.62 (0.6H, dd, J=12.0, 3.9Hz), 5.12-5.23 (0.4H, m), 7.17 (0.4H, s), 7.20 (0.4H, dd, J=8.8, 2.0Hz), 7.28 (0.6H, dd, J=8.8, 2.0Hz), 7.30 (0.6H, s), 7.44 (0.4H, d, J=8.8Hz), 7.50 (0.6H, d, J=8.8Hz), 7.75 (1H, d, J=2.0Hz), 8.20-8.33 (1H, m), 8.71-8.94 (3.6H, m), 9.22-9.35 (0.4H, m), 11.97 (0.4H, s), 12.44 (0.6H, s)
[reference example 200] (3R, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- methyl -5- oxo-pyrrolidine -3- carbamates
It is same with reference example 198, with reference example 181 it is same under conditions of, the compound that the compound and methylamine (40% methanol solution) obtained to reference example 196 is reacted and obtained is handled, and obtains title compound.
1H-NMR(CDCl3)δ：1.43 (9H, s), 2.90 (3H, s), 4.26 (1H, br.s), 4.36 (2H, m), 4.51-4.52 (1H, m), 5.35 (1H, br.s), 6.95-6.99 (2H, m), 7.22-7.32 (3H, m), 7.63 (1H, s), 8.95 (1H, br.s)
[reference example 201] N- [(3S, 4R) -4- amino -1- methyl -2- oxo-pyrrolidine -3- bases] -5- chloro-indole -2- formamides
Figure G2003801097466D01681
It is same with reference example 69, the compound that reference example 200 is obtained is handled, title compound is obtained.
1H-NMR(CDCl3)δ：2.95 (3H, d, J=5.1Hz), 3.91-3.93 (1H, m), 4.19 (1H, d, J=3.7Hz), 4.36 (1H, dd, J=11,1.7Hz), 4.48 (1H, dd, J=11,2.0Hz), 6.90-6.97 (2H, m), 7.21-7.33 (2H, m), 7.62 (1H, d, J=2.0Hz), 8.90 (1H, s)
[reference example 202] 3,6- dihydros -1 (2H)-picolinic acid tert-butyl ester
Di-tert-butyl dicarbonate (6.55g) is added in the mixture of 1,2,3,6- tetrahydropyridine (2.50g) and 10% aqueous sodium carbonate (3.0ml), is stirred 20 hours at room temperature.Add water, be extracted with ethyl acetate in reaction solution.Organic layer is washed successively with 0.5N hydrochloric acid, water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, after anhydrous sodium sulfate drying, and solvent is boiled off under decompression, obtains title compound (5.08g).
1H-NMR(CDCl3)δ：1.47 (9H, s), 2.12 (2H, br.s), 3.48 (2H, t, J=5.6Hz), 3.88 (2H, br.s), 5.60 (1H, br.s), 5.78-5.90 (1H, m)
[reference example 203] (3R*, 4S*) -3,4- dihydroxy -1- piperidinecarboxylates
Figure G2003801097466D01683
The compound (18.45g) that reference example 202 is obtained is dissolved in acetonitrile (200ml), water (38ml), 0.039 mole of the osmium tetroxide aqueous solution (82ml), N- oxidations-N-methylmorpholine (23.13g) are added, is stirred 17 hours at room temperature.Superfluous oxidant is handled with the saturated sodium sulfite aqueous solution, is extracted with ethyl acetate.Organic layer is washed successively with water, 0.5N hydrochloric acid, water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, after anhydrous sodium sulfate drying, and decompression is lower to be concentrated.Residue obtained use silica gel column chromatography (hexane: ethyl acetate=1: 3) refines, obtains title compound (15.0g).
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.60-1.73 (1H, m), 1.77-1.90 (1H, m), 2.68 (1H, br.s), 2.80-3.20 (1H, br), 3.22-3.32 (1H, m), 3.42 (1H, dd, J=14.3,3.4Hz), 3.50-3.62 (2H, m), 3.77 (1H, brs), 3.81-3.92 (1H, m)
[reference example 204] (3R*, 4S*Double [(methyl sulphonyl) the epoxide] -1- piperidinecarboxylates of) -3,4-
Same with reference 169, the compound obtained by reference example 203 prepares title compound.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.85-1.97 (1H, m), 2.08-2.20 (1H, m), 3.00-4.20 (4H, m), 3.12 (6H, s), 4.85 (1H, br.s), 4.94 (1H, br.s)
[reference example 205] (3R*, 4S*) -3,4- diazido -1- piperidinecarboxylates
Same with reference example 170, the compound obtained by reference example 204 prepares title compound.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.70-1.80 (1H, m), 1.90-2.00 (1H, m), 3.05-4.00 (6H, m)
[reference example 206] (3R*, 4S*) -3,4- diaminostilbenes-piperidinecarboxylate
Same with reference example 171, the compound obtained by reference example 205 prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.48-1.60 (2H, m), 1.80-2.10 (4H, br), 2.85-2.91 (2H, m), 2.97 (1H, br.s), 3.09 (1H, dd, J=13.6,2.7Hz), 3.74 (1H, dd, J=13.6,4.2Hz), 3.81 (1H, s)
[reference example 207] (3R*, 4S*) -3- amino -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- piperidinecarboxylates
Figure G2003801097466D01701
The compound (3.23g) that reference example 206 is obtained is dissolved in DMF (100ml), adds the compound (3.80g) that triethylamine (2.08ml) and reference example 52 are obtained, stirs 3 days at room temperature.The lower concentration of reaction solution of decompression, adds water in residue and is extracted with dichloromethane.Organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing, after anhydrous sodium sulfate drying, decompression is lower to be concentrated.Residue obtained use silica gel column chromatography (dichloromethane: methanol=20: 1~10: 1) refines, obtains title compound (2.70g).
1H-NMR(DMSO-d6)δ：1.40-1.58 (3H, m), 1.41 (9H, s), 1.75-1.90 (1H, m), 2.95 (1H, br.s), 2.98-3.05 (1H, m), 3.19-3.28 (1H, m), 3.74 (1H, dd, J=19.5, 15.4Hz), 3.79 (1H, br.s), 4.04-4.12 (1H, m), 7.17 (1H, dd, J=8.7, 1.9Hz), 7.21 (1H, s), 7.42 (1H, d, J=8.7Hz), 7.68 (1H, d, J=1.9Hz), 8.00 (1H, br.d, J=7.6Hz), 11.80 (1H, s)
[reference example 208] (3R*, 4S*) -3- amino -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -1- piperidinecarboxylates
Figure G2003801097466D01702
The compound (3.23g) that reference example 206 is obtained is dissolved in DMF (100ml), adds triethylamine (2.08ml).Then, the compound (3.83g) that reference example 149 is obtained is added, stirred 3 days at room temperature.The lower concentration of reaction solution of decompression, adds water in residue and is extracted with dichloromethane.Organic layer saturated sodium bicarbonate aqueous solution, saturated common salt water washing, with after anhydrous sodium sulfate drying depressurize under boil off solvent.Residue obtained use silica gel column chromatography (dichloromethane: methanol=10: 1~5: 1) separates, obtains title compound (2.27g).
1H-NMR(CDCl3)δ：1.30-1.62 (3H, m), 1.47 (9H, s), 1.78-1.88 (1H, m), 2.51 (3H, s), 2.81 (2H, t, J=5.9Hz), 2.85-2.98 (3H, m), 3.00-3.15 (2H, m), 3.71 (2H, s), 3.80-4.15 (3H, m), 7.79 (1H, br.s)
[reference example 209] (3R*, 4S*) -3- amino -4- { [(5- fluoro indole -2- bases) carbonyl] amino } -1- piperidinecarboxylates
Same with reference example 172, the compound and 5- fluoro indole -2- carboxylic acids obtained by reference example 206 prepares title compound.
1H-NMR(CDCl3)δ：1.40-1.70 (3H, m), 1.48 (9H, s), 2.79-2.92 (1H, m), 2.99-3.14 (1H, m), 4.00-4.23 (3H, m), 6.85 (1H, s), 7.04 (1H, td, J=9.0,2.4Hz), 7.07-7.20 (1H, br), 7.27 (1H, dd, J=9.0,2.4Hz), 7.35 (1H, d, J=9.0,4.4Hz), 9.25-9.50 (1H, br)
MS(ESI)m/z：377(M+H)+.
[reference example 210] (3S, 4R) -5- azidos -3- { [(benzyloxy) carbonyl] amino } -4- [(tert-butoxycarbonyl) amino] ethyl valerate
Under ice cooling, (the 3S obtained in reference example 168, instill under triethylamine (4.80ml) and mesyl chloride (1.55mml), ice cooling and stir 30 minutes successively in dichloromethane (100ml) solution of 4S)-compound (low polar compound) (7.1g).Reaction solution is diluted with chloroform, with 10% aqueous citric acid solution and saturated sodium bicarbonate aqueous solution, saturated common salt water washing.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, methylsulfonyl body (9.20g) is obtained.In 80 DEG C, the mixed solution of gained methylsulfonyl body, sodium azide (5.64g) and DMF (100ml) formation is stirred 20 hours.Ethyl acetate dilute reaction solution is used, with water and saturated common salt water washing.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue obtained use silica gel column chromatography (chloroform) refines, and obtains title compound (5.42g).
1H-NMR(CDCl3)δ：1.24 (3H, t, J=7.1Hz), 1.43 (9H, s), 2.56-2.68 (2H, m), 3.48-3.60 (2H, m), 3.88-3.97 (1H, m), 4.04-4.20 (3H, m), 4.88-4.97 (1H, br), 5.10 (2H, s), 5.60-5.75 (1H, br), 7.30-7.40 (5H, m)
MS(ESI)m/z：436(M+H)+.
[reference example 211] (4S, 5R) -5- [(tert-butoxycarbonyl) amino] -2- oxo-piperidine -4- aminocarbamic acid benzyl esters
Lindlar catalyst (2.71g) is added in ethanol (150ml), tetrahydrofuran (10.0ml) mixed solution in the compound (5.42g) that reference example 210 is obtained, after being stirred 3 hours in nitrogen atmosphere, stirred 14 hours under the conditions of nitrogen.Filtered off by Celite pad after insoluble matter, the lower concentration filtrate of decompression, by residue obtained formation tetrahydrofuran (30ml) solution, add triethylamine (3.0ml), stir 1.5 hours at room temperature.Reaction solution is diluted with ethyl acetate, with 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue obtained use silica gel column chromatography (chloroform: methanol=25: 1) refines, obtains title compound (2.50g).
1H-NMR(CDCl3)δ：1.44 (9H, s), 2.30-2.50 (1H, br), 2.65-2.90 (1H, br), 3.15-3.30 (1H, br), 3.35-3.65 (1H, br), 4.00-4.25 (2H, br), 5.11 (2H, s), 5.55-5.60 (1H, br), 5.65-5.90 (1H, br), 6.25-6.55 (1H, br), 7.28-7.40 (5H, m)
MS(ESI)m/z：364(M+H)+.
[reference example 212] (3R, 4S) -3- [(tert-butoxycarbonyl) amino] piperidin-4-yl benzyq carbamate
Under ice cooling, 1 mole of borine tetrahydrofuran complex (tetrahydrofuran solution is instilled in tetrahydrofuran (70ml) solution for the compound (2.49g) that reference example 211 is obtained, 34.0ml), it is slowly ramped to stir 20 hours while room temperature.Methanol (100ml) is added in reaction solution, solvent is boiled off under decompression.In residue obtained middle addition ethanol (45ml), water (5ml) and triethylamine (10ml), it is heated to reflux 24 hours.Concentration of reaction solution, residue obtained use silica gel column chromatography (chloroform: methanol: water=7: 3: 1, lower floor) refines, and obtains title compound (1.61g).
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.65-1.72 (2H, m), 2.67 (1H, t, J=12.0Hz), 2.82 (12H, d, J=12.0Hz), 2.90-3.10 (1H, br), 3.60-3.80 (2H, m), 3.90-4.00 (1H, m), 5.00-5.20 (2H, m), 5.40-5.60 (2H, br), 7.25-7.74 (5H, m) .MS (FAB) m/z：350(M+H)+.
[reference example 213] (3R, 4S) -1- acetyl group -4- { [(benzyloxy) carbonyl] amino } piperidines -3- carbamates
In dichloromethane, in the presence of triethylamine, the compound and excess acetyl chloride for obtaining reference example 212 obtain title compound.
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.85-2.15 (2H, m), 2.07 (1.5H, s), 2.14 (1.5H, s), 2.75-2.90 (1H, m), 3.10-3.20 (0.5H, m), 3.25-3.35 (0.5H, br.d, J=14.2Hz), 3.65-4.05 (3H, m), 4.38-4.47 (0.5H, br.d, J=13.0Hz), 4.5,4-4.63 (0.5H, m), 4.69-4.83 (1H, br), 4.98-5.20 (2.5H, m), 5.90-6.05 (0.5H, br), 7.30-7.40 (5H, m)
MS(ESI)m/z：392(M+H+).
[reference example 214] (3R, 4S) -1- acetyl group -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- carbamates
Figure G2003801097466D01732
10% palladium carbon (532mg) is added in ethanol (50ml) solution for the compound (745mg) that reference example 213 is obtained, is stirred at room temperature in nitrogen atmosphere 16 hours.It is filtered to remove by diatomite after insoluble matter, be concentrated under reduced pressure filtrate.It is same with reference example 68, handled with 5- chloro-indole -2- carboxylic acids (467mg) residue obtained, obtain title compound (650mg).
1H-NMR(CDCl3)δ：1.52 (9H, s), 1.60-1.80 (2H, m), 2.12 (1H, s), 2.16 (2H, s), 2.30-2.45 (0.5H, m), 2.67-2.82 (0.3H, m), 2.89 (0.7H, d, J=13.7Hz), 3.23 (0.7H, t, J=12.9Hz), 3.37 (0.3H, d, J=13.7Hz), 3.81-3.95 (1H, m), 4.05-4.33 (2H, m), 4.62-4.72 (0.3H, br), 4.77 (0.7H, d, J=13.7Hz), 5.10-5.27 (1H, m), 6.81 (0.3H, br.s), 6.85 (0.7H, s), 7.21 (1H, br.d, J=8.8Hz), 7.34 (1H, d, J=8.8Hz), 7.57 (0.3H, br.s), 7.61 (0.7H, s), 8.55-8.65 (0.5H, br), 9.43-9.53 (0.7H, br), 9.60-9.70 (0.3H, br)
MS(ESI)m/z：435(M+H+).
[reference example 215] (3R, 4R) -5- azidos -3- { [(benzyloxy) carbonyl] amino } -4- [(tert-butoxycarbonyl) amino] ethyl valerate
Figure G2003801097466D01741
Same with reference example 210, (3R, the 4S)-compound (highly polar compound) obtained by reference example 168 prepares title compound.
1H-NMR(CDCl3)δ：1.23 (3H, t, J=6.6Hz), 1.42 (9H, s), 2.51-2.63 (2H, m), 3.43-3.50 (2H, m), 3.84-3.92 (1H, m), 4.03-4.23 (3H, m), 5.10 (2H, s), 5.11-5.24 (1H, m), 5.54-5.60 (1H, m), 7.32-7.44 (5H, m)
[reference example 216] (4R, 5R) -5- [(tert-butoxycarbonyl) amino] -2- oxo-piperidine -4- aminocarbamic acid benzyl esters
It is same with reference example 211, the gained compound of reference example 215 is handled, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.35 (9H, s), 2.19 (1H, dd, J=17.4,9.1Hz), 2.41-2.51 (1H, m), 2.97 (1H, t, J=9.1Hz), 3.00-3.11 (1H, m), 3.51-3.64 (1H, m), 3.67-3.73 (1H, m), 5.00 (2H, s), 6.71-6.80 (1H, m), 7.20-7.30 (5H, m), 7.44-7.52 (1H, m), 8.30 (1H, s)
[reference example 217] (3R, 4R) -3- [(tert-butoxycarbonyl) amino] piperidin-4-yl benzyq carbamate
It is same with reference example 212, the gained compound of reference example 216 is handled, title compound is obtained.
1H-NMR(CDCl3)δ：1.39 (9H, s), 2.05 (2H, d, J=12.9Hz), 2.40 (1H, t, J=11.0Hz), 2.63 (1H, t, J=12.0Hz), 3.09 (1H, d, J=12.0Hz), 3.31 (1H, d, J=11.0Hz), and 3.42-3.53 (2H, m), 4.80-4.91 (1H, m), 5.09 (2H, s), 5.23-5.32 (1H, m), 7.34-7.41 (5H, m)
[reference example 218] (3R, 4R) -1- acetyl group -4- { [(benzyloxy) carbonyl] amino } piperidines -3- carbamates
It is same with reference example 213, the gained compound of reference example 217 is handled, title compound is obtained.
1H-NMR(CDCl3)δ：1.42 (9H, s), 1.53-1.67 (1H, m), 1.89-2.00 (1H, m), 2.09 (1.5H, s), 2.15 (1.5H, s), 2.57 (1H, t, J=12.0Hz), 2.78 (1H, t, J=12.0Hz), 3.20-3.30 (1H, m), 3.40-3.56 (2H, m), 4.23-4.31 (1H, m), 4.45-4.56 (1H, m), 5.01-5.08 (1H, m), 5.10 (2H, s), 7.32-7.44 (5H, m)
[reference example 219] (3R, 4R) -1- acetyl group -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- carbamates
It is same with reference example 214, the gained compound of reference example 218 is handled, title compound is obtained.
1H-NMR(CDCl3)δ：1.35 (9H, s), 1.42-1.56 (2H, m), 2.00-2.10 (1H, m), 2.12 (1.5H, s), 2.17 (1.5H, s), 2.31-2.43 (1H, m), 2.67-3.00 (1H, m), 3.55-3.63 (1H, m), 3.78-4.00 (1H, m), 4.03-4.21 (1H, m), 4.78-5.24 (2H, m), 6.91 (0.5H, s), 6.92 (0.5H, s), 7.22-7.32 (1H, m), 7.33 (1H, d, J=8.8Hz), 7.58 (1H, s), 9.45 (0.5H, s), 9.51 (0.5H, s)
[reference example 220] (3R, 4S) -3- [(tert-butoxycarbonyl) amino] -1- (2- Methoxyacetyls) piperidin-4-yl benzyq carbamate
Figure G2003801097466D01761
Same, the compound and methoxyacetyl chloride obtained by reference example 212 with reference example 213, obtains title compound.
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.70-2.15 (2H, m), 2.70-2.85 (1H, m), 2.90-3.30 (1H.m), 3.35-3.70 (1H, m), 3.43 (3H, s), 3.75-3.90 (2H, m), 3.90-4.25 (3H, m), 4.40-4.80 (1H, m), 5.05-5.09 (1H, m), 5.10 (2H, br.s), 7.30-7.40 (5H, m)
MS(ESI)m/z：322(M+H+).
[reference example 221] (3R, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- carbamates
Figure G2003801097466D01762
Same with reference example 214, the compound obtained by reference example 220 prepares title compound.
1H-NMR(CDCl3)δ：1.52 (9H, s), 1.60-1.80 (1H, m), 2.20-2.40 (1H, m), 2.70-2.80 (0.6H, m), 2.90-3.00 (0.4H, m), 3.15-3.30 (0.4H, m), 3.32-3.40 (0.6H, m), 3.46, 3.49 (whole 3H, each s), 3.85-4.30 (5H, m), 4.55-4.80 (1H, m), 5.11 (0.4H, br.s), 6.05 (0.6H, br.s), 6.86 (1H, s), 7.20 (1H, dd, J=8.7, 2.0Hz), 7.33 (1H, d, J=8.7Hz), 7.61 (1H, s), 8.40-8.60 (1H, m), 9.41 (1H, br.s)
MS(FAB)m/z：465(M+H+).
[reference example 222] (3R, 4R) -3- [(tert-butoxycarbonyl) amino] -1- (2- Methoxyacetyls) piperidin-4-yl benzyq carbamate
Figure G2003801097466D01771
Same with reference example 213, the compound and methoxyacetyl chloride obtained by reference example 217 prepares title compound.
1H-NMR(CDCl3)δ：1.41 (9H, s), 1.45-1.67 (1H, m), 2.01-2.14 (1H, m), 2.63 (1H, t, J=12.0Hz), 2.75 (1H, t, J=12.0Hz), 3.20-3.30 (1H, m), 3.32-3.41 (5H, m), 3.44-3.56 (2H, m), 4.21-4.32 (1H, m), 4.50-4.63 (1H, m), 5.03-5.08 (1H, m), 5.09 (2H, s), 7.32-7.40 (5H, m)
[reference example 223] (3R, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- carbamates
Figure G2003801097466D01772
Same with reference example 214, the compound and 5- chloro-indole -2- carboxylic acids obtained by reference example 222 prepares title compound.
1H-NMR(CDCl3)δ：1.35 (9H, s), 1.41-1.56 (2H, m), 2.11-2.23 (0.5H, m), 2.34-2.50 (0.5H, m), 2.78-2.89 (0.5H, m), 3.01-3.12 (0.5H, m), 3.42 (5H, s), 3.45-3.56 (1H, m), 3.78-3.89 (1H, m), 4.00-4.21 (2H, m), 4.78-5.21 (2H, m), 6.91 (0.5H, s), 6.93 (0.5H, s), 7.23 (1H, dd, J=8.8, 2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.59 (1H, s), 9.37 (0.5H, s), 9.54 (0.5H, s)
[reference example 224] (3R, 4S) -3- { [(benzyloxy) carbonyl] amino } -4- [(tert-butoxycarbonyl) amino] -5- { [tert-butyl group (diphenyl) silicyl] epoxide } ethyl valerate
Figure G2003801097466D01781
Under ice cooling, (the 3R obtained successively in reference example 168, the N of 4S)-compound (highly polar compound) (0.74g), triethylamine (0.47ml), imidazoles (0.19g) and tertiary butyl chloride diphenyl silane (0.7ml) are added in dinethylformamide (30ml) solution, is stirred 4 days while being slowly returned to room temperature.Ethyl acetate dilute reaction solution is used, after 10% aqueous citric acid solution and saturated common salt water washing, organic layer anhydrous sodium sulfate drying boils off solvent under decompression.Residue obtained use silica gel column chromatography (hexane: ethyl acetate=8: 1) refines, obtains title compound (0.85g).
1H-NMR(CDCl3)δ：1.07 (9H, s), 1.19 (3H, t, J=7.4Hz), 1.40 (9H, s), 2.40-2.50 (1H, m), 2.60 (1H, dd, J=15.9,4.5Hz), 3.56-3.67 (1H, m), 3.74 (1H, dd, J=11.2,4.5Hz), 3.78-3.89 (1H, m), 4.08 (2H, q, J=7.4Hz), 4.21-4.30 (1H, m), 4.99-5.13 (3H, m), 5.41-5.52 (1H, m), 7.40-7.53 (6H, m), 7.60-7.72 (4H, m)
[reference example 225] (3R, 4S) -4- [(tert-butoxycarbonyl) amino] -5- { [tert-butyl group (diphenyl) silicyl] epoxide } -3- { [(5- chloro-indole -2- bases) carbonyl] amino } ethyl valerate
It is same with reference example 214, the benzyloxycarbonyl for the compound that reference example 224 is obtained is removed, is condensed with 5- chloro-indole -2- carboxylic acids, title compound is obtained.
1H-NMR(CDCl3)δ：1.10 (9H, s), 1.20 (3H, t, J=7.4Hz), 1.32 (9H, s), 2.40-2.52 (1H, m), 2.71 (1H, dd, J=15.9, 4.5Hz), 3.67-3.81 (2H, m), 4.00-4.20 (2H, m), 4.56-4.74 (1H, m), 5.00-5.11 (1H, m), 6.81 (1H, s), 7.21 (1H, dd, J=8.8, 2.0Hz), 7.32 (1H, d, J=8.8Hz), 7.40-7.50 (6H, m), 7.58 (1H, d, J=8.5Hz), 7.63-7.74 (5H, m), 9.01-9.14 (1H, m)
[reference example 226] (3R*, 4R*) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -4- carbamates
The same, (3R obtained by reference example 179 with reference example 68*, 4R*The compound that)-compound (low polar compound) and reference example 10 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.43 (9H, s), 2.30-2.37 (2H, m), 2.51 (3H, s), 2.82-2.85 (2H, m), 2.92-2.95 (2H, m), 3.17-3.20 (4H, m), 3.40-3.43 (1H, m), 3.69-3.77 (2H, m), 3.97-3.98 (1H, m), 4.98 (1H, br), 5.25 (1H, br)
[reference example 227] N- (3R*, 4R*) -4- amino -1,1- dioxo hexahydro -1- thiapyran -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
It is same with reference example 69, the compound that reference example 226 is obtained is handled, title compound is prepared.
1H-NMR(DMSO-d6)δ：2.29-2.33 (2H, m), 2.93 (3H, s), 3.16 (2H, br), 3.40 (2H, br), 3.52 (2H, br), 3.69-3.76 (3H, m), 4.48 (1H, br), 4.71-4.82 (2H, m), 8.34 (2H, br), 8.82 (1H, br)
MS(ESI)m/z：345(M+H)+.
[reference example 228] (3R*, 4R*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -4- carbamates
Figure G2003801097466D01793
Same with reference example 68, (3R*, the 4R*)-compound (low polar compound) and 5- chloro-indole -2- carboxylic acids obtained by reference example 179 prepares title compound.
1H-NMR(DMSO-d6)δ：1.34 (9H, s), 2.09 (2H, br), 3.07 (1H, d, J=12.6Hz), and 3.24-3.28 (1H, m), 3.48 (2H, br), 4.12 (1H, br), 4.53 (1H, br), 7.04 (1H, s), 7.16-7.18 (2H, m), 7.44 (1H, d, J=8.7Hz), 7.67 (1H, s), 8.37 (1H, br), 11.81 (1H, s)
MS(ESI)m/z：442(M+H)+.
[reference example 229] N- [(3R*, 4R*) -4- amino -1,1- dioxo hexahydro -1- thiapyran -3- bases] -5- chloro-indole -2- carboxamide hydrochlorides
Figure G2003801097466D01801
It is same with reference example 69, the compound that reference example 228 is obtained is handled, title compound is prepared.
1H-NMR(DMSO-d6)δ：2.24-2.33 (2H, m), 3.43-3.55 (3H, m), 3.60-3.66 (1H, m), 3.77 (1H, br), 4.75-4.79 (1H, m), 7.18-7.21 (2H, m), 7.46 (1H, d, J=8.8Hz), 7.72 (1H, d, J=1.7Hz), 8.39 (2H, br), 8.58 (1H, d, J=6.8Hz), 11.93 (1H, s)
MS(ESI)m/z：342(M+H+).
[reference example 230] (3R*, 4S*) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -4- carbamates
The same, (3R obtained by reference example 179 with reference example 98*, 4S*The compound that)-compound (highly polar compound) and reference example 10 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.32 (9H, s), 2.14-2.24 (1H, m), 2.33-2.38 (1H, m), 2.50 (3H, s), 2.78-2.83 (2H, m), 2.86-2.95 (2H, m), 3.08-3.14 (3H, m), 3.55 (1H, d, J=13.4Hz), 3.68 (1H, d, J=15.5Hz), 3.72 (1H, d, J=15.5Hz), 3.86-3.88 (1H, m), 4.45-4.53 (1H, m), (4.75 1H, d, J=8.5Hz), 7.76 (1H, d, J=8.3Hz)
MS(ESI)m/z：445(M+H)+.
[reference example 231] N- [(3R*, 4S*) -4- amino -1,1- dioxo hexahydro -1- thiapyran -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
It is same with reference example 69, the compound that reference example 230 is obtained is handled, title compound is prepared.
1H-NMR(DMSO-d6)δ：2.03-2.12 (1H, m), 2.51 (1H, br), 2.93 (3H, s), 3.14 (2H, d, J=12.2Hz), 3.28 (2H, br), 3.33 (2H, br), 3.48 (3H, br), 3.72 (2H, br), 4.49 (2H, br), 4.71-4.74 (1H, m), 8.38 (2H, br), 9.21-9.24 (1H, m)
MS(ESI)m/z：345(M+H+).
[reference example 232] (3R*, 4R*) -3- { [(5- fluoro indole -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -4- carbamates
The same, (3R obtained by reference example 179 with reference example 68*, 4R*)-compound (low polar compound) and 5- fluoro indole -2- carboxylic acids prepare title compound.
1H-NMR(DMSO-d6)δ：1.37 (9H, s), 2.10-2.13 (2H, m), 3.06 (1H, br), 3.37-3.49 (3H, m), 4.13 (1H, br), 4.57 (1H, br), 6.95-7.01 (2H, m), 7.14 (1H, br), 7.30 (1H, d, J=8.5Hz), 7.41 (1H, dd, J=8.8,4.5Hz), 8.28 (1H, br), 11.68 (1H, s)
MS(ESI)m/z：426(M+H+).
[reference example 233] N- [(3R*, 4R*) -4- amino -1,1- dioxo hexahydro -1- thiapyran -3- bases] -5- fluoro indole -2- carboxamide hydrochlorides
It is same with reference example 69, the compound that reference example 232 is obtained is handled, title compound is prepared.
1H-NMR(DMSO-d6)δ：2.25-2.31 (1H, m), 2.47 (1H, br), 3.30 (1H, br), 3.49-3.53 (2H, m), 3.60-3.66 (1H, m), 3.78 (1H, br), 4.79 (1H, br), 7.01-7.05 (1H, m), 7.21 (1H, s), 7.38 (1H, d, J=9.0Hz), 7.44 (1H, dd, J=8.8,4.4Hz), 8.40 (2H, br), 8.56 (1H, br), 11.81 (1H, s)
MS(ESI)m/z：326(M+H+).
[reference example 234] (3R) -3- { [(benzyloxy) carbonyl] amino } -4- [(tert-butoxycarbonyl) amino] -5- oxopentanoic acid methyl esters
Figure G2003801097466D01822
At room temperature, (the 3R obtained in reference example 168, the in the mixed solvent of 4S)-compound (highly polar compound) (0.5g), dimethyl sulfoxide (6.8ml) and triethylamine (2.6ml) formation is slowly added into sulfur trioxide pyridine complex salt (1.5g), stirs 20 minutes.Reaction solution is injected in water, is extracted with ethyl acetate, gained organic layer saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression, residue obtained use silica gel column chromatography (hexane: ethyl acetate=3: 1) refines, obtains title compound (0.51g).
1H-NMR(CDCl3)δ：1.25 (3H, t, J=7.4Hz), 1.44 (9H, s), 2.51-2.70 (2H, m), 4.01-4.23 (2H, m), 4.45-4.67 (1H, m), 5.00-5.23 (2H, s), 5.24-5.42 (1H, m), 7.23-7.43 (5H, m), 9.63 (0.5H, s), 9.67 (0.5H, s)
[reference example 235] (4R) -5- [(tert-butoxycarbonyl) amino] -1- methyl -2- oxo-piperidine -4- aminocarbamic acid benzyl esters
Under ice cooling, acetic acid (0.27ml) and 2M methylamine (tetrahydrofuran solution are sequentially added in ethanol (10ml) solution for the compound (0.51g) that reference example 234 is obtained, 1.0ml), stirred 1 hour while being slowly returned to room temperature, add sodium cyanoborohydride (0.15g) and stir 18 hours.Reaction solution is diluted with chloroform, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression, it is residue obtained to be dissolved in toluene (20ml).Triethylamine (2ml) is added in the solution, is heated to reflux 2 hours, the lower concentration of reaction solution of decompression, residue obtained use silica gel column chromatography (chloroform: methanol=98: 2) refines, obtains title compound (0.28g).
1H-NMR(DMSO-d6)δ：1.36 (3.6H, s), 1.38 (5.4H, s), 2.22-2.43 (1H, m), 2.44-2.61 (1H, m), 2.72 (1.2H.s), 2.80 (1.8H.s), 3.10 (0.5H, dd, J=12.5, 8.3Hz), 3.21-3.30 (0.5H, m), 3.33-3.45 (1H, m), 3.56-3.82 (1H, m), 3.89-4.00 (1H, m), 4.94 (1H, d, J=8.1Hz), 5.00 (1.2H.s), 5.01 (0.8H, s), 6.89-7.02 (0.5H, m), 7.23-7.44 (5.5H, m)
[reference example 236] (4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- methyl -6- oxo-piperidine -3- carbamates
Figure G2003801097466D01832
Same with reference example 214, the compound and 5- chloro-indole -2- carboxylic acids obtained by reference example 235 prepares title compound.
1H-NMR(DMSO-d6)δ：1.24 (5.4H, s), 1.35 (3.6H, s), 2.43-2.56 (2H, m), 2.80 (3H, s), 3.10-3.20 (1H, m), 3.30-3.52 (1H, m), 3.83-3.91 (0.4H, m), 4.02-4.10 (0.6H, m), 4.20-4.31 (0.6H, m), 4.43-4.54 (0.4H, m), 6.94 (0.6H, d, J=8.1Hz), 7.08 (1H, s), 7.16 (1H, dd, J=8.8, 2.0Hz), 7.42 (1H, d, J=8.8Hz), 7.69 (1H, d, J=2.0Hz), 8.30 (0.4H, s), 8.36 (0.4H, d, J=7.3Hz), 8.43 (0.6H, d, J=8.3Hz), 11.75 (0.6H, s), 11.78 (0.4H, s)
[reference example 237] 4- (pyridin-4-yl) benzoate hydrochlorate
4- bromopyridine hydrochlorides (11.7g) and 4- carboxyphenyl boronic acids (10.0g) are dissolved in the in the mixed solvent of toluene (250ml)-water (250ml), four (triphenyl phasphine) palladiums (0) (5.0g) and natrium carbonicum calcinatum (25.4g) are sequentially added, is heated to reflux in 120 DEG C 19 hours.It is cooled to after room temperature, adds ethyl acetate, extracted with water, concentrated hydrochloric acid is added in water layer makes it in acidity.After aqueous layer with ethyl acetate washing, water layer is concentrated, the solid that leaching is separated out prepares title compound (8.37g).
1H-NMR(DMSO-d6)δ：(2H, d, the J=6.6Hz) of 8.11 (2H, d, J=8.8Hz), 8.14 (2H, dJ=8.8Hz), 8.35 (2H, d, J=6.6Hz), 8.97
MS(FAB)m/z：200(M+H)+.
[reference example 238] 4- (pyridin-4-yl) methyl benzoate
Figure G2003801097466D01842
The compound (12.4g) that reference example 237 is obtained is dissolved in methanol (200ml), and the concentrated sulfuric acid (5ml) is added at room temperature, is heated to reflux 3 hours.Reaction boils off solvent after terminating, and saturated sodium bicarbonate aqueous solution is added in residue, is extracted with ethyl acetate, anhydrous sodium sulfate drying is used.Solvent is boiled off, hexane is added in residue and is solidified, title compound (9.86g) is obtained.
1H-NMR(CDCl3)δ：3.96 (3H, s), 7.54 (2H, d, J=5.9Hz), 7.71 (2H, dJ=8.3Hz), 8.16 (2H, d, J=8.3Hz), 8.71 (2H, d, J=5.9Hz)
[reference example 239] 4- [4- (methoxycarbonyl) phenyl] pyridine N-oxides
Figure G2003801097466D01843
The compound (1.49g) that reference example 238 is obtained is dissolved in dichloromethane (30ml), adds 70% metachloroperbenzoic acid (3.46g), stirs 1 hour at room temperature.Add sodium sulfite aqueous solution and carry out a point liquid, after organic layer is washed with saturated sodium bicarbonate aqueous solution, use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, title compound (1.33g) is obtained.
1H-NMR(DMSO)δ：3.88 (3H, s), 7.86 (2H, d, J=7.2Hz), 7.94 (2H, d, J=8.3Hz), 8.05 (2H, d, J=8.3Hz), 8.30 (2H, d, J=7.2Hz)
MS(FAB)m/z：230(M+H)+.
[reference example 240] 4- (4- carboxyl phenyls) pyridine N-oxides
The compound (802mg) that reference example 239 is obtained is dissolved in dioxane (20ml), adds 1N sodium hydrate aqueous solution (5ml), after flowing back 1 hour, stirs 2 hours at room temperature.The aqueous hydrochloric acid solution (5ml) for adding 1N is neutralized, and is added water (5ml), the precipitation of leaching generation, obtains title compound (627mg).
1H-NMR(DMSO)δ：(2H, d, the J=7.2Hz) of 7.85 (2H, d, J=7.2Hz), 7.91 (2H, d, J=8.3Hz), 8.03 (2H, d, J=8.3Hz), 8.30
[reference example 241] 2- (4- carboxyl phenyls) -1- pyridine N-oxides
It is same with reference example 237,238,239,240 by 2- bromopyridines, obtain title compound.
1H-NMR(DMSO-d6)δ：7.41-7.45 (2H, m), 7.65-7.69 (1H, m), 7.94 (2H, d, J=8.3Hz), 8.02 (2H, d, J=8.3Hz), 8.34-8.38 (1H, m), 13.09 (1H, s)
MS(FAB)m/z：216(M+H)+.
[referring to 242] 2- (4- chloroanilinos) -2- ethyls
Under ice cooling, triethylamine (1.52ml) and chlorine ethyl (1.11ml) are sequentially added in the solution of 4- chloroanilines (1.16g) and dichloromethane (26ml), is stirred 14 hours at room temperature.Add saturated sodium bicarbonate aqueous solution in reaction solution to carry out after point liquid operation, organic layer with 10% aqueous citric acid solution and saturated common salt water washing, uses anhydrous sodium sulfate drying successively.After the lower concentrated solvent of decompression, addition hexane separates out crystallization in residue, and leaching is dried, and obtains title compound (1.89g).
1H-NMR(CDCl3)δ：(1H, the br.s) of 1.43 (3H, t, J=7.1Hz), 4.42 (2H, q, J=7.1Hz), 7.34 (2H, d, J=8.8Hz), 7.60 (2H, d, J=8.8Hz), 8.86
MS(ESI)m/z：228(M+H)+.
[reference example 243] 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetic acid methyl esters
Figure G2003801097466D01861
2- amino -5- chloropyridines (1.16g) and triethylamine (1.51ml) are dissolved under dichloromethane (26ml), ice cooling, chlorine ethyl (1.10ml) is added, stirred 14 hours at room temperature.Add saturated sodium bicarbonate aqueous solution in reaction solution to carry out after point liquid operation, organic layer anhydrous sodium sulfate drying boils off solvent under decompression.Residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography.The faint yellow solid of gained is dissolved in methanol (20ml), stirred 11 hours in 50 DEG C.The lower concentration of reaction solution of decompression, the crystallization that leaching is separated out obtains title compound (0.43g) after drying.
1H-NMR(CDCl3)δ：3.99 (3H, s), 7.73 (1H, dd, J=8.8,2.2Hz), 8.24 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.2Hz), 9.39 (1H, br.s)
MS(ESI)m/z：215(M+H)+.
[reference example 244] (1S) -3- cyclohexene -1- carboxylic acids
By (R)-(+) of (1S) -3- cyclohexene -1- carboxylic acids-Alpha-Methyl benzylamine salt (J.Am.Chem.Soc., 1978, volume 100,5199-5203 pages) (95.0g) be dissolved in ethyl acetate (1.61) and 2N hydrochloric acid (1.61), divide and take after organic layer, aqueous layer with ethyl acetate (500ml × 2 time) is extracted, merge organic layer, washed with saturated common salt water washing (300ml × 2 time), divide and take organic layer.After aqueous layer with ethyl acetate (200ml) extraction, organic layer is washed with saturated aqueous common salt (100ml), merges all organic layers, after anhydrous sodium sulfate drying, and decompression is lower to be concentrated, and obtains title compound (48.3g).
[α]25 D=-104 ° of (c=1, chloroform)
1H-NMR(CDCl3)δ：1.66-1.77 (1H, m), 2.00-2.20 (3H, m), 2.20-2.38 (2H, m), 2.57-2.65 (1H, m), 5.65-5.75 (2H, m)
Iodo- 6- oxabicyclos [3.2.1] octane-7-ketones of [reference example 245] (1S, 4S, 5S) -4-
Figure G2003801097466D01871
At interior 5 DEG C of temperature, iodine (125.4g) is added in the mixture of the compound (48.0g) that reference example 244 is obtained, dichloromethane (580ml), KI (82.1g), sodium acid carbonate (42.0g) and water (530ml), is stirred 3 hours at room temperature.Added in reaction solution after 1N sodium thiosulfate solution (800ml), with dichloromethane (1L, 500ml) extract, organic layer is washed with sodium bicarbonate aqueous solution (300ml), water (500ml) and saturated aqueous common salt (300ml), is concentrated after being dried with anhydrous magnesium sulfate.The crystallization that leaching is separated out, is dried after being washed with hexane, obtains title compound (89.5g).
Fusing point：130~131 DEG C
[α]25 D=-41 ° (c=1, chloroform)
1H-NMR(CDCl3)δ：1.78-1.96 (2H, m), 2.12 (1H, dd, J=16.5Hz, 5.2Hz), 2.35-2.50 (2H, m), 2.65-2.70 (1H, m), 2.80 (1H, d, J=12.2Hz), 4.45-4.55 (1H, m), 4.77-4.87 (1H, m)
[reference example 246] (1S, 3S, 6R) -7- oxabicyclos [4.1.0] heptane -3- carboxylic acid, ethyl esters
Figure G2003801097466D01872
At room temperature, while ethanol (810ml) suspension of the compound (89.3g) obtained to reference example 245 is stirred the sodium hydrate aqueous solution (213ml) for adding 2N wherein on one side, stir 3 hours.It is concentrated under reduced pressure after reaction solution, add water (500ml) in gained grease, is extracted with dichloromethane (500ml and 300ml) in 35 DEG C of bath temperature.Organic layer is washed with water (300ml), after being dried with anhydrous magnesium sulfate, and decompression is lower to be concentrated.Gained grease (hexane: ethyl acetate=85: 15) is refined with silica gel column chromatography, obtains title compound (41.3g).
[α]25 D=-58 ° of (c=1, chloroform)
1H-NMR(CDCl3)δ：1.25 (3H, t, J=7.2Hz), 1.50-1.70 (2H, m), 1.71-1.82 (1H, m), 2.08-2.28 (4H, m), 3.16 (2H, s), 4.12 (2H, q, J=7.2Hz)
[reference example 247] (1S, 3R, 4R) -3- azido -4- hydroxy cyclohexane carboxylic's ethyl esters
Figure G2003801097466D01881
The stirring of 13 hours is carried out in the mixture of 76 DEG C of compounds (41.0g) obtained to reference example 246, DMF (300ml), ammonium chloride (19.3g) and sodium azide (23.5g).After leaching insoluble matter, it is concentrated under reduced pressure in the state of filtrate is not solid, previous leaching thing is added in residue, is dissolved in water (500ml).Extracted with ethyl acetate (500ml, 300ml), saturated common salt water washing is used in washing, is concentrated after being dried with anhydrous magnesium sulfate, obtains title compound (51.5g).
[α]25 D=+8 ° (c=1, chloroform)
1H-NMR(CDCl3)δ：1.28 (3H, t, J=7.1Hz), 1.37-1.64 (3H, m), 1.86-1.95 (1H, m), 2.04-2.16 (1H, m), 232-2.41 (1H, m), 2.44 (1H, br.s), 2.68-2.78 (1H, m), 3.45-3.60 (2H, m), 4.17 (2H, q, J=7.1Hz)
[reference example 248] (1S, 3R, 4R) -3- [(tert-butoxycarbonyl) amino] -4- hydroxy cyclohexane carboxylic's ethyl esters
Figure G2003801097466D01882
Hydrogen pressure (7kg/cm2) under, stir the mixture of compound (51.2g), di-tert-butyl dicarbonate (68.1g), 5% palladium carbon (5.0g) and the ethyl acetate (1000ml) of the acquisition of reference example 247 all night in room temperature.Filtering reacting liquid, concentration, gained grease (hexane: ethyl acetate=4: 1 → 3: 1) is refined with silica gel column chromatography.Crystallized with hexane, obtain title compound (46.9g).In addition, mother liquor (chloroform: methanol=100: 1) is refined with silica gel column chromatography, obtains title compound (6.74g).
[α]25 D=+25 ° of (c=1, chloroform)
1H-NMR(CDCl3)δ：1.28 (3H, t, J=7.1Hz), 1.38-1.57 (3H, m), 1.45 (9H, s), 1.86-1.95 (1H, m), 2.05-2.17 (1H, m), 2.29-2.39 (1H, m), 2.61-2.68 (1H, m), 3.34 (1H, br.s), 3.39-3.48 (1H, m), 3.53-3.64 (1H, m), 4.10-4.24 (2H, m), 4.54 (1H, br.s)
[reference example 249] (1S, 3R, 4S) -4- azidos -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
In -10 DEG C~-15 DEG C, mesyl chloride (42ml) was instilled in the solution of the compound (53.5g) that reference example 248 is obtained, dichloromethane (500ml) and triethylamine (130ml) with 20 minutes.Temperature was warmed to room temperature with 2 hours, is stirred 2 hours.In 0 DEG C, 0.5N hydrochloric acid (800ml) is instilled in reaction solution makes solution in acidity, is extracted with dichloromethane (500ml, 300ml).Organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing, are concentrated after being dried with anhydrous magnesium sulfate.Gained crystallization is dissolved in DMF (335ml), sodium azide (60.5g) is added, is stirred 16 hours in 67~75 DEG C.After filtering reacting liquid, filtrate decompression is concentrated to the solvent that 250ml is evaporated off.Merge residue and previous leaching thing, be dissolved in water (500ml), extracted with ethyl acetate (11 and 300ml).Organic layer is washed with saturated aqueous common salt (400ml, 200ml), is concentrated after being dried with anhydrous magnesium sulfate, and gained crystallization (hexane: ethyl acetate=4: 1) is refined with silica gel column chromatography, obtains title compound (18.4g).
[α]25 D=+62 ° of (c=1, chloroform)
1H-NMR(CDCl3)δ：(1.26 3H, t, J=7.1Hz), and 1.35-2.00 (15H, s), 2.60-2.68 (1H, m), 3.80-3.96 (2H, m), 4.15 (2H, q, J=7.1Hz), 4.61 (1H, br.s)
[reference example 250] (1S, 3R, 4S) -4- azidos -3- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid
Figure G2003801097466D01892
Lithium hydroxide (102mg) and water (5ml) are added in tetrahydrofuran (25ml) solution for the compound (1.0g) that reference example 249 is obtained, after stirring 17 hours, add lithium hydroxide (50mg) and stir 4 hours.1N aqueous hydrochloric acid solution (6.3ml) is added in reaction solution, is extracted with ethyl acetate.After organic layer is dried, solvent is boiled off under decompression, title compound (980mg) is obtained.
1H-NMR(CDCl3)δ：1.30-2.20 (6H, m), 1.45 (9H, s), 2.70-2.80 (1H, m), 3.94 (2H, br.s), 4.73 (1H, br.s)
[reference example 251] (1R, 2S, 5S) -2- azidos -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D01901
The compound (4.77g) that reference example 250 is obtained is dissolved in dichloromethane (150ml), dimethylamine hydrochloride (3.26g), 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride (4.60g), the hydrate of I-hydroxybenzotriazole 1 (3.24g) and N-methylmorpholine (8.09g) are added, is stirred 18 hours at room temperature.Saturated sodium bicarbonate aqueous solution is added in reaction solution to carry out after point liquid, dries organic layer, solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (methanol: dichloromethane=1: 50) refines, obtains title compound (4.90g).
1H-NMR(CDCl3)δ：1.30-1.90 (4H, m), 1.45 (9H, s), 1.97-2.18 (2H, m), 2.75-2.85 (1H, m), 2.92 (3H, s), 3.02 (3H, s), 3.68-3.80 (1H, m), 4.05-4.20 (1H, m), 4.55-4.75 (1H, m)
[reference example 252] N- { (1R, 2S, 5S) -2- azidos -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The compound (9.13g) that reference example 251 is obtained is dissolved in dichloromethane (100ml), adds ethanol solution hydrochloride (100ml), stirs 1 minute at room temperature.The lower concentration of reaction solution of decompression, N is dissolved in by residue obtained, dinethylformamide (200ml), compound (7.75g), the hydrate of I-hydroxybenzotriazole 1 (4.47g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (11.2g) and triethylamine (2.02ml) that reference example 10 is obtained are added, an evening is stirred at room temperature.Then, compound (2.38g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (5.60g) that reference example 10 is obtained are added, is stirred 3 days.The lower concentration of reaction solution of decompression, dichloromethane is added in residue and saturated sodium bicarbonate aqueous solution carries out a point liquid, gained organic layer anhydrous sodium sulfate drying.Boiled off under decompression after solvent, residue (dichloromethane: methanol=47: 3) is refined with silica gel column chromatography, obtains title compound (7.38g).
1H-NMR(CDCl3)δ：1.72-1.97 (4H, m), 2.10-2.27 (2H, m), 2.51 (3H, s), 2.77-3.05 (11H, m), 3.68 (1H, d, J=15.4Hz), 3.74 (1H, d, J=15.4Hz), 3.86-3.93 (1H, m), 4.54-4.60 (1H, m), 7.25 (1H, d, J=7.6Hz)
[referring to 253] N- { (1R, 2S, 5S) -2- amino -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
10% palladium carbon (6.0g) is added in methanol (300ml) solution for the compound (9.0g) that reference example 252 is obtained, 4 hydrogen pressures are stirred vigorously 11 hours at room temperature.Catalyst is filtered off, filtrate is concentrated, title compound (7.67g) is obtained.
1H-NMR(CDCl3)δ：1.42-1.54 (1H, m), 1.66-1.89 (5H, m), 2.30-2.40 (1H, m), 2.51 (3H, s), 2.68-3.05 (6H, m), 2.92 (3H, s), 3.00 (3H, s), 3.10-3.18 (1H, m), 3.65-3.77 (2H, m), 4.21-4.28 (1H, m), 7.52 (1H, d, J=6.1Hz)
[reference example 254] 2- (4- fluoroanilinos) -2- oxoacetic acid methyl esters
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 4- fluoroanilines and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.98 (3H, s), 7.00-7.14 (2H, m), 7.55-7.68 (2H, m), 8.85 (1H, br.s)
MS(ESI)m/z：198(M+H)+.
[reference example 255] 2- (4- bromobenzenes amido) -2- oxoacetic acid methyl esters
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 4- bromanilines and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.98 (3H, s), 7.49 (2H, d, J=9.0Hz), 7.55 (2H, d, J=9.0Hz), 8.85 (1H, br.s)
MS(FAB)m/z：258M+.
[reference example 256] 2- (4- chloro-2-methyl anilines base) -2- oxoacetic acid methyl esters
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 4- chloro-2-methyl anilines and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：2.31 (3H, s), 3.99 (3H, s), 7.15-7.30 (2H, m), 7.98 (1H, d, J=8.8Hz), 8.77 (1H, br)
MS(FAB)m/z：228(M+H)+.
[reference example 257] 2- [(the chloro- 3- toluidines of 4-) -2- oxoacetic acid methyl esters
Using the method same with the method that reference example 242 is recorded, title compound is obtained by the chloro- 3- methylanilines of 4- and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：2.39 (3H, s), 3.98 (3H, s), 7.33 (1H, d, J=12.5Hz), 7.44 (1H, dd, J=12.5,2.5Hz), 7.53 (1H, d, J=2.5Hz), 8.81 (1H, br.s)
MS(ESI)m/z：228(M+H)+.
[reference example 258] 2- (the chloro- 2- fluoroanilinos of 4-) -2- oxoacetic acid methyl esters
Using the method same with the method that reference example 242 is recorded, title compound is obtained by the chloro- 2- fluoroanilines of 4- and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.99 (3H, s), 7.15-7.24 (2H, m), 8.33 (1H, t, J=8.4Hz), 9.05 (1H, br.s)
MS(ESI)m/z：232(M+H)+.
[reference example 259] 2- (2,4- difluorobenzene amido) -2- oxoacetic acid methyl esters
Figure G2003801097466D01932
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 2,4- difluoroanilines and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.99 (3H, s), 6.87-7.00 (2H, m), 8.29-8.38 (1H, m), 8.99 (1H, br.s)
MS(ESI)m/z：215M+.
[reference example 260] 2- (3,4- difluorobenzene amido) -2- oxoacetic acid methyl esters
Figure G2003801097466D01933
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 3,4- difluoroanilines and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.98 (3H, s), 7.10-7.28 (2H, m), 7.67-7.78 (1H, m), 8.83 (1H, br.s)
MS(ESI)m/z：215M+.
[reference example 261] 2- oxos -2- (pyridin-4-yl amino) methyl acetate
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 4-aminopyridine and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.99 (3H, s), 7.58 (2H, dd, J=4.8,1.6Hz), 8.60 (2H, dd, J=4.8,1.6Hz), 9.04 (1H, br.s)
MS(ESI)m/z：181(M+H)+.
[reference example 262] 2- [(5- bromopyridine -2- bases) amino] -2- oxoacetic acid methyl esters
Figure G2003801097466D01942
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 2- amino -5- bromopyridines and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.99 (3H, s), 7.87 (1H, dd, J=8.8,2.4Hz), 8.19 (1H, d, J=8.8Hz), 8.41 (1H, d, J=2.4Hz), 9.38 (1H, br.s)
MS(FAB)m/z：259M+.
[reference example 263] 2- [(6- chloropyridine -3- bases) amino] -2- ethyls
5- Amino-2-Chloropyridines (386mg) are dissolved in N, in dinethylformamide (8ml), 2- ethyoxyl -2- Oxoacetic Acids sylvite (469mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (863mg) and the hydrate of I-hydroxybenzotriazole 1 (203mg) are added, is stirred 2 days at room temperature.Solvent is boiled off under decompression, dichloromethane is added and saturated sodium bicarbonate aqueous solution is carried out after point liquid, organic layer anhydrous sodium sulfate drying.After the lower concentrated solvent of decompression, (hexane: ethyl acetate=2: 1) refined with silica gel flash column chromatography, obtain the residue (200mg) containing title compound.
1H-NMR(CDCl3)δ：1.43 (3H, t, J=7.2Hz), 4.44 (2H, q, J=7.2Hz), 7.36 (1H, d, J=8.7Hz), 8.24 (1H, dd, J=8.7,2.7Hz), 8.55 (1H, d, J=2.7Hz), 9.03 (1H, br.s)
[reference example 264] 2- [(6- chlorine pyridazine -3- bases) amino] -2- oxoacetic acid methyl esters
Figure G2003801097466D01951
3- amino -6- chlorine pyridazines (516mg) are dissolved in pyridine (26ml), under ice cooling, triethylamine (665 μ l), chlorine oxoacetic acid methyl ester (441 μ l) are sequentially added, stirred 14 hours at room temperature.Point liquid, organic layer anhydrous sodium sulfate drying after being added water in reaction solution.Solvent is boiled off under decompression, title compound (748mg) is obtained.
1H-NMR(CDCl3)δ：4.03 (3H, s), 7.59 (1H, d, J=9.3Hz), 8.52 (1H, d, J=9.3Hz), 9.88 (1H, br.s)
MS(FAB)m/z：215M+.
[reference example 265] 2- [(5- chlorine thiazol-2-yl) amino] -2- oxoacetic acid methyl esters
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 2- amino -5- diurils azoles and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：4.02 (3H, s), 7.48 (1H, s), 11.03 (1H, br.s)
MS(ESI)m/z：221(M+H)+.
[reference example 266] 2- [(5- chloropyridine -2- bases) amino] -2- Oxoacetic Acid lithium salts
At room temperature, water (5.0ml) and lithium hydroxide (128mg) are added in the tetrahydrofuran solution (20ml) for the compound (1.12g) that reference example 243 is obtained, is stirred 5 hours.Solvent is boiled off under decompression, hexane (30ml) is added in gained white solid and is stirred 30 minutes, after leaching solid, dries and obtains title compound (1.02g).
1H-NMR(DMSO-d6)δ：7.90 (1H, dd, J=8.9,2.6Hz), 8.12 (1H, d, J=8.9Hz), 8.34 (1H, d, J=2.6Hz), 10.18 (1H, s)
[reference example 267] 2- (4- chloroanilinos) ethyl acetate
Figure G2003801097466D01961
4- chloroanilines (2.0g) are dissolved in acetonitrile (20ml), bromoacetate (2.1g) and lithium carbonate (2.2g) is added, stirred 2 days in 60 DEG C.By Celite pad filtering reacting liquid, the lower concentration filtrate of decompression.Residue obtained use silica gel column chromatography (hexane: chloroform=2: 1) refines, obtains title compound (2.3g).
1H-NMR(CDCl3)δ：1.30 (3H, t, J=7.3Hz), 3.86 (2H, s), 4.24 (2H, q, J=7.3Hz), and 4.26-4.35 (1H, m), 6.53 (2H, dd, J=6.6,2.2Hz), 7.14 (2H, dd, J=6.6,2.2Hz)
[reference example 268] 2- (the chloro- 2- fluoroanilinos of 4-) ethyl acetate
Using the method same with the method that reference example 267 is recorded, title compound is obtained by the chloro- 2- fluoroanilines of 4- and bromoacetate.
1H-NMR(CDCl3)δ：1.29 (3H, t, J=7.3Hz), 3.91 (2H, s), 4.22 (2H, q, J=7.3Hz), 4.42-4.51 (1H, m), 6.49 (1H, t, J=8.8Hz), 6.98 (1H, dt, J=8.8,2.5Hz), 7.01 (1H, dd, J=11.3,2.5Hz)
[reference example 269] 2- [((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) amino] -2- ethyls
The compound (1.5g) that reference example 253 is obtained is dissolved in N, in dinethylformamide (15ml), 2- ethyoxyl -2- Oxoacetic Acids sylvite (962mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (1.18g) and the hydrate of I-hydroxybenzotriazole 1 (277mg) are added, is stirred 14 hours at room temperature.Solvent is boiled off under decompression, point liquid after sodium bicarbonate aqueous solution and dichloromethane is added in residue.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue (dichloromethane: methanol=47: 3) is refined with silica gel flash column chromatography, obtains title compound (1.13g).
1H-NMR(CDCl3)δ：1.37 (3H, t, J=7.1Hz), 1.55-2.15 (6H, m), 2.52 (3H, s), 2.77-2.89 (3H, m), 2.94 (5H, br.s), 3.06 (3H, s), 3.71 (1H, d, J=15.5Hz), 3.73 (1H, d, J=15.5Hz), 4.06-4.13 (1H, m), 4.32 (2H, q, J=7.1Hz), 4.60-4.63 (1H, m), 7.39 (1H, d, J=8.3Hz), 7.83 (1H, d, J=7.6Hz)
MS(ESI)m/z：466(M+H)+.
[reference example 270] 2- [((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) amino] -2- Oxoacetic Acid lithium salts
The compound (1.13g) that reference example 269 is obtained is dissolved in tetrahydrofuran (20ml), methanol (10ml) and water (10ml), adds lithium hydroxide (58mg), is stirred 30 minutes at room temperature.Solvent is boiled off under decompression, title compound (1.10g) is obtained.
1H-NMR(DMSO-d6)δ：1.41-1.73 (4H, m), 2.00-2.07 (2H, m), 2.39 (3H, s), 2.74-2.99 (11H, m), 3.67 (2H, s), 3.82-3.88 (1H, m), 4.28-4.30 (1H, m), 8.66-8.70 (2H, m)
[reference example 271] N- { (1S, 2S, 5S) -2- azidos -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- formamides
Figure G2003801097466D01972
Using the method same with the method that reference example 252 is recorded, the compound that the compound obtained by reference example 293 and reference example 251 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.73-1.87 (4H, m), 2.11-2.20 (2H, m), 2.67 (3H, s), 2.85-2.90 (1H, m), 2.93 (3H, s), 3.00 (3H, s), 3.90-4.10 (5H, m), 4.57-4.62 (1H, m), 7.20-7.22 (1H, m)
MS(FAB)m/z：378(M+H)+.
[reference example 272] N- { (1R, 2S, 5S) -2- amino -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- formamides
Figure G2003801097466D01981
Using the method same with the method that reference example 253 is recorded, the compound obtained by reference example 271 prepares title compound.
1H-NMR(CDCl3)δ：1.67-1.97 (6H, m), 2.36-2.40 (1H, m), 2.67 (3H, s), 2.92 (3H, s), 3.00 (3H, s), 3.07-3.18 (1H, m), 3.92-3.95 (2H, m), 4.02-4.06 (2H, m), 4.23-4.26 (1H, m), 7.50-7.52 (1H, m)
The chloro- 4- fluoro indoles -2- carboxylate methyl esters of [reference example 273] 5-
In argon atmospher, add ethanol (100ml) in sodium hydride (containing 60%, 4.7g) in 0 DEG C and stir 10 minutes.After 2- nitropropanes (11ml) stirring being added in reaction solution 10 minutes, the chloro- 2- fluorobenzene (10g) of 1- (bromomethyl) -3- are added, are stirred 3.5 hours at room temperature.Filter off the lower concentration filtrate of precipitation decompression.Residue is dispensed into ether and water, organic layer after 1N sodium hydrate aqueous solution, water and saturated common salt water washing successively with using anhydrous sodium sulfate drying.Solvent is boiled off, residue (ethyl acetate: hexane=3: 7) is refined with silica gel column chromatography, obtains the chloro- 2- fluorobenzaldehydes (5.5g) of rough 3- in faint yellow oily compound.In argon atmospher, add methanol (20ml) in sodium hydride (containing 60%, 1.6g) in 0 DEG C and stir 10 minutes.Reaction solution is cooled to -20 DEG C, methanol (10ml) solution of the chloro- 2- fluorobenzaldehydes (5.5g) of rough 3- and 2- nitrine methyl acetate (5.0g) was added within 20 minutes.Reaction solution is warming up to 0 DEG C, stirring adds water (40ml) after 2.5 hours.The lower concentration of reaction solution of decompression, the mixed liquor extraction of residue dichloromethane and ethyl acetate.Extract saturated common salt water washing, uses anhydrous sodium sulfate drying.Solvent is boiled off, residue (toluene: hexane=3: 17) is refined with silica gel column chromatography, obtains rough 2- azidos -3- [(the chloro- 2- fluorine of 3-) phenyl] methyl acrylate (2.6g).Dimethylbenzene (50ml) is dissolved in, is stirred 3 hours in 130~140 DEG C.Concentration of reaction solution, after residue obtained use silica gel column chromatography (dichloromethane) is refined, is recrystallized with ether-hexane, obtains title compound (440mg).
1H-NMR(DMSO-d6)δ：4.08 (3H, s), 7.20 (1H, s), 7.31-7.38 (2H, m)
MS(FAB)m/z：228(M+H)+.
The chloro- 4- fluoro indoles -2- carboxylic acids of [reference example 274] 5-
Figure G2003801097466D01991
The compound (440mg) that reference example 273 is obtained is dissolved in tetrahydrofuran (10ml), adds the aqueous solution (5ml) of lithium hydroxide (160mg), stirs 3 hours at room temperature.The aqueous solution (5ml) of additional lithium hydroxide (240mg), was stirred for after 1 hour at room temperature in reaction solution, the lower concentration of reaction solution of decompression.Residue is neutralized with 1N aqueous hydrochloric acid solution, is extracted with ethyl acetate 3 times.The organic layer merged with saturated common salt water washing, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, title compound (390mg) is obtained.
1H-NMR(DMSO-d6)δ：6.79 (1H, s), 7.16-7.26 (2H, m)
MS(FAB)m/z：214(M+H)+.
[reference example 275] 1- benzyl -5- chloro-indole -2- carboxylic acid, ethyl esters
5- chloro-indole -2- carboxylic acid, ethyl esters (1.4g) are dissolved in DMF (30ml), potassium carbonate (2.9g) and benzyl chloride (2.4ml) is added, heating stirring 1.5 hours under 100 DEG C of bath temperature.The lower concentration of reaction solution of decompression, residue is injected in frozen water, is extracted with ethyl acetate.Organic layer saturated common salt water washing, uses anhydrous sodium sulfate drying.Solvent is boiled off, residue (ethyl acetate: hexane=1: 19) is refined, crystallized with ether-hexane, obtain title compound (1.6g) with silica gel column chromatography.
1H-NMR(CDCl3)δ：(1.36 3H, t, J=7.1Hz), 4.33 (2H, q, J=7.1Hz), 5.83 (2H, s), 7.00-7.02 (2H, d), 7.20-7.38 (6H, m), 7.67 (1H, d, J=1.7Hz)
The chloro- 3- fluoro indoles -2- carboxylic acid, ethyl esters of [reference example 276] 1- benzyls -5-
Figure G2003801097466D01993
Fluoro- 2, the 6- dichloropyridines fluoroform sulphonates (4.4g) of 1- are added in the dichloromethane solution (30ml) for the compound (2.2g) that reference example 275 is obtained, are heated to reflux 3 days.Reaction solution is distributed into ethyl acetate and water, aqueous layer with ethyl acetate extraction.Merge organic layer, washed successively with 1N hydrochloric acid, water and saturated aqueous common salt, use anhydrous sodium sulfate drying.Solvent is boiled off, residue (ethyl acetate: hexane=1: 24) is refined with silica gel column chromatography, obtains rough title compound (2.8g).One part is refined with silica gel thin-layer chromatography is prepared, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.25 (3H, t, J=7.1Hz), 4.29 (2H, q, J=7.1Hz), 5.77 (2H, s), 6.97-6.99 (2H, m), 7.18-7.28 (3H, m), 7.39 (1H, dd, J=9.0,2.1Hz), 7.69 (1H, dd, J=9.0,2.1Hz), (7.78 1H, d, J=2.1Hz)
The chloro- 3- fluoro indoles -2- carboxylic acid, ethyl esters of [reference example 277] 5-
Figure G2003801097466D02001
The rough compound (1.4g) that reference example 276 is obtained is dissolved in methyl phenyl ethers anisole (30ml), marginally adds aluminium chloride (2.9g) every time under ice-cooling.Reaction solution is stirred 30 minutes at room temperature, aluminium chloride (2.9g) is added and stirs 18 hours.Add after aluminium chloride (8.0g) is stirred 5 hours and add water in reaction solution.Reaction solution is extracted with ethyl acetate, after being washed successively to the organic layer of merging with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue is refined with silica gel column chromatography (dichloromethane), obtains title compound (470mg).
1H-NMR(CDCl3)δ：1.43 (3H, t, J=7.2Hz), 4.45 (2H, q, J=7.2Hz), 7.25-7.31 (2H, m), 7.66 (1H, d, J=0.73Hz), 8.53 (1H, br.s)
MS(FAB)m/z：242(M+H)+.
The chloro- 3- fluoro indoles -2- carboxylic acids of [reference example 278] 5-
Figure G2003801097466D02002
Using the method same with reference example 274, the compound obtained by reference example 277 prepares title compound.
1H-NMR(DMSO-d6)δ：7.31 (1H, dd, J=8.8,1.9Hz), 7.42 (1H, dd, J=8.8,1.9Hz), 7.70 (1H, d, J=1.9Hz), 11.78 (1H, s)
MS(FAB)m/z：214(M+H)+.
[reference example 279] (1R, 2S, 5S)-{ [(the chloro- 3- fluoro indoles -2- bases of 5-) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 97, the compound that the compound obtained by reference example 144 and reference example 278 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.73-2.11 (6H, m), 2.65 (1H, br.s), 2.96 (3H, s), 3.07 (3H, s), 4.20 (1H, br.s), 4.28 (1H, br.s), 4.78 (1H, br), 7.23-7.30 (3H, m), 7.58 (1H, s), 9.03 (1H, s)
MS(FAB)m/z：481(M+H)+.
The bromo- 5- chloro-indoles -2- carboxylic acid, ethyl esters of [reference example 280] 3-
Under ice cooling, N- bromines succinimide (440mg) is added in DMF (10ml) solution of 5- chloro-indole -2- carboxylic acid, ethyl esters (500mg).Solvent is boiled off under being depressurized after being stirred 18 hours to reaction solution at room temperature.Residue is distributed into ethyl acetate and water, aqueous layer with ethyl acetate extraction.After being washed with saturated aqueous common salt to the organic layer of merging, anhydrous sodium sulfate drying is used.Solvent is boiled off, residue (ethyl acetate: hexane=1: 9) is refined with silica gel column chromatography, gained white powder is washed with hexane, obtain title compound (680mg).
1H-NMR(CDCl3)δ：1.42-1.48 (3H, m), 4.43-4.49 (2H, m), 7.30-7.32 (2H, m), 7.65 (1H, d, J=0.74Hz), 9.11 (1H, s)
MS(FAB)m/z：303(M+H)+.
The bromo- 5- chloro-indoles -2- carboxylic acids of [reference example 281] 3-
Figure G2003801097466D02013
Using the method same with reference example 274, the compound obtained by reference example 280 prepares title compound.
1H-NMR(DMSO-d6)δ：7.35 (1H, dd, J=8.8,2.0Hz), 7.48-7.53 (2H, m), 12.33 (1H, s)
MS(FAB)m/z：275(M+H)+.
[reference example 282] (1R, 2S, 5S) -2- { [(the bromo- 5- chloro-indoles -2- bases of 3-) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02021
Using the method same with reference example 97, the compound that the compound obtained by reference example 144 and reference example 281 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.42 (9H, s), 1.58-2.17 (6H, m), 2.70 (1H, br.s), 2.96 (3H, s), 3.07 (3H, s), 4.23-4.28 (2H, m), 4.83 (1H, br), 7.34-7.41 (3H, m), 7.52 (1H, s), 9.76 (1H, s)
MS(FAB)m/z：542(M+H)+.
The chloro- 5- fluoro indoles -2- carboxylic acid, ethyl esters of [reference example 283] 3-
Figure G2003801097466D02022
5- fluoro indole -2- carboxylic acid, ethyl esters (2.0g) are dissolved in N, under dinethylformamide (20ml), ice cooling, the N of N-chloro-succinimide (1.4g) is instilled, dinethylformamide (10ml) solution, is stirred 18 hours at room temperature.After reaction solution ethyl acetate dilutes, washed successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=5: 1) is refined with silica gel column chromatography, obtains title compound (1.9g).
1H-NMR(CDCl3)δ：1.45 (3H, t, J=7.4Hz), 4.46 (2H, q, J=7.4Hz), 7.14 (1H, dt, J=8.0,2.7Hz), 7.32-7.36 (2H, m), 8.91 (1H, br)
The chloro- 5- fluoro indoles -2- carboxylic acids of [reference example 284] 3-
Using the method same with reference example 274, the compound obtained by reference example 283 prepares title compound.
1H-NMR(DMSO-d6)δ：(7.20 1H, dt, J=8.8,2.4Hz), 7.31 (1H, dd, J=8.8,2.4Hz), 7.46 (1H, dd, J=8.8,4.4Hz), 12.12 (1H, br)
The chloro- 3- formyl indoles -2- carboxylic acid, ethyl esters of [reference example 285] 5-
Phosphorus oxychloride (2.0ml) is added in N- methyl formanilides (2.9g), stirring adds 1,2- dichloroethanes (50ml) and 5- chloro-indole -2- carboxylic acid, ethyl esters (4.0g) after 15 minutes, is heated to reflux 1 hour.Under ice cooling, in the aqueous solution (28ml) that reaction solution is injected to sodium acetate (14g), leaching insoluble matter after stirring 18 hours.After it is washed with water and ether successively, title compound (3.56g) is obtained.
1H-NMR(DMSO-d6)δ：1.38 (3H, t, J=7.1Hz), 4.44 (2H, q, J=7.1Hz), 7.38 (1H, dd, J=8.0,1.4Hz), 7.56 (1H, d, J=8.0Hz), 8.19 (1H, d, J=1.4Hz), 10.53 (1H, s)
The chloro- 3- formyl indoles -2- carboxylic acids of [reference example 286] 5-
The compound (1.0g) that reference example 285 is obtained was dissolved in ethanol (10ml), after the sodium hydrate aqueous solution (10ml) for instilling 1N, in 50 DEG C of heating stirrings 2 hours.1N aqueous hydrochloric acid solution (11ml) is added in reaction solution, the insoluble matter that leaching is separated out after stirring obtains title compound (0.86g).
1H-NMR(DMSO-d6)δ：7.39 (1H, d, J=8.0Hz), 7.55 (1H, d, J=8.0Hz), 8.20 (1H, s), 10.58 (1H, s), 12.90 (1H, br)
[reference example 287] 5- chloro-2-ethoxy carbonyl indole -3-carboxylic acids
The compound (1.5g) and sulfamic acid (1.7g) that reference example 286 is obtained are dissolved in the tert-butyl alcohol (30ml)-water (30ml), are added sodium chlorite (1.6g) and are stirred 8 hours.Reaction solution is diluted with water, then is extracted with ethyl acetate, successively with after 1N aqueous hydrochloric acid solution and saturated common salt water washing, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue is recrystallized with the mixed solvent of isopropyl ether-hexane formation, obtains title compound (0.7g).
1H-NMR(DMSO-d6)δ：1.34 (3H, t, J=7.1Hz), 4.38 (2H, q, J=7.1Hz), 7.33 (1H, dd, J=8.0,1.4Hz), 7.52 (1H, d, J=8.0Hz), 7.97 (1H, d, J=1.4Hz), 12.75 (1H, br)
The chloro- 3- of [reference example 288] 5- [(dimethylamino) carbonyl] indole -2-carboxylic ethyl ester
The compound (0.7g) that reference example 287 is obtained is dissolved in N, dinethylformamide (10ml), dimethylamine hydrochloride (0.26g), the hydrate of I-hydroxybenzotriazole 1 (0.43g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (1.0g) are added, is stirred 2 days at room temperature.Ethyl acetate dilute reaction solution is used, successively with after 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue is recrystallized with the mixed solvent of isopropyl ether-hexane, obtains title compound (0.6g).
1H-NMR(DMSO-d6)δ：1.29 (3H, t, J=7.1Hz), 2.78 (3H, s), 3.04 (3H, s), 4.30 (2H, q, J=7.1Hz), 7.31 (1H, dd, J=8.0,1.4Hz), 7.45 (1H, d, J=1.4Hz), 7.48 (1H, d, J=8.0Hz), 12.29 (1H, s)
The chloro- 3- of [reference example 289] 5- [(dimethylamino) carbonyl] indole-2-carboxylic acid
Figure G2003801097466D02043
Using the method same with reference example 286, by preparing title compound with reference to 288 compounds obtained.
1H-NMR(DMSO-d6)δ：2.91 (6H, s), 7.29 (1H, d, J=8.0Hz), 7.44 (1H, d, J=8.0Hz), 7.47 (1H, s), 12.16 (1H, s)
[reference example 290] 5- (phenyl sulfonyl) -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole
Under ice cooling, make benzsulfamide (638mg) and double (bromomethyl) thiazole (M.Al.Hariri, the O.Galley of 4,5-, F.Pautet, H.Fillion, Eur.J.Org.Chem.1998,593-594) (1.10g) be dissolved in N, dinethylformamide (10ml), sodium hydride (60% oiliness, 357mg) is added quickly, is stirred 3 hours at room temperature.Add water and dichloromethane carries out a point liquid, organic layer anhydrous sodium sulfate drying boils off solvent, (dichloromethane: ethyl acetate=9: 1) refined with silica gel column chromatography, obtain title compound (137mg).
1H-NMR(CDCl3)δ：4.60-4.63 (2H, m), 4.70-4.73 (2H, m), 7.52-7.64 (3H, m), 7.88-7.92 (2H, m), 8.71 (1H, s)
MS(FAB)m/z：267(M+H)+.
The hydrobromate of [reference example 291] 5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole 2
The mixture of compound (800mg), phenol (800 μ l) and 47% hydrobromic acid aqueous solution (5.00ml) of the acquisition of reference example 290 is set to be heated to reflux 2 hours.It is cooled to after room temperature, adds ethyl acetate and water carries out a point liquid, boil off solvent under decompression from water layer.Ethyl acetate leaching precipitate is added in residue, title compound (521mg) is obtained after drying.
1H-NMR(DMSO-d6)δ：4.42 (2H, br s), 4.56 (2H, br s), 9.14 (1H, s)
MS(FAB)m/z：127(M+H)+.
[reference example 292] 5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole
Using the same method recorded with reference example 9, the compound obtained by reference example 291 prepares title compound.
1H-NMR(CDCl3)δ：2.67 (3H, s), 3.95-3.99 (2H, m), 4.01-4.05 (2H, m), 8.69 (1H, s)
MS(ESI)m/z：141(M+H)+.
[reference example 293] 5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- carboxylic acid lithium salts
Using the same method recorded with reference example 5, the compound obtained by reference example 292 prepares title compound.
1H-NMR(DMSO-d6)δ：2.52 (3H, s), 3.73 (2H, t, J=3.2Hz), 3.87 (2H, t, J=3.2Hz)
[reference example 294] (1R, 2S, 5S) -2- [(the chloro- 2- naphthoyls of 6-) amino] -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02062
Using the method same with reference example 97, the compound obtained by reference example 144 and 6- chloronaphthalene -2- carboxylic acids (Eur.J.Chem-Chim.Ther., volume 19,205-214 pages in 1984) obtain title compound.
1H-NMR(CDCl3)δ：1.30-2.00 (15H, m), 2.60-2.80 (1H, m), 2.96 (3H, s), 3.09 (3H, s), 4.00-4.20 (1H, m), 4.20-4.30 (1H, m), 4.75-4.95 (1H, m), 7.44 (1H, d, J=9.0Hz), 7.70-7.95 (5H, m), 8.31 (1H, s)
MS(FAB)m/z：474(M+H)+.
[reference example 295] (E) -3- (morpholine -4- bases) -2- ethyl acrylates
Ethyl propionate (2.0ml) is dissolved in dichloromethane (20ml), morpholine (1.70ml) is instilled under ice-cooling, after stirring 1 hour at room temperature, it is concentrated under reduced pressure, (dichloromethane: methanol=20: 1) refined by silica gel column chromatography, obtain title compound (3.72g).
1H-NMR(CDCl3)δ：1.26 (3H, t, J=7.1Hz), 3.21 (4H, t, J=5.1Hz), 3.71 (4H, t, J=5.1Hz), 4.14 (2H, q, J=7.1Hz), 4.70 (1H, d, J=13.4Hz), 7.36 (1H, d, J=13.4Hz)
MS(FAB)m/z：186(M+H)+.
[reference example 296] 3- chlorine diazobenzene tetrafluoroborates
3- chloroanilines (2.0g) are dissolved in the in the mixed solvent of water (30ml) and concentrated hydrochloric acid (3.5ml), natrium nitrosum (1.30g) is added under ice-cooling and is stirred 10 minutes.Then, concentrated hydrochloric acid (5.3ml), sodium tetrafluoroborate (6.90g) are added, after stirring 30 minutes under ice-cooling, leaching precipitate is washed with water, methanol, ether, obtains title compound (2.63g).It is directly used in reaction thereafter.
[reference example 297] 7- chlorine cinnolines -3- carboxylic acid, ethyl esters
Figure G2003801097466D02072
The compound (1.45g) that reference example 295 is obtained is dissolved in acetonitrile (100ml), adds the compound (1.73g) that reference example 296 is obtained, is heated to reflux 7 days after stirring 1 hour at room temperature.Decompression boils off solvent, residue silica gel column chromatography (dichloromethane → dichloromethane: ethyl acetate 10: 1, then hexane: ethyl acetate=4: 1 → 1: 1) refine, obtain title compound (0.25g).
1H-NMR(CDCl3)δ：1.53 (3H, t, J=7.1Hz), 4.62 (2H, q, J=7.1Hz), 7.80 (1H, dd, J=8.8,2.0Hz), 7.95 (1H, d, J=8.8Hz), 8.64 (1H, s), 8.68 (1H, d, J=2.0Hz)
[reference example 298] 7- chlorine cinnolines -3- carboxylic acids
Using the method same with reference example 286, the compound obtained by reference example 297 prepares title compound.
1H-NMR(DMSO-d6)δ：8.02 (1H, dd, J=8.8,2.0Hz), 8.34 (1H, d, J=8.8Hz), 8.70 (1H, s), 8.90 (1H, s)
MS(FAB)m/z：209(M+H)+.
[reference example 299] (1R, 2S, 5S) -2- { [(7- chlorine cinnolines -3- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02081
Using the method same with reference example 97, the compound that the compound obtained by reference example 144 and reference example 298 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.36 (9H, s), 1.80-2.20 (5H, m), 2.72 (1H, m), 2.96 (3H, s), 3.07 (3H, s), 3.49 (1H, d, J=3.7Hz), 4.30-4.45 (2H, m), 4.87 (1H, br), 7.77 (1H, dd, J=8.8,2.0Hz), 7.96 (1H, d, J=8.8Hz), 8.59 (2H, br), 8.72 (1H, s)
MS(FAB)m/z：476(M+H)+.
[reference example 300] (1R, 2S, 5S) -2- { [(the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
10% palladium carbon (50mg) is added in tetrahydrofuran (5.0ml) solution for the compound (235mg) that reference example 143 is obtained, is stirred all night in room temperature in nitrogen atmosphere.Filtrate is concentrated after filtering reaction mixture, then, at room temperature in gained product and 5- chloro benzimidazole -2- carboxylic acids (Bull.Chem.Soc.Jpn., 1989, volume 62, page 2668) hydrate of I-hydroxybenzotriazole 1 (100mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (171mg) are added in DMF (5.0ml) solution of (165mg), stir 4 days.Concentrate after reaction mixture, add dichloromethane, sodium bicarbonate aqueous solution and water and carry out a point liquid, water layer is extracted with dichloromethane.Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: methanol=10: 1) is refined with silica gel flash column chromatography, obtains title compound (250mg).
1H-NMR(DMSO-d6)δ：1.01-2.00 (6H, m), 1.34 (9H, s), 2.79 (3H, s), 2.80-2.95 (1H, m), 2.98 (3H, s), 3.89-4.06 (2H, m), 7.08 (1H, d, J=6.6Hz), 7.31 (1H, d, J=8.5Hz), 7.62 (2H, br.s), 8.47 (1H, d, J=8.5Hz), 13.46 (1H, br.s)
MS(ESI)m/z：466(M+H)+.
[reference example 301] 3- (4- fluorophenyls) -2- { [(4- aminomethyl phenyls) sulfonyl] amino } methyl propionate
Figure G2003801097466D02091
2- amino -3- (4- fluorophenyls) methyl propionate (2.01g), paratoluensulfonyl chloride (2.25g), 4-dimethylaminopyridine (309mg) are dissolved in chloroform (30ml), pyridine (3.0ml) is added and is heated to reflux 4.5 hours.Add paratoluensulfonyl chloride 92.20g), it is heated to reflux 3.5 hours.Carried out in the hydrochloric acid (17ml) that reaction solution is injected to ice and 1N after point liquid, organic layer is washed successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=9: 1 → 2: 1) is refined with silica gel column chromatography, obtains title compound (2.89g).
1H-NMR(CDCl3)δ：2.41 (3H, s), 2.90-3.10 (2H, m), 3.51 (3H, s), 4.10-4.20 (1H, m), 5.04 (1H, d, J=9.0Hz), 6.85-6.95 (2H, m), 7.00-7.10 (2H, m), 7.20-7.30 (2H, m), 7.60-7.70 (2H, m)
MS(ESI)m/z：352(M+H)+.
The fluoro- 2- of [reference example 302] 7- [(4- aminomethyl phenyls) sulfonyl] -1,2,3,4- tetrahydroisoquinoline -3- carboxylate methyl esters
Compound (1.50g) that reference example 301 is obtained, paraformaldehyde (207mg) are dissolved in chloroform (40ml), are replaced with argon gas.Then, trifluoroboranes-etherate (1.20ml) is added, is stirred 7.5 hours at room temperature.Reaction solution is injected in ice, saturated sodium bicarbonate aqueous solution and carried out after point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography, obtains title compound (1.45g).
1H-NMR(CDCl3)δ：2.42 (3H, s), 3.15 (2H, d, J=3.9Hz), 3.46 (3H, s), 4.45 (1H, d, J=15.9Hz), 4.69 (1H, d, J=15.9Hz), 5.01 (1H, t, J=4.4Hz), 6.70-6.80 (1H, m), 6.80-6.90 (1H, m), 7.00-7.10 (1H, m), 7.29 (2H, d, J=8.1Hz), 7.72 (2H, d, J=8.3Hz)
MS(ESI)m/z：364(M+H)+.
[reference example 303] 7- fluorine isoquinolin -3- carboxylate methyl esters
The compound (1.45g) that reference example 302 is obtained is dissolved in DMF (40ml).Oxygen is imported in the reaction solution, is stirred 3.5 hours in 100 DEG C.Reaction solution is concentrated under decompression, saturated sodium bicarbonate aqueous solution and dichloromethane are added in residue and is carried out after point liquid, organic layer is successively with 10% aqueous citric acid solution and saturated common salt water washing, then uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=1: 1) is refined with silica gel column chromatography, obtains title compound (0.59g).
1H-NMR(CDCl3)δ：4.07 (3H, s), 7.55-7.65 (1H, m), 7.65-7.75 (1H, m), 8.00-8.05 (1H, m), 8.61 (1H, s), 9.30 (1H, s)
MS(ESI)m/z：206(M+H)+.
[reference example 304] 7- fluorine isoquinolin -3- carboxylic acid hydrochlorides
The compound (1.45g) that reference example 303 is obtained is dissolved in concentrated hydrochloric acid (18ml), is heated to reflux 2.5 hours.The crystallization that leaching is separated out after reaction solution is cooled down, is dried after being washed with water, title compound (0.46g) is obtained.
1H-NMR(DMSO-d6)δ：7.90-8.00 (1H, m), 8.15-8.25 (1H, m), 8.40-8.50 (1H, m), 8.82 (1H, s), 9.55 (1H, s)
MS(FAB)m/z：192(M+H)+.
The chloro- 2H- chromenes -3- carboxylic acid, ethyl esters of [reference example 305] 7-
By 4- chlorine-2-hydroxyl benzaldehydes (Acta.Chem.Scand., 1999, volume 53, page 258) (510mg) be dissolved in tetrahydrofuran (40ml), sodium hydride (60% oiliness, 157mg) is added to be stirred at room temperature 2 hours.Then, the tetrahydrofuran solution (10ml) of 2- diethyl phosphonyls ethyl acrylate (J.Org.Chem.1978, volume 43, page 1256) (769mg) is added in reaction solution, an evening is heated to reflux after stirring 2 hours at room temperature.Reaction solution is cooled to after room temperature, water is added and ether carries out a point liquid.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue (hexane: ethyl acetate=10: 1) is refined with silica gel column chromatography, obtains title compound (247mg).
1H-NMR(DMSO-d6)δ：1.33 (3H, t, J=7.1Hz), 4.27 (2H, q, J=7.1Hz), 4.99 (2H, d, J=1.2Hz), 6.85 (1H, d, J=1.2Hz), 6.89 (1H, dd, J=8.1,2.0Hz), 7.04 (1H, d, J=8.1Hz), 7.38 (1H, d, J=1.0Hz)
MS(EI)m/z：238(M+).
The chloro- 2H- chromenes -3- carboxylic acids of [reference example 306] 7-
Figure G2003801097466D02111
Using the method same with reference example 274, the compound obtained by reference example 305 prepares title compound.
1H-NMR(DMSO-d6)δ：(4.92 1H, d, J=2.0Hz), 6.95 (1H, d, J=2.0Hz), 7.01 (1H, dd, J=8.1,2.2Hz), 7.35 (1H, d, J=8.1Hz), 7.44 (1H, s) .MS (EI) m/z：210(M)+.
[reference example 307] (1R, 2S, 5S) -2- { [(E) -3- (4- chlorphenyls) -2- acryloyl groups] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02112
Using the method same with reference example 97, the compound obtained by reference example 144 and 4- chloro-cinnamic acids prepare title compound.
1H-NMR(CDCl3)δ：1.30-1.55 (3H, m), 1.48 (9H, s), 1.60-2.30 (4H, m), 2.57-2.70 (1H, m), 2.95 (3H, s), 3.06 (3H, s), 4.01 (1H, br s), 4.10-4.20 (1H, m), 4.78 (1H, br.s), 6.30 (1H, d, J=15.6Hz), 7.02 (1H, s), 7.31 (2H, d, J=8.5Hz), 7.40 (2H, d, J=8.5Hz), 7.52 (1H, d, J=15.6Hz)
MS(ESI)m/z：450(M+H)+.
The chloro- 4- oxos-Isosorbide-5-Nitrae-EEDQ -2- carboxylate methyl esters of [reference example 308] 6-
Figure G2003801097466D02113
Dimethyl acetylenedicarbexylate (13.5ml) is added in 4- chloroanilines (12.76g) methanol (150ml) solution to be heated to reflux 8 hours.The lower concentration of reaction solution of decompression, diphenyl ether (70ml) was dissolved in by residue, in 240 DEG C of heating stirrings 4 hours.The mixed solvent that hexane and ether are added after reaction solution is cooled down, crystallization and washing that leaching is separated out obtain title compound (11.09g).
1H-NMR(DMSO-d6)δ：3.97 (3H, s), 7.76 (1H, dd, J=9.0,2.5Hz), 7.90-8.05 (2H, m), 12.28 (1H, br.s)
MS(ESI)m/z：238(M+H)+.
The chloro- 4- oxos-Isosorbide-5-Nitrae-EEDQ -2- carboxylic acids of [reference example 309] 6-
Figure G2003801097466D02121
Using the method same with reference example 286, the compound obtained by reference example 308 prepares title compound.
1H-NMR(DMSO-d6)δ：6.90-7.05 (1H, m), 7.90-8.05 (2H, m), 10.10-10.30 (1H, m), 12.13 (1H, br.s)
MS(ESI)m/z：224(M+H)+.
[reference example 310] (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Water (10ml) and lithium hydroxide (263mg) are added in tetrahydrofuran (40ml) solution for the compound (5.00g) that reference example 97 is obtained, is stirred all night at room temperature.Filtrate is concentrated after filtering reaction mixture, at room temperature in residue obtained and dimethylamine hydrochloride (1.85g) N, the hydrate of I-hydroxybenzotriazole 1 (1.75g), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (3.32g) and diisopropylethylamine (11.3ml) are added in dinethylformamide (100ml) solution, is stirred 2 days.Concentrate after reaction mixture, add dichloromethane, sodium bicarbonate aqueous solution and water and carry out a point liquid, water layer is extracted with dichloromethane.Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: acetone=2: 1 → 1: 1) is refined with silica gel column chromatography, obtains title compound (4.59g).
1H-NMR(CDCl3)δ：1.60-1.76 (2H, m), 1.73 (9H, s), 1.76-1.87 (1H, m), 1.93 (1H, br.s), 2.14 (1H, br.s), 2.28 (1H, br.s), 2.65 (1H, br.s), 2.95 (3H, s), 3.05 (3H, s), 4.01 (1H, br.s), 4.21 (1H, br.s), 4.84 (1H, br.s), 6.81 (1H, br.s), 7.20 (1H, dd, J=8.8, 1.9Hz), 7.36 (1H, d, J=8.8Hz), 7.59 (1H, br.s), 8.02 (1H, br.s), 10.06 (1H, br.s)
MS(FAB)m/z：465(M+H)+.
[reference example 311] (1R, 2S, 5S) -2- { [(5- fluoro indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02131
1) it is same with reference example 91, the compound and 5- fluoro indole -2- carboxylic acids obtained by reference example 96 obtains (1R, 3R, 4S) -3- [(tert-butoxycarbonyl) amino] -4- { [(5- fluoro indole -2- bases) carbonyl] amino } cyclohexane carboxylic acid ethyl ester
1H-NMR(CDCl3)δ：1.26 (3H, t, J=7.1Hz), 1.52 (9H, s), 1.67-2.41 (7H, m), 3.97 (1H, br.s), 4.15 (2H, q, J=7.1Hz), 4.08-4.22 (1H, m), 6.83 (1H, s), 7.00-7.05 (1H, m), 7.32-7.36 (1H, m), 8.02 (1H, s), 9.51 (1H, s)
MS(FAB)m/z：448(M+H)+.
2) method same with reference example 310 is used, title compound is prepared by above-claimed cpd.
1H-NMR(CDCl3)δ：1.52 (9H, s), 1.57-1.79 (2H, m), 1.79-2.00 (2H, m), 2.14 (1H, br.s), 2.31 (1H, br.s), 2.65 (1H, br.s), 2.95 (3H, s), 3.07 (3H, s), 4.02 (1H, br.s), 4.17-4.25 (1H, m), 4.80 (1H, br.s), 6.82 (1H, br.s), 7.02 (1H, dt, J=2.3, 9.0Hz), 7.24 (1H, br.s), 7.35 (1H, dd, J=9.0, 4.3Hz), 7.91 (1H, br.s), 9.49 (1H, br.s)
MS(FAB)m/z：447(M+H)+.
[reference example 312] 2- amino -6,6- dimethyl -6,7- thiazoline simultaneously [4,5-c] pyridine -5 (4H)-carboxylic acid, ethyl ester
Under argon gas stream, copper cyanider (I) (918mg) is dissolved in tetrahydrofuran (50ml), is cooled to after -20 DEG C and instilled n-BuLi (1.56N hexane solution, 6.41ml) with 5 minutes, is stirred 30 minutes in -20 DEG C.The reaction solution is cooled to after -50 DEG C, diisobutylaluminium hydride (1.00 hexane solution) was instilled with 20 minutes, is stirred 1 hour in -50 DEG C.(the Helv.Chim.Acta containing 2,2- dimethyl -5- oxo -5,6- dihydro -2H- pyridine -1- carboxylic acid, ethyl esters was instilled in the reaction solution with 5 minutes, 1998, volume 81, page 303) tetrahydrofuran (5ml) solution of (986mg), is stirred 2 hours in -50 DEG C.It is warming up to after -20 DEG C, once instills bromine (4.90ml), is stirred 30 minutes in -20 DEG C.Water is added in reaction solution and ethyl acetate carries out a point liquid, organic layer is dried after being washed with the saturated sodium sulfite aqueous solution with anhydrous magnesium sulfate.Solvent is boiled off, residue is dissolved in DMF (10ml), thiocarbamide (760mg) is added and is stirred all night in 50 DEG C.Boil off and dichloromethane and a saturated sodium bicarbonate aqueous solution progress point liquid are added after solvent, organic layer anhydrous sodium sulfate drying boils off solvent.Residue (ethyl acetate: hexane=4: 1) is refined with silica gel column chromatography, obtains title compound (412mg).
1H-NMR(CDCl3)δ：1.25 (3H, t, J=7.1Hz), 1.54 (6H, s), 2.65-2.67 (2H, m), 4.09 (2H, q, J=7.1Hz), 4.44-4.46 (2H, m), 4.78 (2H, br.s)
Bromo- 6,6- dimethyl -6, the 7- thiazolines of [reference example 313] 2- simultaneously [4,5-c] pyridine -5 (4H)-carboxylic acid, ethyl ester
Figure G2003801097466D02141
Copper bromide (431mg) is suspended in acetonitrile (8ml), nitrite tert-butyl (249mg) is instilled at room temperature.50 DEG C are warming up to after the acetonitrile solution (8ml) for adding the compound (412mg) that reference example 312 is obtained under ice cooling in reaction solution, is stirred 15 minutes.Solvent is boiled off, ether is added in residue and 10% hydrochloric acid carries out a point liquid, organic layer is dried with anhydrous magnesium sulfate, decompression is lower to be concentrated.Residue (hexane: ethyl acetate=6: 1) is refined with silica gel column chromatography, obtains title compound (151mg).
1H-NMR(CDCl3)δ：1.26 (3H, t, J=7.1Hz), 1.55 (6H, s), 2.79-2.81 (2H, m), 4.10 (2H, q, J=7.1Hz), 4.65-4.67 (2H, m)
MS(ESI)m/z：319(M+H)+.
[reference example 314] 6,6- dimethyl -6,7- thiazoline simultaneously [4,5-c] pyridine -5 (4H)-carboxylic acid, ethyl ester
Figure G2003801097466D02142
N-BuLi (1.56N hexane solution, 1.04ml) is added in the diethyl ether solution (5ml) for the compound (432mg) that reference example 313 is obtained in -78 DEG C, is stirred 30 minutes in -78 DEG C.Added water in the reaction solution and carry out a point liquid with ether, organic layer is dried with anhydrous magnesium sulfate, boil off solvent, obtain title compound (307mg).
1H-NMR(CDCl3)δ：1.28 (3H, t, J=7.1Hz), 1.55 (6H, s), 2.90 (2H, s), 4.12 (2H, q, J=7.1Hz), 4.75 (2H, m), 8.63 (1H, s)
[reference example 315] 6,6- dimethyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-c] pyridine
Figure G2003801097466D02143
The compound (307mg) that reference example 314 is obtained is dissolved in water (5ml), ethanol, and (5ml) are Ji the in the mixed solvent of dioxane (5ml), addition lithium hydroxide (598mg) is heated to reflux 7 days in the reaction solution.Place to room temperature, add water and dichloromethane carries out a point liquid, water layer is extracted 6 times with dichloromethane.Organic layer obtains title compound (207mg) with solvent is boiled off after anhydrous sodium sulfate drying.
1H-NMR(CDCl3)δ：1.23 (6H, s), 2.71-2.73 (2H, m), 4.09-4.11 (2H, m), 8.61 (1H, s)
MS(ESI)m/z：168(M+).
[reference example 316] 6,6- dimethyl -6,7- thiazoline simultaneously [4,5-c] pyridine -5 (4H)-carboxylic acid tert-butyl ester
The compound (207mg) that reference example 315 is obtained is dissolved in dichloromethane (5ml), add di-tert-butyl dicarbonate (404mg) and 4- (N, N- dimethylaminos) pyridine (151mg), is stirred 2 hours at room temperature.Then, add di-tert-butyl dicarbonate (404mg) to stir all night in room temperature, be added followed by di-tert-butyl dicarbonate (1.00g) and stir 1 hour.Add dichloromethane and 10% aqueous hydrochloric acid solution and carry out a point liquid, organic layer after anhydrous sodium sulfate drying with boiling off solvent.Residue (hexane: ethyl acetate=4: 1) is refined with silica gel column chromatography, obtains title compound (95.4mg).
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.52 (6H, s), 2.87 (2H, s), 4.69 (2H, s), 8.62 (1H, s)
MS(ESI)m/z：269(M+H)+.
The chloro- 5- of [reference example 317] 4- (DOX -2- bases) thiazole -2- carboxylic acid lithium salts
By 2,4- dichloro thiazole -5- formaldehyde condensed ethandiols (J.Che m.Soc.Perkin Trans.1,1992, page 973) (2.26g) be dissolved in tetrahydrofuran (15ml), n-BuLi (1.5N hexane solution is added with dry ice-propanone cooling is lower, 6.8ml), introducing carbon dioxide at the same temperature after stirring 20 minutes.It was slowly ramped to depressurize lower concentration after room temperature with 1.5 hours from the state, adds hexane powdered, ethyl acetate is suspended in after leaching, leaching powder obtains title compound (1.65g) again
The chloro- 5- of [reference example 318] 4- (DOX -2- bases) thiazole -2- carboxylic acid, ethyl esters
The compound (242mg) and ethanol (0.2ml) that reference example 317 is obtained are dissolved in N, dinethylformamide (2ml), the hydrate of I-hydroxybenzotriazole 1 (136mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (250mg) are added, an evening is stirred at room temperature.The lower concentrated solvent of decompression, adds ether and watery hydrochloric acid separation organic layer.Organic layer is washed with water and saturated sodium bicarbonate aqueous solution, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, title compound (170mg) is obtained.
1H-NMR(CDCl3)δ：1.43 (3H, t, J=7.3Hz), 4.00-4.10 (2H, m), 4.10-4.20 (2H, m), 4.48 (2H, q, J=7.3Hz), 6.15 (1H, s)
MS(ESI)m/z：264(M+H)+.
The chloro- 5- formyl thiazoles -2- carboxylic acid, ethyl esters of [reference example 319] 4-
The compound (132mg) that reference example 318 is obtained is dissolved in ether (5ml), adds 20% aqueous hydrochloric acid solution (0.3ml) and stirs 7 hours at room temperature.Saturated sodium bicarbonate aqueous solution is added in reaction solution, is extracted with ether, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, title compound (110mg) is obtained.
1H-NMR(CDCl3)δ：1.46 (3H, t, J=7.1Hz), 4.52 (2H, q, J=7.1Hz), 10.12 (1H, s)
[reference example 320] 4- azido -5- formyl thiazole -2- carboxylic acid, ethyl esters
Figure G2003801097466D02163
The compound (5.15g) that reference example 319 is obtained is dissolved in dimethyl sulfoxide (30ml), is added sodium azide (1.52g) and is stirred 2.5 hours at room temperature.Frozen water is added in reaction solution, is extracted with ether, is dried after washing 2 times with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (dichloromethane: methanol=24: 1) is refined with silica gel column chromatography, obtains title compound (1.78g).
1H-NMR(CDCl3)δ：1.45 (3H, t, J=7.1Hz), 4.50 (2H, q, J=7.1Hz), 9.95 (1H, s)
[reference example 321] 6- methyl -6,7- thiazoline simultaneously [4,5-d] pyridine-2-carboxylic acids ethyl ester
The compound (1.56g) that reference example 320 is obtained is dissolved in dichloromethane (20ml), acetic acid (2ml), methylamine (2N tetrahydrofuran solution, 21ml) and sodium triacetoxy borohydride (2.98g) is added to be stirred.Additional sodium triacetoxy borohydride (2.98g), is further continued for stirring 4.5 hours after 1 hour.0.5N sodium hydrate aqueous solution (100ml) is added in reaction solution makes it in alkalescence, is dried after being extracted with dichloromethane with anhydrous magnesium sulfate.Solvent is boiled off under decompression, brown oil (1.43g) is obtained.The grease is dissolved in ethanol (50ml), adds under 10% palladium carbon (2.0g), normal temperature and pressure and carries out hydrogenation.Catalyst is filtered off after 2.5 hours, filtrate is concentrated, residue is dissolved in dichloromethane (30ml), trimethyl orthoformate (0.7ml) and boron trifluoride-ether complex (0.3ml) is added, is stirred 15 hours at room temperature.Saturated sodium bicarbonate aqueous solution is added in reaction solution, is extracted with dichloromethane, then uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=97: 3) is refined with silica gel column chromatography, obtains title compound (100mg).
1H-NMR(CDCl3)δ：1.41 (3H, t, J=7.1Hz), 2.95 (3H, s), 4.44 (2H, q, J=7.1Hz), 4.87 (2H, s), 7.06 (1H, s)
MS(ESI)m/z：226(M+H)+.
[reference example 322] 6- methyl -6,7- thiazoline simultaneously [4,5-d] pyrimidine -2- carboxylic acid lithium salts
The compound (463mg) that reference example 321 is obtained is dissolved in tetrahydrofuran (20ml), adds lithium hydroxide (54.1mg) and water (4ml) is stirred 4.5 hours at room temperature.Solvent is boiled off under decompression, is dried with vavuum pump and obtains title compound (460mg).
1H-NMR(DMSO-d6)δ：2.86 (3H, s), 4.71 (2H, s), 7.03 (1H, s)
[reference example 323] (1R, 2S, 5S) -2- azidos -5- { [ethyl (methyl) amino] carbonyl } Cyclohexylamino t-butyl formate
Figure G2003801097466D02173
The condensation of compound and ethylmethylamine that reference example 250 is obtained is carried out, title compound is obtained.
1H-NMR(CDCl3)δ：1.08,1.18 (3H, each t, J=7.1Hz), 1.46 (9H, s), 1.52-1.80 (4H, m), 2.04-2.08 (2H, m), 2.71-2.77 (1H, m), 2.89,2.98 (3H, it is each s), 3.32,3.39 (2H, each q, J=7.1Hz), and 3.74-3.76 (1H, m), 4.09-4.11 (1H, m), 4.60 (1H, br.s)
MS(EI)m/z：326(M+H)+.
[reference example 324] (1R, 2S, 5S) -2- { [(7- chlorine isoquinolin -3- bases) carbonyl] amino } -5- { [ethyl (methyl) amino] carbonyl } Cyclohexylamino t-butyl formate
The compound (1.44g) that reference example 323 is obtained is dissolved in methanol (20ml), adds 10% palladium carbon (150mg) and is stirred under hydrogen stream.Catalyst is filtered off after 24 hours, the lower concentrated solvent of decompression obtains colorless oil, is directly used in following reaction.
The grease is dissolved in dichloromethane (30ml), the compound (850mg) of the addition acquisition of reference example 57,1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride (1.27g), the hydrate of I-hydroxybenzotriazole 1) (900mg), N-methylmorpholine (1.34g), it is stirred at room temperature.After 17 hours, dichloromethane is added in reaction solution and saturated sodium bicarbonate aqueous solution is carried out after point liquid, organic layer is dried with anhydrous magnesium sulfate, solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 50) is refined with silica gel column chromatography, obtains title compound (1.61g).
1H-NMR(CDCl3)δ：1.10,1.22 (3H, each t, J=7.1Hz), 1.43 (9H, s), 1.84-2.17 (6H, m), 2.66 (1H, br.s), 2.92,3.03 (3H, each s), 3.35-3.44 (2H, m), 4.20-4.30 (2H, m), 5.30 (1H, br.s), 7.70 (1H, d, J=8.6Hz), 7.92 (1H, d, J=8.6Hz), 8.00 (1H, s), 8.40 (1H, br.s), 8.56 (1H, s), 9.03 (1H, s)
MS(FAB)m/z：489(M+H)+.
[reference example 325] N- ((1S, 2R, 4S) -2- amino -4- [(7- chlorine isoquinolin -3- bases) carbonyl] -4- { [ethyl (methyl) amino] carbonyl } cyclohexyl) -7- chlorine isoquinolin -3- formamides
The compound (1.60g) that reference example 324 is obtained is dissolved in ethanol solution hydrochloride (25ml), stirs 30 minutes at room temperature.Solvent is boiled off under decompression, a point liquid is carried out with the sodium hydrate aqueous solution for adding dichloromethane and 1N in residue.Extracted, with potassium carbonate the organic layer of merging is dried with dichloromethane by water layer, solvent is boiled off under decompression.Hexane leaching precipitation is added in residue, title compound (1.22g) is obtained.
1H-NMR(DMSO-d6)δ：1.10,1.23 (3H, each t, J=7.1Hz), 1.26 (2H, br.s), 1.69-2.11 (6H, m), 2.89 (1H, br.s), 2.93,3.05 (3H, each s), 3.38-3.45 (2H, m), 3.52 (1H, s), 4.18 (1H, br.s), 7.70 (1H, dd, J=8.8,2.0Hz), 7.94 (1H, d, J=8.8Hz), 8.02 (1H, d, J=2.0Hz), 8.50 (1H, br.s), 8.59 (1H, s), 9.11 (1H, s)
MS(FAB)m/z：389(M+H)+.
[reference example 326] (1R*, 3S*, 4S*) -3- [(tert-butoxycarbonyl) amino] -4- { [tert-butyl group (diphenyl) silicyl] epoxide } cyclohexanecarboxylate
Figure G2003801097466D02192
The compound (28.0g) that reference example 88 is obtained is dissolved in DMF (500ml), adds t-butyldiphenylsilyl chlorine (63.5ml) and imidazoles (19.9g).After stirring 10 hours at room temperature, ethyl acetate is added in reaction solution and water carries out a point liquid.Extracted, the organic layer of merging is washed 2 times with water by aqueous layer with ethyl acetate.With anhydrous sodium sulfate drying, boiled off under decompression after solvent, residue (dichloromethane: methanol=1: 0 → 47: 3) is refined with silica gel column chromatography, obtains the title compound (52.5g) for the DMF for being mixed with 0.4 molecule.
1H-NMR(CDCl3)δ：1.07 (9H, s), 1.27 (3H, t, J=7.1Hz), 1.38 (9H, s), 1.43-1.59 (3H, m), 1.63-1.67 (1H, m), 1.92-1.98 (1H, m), 2.25-2.32 (1H, m), 2.37-2.42 (1H, m), 3.66 (1H, br.s), 3.80 (1H, br.s), 4.16 (2H, q, J=7.1Hz), 4.32 (1H, d, J=8.1Hz), 7.34-7.46 (6H, m), 7.65-7.73 (4H, m)
[reference example 327] (1R*, 2R*, 5S*) -2- { [tert-butyl group (diphenyl) silicyl] epoxide } -5- (hydroxymethyl) hexamethylene t-butyl carbamate
Figure G2003801097466D02201
Under argon gas displacement, lithium aluminium hydride reduction (7.11g) is set to be suspended in dry ether (100ml) in 0 DEG C, with the diethyl ether solution (500ml) for instilling the compound (52.5g) that reference example 326 is obtained for 30 minutes.After 0 DEG C is stirred 30 minutes, methanol (100ml) is instilled in reaction solution.The slurry of generation is filtered off with diatomite, filtrate is concentrated, residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography, obtains title compound (29.6g).
1H-NMR(CDCl3)δ：1.07 (9H, s), 1.32-1.74 (16H, m), 1.87 (1H, t, J=10.4Hz), 3.35-3.55 (2H, m), 3.71 (1H, br.s), 3.79 (1H, br.s), 4.36 (1H, br.s), 7.34-7.44 (6H, m), 7.65-7.72 (4H, m)
[reference example 328] methanesulfonic acid ((1R*, 3S*, 4S*) -3- [(tert-butoxycarbonyl) amino] -4- { [tert-butyl group (diphenyl) silicyl] epoxide } cyclohexyl) methyl esters
The compound (29.5g) that reference example 327 is obtained is dissolved in dichloromethane (200ml) and pyridine (20ml), adds mesyl chloride (9.5ml), is stirred 6 hours at room temperature.Solvent is boiled off under decompression, ethyl acetate is added in residue and water carries out a point liquid.Extracted by aqueous layer with ethyl acetate, the organic layer of merging is carried out after 2 washings with water, use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=2: 1) is refined with silica gel column chromatography, obtains title compound (29.8g).
1H-NMR(CDCl3)δ：1.08 (9H, s), 1.38 (9H, s), 1.43-1.61 (5H, m), 1.86-1.89 (2H, m), 3.02 (3H, s), 3.77 (1H, br.s), 3.81 (1H, br.s), 4.10 (2H, d, J=5.4Hz), 4.32 (1H, br.s), 7.35-7.45 (6H, m), 7.64-7.68 (4H, m)
MS(ESI)m/z：562(M+H)+.
[reference example 329] (1R*, 2R*, 5S*) -2- { [tert-butyl group (diphenyl) silicyl] epoxide } -5- (cyano methyl) hexamethylene t-butyl carbamate
Figure G2003801097466D02211
The compound (29.8g) that reference example 328 is obtained is dissolved in DMF (400ml), adds Cymag (3.64g), is stirred 11 hours in 80 DEG C.Ethyl acetate is added in reaction solution and saturated sodium bicarbonate aqueous solution carries out a point liquid.Extracted 2 times by aqueous layer with ethyl acetate, after being washed with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt to the organic layer of merging, use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=5: 1) is refined with silica gel column chromatography, obtains title compound (20.6g).
1H-NMR(CDCl3)δ：1.08 (9H, s), 1.38 (9H, s), 1.43-1.68 (5H, m), 1.79-1.85 (1H, m), 1.88-1.95 (1H, m), 2.32 (2H, d, J=7.1Hz), 3.77 (1H, br.s), 3.82 (1H, br.s), 4.32 (1H, br.d, J=6.8Hz), 7.35-7.45 (6H, m), 7.65-7.71 (4H, m)
[reference example 330] (1R*, 2R*, 5S*) -2- { [tert-butyl group (diphenyl) silicyl] epoxide } -5- (2- oxoethyls) hexamethylene t-butyl carbamate
The compound (2.00g) that reference example 329 is obtained is dissolved in anhydrous methylene chloride (20ml), after being replaced with argon gas, is cooled to -78 DEG C.Diisobutylaluminium hydride (0.95M hexane solutions, 8.55ml) is instilled wherein, is then heated to and is stirred at room temperature 3 hours.Reaction solution is cooled to after 0 DEG C, methanol (10ml) is instilled.The slurry of generation is filtered off with diatomite, filtrate is boiled off under decompression, residue (dichloromethane: methanol=1: 0 → 49: 1) is refined with silica gel column chromatography, obtains title compound (1.45g).
1H-NMR(CDCl3)δ：1.07 (9H, s), 1.38 (9H, s), 1.43-1.54 (5H, m), 1.82-1.88 (1H, m), 2.06 (1H, br.s), 2.42-2.43 (2H, m), 3.72 (1H, br.s), 3.77 (1H, br.s), 4.38 (1H, br.s), 7.34-7.44 (6H, m), 7.65-7.68 (4H, m), 9.77 (1H, t, J=1.7Hz)
MS(FAB)m/z：496(M+H)+.
[reference example 331] 2- ((1R*, 3S*, 4S*) -3- [(tert-butoxycarbonyl) amino] -4- { [tert-butyl group (diphenyl) silicyl] epoxide } cyclohexyl) acetic acid
Figure G2003801097466D02221
The compound (8.40g) that reference example 330 is obtained is dissolved in water (33ml), the in the mixed solvent of the tert-butyl alcohol (120ml), 2- methyl-2-butenes (8.08ml), sodium dihydrogen phosphate dihydrate (2.64g) and sodium chlorite (3.45g) are added, is stirred 1.5 hours at room temperature.Dichloromethane is added in reaction solution and water is diluted, and pH is adjusted to 4 or so by water layer with 1N aqueous hydrochloric acid solution.Water layer after liquid is divided to be extracted 2 times with dichloromethane.Merge organic layer, dried with anhydrous magnesium sulfate, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=2: 1 → 1: 1) is refined with silica gel column chromatography, obtains title compound (7.62g).
1H-NMR(CDCl3)δ：1.07 (9H, s), 1.22-1.63 (15H, m), 1.82 (1H, br.s), 2.17 (1H, br.s), 2.27-2.33 (1H, m), 3.69 (1H, br.s), 3.84 (1H, br.s), 7.00 (1H, br.s), 7.33-7.42 (6H, m), 7.63-7.65 (4H, m) .MS (ESI) m/z：512(M+H)+.
[reference example 332] (1R*, 2R*, 5S*) -2- { [tert-butyl group (diphenyl) silicyl] epoxide } -5- [2- (dimethylamino) -2- oxoethyls] hexamethylene t-butyl carbamate
The compound (7.62g) that reference example 331 is obtained is dissolved in N, dinethylformamide (150ml), dimethylamine hydrochloride (6.07g), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (8.56g), the hydrate of I-hydroxybenzotriazole 1 (1.01g) and triethylamine (10.3ml) are added, is stirred 4 days at room temperature.Solvent is boiled off under decompression, dichloromethane is added in residue and saturated sodium bicarbonate aqueous solution carries out a point liquid.Extracted by water layer with dichloromethane, merge organic layer, be dried with anhydrous sodium sulfate.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=1: 1) is refined with silica gel column chromatography, boils off solvent, add hexane, the white precipitate of leaching generation obtains title compound (6.42g).
1H-NMR(CDCl3)δ：1.08 (9H, s), 1.38 (9H, br.s), 1.43-1.55 (5H, m), 1.79-1.86 (1H, m), 2.03 (1H, br.s), 2.21-2.32 (2H, s), 2.94 (3H, s), 3.03 (3H, s), 3.74 (1H, br.s), 3.80 (1H, br.s), 4.49 (1H, br.s), 7.33-7.44 (6H, m), 7.64-7.69 (4H, m)
MS(ESI)m/z：539(M+H)+.
[reference example 333] (1R*, 2R*, 5S*) -5- [2- (dimethylamino) -2- oxoethyls] -2- hydroxycyclohexan t-butyl carbamates
Figure G2003801097466D02231
The compound (6.36g) that reference example 332 is obtained is dissolved in tetrahydrofuran (50ml), adds tetrabutylammonium (1N tetrahydrofuran solution, 17.85ml), stirs 13 hours at room temperature.Solvent is boiled off under decompression, residue (dichloromethane: methanol=24: 1) is refined with silica gel flash column chromatography, obtains title compound (3.49g).
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.46-1.60 (4H, m), 1.79-1.84 (2H, m), 2.28-2.35 (3H, s), 2.82 (1H, br.s), 2.95 (3H, s), 3.01 (3H, s), 3.56 (2H, br.s), 4.67 (1H, br.s)
MS(ESI)m/z：301(M+H)+.
[reference example 334] methanesulfonic acid (1R*, 2R*, 4S*) -2- [(tert-butoxycarbonyl) amino] -4- [2- (dimethylamino) -2- oxoethyls] cyclohexyl
The compound (8.05mg) that reference example 333 is obtained is dissolved in dichloromethane (50ml), under an argon, is cooled to -78 DEG C, instills mesyl chloride (2.70ml).Be warming up to 0 DEG C stirring 30 minutes after, at room temperature stir 2 hours.Add water progress point liquid in reaction solution, is extracted by water layer with dichloromethane.The organic layer of merging is washed with water, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=1: 1 → 0: 1) is refined with silica gel flash column chromatography, obtains title compound (3.63g).
1H-NMR(CDCl3)δ：1.43 (9H, s), 1.59-1.74 (4H, m), 1.85-2.30 (5H, m), 2.95 (3H, s), 3.00 (3H, s), 3.10 (3H, s), 3.79-3.83 (1H, m), 4.72 (1H, br.s), 4.91 (1H, br.s)
MS(ESI)m/z：379(M+H)+.
[reference example 335] (1R*, 2S*, 5S*) -2- azidos -5- [2- (dimethylamino) -2- oxoethyls] hexamethylene t-butyl carbamate
The compound (3.62g) that reference example 334 is obtained is dissolved in DMF (20ml), adds after sodium azide (3.11g), is stirred 17 hours in 75 DEG C.A point liquid is carried out in the mixed liquor that reaction solution is injected to water and ethyl acetate.Extracted 2 times by aqueous layer with ethyl acetate, the organic layer of merging is washed with water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue is refined with silica gel flash column chromatography (ethyl acetate), obtains title compound (1.30g).
1H-NMR(CDCl3)δ：1.14-1.21 (1H, m), 1.33-1.40 (1H, m), 1.45 (9H, s), 1.61-1.71 (1H, m), 1.78-1.91 (3H, m), 2.22-2.27 (3H, m), 2.94 (3H, s), 3.00 (3H, s), 3.60-3.62 (1H, m), 3.97 (1H, br.s), 4.76 (1H, br.s)
MS(ESI)m/z：326(M+H)+.
[reference example 336] N- { (1R*, 2S*, 4S*) -2- amino -4- [2- (dimethylamino) -2- oxoethyls] cyclohexyl -5- chloro-indole -2- carboxamide hydrochlorides
Figure G2003801097466D02242
Using the method same with reference example 324, make after the compound for catalysis reduction that reference example 335 is obtained, pair product for being condensed and obtaining with 5- chloro-indole -2- carboxylic acids is carried out and the same processing of reference example 69, obtains title compound.
1H-NMR(DMSO-d6)δ：1.16-1.19 (1H, m), 1.51-1.56 (1H, m), 1.70-1.73 (1H, m), 1.81-1.91 (2H, m), 1.99-2.03 (1H, m), 2.19-2.30 (3H, m), 2.83 (3H, s), 2.99 (3H, s), 3.63 (1H, br.s), 4.08 (1H, br.s), 7.19 (1H, dd, J=8.7, 1.7Hz), 7.35 (1H, s), 7.44 (1H, d, J=8.7Hz), 7.69 (1H, d, J=1.7Hz), 8.22 (3H, br.s), 8.62 (1H, d, J=7.1Hz), 11.91 (1H, s) .MS (ESI) m/z：377(M+H)+.
[reference example 337] (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (hydroxymethyl) hexamethylene t-butyl carbamate
Figure G2003801097466D02251
Using 2) the same method with reference example 129, the compound obtained by reference example 97 prepares title compound.
[reference example 338] methanesulfonic acid ((1S, 3R, 4S) -3- [(tert-butoxycarbonyl) amino] -4- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) methyl esters
The compound (500mg) and triethylamine (329ml) that reference example 337 is obtained are dissolved in tetrahydrofuran (8ml)-dichloromethane (8ml), are cooled down in -78 DEG C.Instilled in the solution after mesyl chloride (138ml), liquid temperature is slowly risen under -5 DEG C, equality of temperature and stirred 15 hours.Add water, extracted 3 times with dichloromethane in residue after concentration of reaction solution.Organic layer saturated common salt water washing, after anhydrous sodium sulfate drying, boils off solvent, obtains title compound (654mg) under decompression.
1H-NMR(CDCl3)δ：1.57 (9H, s), 1.84-2.01 (4H, m), 2.28-2.31 (1H, m), 3.04 (3H, s), 3.68 (1H, s), 3.74-3.75 (1H, m), 3.91-3.93 (1H, m), 4.02-4.12 (2H, m), 4.18-4.20 (1H, m), 4.85 (1H, br.s), 6.81 (1H, s), 7.21 (1H, dd, J=2.0,8.8Hz), (7.34 1H, d, J=8.8Hz), 7.60 (1H, s), 8.02 (1H, br.s), 9.27 (1H, br.s)
MS(ESI)m/z：500(M+H)+.
[reference example 339] (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(methyl mercapto) methyl] hexamethylene t-butyl carbamate
Figure G2003801097466D02261
The compound (654mg) that reference example 338 is obtained is dissolved in DMF (8ml), adds 15% sulphur methanol sodium water solution (1.8ml), stirs 4 hours at room temperature.Reaction solution is injected in water, is extracted with ethyl acetate 3 times.Organic layer is concentrated again with after saturated common salt water washing with after anhydrous sodium sulfate drying.Residue (dichloromethane: methanol=24: 1) is refined with silica gel column chromatography, obtains title compound (492mg).
1H-NMR(CDCl3)δ：1.52 (9H, s), 1.87-3.04 (13H, m), 3.91-3.94 (1H, m), 4.12-4.15 (1H, m), 4.95 (1H, br.s), 6.81 (1H, s), 7.19 (1H, dd, J=8.8,1.2Hz), 7.35 (1H, d, J=8.8Hz), 7.57 (1H, s), 9.82 (1H, br.s)
MS(ESI)m/z：452(M+H)+.
[reference example 340] (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(methyl sulphonyl) methyl] hexamethylene t-butyl carbamate
Figure G2003801097466D02262
The compound (300mg) that reference example 339 is obtained is dissolved in dichloromethane (10ml), in the lower addition metachloroperbenzoic acid (70%, 400mg) of 0 DEG C of stirring.After directly stirring 1 hour, reaction solution is injected in water, extracted 3 times with dichloromethane.Organic layer saturated common salt water washing, with anhydrous sodium sulfate drying, decompression is lower to be concentrated.Residue (dichloromethane: methanol=24: 1) is refined, carried out by saturated sodium bicarbonate aqueous solution and ethyl acetate after point liquid, concentration of organic layers obtains title compound (254mg) with silica gel column chromatography.
1H-NMR(CDCl3)δ：1.44-2.19 (13H, m), 2.22-2.30 (2H, m), 2.89-3.25 (7H, m), 3.93-4.15 (2H, m), 4.98 (1H, br.s), 6.82 (1H, s), 7.21 (1H, dd, J=8.8,2.0Hz), 7.34 (1H, d, J=8.8Hz), 7.60 (1H, br.s), 9.54 (1H, br.s)
[reference example 341] (5- chlorothiophene -3- bases) methanol
Figure G2003801097466D02271
By 5- chlorothiophene -3- carboxylic acids (Monatsh.Chem., 1989, volume 120, page 53) (6.93g) be dissolved in tetrahydrofuran (750ml), triethylamine (27.3ml), ethyl chloroformate (18.7ml) are added, is stirred 2 and a half hours at room temperature.Then, with the aqueous solution (41ml) for instilling sodium borohydride (19.3g) for 10 minutes, stir 18.5 hours at room temperature.After addition acetic acid makes it in acidity in reaction solution, solvent is boiled off under decompression.After addition water and dichloromethane are separated in residue, organic layer is washed with water and saturated sodium bicarbonate aqueous solution.After being dried with anhydrous magnesium sulfate, solvent is boiled off under decompression, residue (ethyl acetate: hexane=1: 4) is refined with silica gel flash column chromatography, obtains title compound (5.17g).
1H-NMR(CDCl3)δ：1.63 (1H, t, J=5.8Hz), 4.59 (2H, d, J=5.3Hz), 6.91 (1H, d, J=1.7Hz), 6.98-6.99 (1H, m)
[reference example 342] 5- chlorothiophene -3- formaldehyde
Figure G2003801097466D02272
The compound (5.17g) that reference example 341 is obtained is dissolved in dichloromethane, and (400mD, adds manganese dioxide (51.3g), stirs 15 hours at room temperature.After filtering reacting liquid, solvent is boiled off under decompression, title compound (2.84g) is obtained.
1H-NMR(CDCl3)δ：7.35 (1H, d, J=1.7Hz), 7.88 (1H, d, J=1.7Hz), 9.75 (1H, s)
[reference example 343] 2- azidos -3- (5- chlorothiophene -3- bases) ethyl acrylate
Figure G2003801097466D02273
Ethanol (15ml) is added in the ethanol solution (10.7ml) of 20% caustic alcohol, after 0 DEG C cools down, the compound (1.01g) of the acquisition of reference example 342 and the mixture of ethyl triazoacetate (3.55g) were instilled in 30 minutes, is stirred 3 hours in 0 DEG C.Cold aqueous ammonium chloride solution is added in reaction solution, is extracted 3 times with ether.Merge organic layer, solvent is boiled off under decompression.Residue (ethyl acetate: hexane=1: 49) is refined with silica gel flash column chromatography, obtains title compound (1.04g).
1H-NMR(CDCl3)δ：1.38 (3H, t, J=7.1Hz), 4.34 (2H, q, J=7.1Hz), 6.75 (1H, s), 7.39 (1H, d, J=1.7Hz), 7.54 (1H, d, J=1.7Hz)
Chloro- 6H- thienos [2, the 3-b] pyrroles's -5- carboxylic acid, ethyl esters of [reference example 344] 2-
Figure G2003801097466D02281
The compound (0.97g) that reference example 343 is obtained is dissolved in dimethylbenzene (20ml), is heated to reflux 30 minutes.Solvent is boiled off under being depressurized after letting cool.Hexane is added in residue, the solid of leaching generation obtains title compound (0.608g).
1H-NMR(CDCl3)δ：(1.38 3H, t, J=7.0Hz), 4.35 (2H, q, J=7.0Hz), 6.90 (1H, s), 7.00 (1H, d, J=1.9Hz), 9.32 (1H, br)
Chloro- 6H- thienos [2, the 3-b] pyrroles's -5- carboxylic acids of [reference example 345] 2-
Using the method same with reference example 274, the compound obtained by reference example 344 prepares title compound.
1H-NMR(CD3OD)δ：3.35 (1H, s), 6.94 (1H, s), 6.96 (1H, s)
MS(ESI)m/z：200(M-H)-.
[reference example 346] 1- chloro- 4- (2,2- dibromo vinyl) benzene
4- chlorobenzaldehydes (2.81g) are dissolved in dichloromethane (300ml), carbon tetrabromide (13.3g) and triphenyl phasphine (21.0g) is added, stirred 90 minutes at room temperature.Filter off after the insoluble matter separated out, the lower concentration filtrate of decompression.Residue (hexane: ethyl acetate=20: 1) is refined with silica gel column chromatography, obtains title compound (5.54g).
1H-NMR(CDCl3)δ：7.33 (2H, d, J=8.5Hz), 7.43 (1H, s), 7.47 (2H, d, J=8.5Hz)
MS(EI)m/z：296(M+).
[reference example 347] 3- (4- chlorphenyls) -2- propiolic acids
The compound (1.0g) that reference example 346 is obtained is dissolved in tetrahydrofuran (30ml), under argon gas stream, and n-BuLi (1.59N hexane solution, 4.46ml) is instilled in -78 DEG C.Reaction solution is warming up to after room temperature and stirred 1 hour.Reaction solution is again cooled to -78 DEG C, after being stirred 2 minutes under carbon dioxide gas stream, room temperature is warming up to.After the lower concentration of reaction solution of decompression, saturated aqueous common salt is added in residue and ethyl acetate carries out a point liquid.3N hydrochloric acid is added in water layer, makes it in acidity, is extracted with ethyl acetate, organic layer anhydrous sodium sulfate drying.Decompression is lower to be concentrated, and obtains title compound (453mg).
1H-NMR(DMSO-d6)δ：(1H, the br.s) of 7.55 (2H, d, J=8.5Hz), 7.66 (2H, d, J=8.5Hz), 13.90
MS(EI)m/z：180(M+).
The chloro- 4- oxos-Isosorbide-5-Nitrae-dihydroquinazoline -2- carboxylic acid, ethyl esters of [reference example 348] 6-
Figure G2003801097466D02291
Chlorine ethyl (2.0ml) is added in 2-Amino-5-chlorobenzamide (2.50g) pyridine (15ml) solution, is stirred 18 hours at room temperature.The lower concentration of reaction solution of decompression, is dissolved in acetic acid (50ml) by residue obtained, adds acetic anhydride (5.0ml) and be heated to reflux 16 hours.Solvent is boiled off under decompression, ethanol is added in residue, the crystallization that leaching is separated out, washing obtains title compound (2.71g).
1H-NMR(DMSO-d6)δ：1.35 (3H, t, J=7.1Hz), 4.38 (2H, q, J=7.1Hz), 7.85 (1H, d, J=8.6Hz), 7.91 (1H, dd, J=8.6,2.3Hz), 8.10 (1H, d, J=2.3Hz), 12.85 (1H, br.s)
MS(ESI)m/z：253(M+H)+.
The chloro- 4- oxos-Isosorbide-5-Nitrae-dihydroquinazoline -2- carboxylic acids of [reference example 349] 6-
Lithium hydroxide (263mg) is added in the mixed solution of water (the 5ml)-tetrahydrofuran (15ml) for the compound (1.26g) that reference example 348 is obtained, is stirred 18 hours at room temperature.Under ice-cooling, with 1N hydrochloric acid (11ml) neutralization reaction liquid, stir 1 hour.The crystallization that leaching is separated out, obtains title compound (0.96g) after washing.
1H-NMR(DMSO-d6)δ：7.50-8.20 (3H, m), 12.44 (1H, br.s)
MS(ESI)m/z：265(M+H+CH3CN)+.
[reference example 350] 2- chloro- N- (4- chlorphenyls) acetamide
Parachloroanilinum (3.82g) is dissolved in ethyl acetate (30ml), chloracetyl chloride (2.39ml) is added at room temperature, is stirred 1 hour.In 60 DEG C to reaction solution heating stirring 3.5 hours after, leaching separate out crystallization, obtain title compound (4.78g).Then, about 1/4 is concentrated the filtrate to, the crystallization that leaching is separated out obtains title compound (1.01g).
1H-NMR(CDCl3)δ：4.19 (2H, s), 7.33 (2H, d, J=9.0Hz), 7.51 (2H, d, J=9.0Hz), 8.22 (1H, br.s)
[reference example 351] S- [2- (4- chloroanilinos) -2- oxoethyls] thiosulfuric acid sodium salt
The compound (5.79g) that reference example 350 is obtained is dissolved in ethanol (140ml), adds the aqueous solution (140ml) of the hydrate of sodium thiosulfate 5 (7.04g) next time in 70 DEG C of stirrings, is heated to reflux 1.5 hours.After reaction solution is concentrated into about 1/10, the powder that leaching is separated out obtains title compound (8.20g).
1H-NMR(DMSO-d6)δ：3.73 (2H, s), 7.35 (2H, d, J=8.8Hz), 7.57 (2H, d, J=8.8Hz), 10.30 (1H, s)
The chloro- N- of [reference example 352] 2- (5- chloropyridine -2- bases) acetamide hydrochloride
2- amino -5- chloropyridines (3.85g) are dissolved in ethyl acetate (60ml), chloracetyl chloride (2.39ml) is added at room temperature and is stirred 1 hour.In 60 DEG C to reaction solution heating stirring 30 minutes after, additional chloracetyl chloride (0.5ml) is stirred 1 hour then at 60 DEG C.The powder that leaching is separated out, obtains title compound (6.18g).
1H-NMR(DMSO-d6)δ：4.36 (2H, s), 7.94 (1H, dd, J=8.8,2.7Hz), 8.09 (1H, d, J=8.8Hz), 8.40 (1H, d, J=2.7Hz), 11.03 (1H, s)
[reference example 353] S- { 2- [(5- chloropyridine -2- bases) amino] -2- oxoethyls } thiosulfuric acid sodium salt
Under 80 DEG C are stirred, the compound (6.18g) obtained in reference example 352 is dissolved in solution formed by ethanol (130ml), the aqueous solution (130ml) for having dissolved the hydrate of sodium thiosulfate 5 (6.35g) and sodium acid carbonate (2.15g) is once added, is heated to reflux 2 hours at outer 110 DEG C of temperature.Solid, the addition ethanol (500ml) in residue, heating, extraction 2 times are concentrated under decompression.Extract is concentrated into about 1/20, ether is added, the insoluble matter that leaching is separated out obtains title compound (6.65g).
1H-NMR(DMSO-d6)δ：3.77 (2H, s), 7.89 (1H, dd, J=9.0,2.7Hz), 8.09 (1H, d, J=9.0Hz), 8.34 (1H, d, J=2.7Hz), 10.57 (1H, s)
[reference example 354] N- { (1R, 2S, 5S) -2- [(2- chloracetyls) amino] -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (100mg) that reference example 253 is obtained was dissolved in ethyl acetate (10ml), adds chloracetyl chloride (21.6 μ l), in 60 DEG C of heating stirrings 30 minutes.Rear leaching insoluble matter is let cool, is dissolved in after methylene chloride-methanol, solvent is boiled off under decompression, rough title compound (112mg) is obtained.
1H-NMR(DMSO-d6)δ：1.35-1.50 (1H, m), 1.55-2.00 (5H, m), 2.78 (3H, s), 2.98 (3H, s), 3.00-3.25 (5H, m), 3.17 (3H, s), 3.80-3.90 (1H, m), 3.96 (1H, d, J=12.9Hz), 4.00-4.15 (1H, m), 4.02 (1H, d, J=12.9Hz), 4.45-4,70 (2H, m), 7.85-8.00 (1H, br), 8.12 (1H, d, J=7.3Hz), 8.35 (1H, d, J=8.3Hz)
MS(ESI)m/z：442(M+H)+.
[reference example 355] S- { 2- [((1R, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) amino] -2- oxoethyls } thiosulfuric acid sodium salt
The compound (106mg) that reference example 354 is obtained is dissolved in ethanol (1.5ml), add the aqueous solution (1.5ml) for having dissolved the hydrate of sodium thiosulfate 5 (55mg) and sodium acid carbonate (18.6mg) next time in 90 DEG C of stirrings, be heated to reflux 1 hour.Be concentrated under decompression it is solid, in residue add ethanol (10ml), extracted during heating.Extract is concentrated into about 1/2, isopropyl ether (10ml) is added, the insoluble matter that leaching is separated out obtains title compound (72mg).
1H-NMR(DMSO-d6)δ：1.35-1.50 (1H, m), 1.55-1.90 (5H, m), 2.40 (3H, s), 2.78 (3H, s), 2.80-3.10 (5H, m), 2.96 (3H, s), (3.44 1H, d, J=14.2Hz), (3.50 1H, d, J=14.2Hz), 3.68 (2H, s), 3.75-3.90 (1H, m), 4.45-4.50 (1H, m), (8.01 1H, d, J=7.4Hz), 8.15 (1H, d, J=8.3Hz)
[reference example 356] 2- [(5- chlorothiophene -2- bases) amino] -2- oxoacetic acid methyl esters
Figure G2003801097466D02321
Triethylamine (1.25ml) and diphenylphosphoryl azide (1.55ml) are added in toluene (20ml) suspension of 5- chlorothiophene -2- carboxylic acids (0.99g), is stirred 1 hour in 80 DEG C.Reaction solution, which is cooled to after room temperature, adds the tert-butyl alcohol (2ml), is heated to reflux 19 hours.The lower concentration of reaction solution of decompression, in residue obtained middle addition dichloromethane (200ml), after being washed successively with distilled water, 10% aqueous citric acid solution, distilled water, saturated sodium bicarbonate aqueous solution, saturated aqueous common salt, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=4: 1) is refined with silica gel column chromatography, obtains the chloro- 2- thiophene carbamates (1.05g) of 5-.
1H-NMR(CDCl3)δ：1.51 (9H, s), 6.21 (1H, d, J=3.1Hz), 6.60 (1H, d, J=3.1Hz), 6.91 (1H, br.s)
MS(ESI)m/z：234(M+H)+.
In the Yan Suan dioxane solutions (40ml) that above-mentioned product (1.87g) is added to 4N, after stirring 4 hours at room temperature, solvent is boiled off under decompression.Residue is suspended in tetrahydrofuran (50ml), sodium acid carbonate (2.02g) and chlorine oxoacetic acid methyl ester (0.883ml) are added under ice-cooling, is stirred 18 hours at room temperature.Solvent is boiled off under decompression, water is added in residue and dichloromethane is carried out after point liquid, organic layer saturated common salt water washing, after anhydrous sodium sulfate drying, decompression is lower to be concentrated.Residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography, boils off solvent, obtain title compound (1.44g).
1H-NMR(CDCl3)δ：3.98 (3H, s), 6.61 (1H, d, J=4.2Hz), 6.75 (1H, d, J=4.2Hz), 9.42 (1H, br.s)
MS(FAB)m/z：220(M+H)+.
[reference example 357] 2- [(5- fluorine pyridine -2- bases) amino] -2- oxoacetic acid methyl esters
Using the method same with the method that reference example 242 is recorded, title compound is obtained by 2- amino-5-fluorines pyridine and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.99 (3H, s), 7.48-7.53 (1H, m), 8.21 (1H, d, J=2.9Hz), 8.27-8.31 (1H, m), 9.41 (1H, br.s)
MS(FAB)m/z：198(M+H)+.
[reference example 358] 2- [4- chloro- 2- (trifluoromethyl) anilino-] -2- oxoacetic acid methyl esters
Using the method same with the method that reference example 242 is recorded, title compound is obtained by the chloro- 2- trifluoromethyl anilines of 4- and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：4.01 (3H, s), 7.58 (1H, dd, J=8.8,2.2Hz), 7.65 (1H, d, J=2.2Hz), 8.34 (1H, d, J=8.8Hz), 9.30 (1H, br.s)
MS(EI)m/z：281(M+H)+.
[reference example 359] 2- [4- chloro- 2- (trifluoromethyl) anilino-] -2- Oxoacetic Acids
Lithium hydroxide (28mg) is added in the mixed solution of tetrahydrofuran (the 7ml)-water (3ml) for the compound (297mg) that reference example 358 is obtained, is stirred 2 hours at room temperature.1N hydrochloric acid (8ml) and dichloromethane (20ml) is added in reaction dissolvent, a point liquid operation is carried out.After gained organic layer anhydrous sodium sulfate drying, dry solvent is boiled off under decompression, title compound (291mg) is obtained.
1H-NMR(CDCl3)δ：(1H, the br.s) of 7.61 (1H, dd, J=8.8,2.5Hz), 7.68 (1H, d, J=2.5Hz), 8.26 (1H, d, J=8.8Hz), 9.36
MS (ESI, anion) m/z：267(M-H)-.
[reference example 360] 5- chloro- N, N- dimethyl -2- nitrobenzamides
Figure G2003801097466D02333
Using the method same with reference example 143, the condensation of the chloro- 2- nitrobenzoic acids of 5- and dimethylamine is carried out, title compound is obtained.
1H-NMR(CDCl3)δ：2.86 (3H, s), 3.16 (3H, s), 7.38 (1H, d, J=2.2Hz), 7.51 (1H, dd, J=8.8,2.2Hz), 8.15 (1H, d, J=8.8Hz)
[reference example 361] chloro- N of 2- amino -5-, N- dimethyl benzamides
The N of the compound (2.8g) obtained in reference example 360, the hydrate of ferric trichloride 6 (9.93g) and zinc powder (8.01g) are added in dinethylformamide (80ml)-water (40ml) mixed solution, is heated to reflux 20 minutes.Reaction solution diatomite 545 is filtered, and ethyl acetate (200ml) is added in filtrate and carries out a point liquid operation.Aqueous layer with ethyl acetate (100ml × 2) is washed, and the organic layer merged is washed with distilled water (100ml), anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, gained residue (dichloromethane: hexane=1: 1 → 1: 0 → methanol: dichloromethane=1: 100) is refined with silica gel column chromatography, obtains title compound (2.41g).
1H-NMR(CDCl3)δ：3.13 (6H, s), 4.33 (2H, br), 6.65 (1H, d, J=8.5Hz), 7.07 (1H, d, J=2.2Hz), 7.11 (1H, dd, J=8.5,2.2Hz)
MS(ESI)m/z：240(M+MeCN)+.
[reference example 362] 2- { the chloro- 2- of 4- [(dimethylamino) carbonyl] anilino- } -2- oxoacetic acid methyl esters
Using the method same with reference example 242, the compound obtained by reference example 361 and chlorine oxoacetic acid methyl ester obtain title compound.
1H-NMR(CDCl3)δ：3.09 (6H, br), 3.96 (3H, s), 7.30 (1H, d, J=2.4Hz), 7.41 (1H, d, J=8.8,2.4Hz), 8.34 (1H, d, J=8.8Hz), 10.46 (1H, br)
MS(ESI)m/z：285(M+H)+.
The chloro- 2- aminoanisoles of [reference example 363] 4-
Figure G2003801097466D02343
Using the method same with reference example 361, title compound is obtained by the chloro- 2- Nitroanisoles of 5-.
1H-NMR(CDCl3)δ：3.65-3.95 (2H, br), 3.87 (3H, s), 6.61 (1H, d, J=8.8Hz), 6.74-6.78 (2H, m)
MS(ESI)m/z：199(M+MeCN+H)+.
[reference example 364] 2- (the chloro- 2- methoxybenzenes amidos of 4-) -2- oxoacetic acid methyl esters
Figure G2003801097466D02351
Using the method same with reference example 242, the compound obtained by reference example 363 and chlorine oxoacetic acid methyl ester obtain title compound.
1H-NMR(CDCl3)δ：3.92 (3H, s), 3.97 (3H, s), 6.90 (1H, d, J=2.2Hz), 6.98 (1H, dd, J=8.8,2.2Hz), 8.35 (1H, d, J=8.8Hz), 9.33-9.44 (1H, br)
MS(ESI)m/z：244(M+H)+.
[reference example 365] 2- (4- chloroanilinos) -2- (oxyimino) ethyl acetate
Figure G2003801097466D02352
Using with document (Cilchrist, T.L.；Peek, M.E.；Rees, C.W.；J.Chem.Soc.Chem.Commun., 1975,913.) the same method of the method for record, title compound is prepared by 4- chloroanilines (3.03g) and 2- chlorine-2-hydroxyl ethyl acetimidates.
1H-NMR(CDCl3)δ：1.26 (3H, t, J=7.1Hz), 1.60-1.80 (1H, br), 4.28 (2H, q, J=7.1Hz), 6.85 (2H, d, J=8.6Hz), 7.24 (2H, d, J=8.6Hz), 8.15-8.45 (1H, br)
MS(ESDm/z：243(M+H)+.
[reference example 366] (1R, 2S, 5S) -2- { [2- (4- chloroanilinos) -2- (oxyimino) acetyl group] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02361
The compound (597mg) that reference example 144 is obtained is added in ethanol (5.0ml) solution for the compound (350mg) that reference example 365 is obtained, is stirred 3 days in 70 DEG C.It is concentrated under reduced pressure after reaction solution, residue (dichloromethane: methanol=30: 1) is refined with silica gel column chromatography, obtains title compound (180mg).
1H-NMR(CD3OD)δ：1.46 (9H, s), 1.47-1.84 (6H, m), 1.88-1.95 (1H, m), 2.90 (3H, s), 3.08 (3H, s), 3.90-3.97 (1H, m), 4.11-4.17 (1H, m), (6.84 2H, d, J=8.8Hz), 7.18 (2H, d, J=8.8Hz)
MS(ESI)m/z：504(M+Na)+.
[reference example 367] (3R, 4S) -4- { [2- (4- chloroanilinos) -2- oxoacetyls] amino } -1- (2- Methoxyacetyls) piperidines -3- carbamates
The compound that the compound and reference example 220 obtained by reference example 374 is obtained, title compound is prepared in the method same with reference example 214.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.55-1.75 (1H, br), 1.94-2.07 (1H, br), 2.70-3.00 (1H, m), 3.10-3.37 (1H, m), 3.44 (3H, s), 3.88-4.22 (4H, m), 4.55-4.69 (1H, br), 4.80-4.90 (0.5H, br), 5.36-5.48 (0.5H, br), 7.20-7.30 (1H, br), 7.32 (2H, d, J=8.8Hz), 7.62 (2H, d, J=8.8Hz), 8.20-8.40 (1H, br), 9.15-9.25 (1H, br)
MS(ESI)m/z：469(M+H)+.
[reference example 368] (3R, 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -1- (2- Methoxyacetyls) piperidines -3- carbamates
Figure G2003801097466D02371
Using the method same with reference example 214, the compound that the compound obtained by reference example 266 and reference example 220 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.65-2.30 (2H, br), 2.68-3.02 (1H, m), 3.10-3.35 (1H, m), 3.44 (3H, s), 3.80-4.25 (4H, m), 4.45-4.70 (1H, m), 5.05-5.20 (0.5H, m), 5.80-5.93 (0.5H, m), 7.30-7.40 (1H, br), 7.71 (1H, brd, J=8.7Hz), 7.95-8.05 (0.3H, br), 8.19 (1H, br d, J=8.8Hz), 8.31 (1H, br.s), 8.38-8.53 (0.7H, br), 9.74-9.84 (1H, br)
MS(ESI)m/z：470(M+H)+.
[reference example 369] (3R, 4S) -4- ({ 2- [(5- bromopyridine -2- bases) amino] -2- oxoacetyls } amino) -1- (2- Methoxyacetyls) piperidines -3- carbamates
Figure G2003801097466D02372
Using the method same with reference example 214, the compound that the compound obtained by reference example 375 and reference example 220 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.50-1.75 (1H, m), 1.95-2.13 (1H, br), 2.70-2.98 (1H, m), 3.05-3.36 (1H, m), 3.45 (3H, s), 3.80-4.24 (4H, m), 4.57-4.73 (1H, br), 4.85-4.95 (0.25H, br), 5.10-5.15 (0.25H, br), 5.45-5.58 (0.5H, br), 7.30-7.38 (1H, m), 7.84 (1H, dd, J=8.8, 2.2Hz), 8.16 (1H, d, J=8.8Hz), 8.30-8.55 (1H, br), 8.40 (1H, d, J=2.2Hz), 9.68 (1H, br.s)
[reference example 370] 3- (4- chloroanilinos) -3- oxopropanoates
Figure G2003801097466D02381
At room temperature, successively in 4- chloroanilines (2.0g) N, malonic ester sylvite (3.2g), I-hydroxybenzotriazole (2.1g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (4.5g) are added in dinethylformamide (20ml) solution, is stirred 2 hours at room temperature.Ethyl acetate dilute reaction solution is used, with saturated sodium bicarbonate aqueous solution, 10% aqueous citric acid solution and saturated common salt water washing.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression, title compound (4.0g) is obtained.
1H-NMR(CDCl3)δ：(1.33 3H, t, J=7.3Hz), 3.47 (2H, s), 4.26 (2H, q, J=7.3Hz), 7.29 (2H, d, J=8.8Hz), 7.51 (2H, d, J=8.8Hz), 9.32 (1H, br.s)
[reference example 371] 3- (4- chloroanilinos) -3- oxopropanoic acids
Figure G2003801097466D02382
At room temperature, the sodium hydrate aqueous solution (10ml) that 1N is instilled in ethanol (10ml) solution for the compound (1.0g) that reference example 370 is obtained is stirred 2 hours.1N aqueous hydrochloric acid solution (10ml) is added in reaction solution, the insoluble matter that leaching is separated out after stirring obtains title compound (0.5g).
1H-NMR(DMSO-d6)δ：3.34 (2H, s), 7.35 (2H, d, J=8.8Hz), 7.59 (2H, d, J=8.8Hz), 10.26 (1H, s), 12.66 (1H, br.s)
[reference example 372] 3- (3- chloroanilinos) -3- oxopropanoates
Using the method same with reference example 370, title compound is obtained by the condensation of 3- chloroanilines and malonic ester sylvite.
1H-NMR(CDCl3)δ：1.33 (3H, t, J=7.3Hz), 3.47 (2H, s), 4.26 (2H, q, J=7.3Hz), 7.09 (1H, d, J=8.8Hz), 7.22-7.26 (1H, m), 7.39 (1H, d, J=8.8Hz), 7.69 (1H, s), 9.35 (1H, br.s)
[reference example 373] 3- (3- chloroanilinos) -3- oxopropanoic acids
Using the method same with reference example 371, by preparing title compound with reference to 372 compounds obtained.
1H-NMR(DMSO-d6)δ：3.35 (2H, s), 7.11 (1H, d, J=8.8Hz), 7.33 (1H, t, J=8.8Hz), 7.39 (1H, d, J=8.8Hz), 7.78 (1H, s), 10.31 (1H, s), 12.67 (1H, br.s)
[reference example 374] 2- (4- chloroanilinos) -2- Oxoacetic Acids
Using the method same with reference example 359, the compound obtained by reference example 242 prepares title compound.
1H-NMR(DMSO-d6)δ：7.37 (2H, d, J=8.8Hz), 7.79 (2H, d, J=8.8Hz), 10.66 (1H, s)
[reference example 375] 2- [(5- bromopyridine -2- bases) amino] -2- Oxoacetic Acids
Figure G2003801097466D02393
Using the method same with reference example 359, the compound obtained by reference example 262 prepares title compound.
1H-NMR(DMSO-d6)δ：7.95-8.00 (1H, m), 8.08 (1H, dd, J=8.8,2.0Hz), 8.50 (1H, d, J=2.0Hz), 10.74 (1H, s)
The chloro- 3- fluobenzoic acids of [reference example 376] 4-
Figure G2003801097466D02401
Under ice cooling, it is a small amount of every time in the mixed solution of the chloro- 3- fluorobenzaldehydes (10g) of 4-, sulfamic acid (18g), the tert-butyl alcohol (50ml) and water (50ml) formation to add sodium chlorite (17g), it is slowly ramped to stir 4 days while room temperature.Reaction solution is diluted with ethyl acetate, with water, 1N aqueous hydrochloric acid solution and saturated common salt water washing.Boiled off under organic layer anhydrous sodium sulfate drying, decompression after solvent, the mixed solvent recrystallization of residue obtained use diisopropyl ether and hexane formation obtains title compound (11.2g).
1H-NMR(DMSO-d6)δ：7.72 (1H, dt, J=8.3,1.5Hz), 7.77 (1H, dt, J=8.3,1.6Hz), 7.82 (1H, dt, J=9.7,1.5Hz), 13.45 (1H, s)
[reference example 377] 2- (the chloro- 3- fluoroanilinos of 4-) -2- oxoacetic acid methyl esters
Using the method same with reference example 356, the compound that reference example 376 is obtained is carried out after Ku Ertisi rearrangement reactions, title compound is obtained by the condensation with chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.99 (3H, s), 7.25-7.27 (1H, m), 7.39 (1H, t, J=8.5Hz), 7.72 (1H, dd, J=10.4,2.4Hz), 8.90 (1H, br.s)
[reference example 378] 2- (the chloro- 3- fluoroanilinos of 4-) -2- Oxoacetic Acids
Using the method same with reference example 359, the compound obtained by reference example 377 prepares title compound.
1H-NMR(DMSO-d6)δ：(1H, the br.s) of 7.52 (1H, t, J=8.8Hz), 7.63 (1H, dd, J=8.8,2.2Hz), 7.88 (1H, dd, J=12.0,2.2Hz), 10.83
[reference example 379] 3- (4- chlorphenyls) -3- oxopropanoates
Under ice cooling, triethylamine (17ml) and magnesium chloride (5.5g) are added in malonic ester sylvite (8.2g) ethyl acetate (100ml) suspension, is slowly ramped to stir 18 hours while room temperature.In addition, 4- chlorobenzoic acids (5.0g), thionyl chloride (12ml), DMF (1 drop) and the suspension of toluene (100ml) formation is heated to reflux after 1 hour, concentration of reaction solution.Ethyl acetate is dissolved in by residue obtained, is added dropwise under ice-cooling in above-mentioned reaction solution, is slowly ramped to stir 18 hours while room temperature.10% aqueous citric acid solution is added in reaction solution, stirring divides after 30 minutes takes organic layer, and gained organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression with after saturated common salt water washing.Residue obtained use silica gel column chromatography (chloroform) separation, refines, obtains title compound (6.4g).
1H-NMR(CDCl3)δ：1.26 (3H, t, J=7.3Hz), 3.96 (2H, s), 4.21 (2H, q, J=7.3Hz), 7.46 (2H, d, J=8.8Hz), 7.89 (2H, d, J=8.8Hz)
[reference example 380] 3- (4- chlorphenyls) -3- hydroxypropionates
Figure G2003801097466D02412
Under ice cooling, sodium borohydride (0.2g) is marginally added every time in tetrahydrofuran (10ml) solution for the compound (1.0g) that reference example 379 is obtained, be slowly ramped to stir 2 hours while room temperature.10% aqueous citric acid solution is added in reaction solution, is extracted with ethyl acetate.Organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression with after saturated common salt water washing.Residue obtained use silica gel column chromatography (chloroform) separation and purification, obtains title compound (0.56g).
1H-NMR(CDCl3)δ：1.27 (3H, t, J=7.3Hz), 2.70 (1H, d, J=7.8Hz), 2.71 (1H, d, J=3.4Hz), 3.37 (1H, d, J=3.4Hz), 4.18 (2H, q, J=7.3Hz), 5.09-5.13 (1H, m), 7.30-7.35 (5H, m)
[reference example 381] 3- (4- chlorphenyls) -3- hydracrylic acids
Using the method same with reference example 359, the compound obtained by reference example 380 prepares title compound.
1H-NMR(DMSO-d6)δ：3.25-3.32 (1H, m), 4.89-4.95 (1H, m), 5.45-5.53 (1H, m), 7.35-7.36 (5H, m), 12.11-12.18 (1H, m)
MS (ESI, anion) m/z：198(M-H)-.
[reference example 382] (1R, 2S, 5S) -2- { [3- (4- chlorphenyls) -3- hydroxypropanoyls] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02421
Using the method same with reference example 91, the condensation for the compound that the compound obtained by reference to example 144 and reference example 381 are obtained obtains title compound.
1H-NMR(CDCl3)δ：1.21-1.44 (2H, m), 1.46 (9H, s), 1.76-1.92 (2H, m), 1.95-2.10 (2H, m), 2.40-2.55 (2H, m), 2.55-2.68 (1H, m), 2.94 (3H, s), 3.05 (3H, s), 3.82-3.96 (1H, m), 4.02-4.17 (1H, m), 4.65-4.80 (2H, m), 5.03-5.13 (1H, m), 7.28-7.33 (5H, m)
MS(ESI)m/z：468(M+H)+.
[reference example 383] (1R, 2S, 5S) -2- { [3- (4- chlorphenyls) -3- oxos propiono] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
At room temperature, manganese dioxide (0.47g) is added in the dioxane of Isosorbide-5-Nitrae-(20ml) solution for the compound (0.5g) that reference example 382 is obtained, is stirred 4 days.Insoluble matter is filtered off by Celite pad, the lower concentration gained filtrate of decompression obtains title compound (0.46g).
1H-NMR(DMSO-d6)δ：1.28-1.39 (1H, m), 1.40 (9H, s), 1.41-1.63 (3H, m), 2.25-2.42 (2H, m), 2.76 (3H, s), 2.90-2.97 (1H, m), 2.98 (3H, s), 3.56 (2H, s), 3.89-3.97 (1H, m), 4.88-4.98 (1H, m), 6.65-6.70 (1H, m), 7.30-7.35 (4H, m), 7.33 (1H, dd, J=2.9,1.7Hz)
MS (ESI, anion) m/z：464(M-H)-.
[reference example 384] (1R, 3R, 4R) -4- azidos -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
Using the method same with reference example 249, the compound obtained by reference example 248 prepares title compound.
[α]25 D+ 62 ° (c=1, chloroform)
1H-NMR(CDCl3)δ：1.27 (3H, t, J=7.1Hz), 1.46 (9H, s), 1.61 (1H, s), 1.61-1.71 (2H, m), 1.81-1.90 (1H, m), 1.97-2.03 (1H, m), 2.22-2.28 (1H, m), 2.56-2.60 (1H, m), 3.54 (1H, br.s), 3.63-3.68 (1H, m), 4.16 (2H, q, J=7.1Hz), 4.58 (1H, br.s)
[reference example 385] (1R, 2R, 5S) -2- azidos -5- [(dimethylamino) carbonyl] hexamethylene t-butyl carbamate
Figure G2003801097466D02432
Using with reference example 250 and the same method of reference example 251, the compound obtained by reference example 384 prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.40-2.20 (6H, m), 2.70-2.80 (1H, m), 2.93 (3H, s), 3.03 (3H, s), 3.60-3.78 (1H, m), 3.83-3.95 (1H, m), 4.65 (1H, d, J=7.2Hz)
[reference example 386] (1R, 2R, 5S) -2- (2- [(5- chloropyridine -2- bases) -2- oxoacetyls } amino) -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 90, the azido for the compound that reference example 385 is obtained is changed into after amino, using the method same with reference example 91, by the condensation of the compound obtained with reference example 266, prepares title compound.
1H-NMR(CDCl3)δ：1.13-2.25 (16H, m), 2.94 (3H, s), 3.03 (3H, s), 3.60-3.78 (1H, m), 4.13-4.31 (1H, m), 4.45-4.65 (1H, m), 7.80 (1H, dd, J=8.8,2.4Hz), 8.03 (1H, br.s), 8.21 (1H, d, J=8.8Hz), 8.29 (1H, d, J=2.4Hz), 9.71 (1H, s)
MS(ESI)m/z：468(M+H)+.
[reference example 387] N- { (1R, 2R, 5S) -2- azidos -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Using the method same with reference example 252, the compound that the compound obtained by reference example 385 and reference example 10 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.75-2.08 (6H, m), 2.20-2.32 (1H, m), 2.51 (3H, s), 2.75-2.97 (4H, m), 2.95 (3H, s), 3.04 (3H, s), 3.65-3.80 (3H, m), 4.27-4.39 (1H, m), 7.17-7.28 (1H, m)
MS(ESI)m/z：392(M+H)+.
[reference example 388] 4- [(2- methoxyl group -2- oxoacetyls) amino] piperidines -1- carboxylic acid tert-butyl esters
Using the method same with reference example 242, title compound is obtained by (4- amino-N-Bocs) piperidines and chlorine oxoacetic acid methyl ester.
1H-NMR(DMSO-d6)δ：1.46 (9H, s), 1.34-1.51 (2H, m), 1.89-1.98 (2H, m), 2.82-2.96 (2H, m), 3.91 (3H, s), 3.88-4.14 (3H, m), 6.96-7.07 (1H, m)
MS(FAB)m/z：287(M+H)+.
[reference example 389] 4- { [2- ({ (1R; 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } amino) -2- oxoacetyls] amino } piperidines -1- carboxylic acid tert-butyl esters
Figure G2003801097466D02452
Using the method same with reference example 191, the compound that the compound obtained by reference example 310 and reference example 388 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.46 (9H, s), 1.35-2.28 (11H, m), 2.70-3.18 (9H, m), 3.80-4.57 (4H, m), 6.78 (1H, s), 7.15-8.12 (6H, m), 9.45 (1H, s)
MS(FAB)m/z：617(M+H)+.
[reference example 390] 2- [(5- chloropyridine -2- bases) (methyl) amino] -2- oxoacetic acid methyl esters
Figure G2003801097466D02453
Using the method same with reference example 242, title compound is prepared by 5- chloro-n-methyls -2- pyridines amine and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.43 (3H, s), 3.81 (3H, s), 7.08 (1H, br.s), 7.68-7.78 (1H, m), 8.27 (1H, br.s)
MS(ESI)m/z：229(M+H)+.
[reference example 391] 2- [(the chloro- pyrimidine -2-bases of 5-) amino] -2- oxoacetic acid methyl esters
Figure G2003801097466D02461
Using the method same with reference example 242, title compound is prepared by 2- amino -5- chlorine pyrimidine and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：4.00 (3H, s), 8.63 (2H, s), 9.58 (1H, br.s)
MS(ESI)m/z：215(M+H)+.
[reference example 392] N- ((1R, 2S, 5S) -2- azidos -5- { [ethyl (methyl) amino] carbonyl } cyclohexyl) -5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- formamides
Figure G2003801097466D02462
Using the method same with reference example 252, the compound that the compound obtained by reference example 323 and reference example 293 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.08,1.15 (3H, each t, J=7.1Hz), 1.74-1.88 (4H, m), 2.12-2.22 (2H, m), 2.67 (3H, s), 2.81-2.86 (1H, m), 2.89,2.96 (3H, it is each s), 3.28-3.43 (2H, m), 3.91-4.10 (5H, m), 4.60-4.62 (1H, m), 7.21 (1H, d, J=7.6Hz)
MS(ESI)m/z：392(M+H)+.
[reference example 393] 2- (the chloro- 3- methoxybenzenes amidos of 4-) -2- oxoacetic acid methyl esters
Using the method same with reference example 361, reductase 12-chloro- 5- Nitroanisoles are obtained after amino body, using the method same with reference example 242, are condensed with chlorine oxoacetic acid methyl ester, are obtained title compound.
1H-NMR(CDCl3)δ：3.93 (3H, s), 3.98 (3H, s), 7.00 (1H, dd, J=8.5,2.4Hz), 7.33 (1H, d, J=8.5Hz), 7.57 (1H, d, J=2.4Hz), 8.89 (1H, br.s)
[reference example 394] 2- (the chloro- 3- methoxybenzenes amidos of 4-) -2- Oxoacetic Acids
Using the method same with reference example 359, title compound is obtained by the way that the compound that reference example 393 is obtained is hydrolyzed.
1H-NMR(DMSO-d6)δ：3.81 (3H, s), 7.36 (1H, d, J=8.7Hz), 7.43 (1H, d, J=8.7Hz), 7.65 (1H, d, J=2.2Hz), 10.79 (1H, s)
MS (ESI, anion) m/z：288(M-H)-.
[reference example 395] N1- { (1S, 2R, 4S) -2- amino -4- [(dimethylamino) carbonyl] cyclohexyl }-N2- (the chloro- 3- methoxyphenyls of 4-) oxalamide
Using the method same with reference example 97, make after the compound that reference example 144 is obtained and the compound condensation that reference example 394 is obtained, using the method same with reference example 69, handled with hydrochloric acid, neutralized with 1N sodium hydrate aqueous solution, obtain title compound.
1H-NMR(CDCl3)δ：1.48-2.00 (8H, m), 2.84-2.93 (1H, m), 2.95 (3H, s), 3.08 (3H, s), 3.33-3.35 (1H, m), 3.89-3.94 (4H, m), 7.06 (1H, dd, J=8.5,2.2Hz), 7.32 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2.2Hz), 8.05 (1H, d, J=8.5Hz), 9.43 (1H, br.s)
MS(ESI)m/z：397(M+).
[reference example 396] 2- (4- acetylenylbenzenes amido) -2- oxoacetic acid methyl esters
Using the method same with reference example 242, title compound is obtained by 4- acetylenylanilines and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：3.09 (1H, s), 3.98 (3H, s), 7.50 (2H, d, J=8.4Hz), 7.62 (2H, d, J=8.4Hz), 8.89 (1H, br.s)
[reference example 397] 2- (4- acetylenylbenzenes amido) -2- Oxoacetic Acid sodium salts
Figure G2003801097466D02482
Using the method same with reference example 266, the compound obtained with sodium hydroxide to reference example 396 is hydrolyzed, and title compound is made.
1H-NMR(DMSO-d6)δ：4.06 (1H, s), 7.39 (2H, d, J=8.4Hz), 7.80 (2H, d, J=8.4Hz), 10.33 (1H, br.s)
[reference example 398] 2- [(5- chloropyrazine -2- bases) amino] -2- oxoacetic acid methyl esters
Using the method same with reference example 242, title compound is prepared by the 2- amino -5- chloropyrazines and chlorine oxoacetic acid methyl ester that are synthesized according to document (Sato, Nobuhiro etc., J.Heterocycl.Chem.1982,19 (3), 673-4).
1H-NMR(CDCl3)δ：4.02 (3H, s), 8.35 (1H, d, J=1.5Hz), 9.37 (1H, d, J=1.5Hz), 9.41 (1H, br.s)
MS(FAB)m/z：216(M+H)+.
[reference example 399] 2- [(5- chloropyrazine -2- bases) amino] -3- Oxoacetic Acids
Using the method same with reference example 359, the compound obtained by reference example 398 prepares title compound.
1H-NMR(DMSO-d6)δ：8.62 (1H, s), 9.02 (1H, br.s), 11.30 (1H, s)
MS(EI)m/z：201M+.
[reference example 400] 2- (the chloro- 3- nitrobenzene amidos of 4-) -2- Oxoacetic Acids
Figure G2003801097466D02492
Using the method same with reference example 242, make after the chloro- 3- nitroanilines of 4- and the condensation of chlorine oxoacetic acid methyl ester, be hydrolyzed using the method same with reference example 359, obtain title compound.
1H-NMR(DMSO-d6)δ：7.76 (1H, dd, J=8.8Hz), 8.04 (1H, dd, J=8.8,2.4Hz), 8.55 (1H, d, J=2.4Hz), 11.24 (1H, s) have no the proton of carboxylic acid.
MS(EI)m/z：244M+.
[reference example 401] 2- (4- chloro-2-nitroanilines base) -2- Oxoacetic Acid sodium salts
Using the method same with reference example 242, make after 4- chloro-2-nitroanilines and the condensation of chlorine oxoacetic acid methyl ester, be hydrolyzed according to the method recorded with reference example 266, methanol is dissolved in by residue obtained, 1N sodium hydrate aqueous solution is added, the precipitation of leaching generation obtains title compound.
1H-NMR(DMSO-d6)δ：7.84 (1H, dd, J=9.0,2.5Hz), 8.20 (1H, d, J=2.5Hz), 8.67 (1H, d, J=9.0Hz), 11.89 (1H, s)
The chloro- 4- methyl -3- pyridine amine of [reference example 402] 6-
Figure G2003801097466D02494
The chloro- 4- methyl-5-nitros pyridines (173mg) of 2- are dissolved in ethanol (5ml), the Raney nickel of catalytic amount is added, stirred 9 hours at room temperature under a hydrogen atmosphere.Catalyst is filtered off, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=3: 2) is refined with silica gel column chromatography, obtains title compound (113mg).
1H-NMR(CDCl3)δ：2.13 (3H, s), 3.85 (2H, br.s), 6.96 (1H, s), 7.74 (1H, s)
MS(EI)m/z：142M+.
[reference example 403] N1- (2- aminophenyls)-N2- (4- chlorphenyls) oxalamide
Figure G2003801097466D02501
Using the method same with reference example 59, the condensation of the compound obtained by 1,2- phenylenediamines and reference example 374 prepares title compound.
1H-NMR(DMSO-d6)δ：5.00 (2H, s), 6.59-6.63 (1H, m), 6.78 (1H, dd, J=8.1,1.2Hz), 6.96-7.01 (1H, m), 7.25 (1H, dd, J=7.8,1.2Hz), 7.44 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.8Hz), 10.04 (1H, s), 10.91 (1H, s)
MS(FAB)：290(M+H)+.
[reference example 404] N- ((1R, 2S, 5S) -2- azidos -5- { [ethyl (methyl) amino] carbonyl } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Using the method same with reference example 252, the compound obtained with hydrochloric acid to reference example 323 is handled, after deprotection, by the condensation of the compound obtained with reference example 10, obtains title compound.
1H-NMR(CDCl3)δ：1.08 (1/2 of 3H, t, J=7.2Hz), 1.14 (1/2 of 3H, t, J=7.2Hz), 1.70-1.90 (4H, m), 2.10-2.25 (2H, m), 2.52 (3H, s), 2.78-3.00 (8H, m), 3.25-3.45 (2H, m), 3.69 (1H, d, J=13.4Hz), 3.73 (1H, d, J=13.4Hz), 3.87-3.95 (1H, m), 4.55-4.62 (1H, m), 7.26 (1H, d, J=7.6Hz)
[reference example 405] 2- (4- chlorphenyls) -1- diazanyl carboxylic acid phenyl esters
(4- chlorphenyls) hydrazine hydrochloride (3.00g) is set to be dissolved in tetrahydrofuran (50ml), ether (50ml) and saturated sodium bicarbonate aqueous solution, separate after organic layer, with anhydrous sodium sulfate drying, (4- chlorphenyls) hydrazine as brown solid is obtained after concentration.Be heated to reflux after being dissolved in benzene (15ml), then with 30 minutes instill diphenyl carbonate (5.22g) benzene (8.0ml) solution.After backflow 19 hours, room temperature is naturally cooled to, benzene (15ml) is added after concentration, it is suspended by ultrasonic wave, hexane (50ml) is added, leaching insoluble matter after stirring 30 minutes obtains title compound (1.05g) after drying.
1H-NMR(CDCl3)δ：(5.86 1H, br.s), and 6.83-6.92 (3H, m), 7.17 (1H, br.s), 7.20-7.32 (4H, m), 7.37 (2H, t, J=7.7Hz)
MS(ESI)m/z：263(M+H)+.
[reference example 406] 5- tert-butoxycarbonyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- carboxylic acid lithium salts
Figure G2003801097466D02512
Using the method same with reference example 10, the compound obtained by reference example 33 prepares title compound.
1H-NMR(DMSO-d6)δ：1.46 (9H, s), 4.30-4.70 (4H, m)
[reference example 407] 1- hydroxyl cyclopropane-carboxylic acid benzene methyls
Figure G2003801097466D02513
Triethylamine (1.0ml) and benzyl bromide a-bromotoluene (650 μ l) are added in tetrahydrofuran (3.0ml) solution of 1- hydroxyls cyclopropane-carboxylic acid (409mg), is stirred 23 hours at room temperature.Dichloromethane and 1N aqueous hydrochloric acid solution are added in reaction solution, is divided into 2 layers.After organic layer saturated sodium bicarbonate aqueous solution, saturated common salt water washing, dried with sodium sulphate.Thick product (hexane: ethyl acetate=4: 1) is refined with silica gel column chromatography, obtains title compound (607mg).
1H-NMR(CDCl3)δ：(1.16 2H, dd, J=7.9,4.9Hz), 1.32 (2H, dd, J=7.9,4.9Hz), 3.09 (0.5H, s), 3.11 (0.5H, s), 5.17 (2H, s), 7.30-7.39 (5H, m)
MS(FAB)m/z：192(M+H)+.
[reference example 408] 1- methoxyl group cyclopropane-carboxylic acid benzene methyls
60% oily sodium hydride (345mg) and methyl iodide (900 μ l) are added in tetrahydrofuran (5.0ml) solution for the compound (600mg) that reference example 407 is obtained, is flowed back 28 hours.Ethyl acetate and saturated aqueous ammonium chloride are added in reaction solution, is divided into 2 layers.Organic layer is dried with after saturated common salt water washing with sodium sulphate.Thick product (hexane: ethyl acetate=10: 1) is refined with silica gel column chromatography, obtains title compound (340mg).
1H-NMR(CDCl3)δ：(1.16 2H, dd, J=7.9,4.8Hz), 1.31 (2H, dd, J=7.9,4.8Hz), 3.42 (3H, s), 5.18 (2H, s), 7.30-7.39 (5H, m)
MS(FAB)m/z：207(M+H)+.
[reference example 409] 1- methoxyl group cyclopropane-carboxylic acids
Using the method same with reference example 152, the compound obtained by reference example 408 prepares title compound.
1H-NMR(CDCl3)δ：1.23 (2H, dd, J=8.0,4.9Hz), 1.38 (2H, dd, J=8.0,4.9Hz), 3.45 (3H, s), 8.80-9.00 (1H, br)
[reference example 410] (3R, 4S) -4- { [(7- chlorine isoquinolin -3- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- carbamates
Figure G2003801097466D02523
Using the method same with reference example 214, the compound that the compound obtained by reference example 220 and reference example 57 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, br s), 1.62-1.80 (1H, m), 2.04-2.22 (1H, m), 2.95-3.32 (1H, m), 3.38-3.53 (1H, m), 3.46 (3H, s), 3.84-3.95 (1H, m), 4.02-4.27 (3H, m), 4.30-4.65 (2H, m), 4.87-4.98 (0.5H, br), 5.32-5.43 (0.5H, br), 7.71 (1H, dd, J=8.8, 2.0Hz), 7.94 (1H, d, J=8.8Hz), 8.02 (1H, s), 8.55-8.66 (0.7H, br), 8.58 (1H, s), 8.73-8.85 (0.3H, br), 9.14 (1H, br s)
MS(ESI)m/z：477(M+H)+.
[reference example 411] (3R, 4S) -4- { [2- (the chloro- 3- fluoroanilinos of 4-) -2- oxoacetyls] amino } -1- (2- Methoxyacetyls) piperidines -3- carbamates
Figure G2003801097466D02531
Using the method same with reference example 214, the condensation for the compound that the compound obtained by reference to example 220 and reference example 377 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.60-1.75 (1H, m), 1.92-2.08 (1H, m), 2.68-2.80 (0.5H, m), 2.88-3.03 (0.5H, m), 3.06-3.24 (0.5H, m), 3.27-3.36 (0.5H, m), 3.45 (3H, s), 3.90-4.22 (5H, m), 4.56-4.71 (1H, m), 4.80-4.92 (0.3H, br), 5.44-5.54 (0.7H, br), 7.24 (1H, d, J=12.9Hz), 7.35 (1H, t, J=8.3Hz), 7.72 (1H, dd, J=8.3, 2.3Hz), 8.20-8.
42 (1H, br), 9.18-9.28 (1H, br)
MS(ESI)m/z：487(M+H)+.
[reference example 412] (3R, 4S) -4- ({ 2- [(the chloro- 2- thienyls of 5-) amino] -2- oxoacetyls } amino) -1- (2- Methoxyacetyls) piperidines -3- carbamates
Using the method same with reference example 214, title compound is obtained as the lithium salts of the carboxylic acid obtained by the compound that reference example 220 is obtained and the compound hydrolysis that reference example 356 is obtained.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.55-1.75 (1H, br), 1.90-2.10 (1H, br), 2.68-2.80 (0.7H, m), 2.90-3.03 (0.3H, br), 3.07-3.22 (0.3H, br), 3.25-3.35 (0.7H, br), 3.45 (3H, s), 3.83-4.22 (5H, m), 4.55-4.70 (1H, br), 4.80-4.90 (0.2H, br), 5.07-5.14 (0.2H, br), 5.44-5.55 (0.6H, br), 6.58-6.64 (1H, br), 6.73 (1H, d, J=3.9Hz), 8.05-8.27 (1H, br), 9.65-9.88 (1H, br)
MS(FAB)m/z：475(M+H)+.
[reference example 413] 5- methyl -5H- pyrrolo-es [3,4-d] thiazole simultaneously -2- carboxylic acid, ethyl esters
Figure G2003801097466D02541
1) 2- ethyl thioacetates (26.75g) are added in ethanol (250ml) solution of the bromo- 2- butanone (26.36g) of 3-, are flowed back 14 hours.After reaction solution cooling, it is concentrated under reduced pressure, ethyl acetate and saturated aqueous common salt is added in residue, is divided into 2 layers.After organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate drying is used.Be concentrated under reduced pressure solvent, and residue (hexane: ethyl acetate=6: 1) is refined with silica gel column chromatography, obtains 4,5- dimethylthiazole -2- carboxylic acid, ethyl esters (19.53g).
1H-NMR(CDCl3)δ：1.42 (3H, t, J=7.1Hz), 2.42 (3H, s), 2.44 (3H, s), 4.45 (2H, q, J=7.1Hz)
2) N- bromines succinimide (62.42g) and 2 are added in 1,2- dichloroethanes (500ml) solution of above-mentioned product (19.53g), 2 '-azodiisobutyronitrile (227mg) flows back 42 hours.Cool down after reaction solution, add water and dichloromethane, be divided into 2 layers, organic layer is concentrated under reduced pressure with after saturated common salt water washing, obtain the thick product (40.54g) in dark brown oil.In 0 DEG C, triethylamine (8.0ml) and 2 moles of methylamine tetrahydrofuran solution (11.0ml) are added in the acetonitrile solution (400ml) of the thick product of gained (8.41g), is stirred 3 days at room temperature.It is concentrated under reduced pressure after reaction solution, dichloromethane and saturated aqueous common salt is added in residue, is divided into 2 layers.Organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Be concentrated under reduced pressure solvent, and residue (hexane: ethyl acetate=3: 1) is refined with silica gel column chromatography, obtains title compound (270mg).
1H-NMR(CDCl3)δ：(1.45 3H, t, J=7.1Hz), 3.91 (3H, s), 4.48 (2H, q, J=7.1Hz), 6.73 (1H, d, J=1.7Hz), 7.30 (1H, d, J=1.7Hz)
MS(ESI)m/z：211(M+H)+.
The chloro- 4- oxos -4H- chromenes -2- carboxylic acid, ethyl esters of [reference example 414] 6-
Figure G2003801097466D02542
Under the displacement of argon gas, about 60% sodium hydride (1.68g) of oiliness is added in ethanol (10ml), is stirred 10 minutes at room temperature.Add after diethy-aceto oxalate (3.36ml), the ethanol solution (20ml) of instillation 5 '-chloro- 2 '-hydroxy acetophenone (2.82g), additional ethanol (40ml) after flowing back 1 and a half hours, is stirred 14 hours in 50 DEG C.The concentrated sulfuric acid (1.5ml) and ethanol (10ml) are added in mixed liquor, is flowed back 4 hours.By being concentrated under reduced pressure after cooling, solvent is reduced to half, toluene and 1N sodium hydrate aqueous solution (15ml) are added in concentrate.It is extracted with ethyl acetate, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Be concentrated under reduced pressure solvent, residue silica gel column chromatography (hexane: ethyl acetate=7: after 1) refining, gained solid is washed with hexane, acquisition title compound (1.20g).
1H-NMR(CDCl3)δ：1.44 (3H, t, J=7.1Hz), 4.47 (2H, q, J=7.1Hz), 7.12 (1H, s), 7.58 (1H, d, J=9.0Hz), 7.69 (1H, dd, J=9.0,2.7Hz), 8.16 (1H, d, J=2.7Hz)
MS(ESI)m/z：293(M+MeCN+H)+.
The chloro- 4- oxos -4H- chromenes -2- carboxylic acids of [reference example 415] 6-
Figure G2003801097466D02551
Using the method same with reference example 359, the compound obtained by reference example 414 prepares title compound.
1H-NMR(CDCl3)δ：7.12 (1H, s), 7.60 (1H, d, J=8.8Hz), 7.69 (1H, dd, J=8.8,2.7Hz), 8.15 (1H, d, J=2.7Hz)
MS(FAB)m/z：225(M+H)+.
[reference example 416] (1S, 3R, 4S) -4- amino -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
Using the method same with reference example 90, the compound obtained by reference example 249 prepares title compound.
1H-NMR(CDCl3)δ：1.20-1.80 (4H, m), 1.25 (3H, t, J=7.3Hz), 1.46 (9H, s), 1.85-2.00 (1H, m), 2.10-2.20 (1H, m), 2.30-2.45 (1H, m), 2.90-3.00 (1H, m), 3.84 (1H, br s), 4.12 (2H, q, J=7.3Hz), 4.75 (1H, br s)
[reference example 417] (1R, 2S, 5S) -2- { [(the chloro- 4- oxos -4H- chromenes -2- bases of 6-) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02561
DMF (0.02ml) is added in thionyl chloride (2.0ml) solution for the compound (213mg) that reference example 415 is obtained, is flowed back 15 minutes.Be concentrated under reduced pressure reaction solution, and residue is modulated into tetrahydrofuran (4.0ml) solution, is added the compound (294mg) that triethylamine (500 μ l) and reference example 144 are obtained, is stirred 15 minutes at room temperature.Ethyl acetate and 10% aqueous citric acid solution are added in reaction solution, is divided into 2 layers.After organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing, with anhydrous sodium sulfate drying, it is concentrated under reduced pressure.Residue (dichloromethane: methanol=30: 1) is refined with silica gel column chromatography, obtains title compound (230mg).
1H-NMR(CDCl3)δ：1.33-1.77 (3H, m), 1.50 (9H, s), 1.81-2.34 (3H, m), 2.63-2.80 (1H, m), 2.95 (3H, s), 3.10 (3H, s), 3.90-4.04 (1H, br), 4.18-4.31 (1H, br), 4.93-5.12 (1H, br), 7.13 (1H, s), (7.55 1H, d, J=8.8Hz), 7.66 (1H, dd, J=8.8,2.4Hz), 8.14 (1H, d, J=2.4Hz), 8.77-8.92 (1H, br)
MS(ESI)m/z：492(M+H)+.
[reference example 418] (3R, 4S) -4- { [(7- chlorine cinnolines -3- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- carbamates
Figure G2003801097466D02562
Using the method same with reference example 214, the lithium salts of the carboxylic acid obtained by ester hydrolysis described in the compound obtained as reference example 220 and reference example 297 obtains title compound.
1H-NMR(CDCl3)δ：1.38 (9H, s), 1.65-1.90 (1H, m), 1.90-2.15 (1H, m), 2.80-3.00 (0.6H, m), 3.00-3.15 (0.4H, m), 3.20-3.50 (1H, m), 3.46 (3H, s), 3.80-4.70 (6H, m), 4.87 (0.4H, br s), 5.30 (0.6H, br s), (7.78 1H, d, J=8.8Hz), (7.97 1H, d, J=8.8Hz), 8.61 (1H, s), 8.62-8.90 (1H, br), 8.73 (1H, s)
MS(ESI)m/z：478(M+H)+.
[reference example 419] (1R; 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02571
Using the method same with reference example 68, make the compound that reference example 144 is obtained and the compound condensation that reference example 266 is obtained, prepare title compound.
1H-NMR(CDCl3)δ：1.35-1.65 (1H, m), 1.45 (9H, s), 1.65-1.89 (2H, m), 1.90-2.10 (3H, m), 2.56-2.74 (1H, br), 2.95 (3H, s), 3.06 (3H, s), 3.94-4.01 (1H, m), 4.18-4.27 (1H, m), 4.70-4.90 (0.7H, br), 5.80-6.20 (0.3H, br), 7.68 (1H, dd, J=8.9,2.6Hz), 7.83 (1H, brs), 8.14 (1H, br d, J=7.8Hz), 8.30 (1H, s), 9.72 (1H, s)
MS(ESI)m/z：468(M+H)+.
[reference example 420] N1- { (1S, 2R, 4S) -2- amino -4- [(dimethylamino) carbonyl] cyclohexyl }-N2- (5- chloropyridine -2- bases) oxalamide hydrochloride
Using the method same with reference example 69, the compound obtained by reference example 419 prepares title compound.
1H-NMR(DMSO-d6)δ：1.38-1.51 (1H, m), 1.65-1.85 (3H, m), 1.96-2.10 (2H, m), 2.81 (3H, s), 3.07 (3H, s), 3.23-3.33 (1H, m), 3.74 (1H, br s), 3.84-3.92 (1H, m), 8.02 (1H, dd, J=9.0,2.5Hz), 8.07 (1H, d, J=9.0Hz), 8.34 (3H, br s), 8.46 (1H, d, J=2.5Hz), 8.96 (1H, d, J=6.6Hz), 10.34 (1H, s)
MS(ESI)m/z：368(M+H)+.
[reference example 421] 2- [({ (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } amino) carbonyl] -6; 7- dihydro-thiophenes simultaneously [3,2-c] pyridine -5- (4H)-carboxylic acid tert-butyl ester
Figure G2003801097466D02581
Make compound and 5- (tert-butoxycarbonyl) -4 that reference example 420 is obtained, simultaneously [3,2-c] pyridine-2-carboxylic acids (WO 94/21599) are condensed 5,6,7- tetrahydro-thiazoles, obtain title compound.
1H-NMR(CDCl3)δ：1.50 (9H, s), 1.73-1.95 (3H, m), 1.95-2.06 (1H, m), 2.08-2.20 (2H, m), 2.82 (3H, br s), 2.94 (3H, s), 3.03 (3H, s), 3.60-3.80 (2H, m), 3.96-4.08 (1H, m), 4.44 (2H, br s), 4.66 (1H, br s), 6.74 (1H, br s), 7.20-7.32 (1H, m), 7.66 (1H, dd, J=9.0, 2.4Hz), 8.13 (1H, d, J=9.0Hz), 8.13-8.25 (1H, m), 8.28 (1H, d, J=2.4Hz), 9.75 (1H, s)
MS(ESI)m/z：633(M+H)+.
[reference example 422] 2- chloro- N- (4- fluorophenyls) acetamide
Figure G2003801097466D02582
Using the method same with reference example 350, title compound is obtained by para-fluoroaniline.
1H-NMR(CDCl3)δ：4.19 (2H, s), 7.05 (2H, t, J=8.6Hz), 7.51 (2H, dd, J=9.1,4.7Hz), 8.19 (1H, br s)
[reference example 423] S- [2- (4- fluoroanilinos) -2- oxoethyls] thiosulfuric acid sodium salt
Figure G2003801097466D02583
Using the method same with reference example 351, the compound obtained by reference example 422 prepares title compound.
1H-NMR(DMSO-d6)δ：3.72 (2H, s), 7.14 (2H, t, J=9.0Hz), 7.56 (2H, dd, J=9.0,5.1Hz), 10.21 (1H, s)
[reference example 424] (1R, 2S, 5S) -5- [(dimethylamino) carbonyl] -2- { [2- (4- fluoroanilinos) -2- oxos ethanethioyl] amino } Cyclohexylamino t-butyl formate
The compound (1.24g) that the compound (1.1g) and reference example 423 that reference example 144 is obtained are obtained is dissolved in N-methylmorpholine (20ml), bath temperature is risen to 140 DEG C from room temperature with 15 minutes, at the same temperature heating stirring 15 minutes.After natural cooling, frozen water, leaching insoluble matter are added in reaction solution.With silica gel column chromatography (dichloromethane: methanol=200: 1 → 197: 3) gained insoluble matter is refined, title compound (1.43g) is obtained.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.70-2.10 (5H, m), 2.10-2.30 (1H, m), 2.60-2.80 (1H, m), 2.96 (3H, s), 3.07 (3H, s), 4.30-4.50 (2H, m), 4.65-4.85 (1H, m), 7.06 (2H, t, J=8.5Hz), and 7.50-7.70 (2H, m), 9.75-9.95 (1H, m), 10.13 (1H, s)
MS(ESI)m/z：467(M+H)+.
The chloro- N- of [reference example 425] 2- (5- fluorine pyridine -2- bases) acetamide hydrochloride
Using the method same with reference example 352, title compound is prepared by 2- amino-5-fluorine pyridines.
1H-NMR(DMSO-d6)δ：4.35 (2H, s), 7.74-7.82 (1H, m), 8.10 (1H, dd, J=9.0,4.2Hz), 8.36 (1H, d, J=2.9Hz), (1H, br s)
MS(ESI)m/z：188(M+H)+.
[reference example 426] S- { 2- [(5- fluorine pyridine -2- bases) amino] -2- oxoacetyls } thiosulfuric acid sodium salt
Using the method same with reference example 353, the compound obtained by reference example 425 prepares title compound.
1H-NMR(DMSO-d6)δ：3.75 (2H, s), 7.67-7.77 (1H, m), 8.07 (1H, dd, J=9.2,4.2Hz), 8.28 (1H, d, J=2.9Hz), 10.48 (1H, s)
[reference example 427] (1R; 2S, 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(5- fluorine pyridine -2- bases) amino] -2- oxos ethanethioyl } amino) Cyclohexylamino t-butyl formate
Figure G2003801097466D02601
Heated in pyridine (70ml) solution of 120 DEG C of compounds (1.20g) obtained to reference example 144, add the compound (2.42g) that reference example 426 is obtained, stirring naturally cools under room temperature, decompression after 30 minutes and boils off solvent.After residue obtained middle addition dichloromethane (100ml), saturated sodium bicarbonate aqueous solution (100ml) and water (50ml) carry out point liquid, water layer is extracted with dichloromethane.Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue obtained use silica gel column chromatography (hexane: tetrahydrofuran=1: 1) is refined, gained solid was formed as leaching after slurry with isopropyl ether (40ml) with 1 hour, dry, obtain title compound (920mg).
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.70-2.10 (5H, m), 2.27 (1H, br s), 2.70 (1H, br s), 2.96 (3H, s), 3.08 (3H, s), 4.34-4.44 (2H, m), 4.77 (1H, br s), 7.44-7.51 (1H, m), 8.18-8.27 (2H, m), 9.90 (1H, br s), 10.57 (1H, s)
MS(ESI)m/z：468(M+H)+.
[reference example 428] (1R; 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 427, the compound that the compound obtained by reference example 144 and reference example 353 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.43 (9H, s), 1.65-2.35 (6H, m), 2.70 (1H, br s), 2.95 (3H, s), 3.09 (3H, s), 4.30-4.60 (2H, m), 4.87 (1/2H, br s), 6.92 (1/2H, br s), 7.69 (1H, dd, J=8.9,2.6Hz), 7.95-8.20 (1H, br), 8.29 (1H, s), 9.67 (1/2H, br s), 9.93 (1/2H, br s), 10.54 (1H, br s)
Tetrahydro benzothiazol -6- base the formamides of [reference example 429] 2- chloro- 4,5,6,7-
Figure G2003801097466D02611
In the chloro- 5- oxos -4 of 2-, 5,6,7- tetrahydro benzos [d] thiazole (Helv.Cim.Acta., 1994, volume 77, page 1256) ammonium acetate (18.58g) and sodium cyanoborohydride (10.68g) are added in methanol (200ml) solution of (4.53g), it is heated to reflux.Hydrochloric acid is added after 19 hours, decomposes and lower concentration of reaction solution is depressurized after superfluous reagent, after making reaction solution in alkalescence with 1N sodium hydrate aqueous solution, dichloromethane point liquid is added.Organic layer is dried with anhydrous magnesium sulfate, and solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (dichloromethane: methanol=20: 1) is refined, boils off solvent and obtain pale yellow oil (2.42g).The grease is dissolved in dichloromethane (100ml), formic acid (530 μ l), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (3.68g), I-hydroxybenzotriazole (2.60g) and N-methylmorpholine (3.88g) are added, is stirred at room temperature.Dichloromethane is added in reaction solution and saturated sodium bicarbonate aqueous solution carries out a point liquid after 20 hours.Organic layer boils off solvent under being depressurized after being dried with anhydrous magnesium sulfate, residue obtained use silica gel column chromatography (dichloromethane: methanol=20: 1) refines, obtains title compound (2.21g).
1H-NMR(CDCl3)δ：1.93-2.11 (2H, m), 2.63-2.69 (1H, m), 2.83-2.89 (2H, m), 3.
13 (1H, dd, J=16.2,4.4Hz), 4.46-4.48 (1H, m), 5.76 (1H, br s), 8.17 (1H, s)
[reference example 430] N- (tetrahydro benzothiazol -6- bases of 2- chloro- 4,5,6,7-)-N- methyl carbamic acid tert-butyl esters
1M borines-tetrahydrofuran complex tetrahydrofuran solution (14.6ml) is added in tetrahydrofuran (50ml) solution for the compound (2.11g) that reference example 429 is obtained, is heated to reflux.Additional 1M borines-tetrahydrofuran complex tetrahydrofuran solution (6.0ml), is heated to reflux after 15 hours.Ethanol (10ml), 1N hydrochloric acid (15ml) is added after 4 hours to be heated to reflux.Lower concentration of reaction solution is depressurized after 3 hours, 1N sodium hydrate aqueous solution and dichloromethane is added, organic layer is dried with anhydrous magnesium sulfate after point liquid, and solvent is boiled off under decompression.It is residue obtained to be dissolved in dichloromethane (50ml), triethylamine (1.28g) and di-tert-butyl dicarbonate (2.21g) are added, is stirred at room temperature.After 30 minutes, dichloromethane and 1N hydrochloric acid point liquid are added, organic layer boils off solvent under being depressurized after being dried with anhydrous magnesium sulfate.Residue obtained use silica gel column chromatography (hexane: ethyl acetate=2: 1) refines, obtains title compound (2.26g).
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.96-1.98 (2H, m), 2.80-2.96 (7H, m), 4.40-4.50 (1H, m)
MS(FAB)m/z：303(M+H)+.
[reference example 431] N- (2- [({ (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } amino) carbonyl] -4; 5; 6,7- tetrahydro benzothiazol -6- bases)-N- methyl carbamic acid the tert-butyl esters
Figure G2003801097466D02621
The pentane solution (3.1ml) of the tert-butyl lithium for the 1.6N for being cooled to -78 DEG C is added in ether (10ml)-tetrahydrofuran (5ml) solution for the compound (1.0g) that reference example 430 is obtained, after stirring 20 minutes, with 20 minutes introducing carbon dioxide gas.Reacting liquid temperature is returned back to after room temperature, and decompression is lower to be concentrated, and obtains 6- [(tert-butoxycarbonyl) (methyl) amino] -4,5,6,7- tetrahydro benzothiazol -2- carboxylic acid lithium salts.
The N of the compound (490.5mg) obtained in reference example 420, carboxylic acid lithium salt (350.2mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (287.6mg), I-hydroxybenzotriazole (202.7mg) and the N-methylmorpholine (0.319ml) obtained by above-mentioned reaction are added in dinethylformamide (20ml) solution, is stirred 4 days at room temperature.Solvent is boiled off under decompression, water is added in residue and dichloromethane is carried out after point liquid, organic layer is washed successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt.With lower concentration is depressurized after anhydrous sodium sulfate drying, (dichloromethane: methanol=40: 1 → 20: 1) refined with silica gel column chromatography, obtain title compound (323.9mg).
1H-NMR(CDCl3)δ：1.48, 1.49 (whole 9H, each s), 1.60-1.92 (4H, m), 1.95-2.20 (6H, m), 2.78-3.10 (3H, m), 2.83 (3H, s), 2.95 (3H, s), 3.06, 3.07 (whole 3H, each s), 4.05-4.15 (1H, m), 4.20-4.60 (1H, m), 4.63-4.73 (1H, m), 7.39 (1H, d, J=8.6Hz), 7.68 (1H, dt, J=8.8, 2.6Hz), 7.95-8.10 (1H, m), 8.13-8.22 (1H, m), 8.30-8.35 (1H, m), 9.72 (1H, brs)
MS(ESI)m/z：662(M+H)+.
[reference example 432] N- { (1S, 2R, 4S) -2- amino -4- [(dimethylamino) carbonyl] cyclohexyl } -5- chloro-indole -2- carboxamide hydrochlorides
Figure G2003801097466D02631
Using the method same with reference example 69, the compound that reference example 310 is obtained is deprotected, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.43-1.56 (0.5H, m), 1.72-1.97 (4.5H, m), 2.82 (3H, s), 3.06 (3H, s), 3.11-3.26 (1H, m), 3.75-3.84 (1H, m), 4.07-4.14 (1H, m), 4.22-4.41 (1H, m), 7.19 (1H, dd, J=2.0,8.8Hz), 7.29 (1H, d, J=2.0Hz), 7.45 (1H, d, J=8.8Hz), 7.72 (1H, s), 8.07 (3H, br), 8.47 (1H, m), 11.85 (1H, br)
[reference example 433] 2- [(5- chloropyridine -2- bases) amino] -2- Oxoacetic Acid lithium salts
Figure G2003801097466D02632
In 0 DEG C, chlorine oxoacetic acid methyl ester (78.7ml) is instilled in tetrahydrofuran (2000ml) suspension of 2- amino -5- chloropyridines (100g) and sodium acid carbonate (78.4g), is stirred 2 hours at room temperature.A point liquid is carried out after reaction solution is added in the mixture of ether (2000ml), ammonium chloride (62.4g) and water (1000ml) under stirring, water layer is extracted with dichloromethane.Merge organic layer, with anhydrous sodium sulfate drying, boil off and dried after solvent under decompression, obtain 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetic acid methyl esters (162g).Water (450ml) and lithium hydroxide (18.2g) are added in the tetrahydrofuran (1800ml) of the ester (160g).After stirring 2 hours at room temperature, solvent is boiled off under decompression, is stirred 3 hours in residue obtained middle addition hexane (3000ml).Leaching solid, adds acetonitrile (1000ml) in gained solid (190g) after drying, the solid that leaching is generated after stirring 1 hour is dried after being washed with ether (500ml), obtains title compound (158g).
1H-NMR(DMSO-d6)δ：(7.92 1H, dd, J=9.1,2.7Hz), 8.13 (1H, dd, J=9.1,0.5Hz), 8.36 (1H, dd, J=2.7,0.5Hz), 10.19 (1H, s)
[reference example 434] (1R; 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 91, the compound that the compound obtained by reference example 144 and reference example 433 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.25-1.55 (1H, m), 1.45 (9H, s), 1.60-2.15 (5H, m), 2.56-2.74 (1H, br), 2.95 (3H, s), 3.06 (3H, s), 3.90-4.01 (1H, m), 4.18-4.27 (1H, m), 4.70-4.85 (0.7H, br), 5.70-6.00 (0.3H, br), 7.70 (1H, dd, J=8.8,2.4Hz), 7.75-8.00 (1H, br), 8.16 (1H, br d, J=8.8Hz), 8.30 (1H, d, J=2.4Hz), 9.73 (1H, s)
MS(ESI)m/z：468(M+H)+.
[reference example 435] N1- { (1S, 2R, 4S) -2- amino -4- [(dimethylamino) carbonyl] cyclohexyl }-N2- (5- chloropyridine -2- bases) oxalamide hydrochloride
Using the method same with reference example 69, the compound obtained by reference example 434 prepares title compound.
1H-NMR(DMSO-d6)δ：1.38-1.51 (1H, m), 1.65-1.85 (3H, m), 1.92-2.09 (2H, m), 2.80 (3H, s), 3.06 (3H, s), 3.20-3.32 (1H, m), 3.55-4.40 (2H, br), 8.02 (1H, dd, J=9.1,2.5Hz), 8.07 (1H, d, J=9.1Hz), 8.15-8.40 (3H, br), 8.45 (1H, d, J=2.5Hz), 8.96 (1H, d, J=6.6Hz), 10.33 (1H, s)
[reference example 436] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(methylamino) carbonyl] Cyclohexylamino benzyl formate
Figure G2003801097466D02651
Using the method same with reference example 143, the compound and methylamine hydrochloride obtained by reference example 142 prepares title compound.
1H-NMR(DMSO-d6)δ：1.39 (9H, s), 1.40-1.61 (4H, m), 1.63-1.73 (1H, m), 1.75-1.85 (1H, m), 2.23-2.48 (1H, m), (2.53 3H, d, J=4.6Hz), 3.48 (1H, br.s), 3.80-3.91 (1H, m), 5.01 (1H, 1/2ABq, J=12.1Hz), 5.03 (1H, 1/2ABq, J=12.1Hz), 6.28-6.40 (1H, m), 6.82-6.98 (1H, m), 7.25-7.40 (5H, m), 7.50-7.60 (1H, m)
MS(FAB)m/z：406(M+H)+.
[reference example 437] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(methylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 144, after the compound deprotection that reference example 436 is obtained, using the method same with reference example 91, the compound condensation for making gained amine be obtained with reference example 433 obtains title compound.
1H-NMR(DMSO-d6)δ：1.35-1.75 (3H, m), 1.39 (9H, s), 1.75-1.86 (2H, m), 1.87-1.95 (1H, m), 2.30-2.40 (1H, m), 2.55 (3H, d, J=4.6Hz), 3.79-3.90 (2H, m), 6.73-6.90 (1H, m), 7.58-7.70 (1H, m), 8.00-8.13 (2H, m), 8.46 (1H, dd, J=2.2,1.0Hz), 8.67 (1H, d, J=7.6Hz), 10.26 (1H, s)
MS(ESI：：Anion) m/z：452[(M-H)-, Cl35], 454 [(M-H)-, Cl37]
The chloro- N- of [reference example 438] 2- (5- picoline -2- bases) acetamide hydrochloride
Using the method same with reference example 425, title compound is obtained by 2- amino -5- picolines.
1H-NMR(DMSO-d6)δ：2.30 (3H, s), 4.40 (2H, s), 7.83 (1H, d, J=8.8Hz), 7.91 (1H, d, J=8.5Hz), 8.21 (1H, s), 11.40 (1H, s)
[reference example 439] S- { 2- [(5- picoline -2- bases) amino] -2- oxoethyls } thiosulfuric acid sodium salt
Using the method same with reference example 353, the compound obtained by reference example 438 prepares title compound.
1H-NMR(DMSO-d6)δ：2.24 (3H, s), 3.74 (2H, s), 7.59 (1H, d, J=8.5Hz), 7.94 (1H, d, J=8.3Hz), 8.12 (1H, s), 10.26 (1H, s)
[reference example 440] (1R; 2S, 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(5- picoline -2- bases) amino] -2- oxos ethanethioyl } amino) Cyclohexylamino t-butyl formate
Using the method same with reference example 427, the compound that the compound obtained by reference example 144 and reference example 439 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.60-2.10 (5H, m), 2.15-2.35 (1H, m), 2.31 (3H, s), 2.60-2.80 (1H, m), 2.95 (3H, s), 3.07 (3H, s), 4.30-4.45 (2H, m), 4.65-4.85 (1H, m), 7.54 (1H, dd, J=8.5,2.0Hz), 8.06 (1H, br.d), 8.18 (1H, s), 9.70-9.90 (1H, m), 10.48 (1H, s)
MS(ESI)m/z：464(M+H)+.
[reference example 441] (3R, 4S) -4- { [2- (4- chloroanilinos) -2- oxos ethanethioyl] amido } -1- (2- Methoxyacetyls) piperidines -3- carbamates
Figure G2003801097466D02671
Using the method same with reference example 214, by being catalyzed after the compound deprotection that reduction obtains reference example 220, using the method same with reference example 427, the compound condensation for obtaining gained amine and reference example 351 prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.59-1.84 (1H, m), 2.10-2.33 (1H, m), 2.68-2.81 (0.7H, m), 2.94-2.04 (0.3H, m), 3.15-3.40 (1H, m), 3.44 (3H, s), 3.91-4.32 (4H, m), 4.45-4.58 (1H, m), 4.60-4.77 (1H, m), 5.15-5.30 (0.3H, br), 5.84-5.94 (0.7H, m), 7.32 (2H, d, J=8.6Hz), 7.61 (2H, d, J=8.6Hz), 10.12 (1H, s), 10.19-10.33 (1H, br)
MS(FAB)m/z：485[(M+H)+, Cl35], 487 [(M+H)+, Cl37].
[reference example 442] (1R, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino formic acid 9H- fluorenes -9- base methyl esters
Figure G2003801097466D02672
The compound (856mg) that reference example 144 is obtained is dissolved in acetone (10ml), adds pentafluorophenyl group carbamic acid 9- fluorenyl methyl esters (1.34g) and sodium acid carbonate (302mg), stirs 2.5 hours at room temperature.Then, additional pentafluorophenyl group carbamic acid 9- fluorenyl methyl esters (609mg) and sodium acid carbonate (151mg), are heated to reflux 30 minutes.Solvent is boiled off under decompression, residue (SI-40B, dichloromethane: methanol=93: 7) refines for the flash column chromatography of carrier to silica gel, obtains title compound (1.47g).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.30-2.05 (6H, m), 2.63 (1H, br.s), 2.94 (3H, s), 3.04 (3H, s), 3.69 (1H, br.s), 4.15 (1H, br.s), 4.21 (1H, br.s), 4.37 (2H, br.s), 4.73 (1H, br.s), 5.41 (1H, br.s), 7.29 (2H, t, J=7.3Hz), 7.39 (2H, t, J=7.3Hz), 7.57 (2H, d, J=7.3Hz), 7.75 (2H, d, J=7.3Hz)
MS(ESI)m/z：508(M+H)+.
[reference example 443] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) thioformyl] Cyclohexylamino formic acid 9H- fluorenes -9- base methyl esters
The compound (1.26g) that reference example 442 is obtained is dissolved in toluene (50ml), adds ロ-ソ Application reagents (1.00g), is stirred 1 hour in 60 DEG C.Insoluble matter is filtered off, solvent is boiled off under decompression.Residue is dissolved in ethanol (50ml), di-tert-butyl dicarbonate (541mg) and sodium acid carbonate (208mg) is added.Stir 1 hour at room temperature, solvent is boiled off under decompression, residue (hexane: ethyl acetate=1: 1 → dichloromethane: methanol=9: 1) is refined to silica gel for the flash column chromatography of carrier.Obtain the title compound (609mg) of white solid.
1H-NMR(CDCl3)δ：1.43 (9H, s), 1.43-2.10 (6H, m), 2.92 (1H, br.s), 3.31 (3H, s), 3.47 (3H, s), 3.74 (1H, br.s), 4.09-4.19 (2H, m), 4.38 (2H, br.s), 4.75 (1H, br), 5.29 (1H, br.s), 7.29 (2H, t, J=7.3Hz), 7.38 (2H, t, J=7.3Hz), 7.55 (2H, br.s), 7.75 (2H, d, J=7.3Hz)
[reference example 444] (1R; 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(dimethylamino) thioformyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02682
The compound (1.11g) that reference example 443 is obtained is dissolved in DMF (30ml), adds piperazine (3.0ml), stirs 15 minutes at room temperature.Solvent is boiled off under decompression, ethyl acetate is added in residue and water carries out a point liquid.Aqueous layer with ethyl acetate is extracted 2 times, merges organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Using the method same with reference example 91, the compound condensation for making the residue be obtained with reference example 433 obtains title compound (629mg).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.48-2.23 (6H, m), 2.98 (1H, br.s), 3.36 (3H, s), 3.49 (3H, s), 3.98-4.04 (1H, m), 4.22-4.25 (1H, m), 4.75 (1H, br.s), 7.70 (1H, dd, J=8.8,2.7Hz), 7.85 (1H, br.s), 8.16 (1H, d, J=8.8Hz), 8.30 (1H, d, J=2.7Hz), 9.73 (1H, s)
MS(FAB)m/z：484[(M+H)+, Cl35], 486 [(M+H)+, Cl37].
[reference example 445] N1- { (1S, 2R, 4S) -2- amino -4- [(dimethylamino) thioformyl] cyclohexyl }-N2- (5- chloropyridine -2- bases) oxalamide dihydrochloride
Figure G2003801097466D02691
Using the method same with reference example 69, the compound obtained by reference example 444 prepares title compound.
1H-NMR(DMSO-d6)δ：1.66-2.11 (6H, m), 3.38 (3H, s), 3.42 (3H, s), 3.52 (1H, br.s), 3.75 (1H, br.s), 3.88 (1H, br.s), 8.03-8.09 (2H, m), 8.21 (3H, br.s), 8.48 (1H, d, J=2.2Hz), 9.06 (1H, d, J=6.8Hz), 10.34 (1H, s)
MS(FAB)m/z：384[(M+H)+, Cl35], 386 [(M+H)+, Cl37].
[reference example 446] (3R, 4S) -3- [(tert-butoxycarbonyl) amino] -1- (2- Methoxyacetyls) piperidin-4-yl carbamic acid 9H- fluorenes -9- base methyl esters
Figure G2003801097466D02692
Using the method same with reference example 214, the compound for obtaining reference example 220 by being catalyzed reduction is deprotected, then using the method same with reference example 442, gained amine is handled, and obtains title compound.
1H-NMR(CDCl3)δ：1.48 (9H, s), 1.55-1.80 (1H, m), 1.92-2.20 (1H, m), 2.70-3.35 (2H, m), 3.44 (3H, s), 3.77-4.90 (10H, m), 5.29-5.45 (0.6H, br), 5.75-5.90 (0.4H, br), 7.26-7.34 (2H, m), 7.39 (2H, t, J=7.6Hz), 7.55-7.65 (2H, m), 7.76 (2H, d, J=7.6Hz)
MS(FAB)m/z：510(M+H)+.
[reference example 447] (3R, 4S) -3- [(tert-butoxycarbonyl) amino] -1- (2- methoxyl groups ethanethioyl) piperidin-4-yl carbamic acid 9H- fluorenes -9- base methyl esters
Using the method same with reference example 443, the compound obtained by reference example 446 prepares title compound.
1H-NMR(CDCl3)δ：1.48 (9H, s), 1.50-1.80 (1H, m), 2.07-2.23 (1H, m), 3.04-3.18 (0.5H, m), 3.25-3.37 (0.5H, m), 3.44 (1.5H, s), 3.47 (1.5H, s), 3.88-4.75 (9H, m), 5.00-5.70 (2H, br), 5.98-6.23 (1H, br), 7.26-7.29 (2H, m), 7.39 (2H, t, J=7.3Hz), 7.55-7.68 (2H, m), 7.77 (2H, d, J=7.3Hz)
MS(FAB)m/z：526(M+H)+.
[reference example 448] (3R, 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -1- (2- methoxyl groups ethanethioyl) piperidines -3- carbamates
Figure G2003801097466D02702
Using the method same with reference example 444, the compound obtained with diethylamine to reference example 447 is carried out after processing deprotection, the compound condensation obtained with reference example 433, and title compound is made.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.73-1.88 (1H, m), 2.07-2.22 (1H, m), 3.05-3.15 (1H, m), 3.27-3.42 (1H, m), 3.45 (1H, s), 3.48 (2H, s), 4.10-4.54 (5H, m), 5.12-5.21 (0.3H, br), 5.48-5.56 (0.7H, br), 5.61-5.74 (1H, br), 7.70 (1H, dd, J=8.5, 2.0Hz), 8.21 (1H, d, J=8.5Hz), 8.31 (1H, d, J=2.0Hz), 8.42-8.60 (1H, br), 9.72 (1H, br.s)
MS(ESI)m/z：486[(M+H)+, Cl35], 488 [(M+H)+, Cl37].
[reference example 449] (1S, 3R, 4S) -4- { [(allyloxy) carbonyl] amino } -3- [(tert-butoxycarbonyl) amino] cyclohexanecarboxylate
10% palladium-carbon catalyst (10.2g) is added in the tetrahydrofuran (40ml) of compound (10.0g) and the mixed solution of ethanol (40ml) that reference example 141 is obtained, is stirred at room temperature in nitrogen atmosphere 63 hours.After catalyst is filtered with diatomite, the lower concentration filtrate of decompression.Gained colorless oil is dissolved in tetrahydrofuran (25ml), added at room temperature after pyridine (2.3ml), allyl chlorocarbonate (2.70ml) is instilled in 0 DEG C, is stirred 20 minutes.Ice and ethyl acetate are added in reaction solution, stirring adds 10% aqueous citric acid solution after 5 minutes make it in acidity.Organic layer is washed with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, after anhydrous sodium sulfate drying, and the lower concentration of decompression obtains residue.Residue (dichloromethane: methanol=40: 1) is refined with silica gel column chromatography, obtains title compound (6.03g).
1H-NMR(CDCl3)δ：1.25 (3H, t, J=7.1Hz), 1.31-1.40 (1H, m), 1.45 (9H, s), 1.51-1.65 (1H, m), 1.72-1.86 (1H, m), 1.89-2.10 (3H, m), 2.25-2.50 (1H, br), 3.63-3.72 (1H, m), 4.03-4.15 (1H, br), 4.13 (2H, q, J=7.1Hz), 4.49-4.59 (2H, m), 4.60-4.75 (1H, m), 5.20 (1H, d, J=10.5Hz), 5.22-5.32 (1H, br), 5.29 (1H, dd, J=17.1, 1.7Hz), 5.85-5.97 (1H, m)
MS(ESI)m/z：371(M+H)+.
[reference example 450] (1S, 3R, 4S) -4- { [(allyloxy) carbonyl] amino } -3- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid
Using the method same with reference example 142, the compound obtained by reference example 449 prepares title compound.
1H-NMR(CDCl3)δ：1.35-2.15 (6H, br), 1.45 (9H, s), 2.35-2.65 (1H, br), 3.65-3.75 (1H, m), 4.00-4.15 (1H, br), 4.48-4.63 (2H, m), 4.63-4.80 (1H, br), 5.03-5.33 (1H, br), 5.21 (1H, d, J=10.3Hz), 5.29 (1H, dd, J=17.1,1.5Hz), 5.86-5.97 (1H, m)
MS(ESI)m/z：343(M+H)+.
[reference example 451] (1S, 3R, 4S) -4- { [(allyloxy) carbonyl] amino } -3- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid 2,2,2- trichloro ethyl esters
The N of the compound (5.93g) obtained in reference example 450,1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (4.99g), I-hydroxybenzotriazole (2.81g), 2 are added in dinethylformamide (40ml) solution, 2,2- ethapons (4.15ml) and 4-dimethylaminopyridine (4.15g), are stirred 1.5 hours at room temperature.It is concentrated under reduced pressure after reaction solution, ethyl acetate and water is added in residue.Aqueous layer with ethyl acetate is extracted, and after being washed with 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution to the organic layer of merging, is concentrated under reduced pressure with anhydrous sodium sulfate drying.Residue (dichloromethane: methanol=40: 1) is refined with silica gel column chromatography, obtains title compound (8.88g).
1H-NMR(CDCl3)δ：1.35-1.50 (1H, m), 1.46 (9H, s), 1.55-1.73 (1H, m), 1.77-2.22 (4H, m), 2.50-2.65 (1H, br), 3.66-3.75 (1H, m), 4.05-4.20 (1H, m), 4.50-4.60 (2H, m), 4.60-4.80 (1H, br), 4.71 (1H, d, J=11.8Hz), 4.77 (1H, d, J=11.8Hz), 5.18-5.34 (1H, br), 5.20 (1H, d, J=10.5Hz), 5.30 (1H, dd, J=17.4, 1.0Hz), 5.86-5.97 (1H, m)
MS(ESI)m/z：473[(M+H)+, 3 × Cl35], 475 [(M+H)+, 2 × Cl35, Cl37], 477 [(M+H)+, Cl35, 2 × Cl37].
[reference example 452] (1S, 3R, 4S) -4- amino -3- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid 2,2,2- trichloro ethyl esters
Figure G2003801097466D02731
Diethylamine (20ml), four (triphenyl phasphine) palladiums (719mg) are added in tetrahydrofuran (35ml) solution for the compound (8.83g) that reference example 451 is obtained, are stirred at room temperature in argon gas 2.5 hours.10% aqueous citric acid solution (250ml) is added in reaction solution makes it in acidity, adds ether.After water layer is washed with ether, adding sodium carbonate makes it in alkalescence, is extracted with dichloromethane.After dichloromethane layer is washed with saturated sodium-chloride water solution, with lower concentration is depressurized after anhydrous sodium sulfate drying, title compound (4.35g) is obtained.
1H-NMR(CDCl3)δ：1.20-1.50 (3H, m), 1.46 (9H, s), 1.58-1.69 (1H, m), 1.70-1.81 (2H, m), 1.98-2.07 (1H, m), 2.22-2.31 (1H, m), 2.55-2.66 (1H, m), 2.97-3.04 (1H, m), 3.79-3.93 (1H, br), 4.70 (1H, d, J=12.0Hz), 4.75-4.85 (1H, br), 4.78 (1H, d, J=12.0Hz)
MS(ESI)m/z：389[(M+H)+, 3 × Cl35], 391 [(M+H)+, 2 × Cl35, Cl37], 393 [(M+H)+, Cl35, 2 × Cl37].
[reference example 453] (1S; 3R; 4S) -3- [(tert-butoxycarbonyl) amino] -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) cyclohexane-carboxylic acid 2,2,2- trichloro ethyl esters
Figure G2003801097466D02732
Using the method same with reference example 91, the condensation for the compound that the compound and reference example 433 obtained by reference to example 452 is obtained and prepare title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.50-1.63 (1H, m), 1.65-1.79 (2H, m), 1.87-2.08 (2H, m), 2.10-2.22 (2H, m), 2.50-2.70 (1H, br), 3.94-4.02 (1H, m), 4.17-4.30 (1H, br), 4.73 (1H, d, J=12.0Hz), 4.78 (1H, d, J=12.0Hz), 7.70 (1H, dd, J=8.8, 2.4Hz), 7.90-8.07 (1H, br), 8.18 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.4Hz), 9.72 (1H, br.s)
MS(ESI)m/z：571[(M+H)+, 3 × Cl35], 573 [(M+H)+, 2 × Cl35, Cl37], 575 [(M+H)+, Cl35, 2 × Cl37].
[reference example 454] 2- [((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) amino] -2- (methoxyimino) methyl acetate
Figure G2003801097466D02741
The compound (435mg) and 2- (methoxyimino) -2- (methyl sulphonyl) methyl acetate (WO 99/67209) (233mg) that reference example 144 is obtained are dissolved in tetrahydrofuran (5ml); triethylamine (332 μ l) is added in the solution, is stirred all night in 70 DEG C.The lower concentration of reaction solution of decompression, adds dichloromethane and saturated sodium bicarbonate aqueous solution carries out a point liquid, oil reservoir anhydrous sodium sulfate drying.After concentration, residue obtained use silica gel column chromatography (dichloromethane: methanol=91；9) refine, obtain title compound (111mg).
1H-NMR(CDCl3)δ：1.42-2.10 (6H, m), 2.52 (3H, s), 2.70-3.10 (11H, m), 3.71 (2H, br.s), 3.83 (3H, s), 3.84 (3H, s), 4.22-4.35 (1H, m), 4.55-4.65 (1H, m), 5.16 (1H, d, J=8.8Hz), 7.25-7.30 (1H, m)
MS(ESI)m/z：481(M+H)+.
[reference example 455] N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- { 5- [2- (trimethyl silyl) acetenyl] pyridine -2- bases } oxalamide
The compound (658mg) that embodiment 204 is obtained is dissolved in tetrahydrofuran (10ml), N, in dinethylformamide (10ml) and triethylamine (20ml), triphenyl phasphine (87mg), trimethylsilyl acetylene (471 μ l) and acid chloride (50mg) are added, is stirred 14 hours in 80 DEG C in argon atmospher.Diatomite filtering reacting liquid is used, is fully washed with dichloromethane.Add water progress point liquid in filtrate, and organic layer activated carbon (about 3g) decolourizes, and uses anhydrous sodium sulfate drying.Solvent is boiled off under being depressurized after filtering, residue (dichloromethane: methanol=93: 7) is refined with silica gel column chromatography, obtains title compound (360mg).
1H-NMR(CDCl3)δ：0.25 (9H, s), 1.66-2.13 (6H, m), 2.52 (3H, s), 2.78-2.96 (8H, m), 3.05 (3H, s), 3.70 (1H, d, J=15.4Hz), 3.73 (1H, d, J=15.4Hz), 4.08-4.15 (1H, m), 4.66-4.69 (1H, m), 7.42 (1H, d, J=8.4Hz), 7.77 (1H, dd, J=8.4, 2.1Hz), 8.03 (1H, d, J=8.1Hz), 8.13 (1H, d, J=8.8Hz), 8.43 (1H, d, J=2.1Hz), 9.74 (1H, s)
MS(ESI)m/z：610(M+H)+.
[reference example 456] 5- methyl -5,6- dihydro -4H- thienos [2,3-c] pyrroles's -2- carboxylate methyl esters
Figure G2003801097466D02751
By 4, double (chloromethyl) -2-Thiophene Carboxylic Acid methyl esters (the D.J.Zwanenburg and Hans wynberg of 5-, J.Org.Chem., 34,333-340, (1969)) (520mg) be dissolved in acetonitrile (600ml), adds methylamine (40% methanol solution, 722 μ l), stir 3 days at room temperature.Solvent is boiled off under decompression, residue (dichloromethane: methanol=1: 0 → 19: 1) is refined with silica gel column chromatography, obtains title compound (176mg).
1H-NMR(CDCl3)δ：2.63 (3H, s), 3.82-3.83 (2H, m), 3.86 (3H, s), 3.97-3.99 (2H, m), 7.51 (1H, s)
MS(ESI)m/z：198(M+H)+.
The chloro- N- of [reference example 457] 2- (6- chlorine pyridazine -3- bases) acetamide
3- amino -6- chlorine pyridazines (10.4g) are dissolved in DMF (200ml), chloracetyl chloride (7.48ml) is added and stirs 1 hour at room temperature.Solvent is boiled off under decompression, ethyl acetate and saturated sodium bicarbonate aqueous solution are added in residue.The solid that leaching is separated out, with ethyl acetate and water washing, obtains title compound (9.39g).
1H-NMR(CDCl3)δ：4.30 (2H, s), 7.56 (1H, d, J=9.3Hz), 8.51 (1H, d, J=9.3Hz), 9.68 (1H, br.s)
[reference example 458] S- { 2- [(6- chlorine pyridazine -3- bases) amino] -2- oxoethyls } thiosulfuric acid sodium salt
Using the method same with reference example 353, the compound obtained by reference example 457 prepares title compound.
1H-NMR(DMSO-d6)δ：3.84 (2H, s), 7.87 (1H, d, J=9.4Hz), 8.36 (1H, d, J=9.4Hz), 11.21 (1H, br.s)
[reference example 459] (1R; 2S, 5S) -2- ({ 2- [(6- chlorine pyridazine -3- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 427, the compound that the compound obtained by reference example 458 and reference example 144 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.35-1.58 (10H, m), 1.71-1.80 (1H, m), 1.86-1.94 (2H, m), 2.09 (1H, br.s), 2.30 (1H, br.s), 2.96 (3H, s), 3.08 (3H, s), 4.36 (2H, br.s), 4.79 (1H, br.s), 5.30 (1H, br.s), 7.54 (1H, d, J=9.0Hz), 8.47 (1H, d, J=9.0Hz), 10.03 (1H, br.s), 11.03 (1H, s)
[reference example 460] (1S, 3R, 4S) -3- amino -4- (2- [(6- chlorine pyridazine -3- bases)] amino] and -2- oxos ethanethioyl } amino)-N, N- dimethyl cyclohexane carboxamide hydrochlorides
Figure G2003801097466D02763
Using the method same with reference example 69, the compound obtained by reference example 459 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.53 (1H, m), 1.73-1.85 (3H, m), 2.03-2.07 (1H, m), 2.15-2.24 (1H, m), 2.82 (3H, s), 3.08 (3H, s), 3.32-3.37 (1H, m), 4.06 (1H, br.s), 4.39 (1H, br.s), 8.01 (1H, d, J=9.3Hz), 8.37 (1H, d, J=9.3Hz), 8.43 (3H, br.s), 11.11 (1H, d, J=6.6Hz), 11.37 (1H, s)
MS(FAB)m/z：385[(M+H)+, Cl35], 387 [(M+H)+, Cl37].
The chloro- N- of [reference example 461] 2- (6- chloropyridine -3- bases) acetamide
Using the method same with reference example 457, title compound is prepared by 5- Amino-2-Chloropyridines.
1H-NMR(CDCl3)δ：4.22 (2H, s), 7.34 (1H, d, J=8.5Hz), 8.14 (1H, dd, J=8.5,2.7Hz), 8.30 (1H, br.s), 8.45 (1H, d, J=2.7Hz)
[reference example 462] S- { 2- [(6- chloropyridine -3- bases) amino] -2- oxoethyls } thiosulfuric acid sodium salt
Using the method same with reference example 353, the compound obtained by reference example 461 prepares title compound.
1H-NMR(DMSO-d6)δ：3.77 (2H, s), 7.47 (1H, d, J=8.8Hz), 8.04 (1H, dd, J=8.8,2.7Hz), 8.57 (1H, d, J=2.7Hz), 10.51 (1H, s)
[reference example 463] (1R; 2S, 5S) -2- ({ 2- [(6- chloropyridine -3- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Using the method same with reference example 427, the compound that the compound obtained by reference example 462 and reference example 144 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, br.s), 1.60-2.23 (6H, m), 2.68 (1H, br.s), 2.96 (3H, s), 3.08 (3H, s), 4.34-4.38 (2H, m), 4.78 (1H, m), 7.33 (1H, d, J=8.5Hz), 8.09 (1H, br.s), 8.63 (1H, s), 9.91 (1H, br.s), 10.24 (1H, s)
MS(ESI)m/z：506[(M+Na)+, Cl35], 508 [(M+Na)+, Cl37].
[reference example 464] (1S, 3R, 4S) -3- amino -4- ({ 2- [(6- chloropyridine -3- bases) amino] -2- oxos ethanethioyl } amino)-N, N- dimethyl cyclohexane carboxamide hydrochlorides
Figure G2003801097466D02781
Using the method same with reference example 69, the compound obtained by reference example 463 prepares title compound.
1H-NMR(DMSO-d6)δ：1.46-1.49 (1H, m), 1.79-1.81 (3H, m), 1.99-2.03 (1H, m), 2.14-2.16 (1H, m), 2.82 (3H, s), 3.06 (3H, s), 3.25-3.28 (1H, m), 3.99 (1H, br.s), 4.30-4.60 (1H, br), 7.55 (1H, d, J=8.7Hz), 8.26 (1H, dd, J=8.7,2.4Hz), 8.38 (3H, br.s), 8.85 (1H, d, J=2.4Hz), 10.90 (1H, d, J=6.8Hz), 11.07 (1H, s)
MS(FAB)m/z：384[(M+H)+, Cl35], 386 [(M+H)+, Cl37].
[reference example 465] 2 '-amino-sulfonyl -1,1 '-biphenyl-4-carboxylic acid
Figure G2003801097466D02782
2- bromophenylsulfonyls amine (800mg) and 4- carboxyphenyl boronic acids (563mg) is set to be suspended in the in the mixed solvent of toluene (5ml)-water (5ml).Four (triphenyl phasphine) palladiums (392mg) and natrium carbonicum calcinatum (1.08g) are sequentially added in the reaction solution, is heated to reflux all night.It is cooled to after room temperature, adds ether and water carries out a point liquid, organic layer is extracted 2 times with water.Merge all water layers obtained, 12N aqueous hydrochloric acid solution is added in the solution makes solution in acidity.About 20ml is concentrated under decompression, the colourless powder that leaching is separated out, the lower drying of decompression obtains title compound (539mg).
MS(EI)m/z：277M+.
[reference example 466] 2- [(5- picoline -2- bases) amino] -2- oxoacetic acid methyl esters
Figure G2003801097466D02791
Using the method same with reference example 242, title compound is prepared by 2- amino -5- picolines and chlorine oxoacetic acid methyl ester.
1H-NMR(CDCl3)δ：2.33 (3H, s), 3.98 (3H, s), 7.57 (1H, dd, J=8.4,2.0Hz), 8.14 (1H, d, J=8.4Hz), 8.17 (1H, d, J=2.0Hz)
MS(ESI)m/z：195(M+H)+.
[reference example 467] 2- [(5- picoline -2- bases) amino] -2- Oxoacetic Acid lithium salts
Using the method same with reference example 266, the compound obtained by reference example 466 prepares title compound.
1H-NMR(DMSO-d6)δ：2.25 (3H, s), 7.63 (1H, d, J=8.2Hz), 8.00 (1H, d, J=8.2Hz), 8.15 (1H, s), 10.00 (1H, br.s)
MS(FAB)m/z：181(M-Li+2H)+.
[reference example 468] 2- oxos -2- (4- toluene amido) methyl acetate
Using the method same with reference example 242, title compound is prepared by para-totuidine and chlorine oxoacetic acid methyl ester.
MS(ESI)m/z：194(M+H)+.
[reference example 469] (1R, 2S, 5S) -5- [(dimethylamino) carbonyl] -2- { [2- oxos -2- (4- toluene amido) acetyl group] amino } Cyclohexylamino t-butyl formate
Using the method same with reference example 91, the condensation for the compound that the lithium salts and reference example 144 of the carboxylic acid as obtained by will hydrolyze the ester that reference example 468 is recorded are obtained prepares title compound.
MS(ESI)m/z：447(M+H)+.
[reference example 470] 4- bromomethyl -3- chlorothiophene -2- carboxylate methyl esters
N- bromines succinimide (3.56g) and α are added in carbon tetrachloride (40ml) solution of the chloro- 4- methyl of 3- -2-Thiophene Carboxylic Acid methyl esters (3.81g), α '-azodiisobutyronitrile (200mg), is heated to reflux 2.5 hours.Filter off after insoluble matter, the lower concentration filtrate of decompression, residue (ethyl acetate: hexane=1: 19 → 1: 9) is refined with silica gel column chromatography, obtains the title compound (2.92g) in yellow oil.
1H-NMR(CDCl3)δ：3.91 (3H, s), 4.46 (2H, s), 7.59 (1H, s)
MS(ESI)m/z：269(M+H)+.
[reference example 471] 4- { [(tert-butoxycarbonyl) (methyl) amino] methyl } chloro- 2-Thiophene Carboxylic Acids of -3-
Figure G2003801097466D02803
In tetrahydrofuran (30ml) solution of methylamine (2 mol/Ls, tetrahydrofuran solution, 27ml), with tetrahydrofuran (50ml) solution for instilling the compound (2.92g) that reference example 470 is obtained for 30 minutes.After stirring 1 hour at room temperature, half of reaction solution or so is concentrated under decompression, di-tert-butyl dicarbonate (3.0g) is added, was stirred at room temperature with 75 minutes.The lower concentration of reaction solution of decompression, ethyl acetate is added in residue and places an evening.Add water separation organic layer, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=99: 1 → 19: 1) is refined with silica gel column chromatography, obtains colorless oil (4.0g).Water (5ml) and sodium hydroxide (1.2g) are added in methanol (35ml) solution of the grease (4.0g), is stirred 30 minutes at room temperature.The lower concentration of reaction solution of decompression, adds after frozen water in residue, makes it in acidity with concentrated hydrochloric acid, be extracted with ethyl acetate, dried with anhydrous magnesium sulfate.The lower concentrated solvent of decompression, adding hexane crystallizes it, obtains the title compound (2.67g) in colourless powder.
1H-NMR(CDCl3)δ：1.48 (9H, s), 2.74 (3H, br.s), 4.14 (2H, br.s), 7.40 (0.5H, br.s), 7.48 (0.5H, br.s)
[reference example 472] (1R, 2S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) Cyclohexylamino t-butyl formate
Using the method same with reference example 68, the condensation of the compound obtained by (1R, 2S) -2- aminocyclohexyls carbamate (WO01/74774) and reference example 266 obtains title compound.
1H-NMR(CDCl3)δ：1.35-1.90 (8H, m), 1.46 (9H, s), 3.97 (1H, br.s), 4.00-4.12 (1H, m), 4.73-4.82 (1H, m), 7.69 (1H, dd, J=8.8,2.5Hz), 7.90 (1H, br.S), (1H, the br.s) of 8.17 (1H, dd, J=8.8,0.55Hz), 8.29 (1H, dd, J=2.5,0.55Hz), 9.76
MS(ESI)m/z：397(M+H)+.
[reference example 473] 5- [(4- aminomethyl phenyls) sulfonyl] -5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D02812
- 2- base amine
In the bromo- 1- of 3- [(4- aminomethyl phenyls) sulfonyl] -4- azepine cyclic ketones in heptan (J.Chem.Soc.Perkin Trans.; nineteen ninety-five; volume 1; page 2355) N of (6.54g); thiocarbamide (1.44g) is added in dinethylformamide (100ml) solution, in 60 DEG C of heating stirrings all night.Boiled off under decompression after solvent, dichloromethane (100ml) is added in residue and saturated sodium bicarbonate aqueous solution (100ml) carries out a point liquid.Water layer is extracted with dichloromethane (100ml), is merged with the organic layer previously obtained, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, in residue obtained middle addition ethyl acetate (100ml), the pale yellow powder that leaching is separated out; obtain the 5- [(4- aminomethyl phenyls) sulfonyl] -5,6,7 as the thing that is roughly refined; 8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D02814
- 2- bases formamide (1.86g).The lower concentration filtrate of decompression, residue obtained use silica gel column chromatography (methanol: dichloromethane=1: 19) refines, obtains 5- [(4- aminomethyl phenyls) sulfonyl] -5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D02821
The mixture (4.01g) of 2- bases formamide and title compound.Merge the mixture and foregoing rough thing, them is suspended in dioxane (50ml), add 3N hydrochloric acid (50ml), be heated to reflux 1 hour.Solvent is boiled off under decompression, dichloromethane (250ml) is added and saturated aqueous sodium carbonate (200ml) carries out a point liquid, after oil reservoir is dried with anhydrous magnesium sulfate, boil off solvent.Diisopropyl ether (100ml) is added in residue, the pale yellow powder that leaching is separated out obtains title compound (4.47g).
1H-NMR(CDCl3)δ：1.75-1.87 (2H, m), 2.40 (3H, s), 2.62 (2H, t, J=5.7Hz), 3.53 (2H, t, J=5.7Hz), 4.37 (2H, s), 4.73 (2H, br.s), (7.25 2H, d, J=8.5Hz), 7.61 (2H, d, J=8.5Hz)
MS(ESI)m/z：324(M+H)+.
[reference example 474] 5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine- 2- base amine hydrobromates
The compound obtained to reference example 473 is equally handled with reference example 291, obtains title compound.
1H-NMR(DMSO-d6)δ：1.95 (2H, br.s), 2.70-2.90 (2H, m), 3.38 (2H, br.s), 4.56 (2H, br.s), 9.07 (3H, br.s)
MS(ESI)m/z：170(M+H)+.
[reference example 475] 5- methyl -5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D02824
- 2- base amine
Figure G2003801097466D02825
The compound (2.73g) that reference example 474 is obtained, which is suspended under methanol, ice cooling in the suspension, adds triethylamine (2.30ml), acetic acid (453 μ l), 37% formalin (668 μ l) and sodium cyanoborohydride (544mg).Saturated sodium bicarbonate aqueous solution (20ml) is added stir at room temperature all night after, is concentrated into solid.Residue (methanol: dichloromethane=3: 17) is refined with silica gel column chromatography.It is roughly refined in gained in thing and adds methanol (100ml) and natrium carbonicum calcinatum (20g), insoluble matter is filtered off after stirring 30 minutes at room temperature.After the lower concentration filtrate of decompression, dichloromethane (250ml) and methanol (50ml) are added in residue, insoluble matter is filtered off.After the lower concentration filtrate of decompression, wash with acetonitrile (100ml) obtained by pale yellow powder, acquisition title compound (1.23g).
1H-NMR(CDCl3)δ：1.70-1.85 (2H, s), 2.38 (3H, s), 2.77 (2H, t, J=5.6Hz), 2.97 (2H, t, J=5.6Hz), 3.65 (2H, s), 4.68 (2H, br.s)
MS(ESI)m/z：184(M+H)+.
The bromo- 5- methyl -5,6 of [reference example 476] 2-, 7,8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D02826
Figure G2003801097466D02831
The compound (1.13g) that reference example 475 is obtained is suspended in water (10ml), is added 48% hydrobromic acid aqueous solution (7.0ml), is stirred under ice-cooling.It is careful in the reaction solution to instill the aqueous solution (3.0ml) containing natrium nitrosum (639mg).After completion of dropping, the suspension is stirred all night at room temperature.Under ice cooling, addition saturated aqueous sodium carbonate is neutralized while dichloromethane (100ml) is added in reaction solution and is stirred.Divide water layer after liquid to be extracted with dichloromethane (100ml), merge organic layer, use anhydrous sodium sulfate drying.Then, (methanol: dichloromethane=3: 47) refined with silica gel column chromatography, obtain the title compound (582mg) in light orange.
1H-NMR(CDCl3)δ：1.70-1.85 (2H, s), 2.38 (3H, s), 2.95-3.05 (4H, m), 3.79 (2H, s)
MS(ESI)m/z：247(M+H)+.
[reference example 477] 5- methyl -5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D02832
- 2- carboxylic acid lithium salts
Figure G2003801097466D02833
Using the method same with reference example 10, the compound obtained by reference example 476 prepares title compound.
1H-NMR(DMSO-d6)δ：1.65 (2H, br.s), 2.23 (3H, s), 2.80-2.97 (4H, m), 3.75 (2H, s)
[reference example 478] 4,4,5- trimethyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl amine
Figure G2003801097466D02834
Pyrrolidines (1.31ml) and the hydrate of p-methyl benzenesulfonic acid 1 (7.48mg) are sequentially added in hexamethylene (5ml) solution of 1,2,2- trimethyl pyrrolidines -3- ketone (1.00g), is heated to reflux 3 days.Place to room temperature, decompression is lower to be concentrated, and obtains 1,2,2- rough trimethyl -3- (pyrrolidin-1-yl) -2,5- dihydro -1H- pyrroles (972mg).Curing amitraz hydrochloride (1.20g) is added in dimethylformamide (10ml) solution for dissolved the compound, is stirred 4 days at room temperature.After the lower concentration of decompression, methanol (50ml) and natrium carbonicum calcinatum (20g) are added in residue, is stirred 1 hour at room temperature, insoluble matter is filtered off, is washed with methanol.The lower concentration filtrate of decompression, (methanol: dichloromethane=1: 99 → 1: 9) is refined with silica gel column chromatography, obtains title compound (580mg).
1H-NMR(CDCl3)δ：1.25 (6H, s), 2.48 (3H, s), 3.83 (2H, s), 4.83 (2H, br.s)
MS(ESI)m/z：184(M+H)+.
[reference example 479] 2- bromo- 4,4,5- trimethyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole
Figure G2003801097466D02841
Using the method same with reference example 476, the compound obtained by reference example 478 prepares title compound.
1H-NMR(CDCl3)δ：1.30 (6H, s), 2.49 (3H, s), 3.91 (2H, s)
MS(ESI)m/z：247(M+H)+.
[reference example 480] 2,3- dihydro -1H- pyrrolo-es [3,4-c] pyridine -6- carboxylic acids
Figure G2003801097466D02842
2- [(4- aminomethyl phenyls) sulfonyl] -2,3- dihydro -1H- pyrrolo-es [3,4-c] pyridine -6- carboxylic acid, ethyl esters (Chem.Commun., 2001, page 1102) are carried out and the same processing of reference example 291, acquisition title compound.
1H-NMR(CDCl3)δ：4.60-4.75 (4H, m), 8.17 (1H, s), 8.78 (1H, s), 9.69 (2H, br.s)
MS(ESI)m/z：165(M+H)+.
[reference example 481] 2- (tert-butoxycarbonyl) -2,3- dihydro -1H- pyrrolo-es [3,4-c] pyridine -6- carboxylic acid lithium salts
Thionyl chloride (3.0ml) is added in methanol (100ml) solution for the compound (1.66g) that reference example 480 is obtained, an evening is heated to reflux.Place and boil off solvent under being depressurized to room temperature, dichloromethane (100ml) is added in residue and saturated sodium bicarbonate aqueous solution (100ml) carries out a point liquid.Dichloromethane (100ml) is added in water layer and di-tert-butyl dicarbonate (1.40g) is stirred 2 hours at room temperature.Divide after liquid, organic layer is dried with anhydrous magnesium sulfate, and solvent is boiled off under decompression.Hexane (50ml) is added in residue, the pale yellow powder that leaching is separated out obtains rough 2- (tert-butoxycarbonyl) -1,3- dihydro-2 h-pyrroles simultaneously [3,4-c] pyridine -6- carboxylate methyl esters (602mg).1N lithium hydroxide aqueous solution (2.20ml) is added in methanol (10ml) solution of the rough thing (564mg), is stirred all night at room temperature.Be concentrated under decompression it is solid, obtain in Sandy solid title compound (591mg).
1H-NMR(DMSO-d6)δ：(1H, the br.s) of 1.46 (9H, br.s), 4.63 (2H, br.s), 4.65 (2H, br.s), 7.93 (0.5H, br.s), 7.96 (0.5H, br.s), 8.40
MS(ESI)m/z：265(M-Li+2H)+.
[reference example 482] 5- (pyridin-4-yl) pyrimidine -2- carboxylate methyl esters
The method recorded using reference example 237, using methanol and thionyl chloride, is made the compound esterification of pyridin-4-yl boric acid and the formation of 5- Bromopyrimidine -2- carboxylic acids, obtains title compound.
1H-NMR(CDCl3)δ：4.12 (3H, s), 7.57 (2H, d, J=6.1Hz), 8.83 (2H, d, J=6.1Hz), 9.18 (2H, s)
MS(ESI)m/z：216(M+H)+.
[reference example 483] 5- (pyridin-4-yl) pyrimidine -2- carboxylic acid lithium salts
Using the method same with reference example 322, the compound obtained by reference example 482 prepares title compound.
1H-NMR(DMSO-d6)δ：(7.85 2H, d, J=6.0Hz), 8.69 (2H, d, J=6.0Hz), 9.12 (2H, s)
MS(ESI)m/z：202(M-Li+2H)+.
[reference example 484] 2 '-methyl-[1,1 '-biphenyl] -4- formaldehyde
Figure G2003801097466D02853
Using the method same with reference example 237, title compound is prepared by 2 bromo toluene and 4- formylphenylboronic acids.
1H-NMR(CDCl3)δ：2.28 (3H, s), 7.20-7.33 (4H, m), 7.50 (2H, d, J=8.2Hz), 7.94 (2H, d, J=8.2Hz), 10.07 (1H, s)
MS(ESI)m/z：197(M+H)+.
[reference example 485] 2 '-methyl-[1,1 '-biphenyl] -4- carboxylic acids
The compound (1.51g) that reference example 484 is obtained is suspended in water (100ml), the tert-butyl alcohol (10ml), 2- methyl-2-butenes (20ml), sodium chlorite (3.67g) and sodium dihydrogen phosphate dihydrate (3.62g) are sequentially added in the suspension, is stirred all night at room temperature.Diisopropyl ether (200ml) is added in reaction solution and carries out a point liquid, organic layer is washed with 3N hydrochloric acid (50ml).Organic layer is dried with anhydrous magnesium sulfate, and solvent is boiled off under decompression.Residue is washed with hexane, obtains the title compound (1.43g) in colourless powder.
1H-NMR(CDCl3)δ：2.29 (3H, s), 7.20-7.35 (4H, m), 7.65 (2H, d, J=8.1Hz), 8.18 (2H, d, J=8.1Hz)
MS(ESI)m/z：213(M+H)+.
[reference example 486] 2 '-methyl-[1,1 '-biphenyl] -4- carboxylate methyl esters
Figure G2003801097466D02862
The compound (1.42g) that reference example 485 is obtained is suspended in methanol, and thionyl chloride (1ml) is added in the suspension and is heated to reflux 2 hours.Place to room temperature, saturated sodium bicarbonate aqueous solution (100ml) is added in reaction solution and dichloromethane (100ml) carries out a point liquid.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, the title compound (1.51g) in colorless oil is obtained.
1H-NMR(CDCl3)δ：2.26 (3H, s), 3.94 (3H, s), 7.20-7.35 (4H, m), 7.40 (2H, d, J=7.8Hz), 8.08 (2H, d, J=7.8Hz)
MS(ESI)m/z：227(M+H)+.
[reference example 487] 2 '-[(dimethylamino) methyl]-[1,1 '-biphenyl] -4- carboxylate methyl esters
Figure G2003801097466D02863
The compound (663mg) that reference example 486 is obtained is dissolved in 1,2- dichloroethanes (30ml), N- bromines succinimide (521mg) and 2 are added in the solution, 2 '-azodiisobutyronitrile (48.1mg) is heated to reflux 1 hour.After reaction terminates, mixture is cooled to 0 DEG C, dimethylamine (40% aqueous solution, 0.99ml) is added, stirred 3 days at room temperature.Water (100ml) is added in the mixture and dichloromethane (100ml) carries out a point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue obtained use silica gel column chromatography (methanol: dichloromethane=1: 25) refines, obtains the title compound (607mg) in colorless oil.
1H-NMR(CDCl3)δ：2.13 (6H, s), 3.31 (2H, s), 3.95 (3H, s), 7.23 (1H, dd, J=7.4,1.5Hz), 7.31 (1H, dt, J=1.5,7.4Hz), 7.37 (1H, dt, J=1.5,7.4Hz), 7.46 (2H, d, J=8.2Hz), 7.52 (1H, dd, J=7.4,1.5Hz), 8.07 (2H, d, J=8.2Hz)
MS(ESI)m/z：270(M+H)+.
[reference example 488] 2 '-[(dimethylamino) methyl]-[1,1 '-biphenyl] -4- carboxylic acid lithium salts
Figure G2003801097466D02871
Using the method same with reference example 322, the compound obtained by reference example 487 prepares title compound.
1H-NMR(DMSO-d6)δ：2.06 (6H, s), 3.29 (2H, s), 7.20-7.38 (5H, m), 7.49 (1H, d, J=7.3Hz), 7.88 (2H, d, J=8.0)
MS(ESI)m/z：256(M-Li+2H)+.
[reference example 489] 4- [4- (methoxycarbonyl) phenyl] -2- methyl isophthalic acids-pyridine N-oxides
Figure G2003801097466D02872
The method recorded using reference example 239, title compound is obtained by 4- (2- picoline -4- bases) methyl benzoate (Japanese Patent Laid-Open 2000-143623).
1H-NMR(CDCl3)δ：2.60 (3H, s), 3.96 (3H, s), 7.42 (1H, dd, J=6.8,2.7Hz), 7.53 (1H, d, J=2.7Hz), 7.66 (2H, d, J=8.2Hz), 8.14 (2H, d, J=8.2Hz), 8.3
3 (1H, d, J=6.8Hz)
MS(FAB)m/z：244(M+H)+.
[reference example 490] 4- { 2- [(acetoxyl group) methyl] pyridin-4-yl } methyl benzoate
Figure G2003801097466D02881
The stirring of 30 minutes is carried out in acetic anhydride (25ml) solution of 130 DEG C of compounds (980mg) obtained to reference example 489.It is cooled to after 90 DEG C, adds methanol (50ml) and stir 1 hour.Added in reaction solution after dichloromethane (50ml) and saturated sodium bicarbonate aqueous solution (150ml), add the sodium acid carbonate of solid until reaction solution is in alkalescence.Stirring divides liquid after 3 hours, water layer is extracted with dichloromethane (2 × 50ml).Merge organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue obtained use silica gel column chromatography (dichloromethane: methanol=40: after 1 → 10: 1) refining, (hexane: ethyl acetate=2: 1 → 1: 1) refine for the middle compression leg chromatography of carrier to silica gel, obtain the title compound (749mg) of white solid.
1H-NMR(CDCl3)δ：2.19 (3H, s), 3.96 (3H, s), 5.29 (2H, s), 7.47 (1H, dd, J=5.1,1.7Hz), and 7.57-7.60 (1H, m), 7.70 (2H, d, J=8.5Hz), 8.15 (2H, d, J=8.5Hz), 8.68 (1H, d, J=5.1Hz) .MS (ESI) m/z：286(M+H)+.
[reference example 491] 4- (2- { [(tert-butoxycarbonyl) amino] methyl } pyridin-4-yl) methyl benzoate
At room temperature, water (1.0ml) and lithium hydroxide (137mg) are added in tetrahydrofuran (4.0ml) solution for the compound (532mg) that reference example 490 is obtained.After stirring 24 hours, tetrahydrofuran is boiled off under decompression, water (4.0ml) and 1N hydrochloric acid (5.65ml) is added.It is washed with water after the solid of leaching generation, white solid (400mg) is obtained after drying.A part (272mg) for the solid is suspended in tetrahydrofuran (10ml), methanol (2.0ml) and trimethyl silyl diazomethane (2.0M hexane solutions, 890 μ l) are added at room temperature.After stirring 1 hour, the lower concentration of reaction solution of decompression.At room temperature, ethyl acetate (5.0ml), trimethylamine hydrochloride (12mg), mesyl chloride (140 μ l) and triethylamine (252 μ l) are added in dichloromethane (10ml) solution of gained solid.Stirring adds saturated sodium bicarbonate aqueous solution (20ml) after 3 hours and dichloromethane (20ml) carries out a point liquid, and water layer is extracted with dichloromethane (2 × 15ml).Merge organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.At room temperature, sodium azide (155mg) is added in DMF (5.0ml) solution of gained reddish violet grease.Stirring adds water (100ml) after 1 hour and dichloromethane (30ml) carries out a point liquid, and water layer is extracted with dichloromethane (3 × 20ml).Merge organic layer, after anhydrous sodium sulfate drying, add dioxane (5.0ml), about 5ml is concentrated under decompression.Tetrahydrofuran (5.0ml), di-tert-butyl dicarbonate (400mg) and 10% palladium carbon (100mg) are added in the dark brown solution of gained, is stirred at room temperature under a hydrogen atmosphere 14 hours.Lower concentration filtrate is depressurized after filtering reacting liquid, residue (dichloromethane: acetone=20: 1) is refined with silica gel column chromatography, obtains the title compound (270mg) in pale yellow oil.
1H-NMR(CDCl3)δ：1.48 (9H, s), 3.96 (3H, s), 4.52 (2H, d, J=5.4Hz), 4.94 (0.5H, br.s), 5.59 (0.5H, br.s), 7.42 (1H, dd, J=5.1,1.7Hz), 7.51 (1H, br.s), 7.69 (2H, d, J=8.3Hz), 8.15 (2H, d, J=8.3Hz), 8.61 (1H, d, J=5.1Hz)
MS(ESI)m/z：343(M+H)+.
[reference example 492] 1- (phenyl sulfonyl) piperidines -4- carboxylic acid, ethyl esters
Figure G2003801097466D02891
Triethylamine (1.40ml) is added in tetrahydrofuran (10ml) solution of hexahydro iso-nicotinic acid ethyl ester (1.08ml), benzene sulfonyl chloride (1.02ml) is added in 0 DEG C, is stirred 21 hours at room temperature.Then, stirring on the rocks 10 minutes, add ethyl acetate and 0.5N hydrochloric acid, reaction solution is divided into 2 layers.After organic layer is washed with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, it is concentrated under reduced pressure with anhydrous sodium sulfate drying.Residue (hexane: ethyl acetate=4: 1 → 2: 1) is refined with silica gel column chromatography, obtains the title compound (1.66g) of white solid.
1H-NMR(CDCl3)δ：1.21 (3H, t, J=7.1Hz), 1.76-1.87 (2H, m), 1.92-2.01 (2H, m), 2.20-2.29 (1H, m), 2.49 (2H, dt, J=2.9,11.4Hz), 3.59-3.67 (2H, m), 4.10 (2H, q, J=7.1Hz), 7.51-7.63 (3H, m), 7.74-7.78 (2H, m)
MS(ESI)m/z：298(M+H)+.
[reference example 493] 1- (phenyl sulfonyl) piperidines -4- carboxylic acids
Figure G2003801097466D02892
Using the method same with reference example 274, the compound obtained by reference example 492 prepares title compound.
1H-NMR(CDCl3)δ：1.74-1.90 (2H, m), 1.90-2.04 (2H, m), 2.23-2.33 (1H, m), 2.39-2.54 (2H, m), 3.58-3.72 (2H, m), 7.48-7.64 (3H, m), 7.67-7.80 (2H, m)
MS(ESI)m/z：270(M+H)+.
[reference example 494] 1- (4- fluorobenzoyls) piperidines -4- carboxylic acid, ethyl esters
Using the method same with reference example 492, title compound is prepared by hexahydro iso-nicotinic acid ethyl ester and to fluorobenzoyl chloride.
1H-NMR(CDCl3)δ：1.27 (3H, t, J=7.1Hz), 1.60-2.10 (4H, br), 2.54-2.62 (1H, m), 2.95-3.13 (2H, m), 3.55-3.90 (1H, br), 4.16 (2H, q, J=7.1Hz), 4.30-4.70 (1H, br), 7.09 (2H, t, J=8.8Hz), 7.41 (2H, dd, J=8.8,5.4Hz)
MS(ESI)m/z：280(M+H)+.
[reference example 495] 1- (4- fluorobenzoyls) piperidines -4- carboxylic acids
Figure G2003801097466D02902
Using the method same with reference example 274, the compound obtained by reference example 494 prepares title compound.
1H-NMR(CDCl3)δ：1.60-2.20 (4H, br), 2.57-2.68 (1H, m), 2.98-3.20 (2H, m), 3.55-4.00 (1H, br), 4.25-4.65 (1H, br), 7.09 (2H, t, J=8.5Hz), 7.40 (2H, dd, J=8.5,5.4Hz)
MS(ESI)m/z：252(M+H)+.
[reference example 496] 4- (pyrrolidin-1-yl carbonyl) methyl benzoate
Using the method same with reference example 492, title compound is obtained by pyrrolidines and the methyl esters acyl chlorides of terephthalic acid (TPA) one.
1H-NMR(CDCl3)δ：1.85-1.93 (2H, m), 1.94-2.01 (2H, m), 3.38 (2H, t, J=6.6Hz), 3.66 (2H, t, J=6.6Hz), 3.94 (3H, s), (7.57 2H, d, J=8.6Hz), 8.07 (2H, d, J=8.6Hz)
MS(ESI)m/z：234(M+H)+.
[reference example 497] 4- (pyrrolidin-1-yl carbonyl) benzoic acid
Figure G2003801097466D02911
Using the method same with reference example 274, the compound obtained by reference example 496 prepares title compound.
1H-NMR(CDCl3)δ：1.85-2.03 (4H, m), 3.43 (2H, t, J=6.6Hz), 3.67 (2H, t, J=6.6Hz), 7.61 (2H, d, J=8.6Hz), 8.14 (2H, d, J=8.6Hz)
MS(ESI)m/z：220(M+H)+.
[reference example 498] 4- (pyrrolidin-1-yl methyl) methyl benzoate
Figure G2003801097466D02912
The compound that reference example 496 is obtained is carried out and the same processing of reference example 212, acquisition title compound.
1H-NMR(CDCl3)δ：1.75-1.84 (4H, m), 2.47-2.56 (4H, m), 3.37 (2H, s), 3.90 (3H, s), 7.41 (2H, d, J=8.3Hz), 7.98 (2H, d, J=8.3Hz)
MS(ESI)m/z：220(M+H)+.
[reference example 499] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(methylamino) carbonyl] Cyclohexylamino formic acid 9H- fluorenes -9- base methyl esters
Add and be stirred at room temperature in 10% palladium-carbon catalyst (117mg), nitrogen atmosphere 3 hours in methanol (20ml) solution for the compound (823mg) that reference example 436 is obtained.With glass filter filtration catalytic agent, be concentrated under reduced pressure filtrate.The 1 of the colourless sticky oil thing (622mg) of gained, saturated sodium bicarbonate aqueous solution (5ml), water (2ml), succinimide yl carboxylic acid fluorenes -9- bases methyl esters (867mg) are added in 2- dimethoxy-ethanes (15ml) solution, is stirred 13 hours at room temperature.Ethyl acetate dilute reaction solution is used, adds water and is divided into 2 layers.After organic layer is washed with saturated sodium-chloride water solution, it is concentrated under reduced pressure with anhydrous sodium sulfate drying.Add ethyl acetate in residue to carry out after slurry washing, leaching white powder.In addition, slurry washing, leaching white powder are carried out after the mother liquor that is concentrated under reduced pressure with ether.The powder of leaching is dissolved in after ethyl acetate, is mixed, is boiled off solvent under decompression, dried with vavuum pump, the title compound (939mg) of white powder is obtained.
1H-NMR(CDCl3)δ：1.46 (9H, br.s), 1.60-1.74 (1H, m), 1.78-1.92 (2H, m), 1.92-2.07 (2H, m), 2.10-2.26 (1H, m), 2.81 (3H, d, J=4.9Hz), 3.62-3.77 (1H, br), 3.85-4.63 (5H, m), 5.30-5.67 (2H, br), 7.24-7.33 (2H, m), (7.39 2H, t, J=7.6Hz), (7.58 2H, br.d, J=7.1Hz), 7.76 (2H, d, J=7.6Hz)
MS(ESI)m/z：394(M-COOtBu)+.
[reference example 500] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(methylamino) thioformyl] Cyclohexylamino formic acid 9H- fluorenes -9- base methyl esters
Using the method same with reference example 443, the compound obtained by reference example 499 prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, br.s), 1.55-2.10 (6H, m), 2.45-2.72 (1H, br), 3.17 (3H, d, J=4.4Hz), 3.65-3.77 (1H, br), 3.78-3.88 (0.5H, m), 4.00-4.65 (4H, br), 4.75-5.25 (0.5H, br), 5.30-5.60 (0.5H, br), 6.85-7.00 (0.5H, br), 7.25-7.34 (2H, m), 7.39 (2H, t, J=7.6Hz), 7.42-7.53 (0.5H, br), 7.58 (2H, br.d, J=6.6Hz), 7.75 (2H, d, J=7.6Hz), 7.80-7.90 (0.5H, br)
MS(ESI)m/z：410(M-COOtBu)+.
[reference example 501] (1R; 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(methylamino) thioformyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02922
Using the method same with reference example 444, the compound obtained by reference example 500 prepares title compound.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.50-1.70 (1H, m), 1.80-2.16 (5H, m), 2.60-2.75 (1H, br), 3.19 (3H, d, J=4.9Hz), 3.94-4.05 (1H, br), 4.10-4.28 (1H, br), 4.80-5.00 (0.8H, br), 5.75-5.90 (0.2H, br), 7.40-7.55 (1H, br), 7.68 (1H, dd, J=8.8, 2.2Hz), 7.96-8.07 (1H, br), 8.17 (1H, d, J=8.8Hz), 8.30 (1H, d, J=2.0Hz), 9.76 (1H, s)
MS(ESI)m/z：414(M-tBu+H)+.
[reference example 502] 2,2- bis- chloro- N- (5- chlorine pyrimidine -2-base) acetamide
Figure G2003801097466D02931
Dichloroacetyl chloride (1.44ml) and sodium acid carbonate (1.26g) are added in DMF (30ml) solution of 2- amino -5- chlorine pyrimidines (1.30g), is stirred 1 hour at room temperature.Solvent is boiled off under decompression, dichloromethane is added in residue and water carries out a point liquid.Dichloromethane aqueous layer extracted is used, merges organic layer and is washed with water, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=1: 1) is refined to silica gel for the flash column chromatography of carrier.Gained white solid carries out leaching after slurry washing with the mixed solvent of hexane-ether (4: 1), obtains the title compound (1.24g) of white solid.
1H-NMR(CDCl3)δ：6.43 (1H, br.s), 8.65 (2H, s), 9.07 (1H, br.s)
MS(ESI)m/z：240(M+H)+.
[reference example 503] (1R; 2S, 5S) -2- ({ 2- [(5- chlorine pyrimidine -2-base) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
In N, the compound (8.03g) of the acquisition of reference example 144, the compound (6.76g) that reference example 502 is obtained, sulphur (947mg) are added in dinethylformamide (90ml), in 120 DEG C of heating, add at diisopropylethylamine (9.57ml), identical temperature and stir 10 minutes in the mixture.Solvent is boiled off under decompression, dichloromethane is added in residue, insoluble matter is filtered to remove with diatomite.Add water a point liquid in filtrate, and organic layer is washed with water.(dichloromethane: methanol=19: 1) refine by flash column chromatography using silica gel as carrier, the gained thing that is roughly refined is dissolved in dichloromethane, hexane leaching solid is added, obtains the title compound (940mg) in faint yellow solid.In addition, filtrate is refined with silica gel column chromatography, the title compound (940mg) containing DMF in Sandy solid is obtained.
1H-NMR(DMSO)δ：1.28-2.22 (15H, m), 2.71 (1H, br.s), 2.96 (3H, s), 3.07 (3H, s), 4.25-4.42 (2H, m), 8.62 (2H, s), 9.88 (1H, br.s), 10.89 (1H, s)
The chloro- N- of [reference example 504] 2- (the chloro- 3- nitrobenzophenones of 4-) acetamide
Figure G2003801097466D02941
Using the method same with reference example 502, title compound is prepared by the chloro- 3- nitroanilines of 4- and chloracetyl chloride.
1H-NMR(CDCl3)δ：4.23 (2H, s), 7.54 (1H, d, J=8.8Hz), 7.74 (1H, dd, J=8.8,2.4Hz), 8.22 (1H, d, J=2.4Hz), 8.39 (1H, br.s)
[reference example 505] (1R, 2S, 5S) -2- { [2- (the chloro- 3- nitrobenzene amidos of 4-) -2- oxos ethanethioyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02942
Sulphur (128mg), triethylamine (833 μ l) are added in DMF (4ml) solution for the compound (498mg) that reference example 504 is obtained, is stirred 1 hour at room temperature.Compound (571mg) and 3- (3- dimethylaminopropyls) -1- ethyl-carbodiimide hydrochlorides (767mg) that reference example 144 is obtained are added in reaction solution, an evening is stirred at room temperature.Solvent is boiled off under decompression, dichloromethane and moisture liquid are added in residue, dichloromethane aqueous layer extracted is used.Merge organic layer to be washed with water, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Refined to silica gel for the flash column chromatography (ethyl acetate) of carrier, obtain the title compound (688mg) in yellow solid.
1H-NMR(CDCl3)δ：1.47 (9H, m), 1.48-1.59 (1H, m), 1.72-1.81 (1H, m), 1.86-1.95 (2H, m), 2.04 (1H, br.s), 2.23 (1H, br.s), 2.69 (1H, br.s), 2.96 (3H, s), 3.09 (3H, s), 4.34-4.39 (2H, m), 4.78 (1H, br.s), (7.52 1H, d, J=8.6Hz), (7.69 1H, d, J=8.6Hz), 8.39 (1H, br.s), 9.95 (1H, br.s), 10.37 (1H, s)
MS(ESI)m/z：528(M+H)+.
[reference example 506] (1S, 3R, 4S) -3- [(tert-butoxycarbonyl) amino] -4- { [(7- chlorine cinnolines -3- bases) carbonyl] amino } cyclohexanecarboxylate
It is same with reference example 97, make the compound that reference example 96 is obtained and the compound condensation that reference example 298 is obtained, prepare title compound.
1H-NMR(CDCl3)δ：1.28 (3H, t, J=7.2Hz), 1.36 (9H, s), 1.53-2.16 (6H, m), 2.48 (1H, br.s), 4.17 (2H, q, J=7.2Hz), 4.30-4.35 (2H, m), 4.86 (1H, br.s), 7.78 (1H, dd, J=8.8,2.0Hz), 7.97 (1H, d, J=8.8Hz), 8.59-8.60 (1H, m), 8.64 (1H, d, J=8.6Hz), 8.73 (1H, s)
MS(ESI)m/z：477(M+H)+.
[reference example 507] (1S, 3R, 4S) -3- [(tert-butoxycarbonyl) amino] -4- { [(7- chlorine cinnolines -3- bases) thioformyl] amino } cyclohexanecarboxylate
Using the method same with reference example 443, the compound obtained by reference example 506 prepares title compound.
1H-NMR(CDCl3)δ：1.28 (3H, t, J=7.1Hz), 1.37 (9H, br.s), 1.59-2.26 (6H, m), 2.49 (1H, br.s), 4.17 (2H, q, J=7.1Hz), 4.54 (1H, br.s), 4.83-4.87 (2H, m), 7.76 (1H, dd, J=8.7,1.8Hz), 7.97 (1H, d, J=8.7Hz), 8.57 (1H, s), 9.20 (1H, s), 10.64 (1H, br.s)
MS(ESI)m/z：493(M+H)+.
[reference example 508] (1R, 2S, 5S) -2- { [(7- chlorine cinnolines -3- bases) thioformyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02961
Using the method same with reference example 251, the compound that hydrolysis reference example 507 is obtained makes gained carboxylic acid and dimethylamine hydrochloride condensation, prepares title compound.
1H-NMR(CDCl3)δ：1.37 (9H, br.s), 1.66 (1H, br.s), 1.82-2.05 (4H, m), 2.29-2.32 (1H, m), 2.76 (1H, br.s), 2.97 (3H, s), 3.09 (3H, s), 4.56-4.59 (1H, m), 4.90 (2H, br.s), 7.75 (1H, dd, J=8.7,2.0Hz), 7.97 (1H, d, J=8.7Hz), 8.56 (1H, s), 9.19 (1H, br.s), 10.60 (1H, d, J=7.8Hz)
MS(ESI)m/z：492(M+H)+.
[reference example 509] (1S, 3R, 4S) -3- amino -4- { [(7- chlorine cinnolines -3- bases) thioformyl] amino }-N, N- dimethyl cyclohexane formamides
Using the method same with reference example 325, title compound is prepared by the compound of the gained of reference example 508.
MS(ESI)m/z：392(M+H)+.
[reference example 510] (1R, 2S, 5S) -2- ({ [(4- chlorobenzoyls) amino] carbonyl } amino) -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02971
Oxalyl chloride (435 μ l) is added in chlorobenzamide (311mg) dichloroethanes (20ml) solution, is heated to reflux 3 hours.Solvent is boiled off under decompression, in acetonitrile (20ml) solution that acetonitrile (10ml) solution of residue is instilled to the compound (571mg) that reference example 144 is obtained, is stirred 10 minutes at room temperature.Solvent is boiled off under decompression, ether leaching solid is added in residue, the title compound of white solid is obtained.
1H-NMR(CDCl3)δ：1.42 (9H, s), 1.52-2.01 (6H, m), 2.68 (1H, br.s), 2.95 (3H, s), 3.08 (3H, s), 3.95 (1H, br.s), 4.29 (1H, br.s), 4.84 (1H, br.s), 7.41 (2H, d, J=8.3Hz), 7.88 (2H, br.s), 8.92 (1H, d, J=7.6Hz), 9.78 (1H, s)
MS(ESI)m/z：489(M+Na)+.
[reference example 511] (1S, 3R, 4S) -3- amino -4- ({ [(4- chlorobenzoyls) amino] carbonyl } amino)-N, N- dimethyl cyclohexane formamides
Using the method same with reference example 325, the compound obtained by reference example 510 prepares title compound.
1H-NMR(CDCl3)δ：1.51 (2H, br.s), 1.67-1.96 (6H, m), 2.90 (1H, br.s), 2.95 (3H, s), 3.08 (3H, s), 3.44 (1H, br.s), 3.93 (1H, br.s), 7.47 (2H, d, J=8.5Hz), 7.86 (2H, d, J=8.5Hz), 8.85 (1H, br.s), 8.93 (1H, d, J=7.3Hz)
MS(ESI)m/z：367(M+H)+.
[reference example 512] (E) -3- (5- chloropyridine -2- bases) -2- methyl acrylates
In -30 DEG C; tetrahydrofuran (30ml) solution of 2- (dimethoxyphosphoryl) methyl acetate (2.35ml) is instilled in tetrahydrofuran (30ml) solution for being suspended with sodium hydride (60% oil, 580mg).After being stirred 30 minutes under equality of temperature, tetrahydrofuran (15ml) solution of tetrahydrofuran (10ml) and 5- chloropyridine -2- formaldehyde (J.Med.Chem.1970, volume 13, page 1124) (1.96g) is added.It was slowly ramped to 1 hour after room temperature, adds water (100ml) and ether (50ml) carries out a point liquid, water layer is extracted with ether (50ml).Merge organic layer, after being washed with saturated aqueous common salt (50ml), with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Leaching after hexane (30ml) is stirred 30 minutes is added in gained white solid, the title compound (1.89g) of white solid is obtained.
1H-NMR(CDCl3)δ：3.82 (3H, s), 6.91 (1H, dd, J=15.7,0.9Hz), 7.36 (1H, d, J=8.3Hz), 7.64 (1H, d, J=15.7Hz), 7.68 (1H, ddd, J=8.3,2.4,0.9Hz), 8.59 (1H, d, J=2.4Hz)
MS(ESI)m/z：197(M+).
[reference example 513] (1R, 2S, 5S) -2- { [(E) -3- (5- chloropyridine -2- bases) acryloyl group] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
Figure G2003801097466D02981
Using the method same with reference example 97, gained compound is hydrolyzed the compound obtained using reference example 512, the compound condensation for obtaining the lithium salts and reference example 144 of gained carboxylic acid, obtains title compound.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.65-1.88 (3H, m), 1.88-2.00 (2H, m), 2.05-2.22 (1H, m), 2.65 (1H, br.s), 2.94 (3H, s), 3.05 (3H, s), 4.05 (1H, br.s), 4.10-4.18 (1H, m), 4.78 (1H, br.s), 6.71 (1H, br.s), 6.89 (1H, d, J=15.4Hz), 7.30 (1H, d, J=8.3Hz), 7.54 (1H, d, J=15.4Hz), 7.65 (1H, dd, J=8.3, 2.4Hz), 8.53 (1H, d, J=2.4Hz)
MS(ESI)m/z：451(M+H)+.
The fluoro- 3- hydroxypropionates of [reference example 514] 3- (4- chlorphenyls) -2-
Zinc powder (1.96g) is added in 4- chlorobenzaldehydes (141mg) benzene (20ml) solution, the iodine of catalytic amount is added while being heated to reflux.The benzole soln (2.5ml) of ethyl bromide fluoride (185mg) is instilled wherein, is stirred 2.5 hours.Be cooled with ice reaction solution, adds 1N hydrochloric acid (12.5ml), stirs 1.5 hours at room temperature.Water and ethyl acetate point liquid are added, water layer is extracted with ethyl acetate.Merge organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=3: 1) is refined with preparative thin layer chromatography, obtains the title compound (117mg) of the non-enantiomer mixture in colorless oil.
1H-NMR(CDCl3)δ：1.16-1.24 (3H, m), 3.35 (1H, br.d, J=51.9Hz), 4.15-4.25 (2H, m), 4.89-5.11 (2H, m), 7.31-7.33 (4H, m)
MS(EI)m/z：246(M+).
[reference example 515] (Z) -3- (4- chlorphenyls) -2- perfluoroalkyl acrylate ethyl esters
Figure G2003801097466D02991
Pyridine (100 μ l) is added in dichloromethane (1.0ml) solution for the compound (51mg) that reference example 514 is obtained, in 0 DEG C of cooling, thionyl chloride (20 μ l) is added, is stirred 20 minutes in 0 DEG C.The aqueous hydrochloric acid solution and ethyl acetate for adding 1N carry out a point liquid, aqueous layer with ethyl acetate extraction.Merge organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue is dissolved in dichloromethane (2ml), adds 1,8- diazabicyclos [5.4.0] 11-7- alkene (34 μ l), stirs 3.5 hours at room temperature.1N hydrochloric acid, dichloromethane point liquid is added, water layer is extracted with dichloromethane.Merge organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=4: 1) is refined with preparative thin layer chromatography, obtains the title compound (22mg) in faint yellow solid.
1H-NMR(CDCl3)δ：(1.38 3H, t, J=7.2Hz), 4.35 (2H, q, J=7.2Hz), 6.87 (1H, d, J=34.9Hz), 7.37 (2H, d, J=8.3Hz), 7.57 (2H, d, J=8.3Hz)
[reference example 516] (Z) -3- (4- chlorphenyls) -2- perfluoroalkyl acrylates
Figure G2003801097466D02992
Using the method same with reference example 274, the compound obtained by reference example 515 prepares title compound.
1H-NMR(DMSO-d6)δ：(2H, d, the J=8.2Hz) of 7.06 (1H, d, J=36.4Hz), 7.52 (2H, d, J=8.2Hz), 7.72
MS (ESI- anion) m/z：198(M-H)-.
The trichloro ethyl ester of [reference example 517] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [(dimethylamino) carbonyl] Cyclohexylamino formic acid 2,2,2-
The trichloro ethyl ester (10.6ml) of chloro-carbonic acid 2,2,2- is instilled in pyridine (175ml) solution for the compound (10.0g) that reference example 144 is obtained, an evening is stirred at room temperature.Boil off solvent under decompression, add dichloromethane and 0.5N aqueous hydrochloric acid solution point liquid, gained organic layer washs 2 times with 0.5N aqueous hydrochloric acid solution, then with saturated common salt water washing 1 time.With anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue is dissolved in a small amount of dichloromethane, adds hexane leaching solid.Slurry washing is carried out to it with ether, the title compound (13.6g) of white solid is obtained.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.62-1.97 (6H, m), 2.67 (1H, br.s), 2.94 (3H, s), 3.05 (3H, s), 3.71-3.76 (1H, m), 4.16 (1H, br.s), 4.64-4.86 (3H, m), 5.62 (1H, d, J=7.3Hz)
MS(ESI)m/z：460(M+H)+.
[reference example 518] (1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiazole simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } 2,2,2- trichloro ethyl ester of Cyclohexylamino formic acid
Using the method same with reference example 252, the compound obtained with hydrochloric acid to reference example 517 is handled, after deprotection, is condensed with the compound of gained reference example 10, obtains title compound.
1H-NMR(CDCl3)δ：1.53-2.17 (6H, m), 2.52 (3H, s), 2.74-2.93 (8H, m), 3.03 (3H, s), 3.72 (2H, br.s), 3.83-3.90 (1H, m), 4.62-4.79 (3H, m), (5.65 1H, br.d, J=6.8Hz), 7.36 (1H, br.d, J=8.5Hz)
MS(ESI)m/z：540(M+H)+.
[reference example 519] (1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydrochysenes [1,3] thiazole simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate
Figure G2003801097466D03011
The compound (5.01g) that reference example 518 is obtained is dissolved in ethanol (100ml), the in the mixed solvent of water (5ml), adds zinc (6.06g) and ammonium chloride (2.48g), is stirred 4.5 hours in 40 DEG C.Zinc is filtered off with diatomite, sodium acid carbonate (7.78g) and di-tert-butyl dicarbonate (6.08g) are added in filtrate, an evening is stirred at room temperature.Solvent is boiled off under decompression, dichloromethane and moisture liquid are added in residue, water layer is extracted 2 times with dichloromethane.Merging organic layer anhydrous sodium sulfate drying, boils off solvent under decompression, residue (ethyl acetate: methanol=7: 3) refines for the flash column chromatography of carrier to silica gel, then circulates HPLC (Japanese analytical industry LC908-C60, post with preparing：JAIGEL 1H-40 and 2H-40, solvent：Chloroform) it is refined, obtain the title compound (2.30g) in faint yellow solid.
1H-NMR(CDCl3)δ：1.43 (9H, s), 1.48-2.07 (6H, m), 2.52 (3H, s), 2.70-2.96 (8H, m), 3.00 (3H, s), 3.68-3.77 (3H, m), 4.57-4.60 (1H, m), 4.94 (1H, br.s), 7.33 (1H, br.s)
MS(ESI)m/z：466(M+H)+.
The chloro- N- of [reference example 520] 2,2- bis- (5- chloropyridine -2- bases) acetamide
Using the method same with reference example 457, title compound is prepared by 2- amino -5- chloropyridines.
1H-NMR(CDCl3)δ：6.06 (1H, s), 7.73 (1H, dd, J=8.8,2.4Hz), 8.15 (1H, dd, J=9.0,0.5Hz), 8.30 (1H, dd, J=2.5,0.5Hz), 8.78 (1H, s) .MS (ESI) m/z：239(M+H)+.
[reference example 521] (1R; 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(methylamino) carbonyl] Cyclohexylamino t-butyl formate
10% palladium-carbon catalyst (0.35g) is added in methanol (50ml) solution for the compound (1.01g) that reference example 436 is obtained, is stirred at room temperature in nitrogen atmosphere 16 hours.Filter off the lower concentration filtrate of catalyst decompression.Residue is dissolved in DMF (5.0ml), compound (600mg), diisopropylethylamine (5.0ml) and sulphur (80.3g) that reference example 520 is obtained is added, is stirred 2 hours in 120 DEG C.The lower concentration of reaction solution of decompression, adds water in residue and is extracted 2 times with dichloromethane (200ml).Organic layer is successively with 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, after anhydrous sodium sulfate drying, and decompression is lower to be concentrated.Residue (dichloromethane: methanol=50: 1 → 30: 1) refines for the flash column chromatography of carrier to silica gel, obtains the title compound (812mg) in yellow glassy solid.
1H-NMR(CDCl3)δ：1.25-2.50 (7H, m), 1.46 (9H, s), 2.82 (3H, d, J=4.9Hz), 4.23-4.43 (2H, m), 4.80-5.10 (0.8H, br), 5.50-5.80 (1H, br), 580-6.05 (0.2H, br), 7.69 (1H, dd, J=8.8,22.4Hz), 8.02 (1H, s), 8.10-8.23 (1H, m), (8.31 1H, d, J=2.4Hz), 9.50-9.85 (0.2H, br), 9.85-10.15 (0.8H, br), 10.56 (1H, s)
MS(ESI)m/z：470(M+H)+.
[reference example 522] (1S, 3R, 4S) -3- amino -4- ({ 2- [(5- fluorine pyridine -2- bases) amino] -2- oxos ethanethioyl } amino)-N, N- dimethyl cyclohexane carboxamide hydrochlorides
Using the method same with reference example 69, the compound obtained by reference example 427 prepares title compound.
1H-NMR(DMSO-d6)δ：1.42-1.55 (1H, m), 1.72-1.90 (3H, m), 2.00-2.09 (1H, m), 2.11-2.28 (1H, m), 2.82 (3H, s), 3.08 (3H, s), 3.27-3.40 (1H, m), 4.03 (1H, br.s), 4.35-4.45 (1H, m), 7.89 (1H, dt, J=2.9,9.0Hz), 8.14 (1H, dd, J=9.0,4.2Hz), 8.33 (3H, br.s), 8.44 (1H, d, J=2.9Hz), 10.64 (1H, s), 10.97 (1H, d, J=7.1Hz)
MS(ESI)m/z：368(M+H)+.
[reference example 523] 3- amidino groups ethyl benzoate hydrochlorides
Figure G2003801097466D03031
Under ice-cold stirring, importing hydrogen chloride gas makes solution reach saturation in 3- cyanobenzoic acids (5g) ethanol (100ml) solution.Ethanol (400ml) is added in gained suspension dissolves it, is warming up to sealing after room temperature and places 18 hours.Be concentrated under decompression it is solid, in gained residue add ethanol (100ml) dissolve it, under ice-cold stirring import ammonia solution is reached saturation.It is warming up to after room temperature, sealing is placed 18 hours.Solvent is boiled off under decompression, gained residue (water → acetonitrile: water=1: 4) is refined with synthetic adsorbent HP-20.The gained thing that is roughly refined is dissolved in ethanol/methylene=1/4, insoluble matter is filtered off, (methanol: dichloromethane=1: 4) is refined with silica gel column chromatography, obtain the title compound (5.53g) in colourless powder.
1H-NMR(DMSO-d6)δ：1.36 (3H, t, J=7.0Hz), 4.38 (2H, q, J=7Hz), 7.78 (1H, t, J=7.8Hz), 8.11 (1H, dd, J=7.8,1.0Hz), 8.27 (1H, d, J=7.8Hz), 8.38 (1H, d, J=1.5Hz), 9.41 (1H, br.s), 9.61 (1H, br.s)
MS(FAB)m/z：193(M+H)+
[reference example 524] 3- [[(tert-butoxycarbonyl) amino] (imino group) methyl] ethyl benzoate
Diisopropylethylamine (952 μ l) and two tert-butoxy carbonic esters (480mg) are added in methanol (5.0ml) solution for the compound (250mg) that reference example 523 is obtained.Stirring boils off solvent under being depressurized after 3 days, (dichloromethane: methanol=25: 1) is refined to residue obtained for the middle compression leg chromatography of carrier to silica gel, obtains the title compound (285mg) of white blister solid.
1H-NMR(CDCl3)δ：1.41 (3H, t, J=7.2Hz), 1.56 (9H, s), 4.41 (2H, q, J=7.2Hz), 7.52 (1H, t, J=7.8Hz), 8.14 (1H, d, J=7.8Hz), 8.19 (1H, d, J=7.8Hz), 8.43 (1H, s)
MS(ESI)m/z：293(M+H)+.
[reference example 525] (1R, 2S, 5S) -2- [(3- Cyanophenacyls) amino] -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate
At room temperature, diisopropylethylamine (730 μ l) is added in the compound (800mg) and dichloromethane (30ml) solution of 3- cyano-benzoyl chlorides (560mg) that reference example 144 is obtained.After stirring 4 hours, add water and saturated aqueous ammonium chloride carries out a point liquid, water layer is extracted with dichloromethane.Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression, (dichloromethane: acetone=5: 1 → 1: 1) refined with silica gel column chromatography, obtain the title compound (1.15g) of white blister solid.
1H-NMR(CDCl3)δ：1.40-1.78 (2H, m), 1.47 (9H, s), 1.78-1.94 (2H, m), 2.08-2.40 (2H, m), 2.60-2.70 (1H, m), 2.96 (3H, s), 3.09 (3H, s), 3.94-4.08 (1H, m), 4.16-4.34 (1H, m), 4.79-4.88 (1H, m), 7.55 (1H, t, J=7.9Hz), 7.75 (1H, d, J=7.9Hz), 8.0
6-8.16 (3H, m)
MS(ESI)m/z：415(M+H)+.
[reference example 526] 3- [[(ethoxy carbonyl) amino] (imino group) methyl] ethyl benzoate
Dichloromethane (10ml), diisopropylethylamine (952 μ l) and ethyl chloroformate (160 μ l) are added in the compound (250mg) that reference example 523 is obtained.Stirring adds saturated sodium bicarbonate aqueous solution after 8 hours and dichloromethane carries out a point liquid, and water layer is extracted with dichloromethane.Merge after organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, it is residue obtained (dichloromethane: methanol=25: 1) to refine for the middle compression leg chromatography of carrier to silica gel, obtain the title compound (270mg) of white solid.
1H-NMR(CDCl3)δ：1.36 (3H, t, J=7.1Hz), 1.40 (3H, t, J=7.1Hz), 4.23 (2H, q, J=7.1Hz), 4.39 (2H, q, J=7.1Hz), 6.84 (1H, br.s), 7.51 (1H, t, J=7.8Hz), 8.10-8.25 (2H, m), 8.45 (1H, s), 9.63 (1H, br.s)
MS(ESI)m/z：265(M+H)+.
The chloro- N- of [reference example 527] 2,2- bis- (5- fluorine pyridine -2- bases) acetamide
Figure G2003801097466D03051
At room temperature, add after dichloroacetyl chloride (279 μ l), stirred 2.5 hours in 60~70 DEG C in ethyl acetate (10ml) solution of 2- amino-5-fluorines pyridine (250mg).Saturated sodium bicarbonate aqueous solution is added after cooling reaction solution, organic layer is separated, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, rough title compound (438mg) is obtained.
1H-NMR(CDCl3)δ：6.05 (1H, s), 7.45-7.55 (1H, m), 8.15-8.25 (2H, m), 8.72 (1H, s)
MS(ESI)m/z：223(M+H)+.
[reference example 528] (1R; 2S, 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(5- fluorine pyridine -2- bases) amino] -2- oxos ethanethioyl } amino) Cyclohexylamino t-butyl formate
N is added in the compound (143mg) and sulphur (17mg) that compound (112mg), reference example 144 that reference example 527 is obtained are obtained, dinethylformamide (1.0ml) and diisopropylethylamine (1.0ml), are stirred the mixture for 20 minutes in 130 DEG C.Solvent is boiled off under decompression, saturated sodium bicarbonate aqueous solution is added in residue, is extracted with dichloromethane.The solution (dichloromethane: methanol=99: 1) is refined with silica gel column chromatography, then with diisopropyl ether, obtains title compound (121mg).The compound of NMR data and reference example 424 is completely the same.
[reference example 529] 4- morpholinyl benzoic acid methyl esters
Under ice cooling, thionyl chloride (436 μ l) is instilled in methanol (10ml).4- morpholinyl benzoic acids (207mg) are added in the solution, is heated to reflux after 1.5 hours, solvent is boiled off under decompression.Dichloromethane and moisture liquid, organic layer anhydrous sodium sulfate drying are added in residue.Solvent is boiled off under decompression, title compound is obtained.
1H-NMR(CDCl3)δ：3.28 (4H, t, J=4.9Hz), 3.84-3,87 (7H, m), 6.86 (2H, dt, J=9.6,2.5Hz), 7.94 (2H, dt, J=9.6,2.4Hz)
MS(EI)m/z：222(M+H)+.
[reference example 530] 4- (3- oxomorpholin -4- bases) methyl benzoate
Figure G2003801097466D03061
Benzyltriethylammonium chloride (639mg) and potassium permanganate (222mg) are added in dichloromethane (10ml) solution for the compound (207mg) that reference example 529 is obtained, is stirred 2 hours at room temperature.Saturation aqueous solution of sodium bisulfite is added in reaction solution and carries out a point liquid, organic layer saturated common salt water washing uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=1: 2) refines for the flash column chromatography of carrier to silica gel, obtains title compound (41mg).
1H-NMR(CDCl3)δ：3.80-3.83 (2H, m), 3.92 (3H, s), 4.03-4.07 (2H, m), 4.36 (2H, s), 7.47 (2H, dt, J=9.0,2.2Hz), 8.08 (2H, dt, J=9.0,2.2Hz)
MS(EI)m/z：236(M+H)+.
[reference example 531] 4- (3- oxomorpholin -4- bases) benzoic acid
Figure G2003801097466D03062
Using the method same with reference example 274, the compound obtained by reference example 530 prepares title compound.
1H-NMR(DMSO-d6)δ：3.78-3.82 (2H, m), 3.97-4.01 (2H, m), 4.23 (2H, s), 7.57 (2H, dt, J=9.1,2.2Hz), 7.96 (2H, dt, J=9.1,2.2Hz), 12.97 (1H, br.s)
[reference example 532] 3- (5- chlorothiophene -2- bases) fluoro- 3- hydroxypropionates of -2-
Figure G2003801097466D03063
Zinc powder (19.6g) is added in benzene (200ml) solution of 5- chlorothiophene -2- formaldehyde (1.07ml) to be heated to reflux.The iodine of catalytic amount is added wherein, then instills benzene (25ml) solution of ethyl bromide fluoride (3.70g).It is heated to reflux after 1.5 hours, the iodine of additional catalytic amount reheats backflow 3.5 hours.After natural cooling reaction solution, the aqueous hydrochloric acid solution (125ml) that 1N is added under ice-cooling is stirred 1 hour.Insoluble matter is filtered with diatomite, is washed with ethyl acetate.A point liquid is carried out to filtrate, organic layer saturated common salt water washing uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane → hexane: ethyl acetate=4: 1) is refined with silica gel column chromatography, obtains title compound (2.53g).
1H-NMR(CDCl3)δ：1.24-1.31 (3H, m), 3.09-3.21 (1H, m), 4.21-4.31 (2H, m), 4.97-5.12 (1H, m), 5.21-5.28 (1H, m), 6.79-6.86 (2H, m)
MS(EI)m/z：252(M+).
[reference example 533] (Z) -3- (5- chlorothiophene -2- bases) -2- perfluoroalkyl acrylate ethyl esters
Under ice cooling, pyridine (4.70ml) and thionyl chloride (849 μ l) are added in dichloromethane (50ml) solution for the compound (2.46g) that reference example 532 is obtained, stir 30 minutes, stir 1 hour at room temperature in 0 DEG C.The aqueous hydrochloric acid solution that 1N is added in reaction solution carries out a point liquid, and water layer is extracted with dichloromethane.Organic layer is washed with 1N aqueous hydrochloric acid solution, and with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue is dissolved in dichloromethane (150ml), adds 1,8- diazabicyclos [5.4.0] 11-7- alkene (1.60ml), stirs 1 hour at room temperature.Solvent is boiled off under decompression, (hexane: ethyl acetate=7: 1) refines for the flash column chromatography of carrier to silica gel, obtains title compound (1.05g).
1H-NMR(CDCl3)δ：(1.37 3H, t, J=7.1Hz), 4.34 (2H, q, J=7.1Hz), 6.90 (1H, dd, J=3.9,2.0Hz), 7.06 (1H, d, J=33.7Hz), 7.08-7.10 (1H, m)
MS(FAB)m/z：235(M+H)+.
[reference example 534] (Z) -3- (5- chlorothiophene -2- bases) -2- perfluoroalkyl acrylates
Using the method same with reference example 274, the compound obtained by reference example 533 prepares title compound.
1H-NMR(DMSO-d6)δ：7.22 (1H, dd, J=3.9,2.0Hz), 7.35-7.40 (2H, m), 13.76 (1H, br.s)
MS(ESI-neg.)m/z：205(M-H)-.
[reference example 535] 6- methyl -5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [4,5-d] azepine
Figure G2003801097466D03073
- 2- base amine
Figure G2003801097466D03074
It is same with the method described in reference example 475, by 5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [4,5-d] azepine- 2- bases amine (Japanese Patent Laid-Open 2-45489 publications) obtains title compound.
1H-NMR(CDCl3)δ：2.44 (3H, s), 2.66-2.69 (2H, m), 2.71 (4H, s), 2.80-2.83 (2H, m), 4.66 (2H, s)
MS(ESI)m/z：184(M+H)+.
The bromo- 6- methyl -5,6 of [reference example 536] 2-, 7,8- tetrahydrochysene -4H- thiazoles simultaneously [4,5-d] azepine
Using the method same with reference example 476, the compound obtained by reference example 535 prepares title compound.
1H-NMR(CDCl3)δ：2.45 (3H, s), 2.66-2.72 (4H, m), 2.85-2.88 (2H, m), 3.03-3.06 (2H, m)
MS(ESI)m/z：247(M+H)+.
[reference example 537] 6- methyl -5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [4,5-d] azepine- 2- carboxylic acid lithium salts
Using the method same with reference example 10, the compound obtained by reference example 536 prepares title compound.
1H-NMR(DMSO-d6)δ：2.33 (3H, s), 2.56-2.63 (4H, m), 2.77-2.93 (4H, m)
MS(ESI)m/z：213(M+H)+.
[reference example 538] 5,6,7,8- tetrahydrochysene [1,6] naphthyridines -2- carbonitrile hydrochlorides
In 2- cyano group -7,8- dihydros -5H- [1,6] the 4N dioxane solution of hydrochloric acid-(14ml) is added in dichloromethane (5.0ml) solution of naphthyridines -6- carboxylic acid tert-butyl esters (WO 00/09480) (3.74g), stir at room temperature 65 minutes, 40 DEG C are stirred 40 minutes.The additional 4N dioxane solution of hydrochloric acid-(8ml), is stirred for 75 minutes in 45 DEG C in reaction solution.Ethyl acetate is added in reaction solution, the powder that leaching is separated out obtains the title compound (3.20g) in colourless powder.
1H-NMR(DMSO-d6)δ：3.14 (2H, t, J=6.4Hz), 3.50-3.70 (2H, m), 4.40 (2H, s), 7.93 (1H, s), 8.30 (1H, s), 9.49 (1H, br.s)
[reference example 539] 6- methyl -5,6,7,8- tetrahydrochysenes [1,6] naphthyridines -2- formonitrile HCNs
Using the method same with reference example 9, the compound reaction for obtaining reference example 538 obtains title compound.
1H-NMR(CDCl3)δ：2.49 (3H, s), 2.81 (2H, q, J=6.0Hz), 3.10 (2H, t, J=6.0Hz), 3.71 (2H, s), 7.44 (1H, d, J=8.1Hz), 7.47 (1H, d, J=7.8Hz)
[reference example 540] 6- methyl -5,6,7,8- tetrahydrochysenes [1,6] naphthyridines -2- carboxylic acid hydrochlorides
Concentrated hydrochloric acid (12ml) is added in the compound (2.46g) that reference example 539 is obtained, is heated 5.5 hours in 100~110 DEG C.Add water and added water after being concentrated under depressurizing in reaction solution, make it in alkalescence with 1N sodium hydrate aqueous solution.The hydrochloric acid that the solution is concentrated into the rear use 1N of half or so is neutralized, and solvent is boiled off under decompression.Ethanol is added in residue, in 40~50 DEG C of heatings, insoluble matter is filtered off by diatomite.The lower concentration filtrate of decompression, residue is dissolved in after ethanol, 1N hydrochloric acid-ethanol (18ml) is added, solvent is boiled off under decompression.Ethyl acetate is added in residue, leaching insoluble matter obtains rough title compound (2.33g).
1H-NMR(DMSO-d6)δ：2.93 (3H, s), 3.16 (1H, d, J=16.4Hz), 3.37-3.80 (3H, m), 4.35-4.47 (1H, m), 4.59 (1H, d, J=16.8Hz), 7.83 (1H, d, J=8.1Hz), 7.93 (1H, d, J=8.1Hz)
[reference example 541] (1S, 3R, 4S) -4- { [(benzyloxy) carbonyl] amino } -3- [(tert-butoxycarbonyl) amino] cyclohexane-carboxylic acid tert-butyl ester
The compound (7.15g) that reference example 142 is obtained is dissolved in dichloromethane (100ml), 2- methyl-2-propanols (4.88ml), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (4.89g), 4-dimethylaminopyridine (2.08g) are added, is stirred 19 hours at room temperature.Reaction solution is diluted with dichloromethane (200ml), after 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, and with anhydrous sodium sulfate drying, decompression is lower to be concentrated.Residue (dichloromethane: acetone=30: 1 → 20: 1) is refined with silica gel column chromatography, obtains title compound (7.07g).
1H-NMR(CDCl3)δ：1.20-2.09 (6H, m), 1.43 (9H, s), 1.44 (9H, s), 2.26 (1H, br.s), 3.62-3.72 (1H, m), 4.10 (1H, br.s), 4.52-5.40 (4H, m), 7.27-7.38 (5H, m)
MS(FAB)m/z：449(M+H)+.
[reference example 542] (1S; 3R, 4S) -3- [(tert-butoxycarbonyl) amino] -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) cyclohexane-carboxylic acid tert-butyl ester
Figure G2003801097466D03101
10% palladium-carbon catalyst (wet, 350mg) is added in methanol (7.0ml)-tetrahydrofuran (7.0ml) solution for the compound (700mg) that reference example 541 is obtained, is stirred at room temperature under a hydrogen atmosphere 16 hours.Filter off catalyst, the lower concentration filtrate of decompression.Residue is dissolved in DMF (10ml), adds compound (374mg) and diisopropylethylamine (0.816ml) that sulphur (65mg), reference example 520 are obtained, is stirred 8 hours in 120 DEG C.The lower concentration of reaction solution of decompression, adds dichloromethane in residue, successively with 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, and with anhydrous sodium sulfate drying, decompression is lower to be concentrated.Residue (dichloromethane: methanol=100: 1 → 50: 1) refines for the flash column chromatography of carrier to silica gel, obtains title compound (373mg).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.48 (9H, s), 1.49-1.70 (2H, m), 1.80-2.40 (5H, m), 4.26-4.39 (2H, m), 4.79 (1H, br.s), 7.70 (1H, dd, J=9.0,2.4Hz), 8.19 (1H, d, J=9.0Hz), 8.32 (1H, d, J=2.4Hz), 10.01 (1H, br.s), 10.58 (1H, s)
MS(ESI)m/z：513(M+H)+.
[reference example 543] (1S, 3R, 4S) -3- amino -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) cyclohexane-carboxylic acid t-butyl ester hydrochloride
Figure G2003801097466D03102
1N hydrochloric acid-ethyl acetate solution (1.30ml) is added in ethyl acetate (3.90ml) solution for the compound (530mg) that reference example 542 is obtained, is stirred 3 hours at room temperature.Ethyl acetate is added in reaction solution, the solid that leaching is separated out, the lower drying of decompression obtains title compound (284mg).
1H-NMR(DMSO-d6)δ：1.42 (9H, s), 1.49-1.61 (1H, m), 1.71-1.88 (2H, m), 1.88-2.03 (1H, m), 2.04-2.26 (2H, m), 2.71-2.85 (1H, m), 3.84-4.12 (1H, m), 4.44 (1H, br.s), 8.00-8.29 (5H, m), 8.44-8.51 (1H, m), 10.67 (1H, s), 10.91 (1H, d, J=6.8Hz)
MS(ESI)m/z：413(M+H)+.
[reference example 544] (1S, 3R, 4S) -3- [(tert-butoxycarbonyl) amino] -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) cyclohexane-carboxylic acid tert-butyl ester
Figure G2003801097466D03111
10% palladium-carbon catalyst (wet, 500mg) is added in methanol (20ml)-tetrahydrofuran (20ml) solution for the compound (1.00g) that reference example 541 is obtained, is stirred at room temperature under a hydrogen atmosphere 4 hours.Filter off catalyst, after the lower concentration filtrate of decompression, N is dissolved in by residue obtained, dinethylformamide (10ml), compound (231mg), I-hydroxybenzotriazole (139mg) and 1- (the dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (288mg) of the acquisition of reference example 266 are sequentially added in the solution, is stirred all night at room temperature.After the lower concentration of reaction solution of decompression, ethyl acetate is added in residue and 10% aqueous citric acid solution carries out a point liquid.Oil reservoir saturated aqueous common salt, sodium bicarbonate aqueous solution and saturated common salt water washing.After oil reservoir is dried with anhydrous magnesium sulfate, solvent is boiled off under decompression, title compound (364mg) is obtained.
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.46 (9H, s), 1.54-2.09 (6H, m), 2.20-2.38 (1H, m), 3.83-3.98 (1H, m), 4.08-4.29 (1H, m), 4.71 (1H, br.s), 7.69 (1H, dd, J=8.9,2.6Hz), 8.00 (1H, br.s), 8.18 (1H, d, J=8.9Hz), 8.31 (1H, d, J=2.5Hz), 9.72 (1H, br.s)
MS(ESI)m/z：441(M-tBu)+.
[reference example 545] 2- methyl isophthalic acids, 2,3,4- tetrahydrochysene -6- isoquinolinecarboxylic acid's methyl esters
Figure G2003801097466D03112
Under ice cooling, 3, trifluoroacetic acid (3ml) is added in dichloromethane (6ml) solution of 4- dihydros (1H) isoquinolin -2,6- dicarboxylic acids 2- (tert-butyl group) ester 6- methyl esters (WO 00/09480) (344mg) to stir 30 minutes.After concentration of reaction solution chloroform dilutes, neutralized, extracted with chloroform/methanol (4/1) with saturated sodium bicarbonate aqueous solution.Gained organic layer anhydrous sodium sulfate drying, after the lower concentration of decompression, residue (chloroform: methanol=20: 1 → 1: 1) is refined with silica gel column chromatography, obtains 1,2,3,4- tetrahydroisoquinoline -6- carboxylate methyl esters (154mg).The compound is dissolved in dichloromethane (5ml), formalin (90.6 μ l) is added at room temperature.After stirring 10 minutes, acetic acid (46 μ l) and sodium triacetoxy borohydride (269mg) are added under ice-cooling.After stirring 105 minutes at room temperature, neutralized with saturated sodium bicarbonate aqueous solution, then extracted with chloroform.Organic layer anhydrous sodium sulfate drying, decompression is lower to be concentrated, and obtains title compound (162mg).
1H-NMR(CDCl3)δ：2.47 (3H, s), 2.70 (2H, dd, J=6.0Hz), 2.96 (2H, dd, J=6.0Hz), 3.62 (2H, s), 3.90 (3H, s), 7.08 (1H, d, J=7.6Hz), 7.78 (1H, d, J=7.6Hz), 7.80 (1H, s)
MS(ESI)m/z：206(M+H)+.
[reference example 546] (1R, 2R, 4S) -4- (amino carbonyl) -2- [(tert-butoxycarbonyl) amino] Cyclohexylamino formic acid fluorenes -9- base methyl esters
Under ice cooling, the compound (1.92g) that reference example 142 is obtained is dissolved in N, dinethylformamide (30ml), sequentially added in the solution after ammonium chloride (523mg), I-hydroxybenzotriazole (661mg), 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (1.41g) and diisopropylethylamine (1.70ml), place to temperature and reply as room temperature, stirring 3 days.The lower concentration of reaction solution of decompression, ethyl acetate is added in residue and 10% aqueous citric acid solution carries out a point liquid.Oil reservoir saturated aqueous common salt, sodium bicarbonate aqueous solution and saturated common salt water washing.After anhydrous sodium sulfate drying, solvent is boiled off under decompression, in residue obtained middle addition hexane solidification, obtain rough (1R, 2S, 5S) -5- (amino carbonyl) -2- { [(benzyloxy) carbonyl] amino } Cyclohexylamino t-butyl formate (1.66g).The mixture of the rough thing (1.65g), 10% palladium-carbon catalyst (400mg) and methanol (150ml) is stirred all night in room temperature under a hydrogen atmosphere.Filter off after catalyst, solvent is boiled off under decompression, in residue obtained middle addition succinimide yl carboxylic acid 9- fluorenyl methyl esters (2.13g), 1,2- dimethoxy-ethanes (130ml) and saturated sodium bicarbonate aqueous solution (130ml), stir all night at room temperature.Ethyl acetate, saturated aqueous common salt and water are added in the reaction solution and carries out a point liquid, after gained organic layer is dried with anhydrous magnesium sulfate, solvent is boiled off under decompression, title compound (1.99g) is obtained.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.53-2.08 (6H, m), 2.30 (1H, br.s), 3.71 (1H, br.s), 4.07-4.15 (1H, m), 4.21 (1H, br.s), 4.37 (2H, br.s), 4.70-5.80 (4H, m), 7.26-7.33 (2H, m), 7.39 (2H, t, J=7.3Hz), 7.53-7.61 (2H, m), 7.76 (2H, d, J=7.3Hz)
MS(ESI)m/z：502(M+Na)+.
[reference example 547] (1S, 2R, 4S) -4- (aminothio formoxyl) -2- [(tert-butoxycarbonyl) amino] Cyclohexylamino formic acid fluorenes -9- base methyl esters
Figure G2003801097466D03131
The compound (1.98g) that reference example 546 is obtained is dissolved in tetrahydrofuran (200ml), and ロ-ソ Application reagents (1.22g) are added in the solution, stirs 4 days at room temperature.Then, additional ロ-ソ Application reagents (0.50g) are stirred all night in the reaction solution.Added in reaction solution and solvent is boiled off under silica gel, decompression, residue obtained use silica gel column chromatography (ethyl acetate: hexane=2: 1) is refined.Ether is added in gained grease and is stirred, the powder that leaching is separated out obtains title compound (1.25g).
1H-NMR(CDCl3)δ：1.45 (9H, br.s), 1.57-2.10 (6H, m), 2.69 (1H, br.s), 3.71 (1H, br.s), 4.06-4.27 (2H, m), 4.36 (2H, br.s), 4.89 (1H, br.s), 5.46 (1H, br.s), 7.11 (1H, br.s), 7.26-7.34 (2H, m), 7.39 (2H, t, J=7.3Hz), 7.57 (3H, br.s), 7.76 (2H, d, J=7.1Hz)
MS(ESI)m/z：518(M+Na)+.
[reference example 548] (1R; 2S; 5S) -5- (aminothio formoxyl) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) Cyclohexylamino t-butyl formates and (1R; 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- cyanocyclohexanoic carbamates
Figure G2003801097466D03132
The compound (4.64g) that reference example 547 is obtained is dissolved in DMF (50ml), and piperidines (2.78ml) is added in the solution, stirs 30 minutes at room temperature.Solvent is boiled off under decompression; (methanol: dichloromethane=3: 47 → 3: 17) refined with silica gel column chromatography; obtain rough (1R, 2S, 5S) -2- amino -5- (aminothio formoxyl) Cyclohexylamino t-butyl formate (2.17g).The compound is dissolved in N, dinethylformamide (100ml), compound (1.78g), I-hydroxybenzotriazole (1.07g) and 1- (the dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (2.28g) of the acquisition of reference example 266 are sequentially added in the solution, is stirred all night at room temperature.After the lower concentration of reaction solution of decompression, dichloromethane is added in residue and 10% aqueous citric acid solution carries out a point liquid.Oil reservoir saturated aqueous common salt, sodium bicarbonate aqueous solution and saturated common salt water washing.After being dried with anhydrous magnesium sulfate; solvent is boiled off under decompression; residue (ethyl acetate: hexane=2: 1) is refined with silica gel column chromatography, obtains 5 title compounds (427mg) with cyano group and 5 title compounds (718mg) with aminothio formoxyl.
5- cyano group bodies：1H-NMR(CDCl3)δ：1.46 (9H, s), 1.56-1.66 (1H, m), 1.74-1.87 (1H, m), 1.90-2.23 (4H, m), 2.72 (1H, br.s), 4.02-4.23 (2H, m), 4.71 (1H, br.s), 7.71 (1H, dd, J=8.8,2.4Hz), 7.85 (1H, br.s), 8.15 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.4Hz), 9.69 (1H, br.s)
5- (aminothio formoxyl) body：1H-NMR(CDCl3)δ：1.46 (9H, s), 1.74-2.17 (6H, m), 2.70 (1H, s), 3.94-4.04 (1H, m), 4.23 (1H, br.s), 4.86 (1H, br.s), 6.97 (1H, br.s), 7.50 (1H, br.s), 7.70 (1H, dd, J=8.8,2.4Hz), 7.98 (1H, br.s), 8.18 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.4Hz), 9.72 (1H, s)
MS(ESI)m/z：456(M+H)+.
[reference example 549] (1R, 2S, 5RS) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (thiazol-2-yl) Cyclohexylamino t-butyl formate
Figure G2003801097466D03141
5 compounds (72mg) and bromoacetaldehyde dimethylacetal (20.4 μ l) with aminothio formoxyl that reference example 548 is obtained are dissolved in DMF (5ml), are stirred 8 hours in 50 DEG C.Then, add bromoacetaldehyde dimethylacetal (80 μ l) to stir 13 hours, place to room temperature.Di-tert-butyl dicarbonate (34.5mg) and anhydrous sodium bicarbonate (200mg) are added in the reaction solution, triethylamine (97 μ l) is added after stirring 1 hour at room temperature, stirs 2 hours.Ethyl acetate is added in reaction solution and 10% aqueous citric acid solution carries out a point liquid, organic layer saturated aqueous common salt, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.After being dried with anhydrous magnesium sulfate, solvent is boiled off under decompression.Residue obtained use silica gel column chromatography (ethyl acetate: hexane=2: 1) refines, obtains title compound (37.5mg).
1H-NMR(CDCl3)δ：1.40-1.51 (9H, m), 1.75-2.16 (5H, m), 2.19-2.39 (1H, m), 3.10-3.38 (1H, m), 3.91-4.08 (1H, m), 4.21-4.40 (1H, m), 4.80-4.94 (0.5H, m), 5.61-5.90 (0.5H, m), 7.24-7.26 (1H, m), 7.66-7.74 (2H, m), 7.80-7.90 (0.5H, m), 8.02-8.11 (0.5H, m), 8.16-8.22 (1H, m), 8.27-833 (1H, m), 9.66-9.80 (1H, m)
MS(ESI)m/z：480(M+H)+.
[reference example 550] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (1,2,4- oxadiazole -3- bases) Cyclohexylamino t-butyl formate
5 compounds (427mg) and anhydrous sodium bicarbonate (84.9mg) with cyano group that reference example 548 is obtained are suspended in ethanol, and hydroxylamine sulfate (82.9mg) is added in the suspension, in 60 DEG C of heating, is stirred 6 days.Solvent is boiled off under decompression; (methanol: dichloromethane=1: 9) refined with silica gel column chromatography to residue obtained; obtain rough (1R; 2S, 5S) -5- [amino (oxyimino) methyl] -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) Cyclohexylamino t-butyl formate (183mg).At room temperature, original acid A ester (5ml) and boron trifluoride etherate (1 drop) are added in the compound, in 55 DEG C of heating, is stirred 20 minutes.Place to room temperature, solvent is boiled off under decompression, residue obtained use silica gel column chromatography (methanol: dichloromethane=1: 9) refines, obtains title compound (57.6mg).
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.53-1.70 (1H, m), 1.73-1.94 (1H, m), 1.95-2.30 (4H, m), 3.03 (1H, br.s), 4.00-4.11 (1H, m), 4.27 (1H, br.s), 4.87 (1H, br.s), 7.70 (1H, dd, J=8.9,2.4Hz), 8.04 (1H, s), 8.19 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.4Hz), 8.66 (1H, s), 9.74 (1H, br.s)
MS(ESI)m/z：463(M-H)-.
[reference example 551] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (5- methyl isophthalic acids, 2,4- oxadiazole -2- bases) Cyclohexylamino benzyl formate
The compound (4.0g) that reference example 142 is obtained is dissolved in N, dinethylformamide (100ml), the hydrate of hydrazine 1 (765mg), I-hydroxybenzotriazole (1.38g) and 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (2.93g) are added in the solution, is stirred all night at room temperature.The lower concentration of reaction solution of decompression, dichloromethane is added in residue and sodium bicarbonate aqueous solution carries out a point liquid.Water layer is extracted with dichloromethane, is merged gained organic layer, is used anhydrous sodium sulfate drying.Filter off after anhydrous sodium sulfate, silica gel (25g) and methanol (15ml) are added in gained filtrate and is stirred, insoluble matter is filtered off.Solvent is boiled off under decompression, rough (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (Hydrazinocarbonyl) Cyclohexylamino benzyl formates (3.71g) are obtained.Ortho-acetic acid methyl esters (10ml) and boron trifluoride etherate (2 drop) are added in the rough thing of gained (1.73g), in 70 DEG C of heating, is stirred all night.Place to room temperature, solvent is boiled off under decompression, a point liquid is carried out in residue obtained middle addition dichloromethane and sodium bicarbonate aqueous solution.After water layer is extracted with dichloromethane, merge gained organic layer, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.(methanol: dichloromethane=1: 19) refined with silica gel column chromatography, obtain title compound (1.10g).
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.68-2.27 (6H, m), 2.50 (3H, s), 2.95-3.09 (1H, m), 3.66-3.86 (1H, m), 4.08-4.24 (1H, m), 4.76 (1H, br.s), 5.04-5.16 (2H, m), 5.27-5.36 (1H, m), 7.29-7.39 (5H, m)
MS(ESI)m/z：431(M+H)+.
[reference example 552] (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) Cyclohexylamino t-butyl formate
In nitrogen atmosphere, the mixture of the compound (1.10g), 10% palladium-carbon catalyst (300mg) and the methanol (50ml) that are obtained in room temperature to reference example 551 is stirred 1 hour.Filter off after catalyst, boil off solvent under decompression, DMF (50ml) is dissolved in by residue obtained.Compound (632mg), I-hydroxybenzotriazole (381mg) and 1- (the dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (810mg) of the acquisition of reference example 266 are sequentially added in the solution, is stirred all night at room temperature.The lower concentration of reaction solution of decompression, ethyl acetate is added in residue and 10% aqueous citric acid solution carries out a point liquid.Oil reservoir saturated aqueous common salt, sodium bicarbonate aqueous solution and saturated common salt water washing.After being dried with anhydrous magnesium sulfate, solvent is boiled off under decompression, title compound (944mg) is obtained.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.58-1.88 (2H, m), 1.92-2.31 (4H, m), 2.52 (3H, s), 3.04 (1H, br.s), 3.98-4.09 (1H, m), 4.27 (1H, br.s), 4.83 (1H, br.s), 7.71 (1H, dd, J=8.8,2.4Hz), 8.02 (1H, br.s), 8.19 (1H, d, J=8.8Hz), 8.32 (1H, d, J=2.4Hz), 9.72 (1H, br.s)
MS(ESI)m/z：479(M+H)+.
[reference example 553] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (1,3,4- oxadiazole -2- bases) Cyclohexylamino benzyl formate
Using the method same with reference example 551, make the compound that reference example 142 is obtained with after hydrazine condensation, cyclization being carried out with original acid A ester, title compound is obtained.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.71-2.30 (6H, m), 3.04-3.15 (1H, m), 3.80 (1H, br.s), 4.17 (1H, br.s), 4.75 (1H, br.s), 5.05-5.15 (2H, m), 5.25 (1H, s), 7.30-7.38 (5H, m), 8.35 (1H, s)
MS(ESI)m/z：417(M+H)+.
[reference example 554] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (1,3,4- oxadiazole -2- bases) Cyclohexylamino t-butyl formate
Using the method same with reference example 552, after the compound deprotection obtained to reference example 553, the compound condensation obtained with reference example 266 obtains title compound.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.59-1.92 (2H, m), 2.00-2.33 (4H, m), 3.02-3.22 (1H, m), 3.94-4.10 (1H, m), 4.27 (1H, br.s), 4.83 (1H, br.s), 7.71 (1H, dd, J=8.9,2.6Hz), 8.00 (1H, br.s), 8.19 (1H, d, J=8.9Hz), 8.32 (1H, d, J=2.6Hz), 8.37 (1H, br.s), 9.72 (1H, s)
MS(ESI)m/z：465(M+H)+.
[reference example 555] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- { [(2- hydroxyethyls) amino] carbonyl } Cyclohexylamino benzyl formate
It is same with reference example 143, the compound that reference example 142 is obtained is condensed with 2- ethylaminoethanols, obtain title compound.
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.50-2.07 (6H, m), 2.28-2.39 (1H, m), 3.26-3.49 (1H, m), 3.45-3.63 (1H, m), 3.65-3.84 (3H, m), 3.90-4.07 (1H, m), 5.02-5.28 (4H, m), 6.21-6.35 (1H, m), 7.28-7.39 (5H, m)
MS(ESI)m/z：436(M+H)+.
[reference example 556] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (1,3- oxazole -2- bases) Cyclohexylamino t-butyl formate
Under blanket of nitrogen, dimethyl sulfoxide (3.47ml) is instilled in dichloromethane (50ml) solution for be cooled to -60 DEG C of oxalyl chloride (2.85ml), then with dichloromethane (20ml) solution for instilling the compound (3.55g) that reference example 555 is obtained for 15 minutes.After -60 DEG C are stirred 45 minutes, triethylamine (11.4ml) is instilled, is stirred for 30 minutes.In -60 DEG C, added water in reaction solution, extracted after temperature returns back to room temperature with chloroform, use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (chloroform: methanol=50: 1 → 10: 1) is refined with silica gel column chromatography, obtains yellow solid (2.43g).Dichloromethane (35ml) solution of carbon trichloride (3.32g), triethylamine (4.69ml) and gained yellow solid (2.43g) is sequentially added in triphenyl phasphine (4.41g) dichloromethane (25ml) solution, is stirred 20 hours at room temperature.Saturated sodium bicarbonate aqueous solution is added to be stirred for after 30 minutes, with chloroform extractive reaction mixed liquor, with anhydrous sodium sulfate drying, it is concentrated under reduced pressure, gained concentrated residue with silica gel column chromatography (chloroform: methanol=50: 1) refine, obtain oxazole cyclisation body and triphenyl phosphine oxide mixture.Gained mixture is dissolved in methanol (30ml), 10% palladium-carbon catalyst (2.08g) is added, is stirred at room temperature under a hydrogen atmosphere 14 hours.Additional 10% palladium-carbon catalyst (1.02g), is stirred for filtration catalytic agent after 6 hours, be concentrated under reduced pressure filtrate under a hydrogen atmosphere.Residue silica gel column chromatography (chloroform: methanol=50: after 1 → 10: 1) refining, at room temperature 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (872mg) and the hydrate of I-hydroxybenzotriazole 1 (461mg) are added in DMF (15ml) solution for the compound (612mg) that gained compound and reference example 266 are obtained.After being stirred 12 hours to reaction solution, chloroform is added in reaction solution, after being washed successively with water and protection sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying is used.Decompression is lower to be concentrated, and residue obtained use silica gel flash column chromatography (methanol: chloroform=50: 1) refines, obtains title compound (390mg).
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.54-2.30 (6H, m), 2.90-3.07 (1H, m), 3.97-4.08 (1H, m), 4.15-4.30 (1H, m), 4.91-5.10 (1H, m), 7.03 (1H, s), 7.58 (1H, s), 7.70 (1H, dd, J=8.8,2.4Hz), 7.98-8.11 (1H, m), 8.25 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.4Hz), 9.75 (1H, s)
MS(ESI)m/z：464(M+H)+.
[reference example 557] (1S, 3R, 4S) -3- [(tert-butoxycarbonyl) amino] -4- ({ [2- (trimethyl silyl) ethyoxyl] carbonyl } amino) cyclohexane-carboxylic acid
The mixture of the compound (4.20g), 10% palladium-carbon catalyst (1.0g) and the ethanol (100ml) that are obtained under nitrogen atmosphere in room temperature to reference example 141 is stirred 5 hours.Filter off and boil off solvent under being depressurized after catalyst.In residue obtained middle addition dioxane (50ml), water (50ml) and triethylamine (2.09ml), it is cooled with ice.1- [2- (trimethyl silyl) ethoxy carbonyls epoxide] pyrrolidines -2,5- diketone (2.85g) is added in the mixture, is stirred 24 hours at room temperature.Solvent is boiled off under decompression, ethyl acetate is added in residue and 10% aqueous citric acid solution carries out a point liquid.Oil reservoir is washed successively with saturated aqueous common salt, sodium bicarbonate aqueous solution and saturated aqueous common salt.After being dried with anhydrous magnesium sulfate, solvent is boiled off under decompression, pale yellow oil (4.46g) is obtained.Water (10ml) and lithium hydroxide (479mg) are added in tetrahydrofuran (50ml) solution of the grease, is stirred all night at room temperature.Solvent is boiled off under decompression, ethyl acetate is added in residue and 10% aqueous citric acid solution carries out a point liquid.Oil reservoir saturated common salt water washing, after being dried with anhydrous magnesium sulfate, solvent is boiled off under decompression.Gained colourless powder is washed with hexane, obtains title compound (3.51g).
1H-NMR(CDCl3)δ：0.06 (9H, s), 0.97 (2H, t, J=7.8Hz), 1.46 (9H, br.s), 1.52-2.22 (6H, m), 2.47 (1H, br.s), 3.68 (1H, s), 3.97-4.24 (3H, m), 4.69 (0.5H, br.s), 4.95 (0.5H, br.s), 5.18 (0.5H, br.s), 6.42 (0.5H, br.s)
MS(ESI)m/z：401(M-H)-].
[reference example 558] N- hydroxyl acetamidines
Figure G2003801097466D03201
Azanol (aqueous 50%, 661mg) is dissolved in acetonitrile (10ml), stirred all night in 60 DEG C.Solvent is boiled off under decompression, gained colourless powder is washed with ether, obtain title compound (673mg).
1H-NMR(DMSO-d6)δ：1.62 (3H, s), 5.33 (2H, br.s), 8.66 (1H, br.s)
[reference example 559] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
The compound (37mg) that the compound (201mg) and reference example 558 that reference example 557 is obtained are obtained is suspended in 1,2- dimethoxy-ethanes (5ml), 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (115mg) are added in the suspension, are stirred all night at room temperature.Then, molecular sieve (MS-4A, powder, 1.0g) is added in the reaction solution, is heated to reflux all night.Solvent is boiled off under decompression, residue obtained use silica gel column chromatography (hexane: ethyl acetate=1: 1) refines, obtains title compound (96.5mg).
1H-NMR(CDCl3)δ：0.04 (9H, s), 0.98 (2H, t, J=8.4Hz), 1.46 (9H, s), 1.60-1.83 (2H, m), 1.87-2.28 (4H, m), 2.38 (3H, s), 3.04 (1H, br.s), 3.76 (1H, br.s), 4.07-4.22 (3H, m), 4.72 (1H, br.s), 5.14 (1H, br.s)
MS(ESI)m/z：341(M-Boc+2H)+.
[reference example 560] (1S, 2R, 4S) -4- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Figure G2003801097466D03203
Compound (96.5mg) that reference example 559 is obtained is dissolved in ethanol (10ml), adds p-methyl benzenesulfonic acid (45.8mg) in the solution at room temperature.Reaction solution is heated into 60 DEG C to stir all night.Place and solvent is boiled off under being depressurized to room temperature, obtain colourless powder.Compound (67mg) and DMF (5ml) that reference example 10 is obtained are added in the powder.I-hydroxybenzotriazole (44.5mg) and 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (84mg) are added in the solution, is stirred all night at room temperature.Boiled off under decompression after solvent, dichloromethane and sodium bicarbonate aqueous solution point liquid are added in residue, organic layer anhydrous sodium sulfate drying boils off solvent under decompression.Residue obtained use silica gel column chromatography (methanol: dichloromethane=3: 47) refines, obtains title compound (110mg).
1H-NMR(CDCl3)δ：0.02 (9H, s), 0.97 (2H, dd, J=9.9, 7.0Hz), 1.57-1.72 (1H, m), 1.79-1.92 (1H, m), 2.06-2.37 (4H, m), 2.38 (3H, s), 2.53 (3H, s), 2.84-2.89 (2H, m), 2.93-2.99 (2H, m), 3.12-3.23 (1H, m), 3.76 (2H, br.s), 3.85-3.94 (1H, m), 4.14 (2H, dd, J=9.9, 7.0Hz), 4.60-4.69 (1H, m), 5.23 (1H, d, J=7.6Hz), 7.41 (1H, d, J=8.3Hz)
MS(ESI)m/z：521(M+H)+.
[reference example 561] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (1,3,4- thiadiazoles -2- bases) Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Figure G2003801097466D03211
The compound (1.0g) that reference example 557 is obtained is dissolved in N, dinethylformamide (20ml), formylhydrazine (149mg), I-hydroxybenzotriazole (335mg) and 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (713mg) are sequentially added in the solution, is stirred all night at room temperature.After the lower concentration of reaction solution of decompression, ethyl acetate and 10% aqueous citric acid solution point liquid are added in residue.Oil reservoir saturated aqueous common salt, sodium bicarbonate aqueous solution and saturated common salt water washing.After organic layer is dried with anhydrous magnesium sulfate, solvent is boiled off under decompression, colourless powder (1.12g) is obtained.Add after toluene (50ml) and ロ-ソ Application reagents (2.0g), be heated to reflux 1 hour in the powder at room temperature.Place to room temperature, added in the solution under silica gel, decompression and boil off solvent.Residue obtained use silica gel column chromatography (hexane: ethyl acetate=1: 1 → 0: 1) refines, obtains title compound (511mg).
1H-NMR(CDCl3)δ：0.04 (9H, s), 0.99 (2H, t, J=8.4Hz), 1.46 (9H, s), 1.59-1.85 (2H, m), 1.91-2.02 (1H, m), 2.05-2.14 (1H, m), 2.18-2.27 (1H, m), 2.29-2.40 (1H, m), 3.31-3.44 (1H, m), 3.69-3.86 (1H, m), 4.09-4.23 (3H, m), 4.71-4.93 (1H, m), 5.07-5.34 (1H, m), 9.05 (1H, s)
MS(ESI)m/z：443(M+H)+.
[reference example 562] (1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,3,4- thiadiazoles -2- bases) Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Figure G2003801097466D03221
Using the method same with reference example 560, the compound obtained with p-methyl benzenesulfonic acid to reference example 561 is handled, the compound condensation obtained after deprotection with reference example 10, obtains title compound.
1H-NMR(CDCl3)δ：0.03 (9H, s), 0.97 (2H, t, J=8.5Hz), 1.63-1.75 (1H, m), 1.81-1.93 (1H, m), 2.01-2.22 (2H, m), 2.25-2.37 (1H, m), 2.42-2.51 (1H, m), 2.52 (3H, s), 2.81-2.89 (2H, m), 2.92-2.99 (2H, m), 3.47-3.57 (1H, m), 3.73 (2H, s), 3.86-3.96 (1H, m), 4.14 (2H, t, J=8.5Hz), 4.61-4.69 (1H, m), 5.21-5.28 (1H, m), 7.41-7.53 (1H, m), 9.06 (1H, s)
MS(ESI)m/z：523(M+H)+.
[reference example 563] (1S, 3R, 4S) -3- amino -4- ({ 2- [(5- fluorine pyridine -2- bases) amino] -2- oxos ethanethioyl } amino)-N, N- dimethyl cyclohexane carboxamide hydrochlorides
Figure G2003801097466D03222
4N hydrochloric acid-dioxane solution (350ml) was instilled in dioxane (350ml)-methanol (200ml) suspension for the compound (73.3g) that reference example 427 is obtained with 5 minutes, is stirred at room temperature 2 and a half hours after being stirred 10 minutes in frozen water.The lower concentration of reaction solution of decompression, makes to dry after its Yu dioxane and tetrahydrofuran azeotropic, obtains title compound (76.4mg).
1H-NMR(DMSO-d6)δ：1.34-1.55 (1H, m), 1.64-1.84 (3H, m), 1.97-2.11 (1H, m), 2.11-2.30 (1H, m), 2.80 (3H, br.s), 3.06 (3H, br.s), 3.20-3.58 (1H, m), 3.91-4.07 (1H, m), 4.22-4.42 (1H, m), 7.74-7.91 (1H, m), 8.00-8.16 (1H, m), 8.25-8.60 (4H, m), (10.64 1H, d, J=11.9Hz), 10.89-10.99 (1H, m)
MS(ESI)m/z：367(M+H)+.
[reference example 564] 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxylic acids hydrochloride
Figure G2003801097466D03231
1N ethanol solution hydrochloride (36ml) is added in the compound (3.00g) that reference example 10 is obtained, is stirred 1 hour at room temperature.The crystallization separated out is filtered, is washed with ethanol (9ml).Wet body is dried under reduced pressure at room temperature, obtains title compound (2.76g).
1H-NMR(D2O)δ：4.82-4.88 (1H, d, J=16.0Hz), 4.51-4.57 (1H, d, J=16.0Hz), 3.88-3.96 (1H, m), 3.60-3.70 (1H, m), 3.22-3.33 (2H, m), 3.15 (3H, s)
[reference example 565] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases) Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Using the method same with reference example 561, the compound that reference example 557 is obtained is set to be condensed with acethydrazide, then with after ロ-ソ Application reagent reactings, heating and obtaining title compound.
1H-NMR(CDCl3)δ：0.04 (9H, s), 0.98 (2H, t, J=8.5Hz), 1.46 (9H, s), 1.61-1.75 (1H, m), 1.80-2.00 (3H, m), 2.11-2.20 (1H, m), 2.22-2.31 (1H, m), 2.75 (3H, s), 3.17-3.32 (1H, m), 3.61-3.88 (1H, m), 4.07-4.22 (3H, m), 4.82 (1H, br.s), (5.24 1H, br.s)
MS(ESI)m/z：457(M+H)+.
[reference example 566] (1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases) Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Figure G2003801097466D03233
Using the method same with reference example 560, the compound obtained with p-methyl benzenesulfonic acid to reference example 565 is handled, the compound condensation obtained after deprotection with reference example 564, obtains title compound.
1H-NMR(CDCl3)δ：0.02 (9H, s), 0.97 (2H, t, J=7.8Hz), 1.59-1.73 (1H, m), 1.74-1.87 (1H, m), 1.97-2.08 (1H, m), 2.08-2.20 (1H, m), 2.20-2.31 (1H, m), 2.36-2.45 (1H, m), 2.52 (3H, s), 2.75 (3H, s), 2.84 (2H, t, J=5.5Hz), 2.95 (2H, t, J=5.5Hz), 3.35-3.49 (1H, m), 3.73 (2H, br.s), 3.89 (1H, br.s), 4.14 (2H, t, J=7.8Hz), 4.58-4.69 (1H, m), 5.29 (1H, br.s), 7.47 (1H, d, J=8.1Hz)
MS(ESI)m/z：537(M+H)+.
[reference example 567] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (1,3- oxazole -5- bases) Cyclohexylamino benzyl formate
In 75 DEG C under decompression, N-METHYLFORMAMIDE (0.99ml) is instilled in the mixture of quinoline (8.00ml) and paratoluensulfonyl chloride (4.84g).The gas of generation is cooled down with liebig's condensing tube so that it becomes after liquid, being reclaimed with the eggplant type flask for being cooled to -78 DEG C, obtaining methyl-isocyanide (553mg).In a nitrogen atmosphere n-BuLi (1.57M hexane solutions, 6.95ml) is added in -78 DEG C of tetrahydrofuran (10ml) solution in methyl-isocyanide (349mg) to stir 15 minutes.Tetrahydrofuran (10ml) solution for the compound (1.02g) that reference example 141 is obtained is instilled in reaction solution in -78 DEG C, is stirred 30 minutes.Reaction solution is warming up to 0 DEG C, after stirring 15 minutes, and -78 DEG C are cooled to again, adds acetic acid (0.62ml).After 0 DEG C is stirred for 45 minutes to reaction solution, diluted with ether, successively with after water and saturated common salt water washing, use anhydrous sodium sulfate drying.Decompression is lower to be concentrated, residue obtained (methanol: dichloromethane=1: 49 → 3: 97) to refine for the flash column chromatography of carrier to silica gel, obtain title compound (663mg).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.50-2.20 (6H, m), 2.75-2.88 (1H, m), 3.69-3.81 (1H, m), 4.19-4.23 (1H, m), 4.65-4.84 (1H, m), 5.05-5.18 (2H, m), 6.78 (1H, s), 7.30-7.45 (6H, m), 7.77 (1H, s)
MS(ESI)m/z：416(M+H)+.
[reference example 568] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (1,3- oxazole -5- bases) Cyclohexylamino t-butyl formate
Using the method same with reference example 552, after the compound deprotection obtained to reference example 567, the compound condensation obtained with reference example 266 obtains title compound.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.53-1.68 (1H, m), 1.70-1.92 (2H, m), 1.94-2.24 (3H, m), 2.78-2.95 (1H, m), 3.94-4.05 (1H, m), 4.16-4.30 (1H, m), 4.88-5.04 (1H, m), 6.78 (1H, s), 7.69 (1H, dd, J=8.8,2.4Hz), 7.78 (1H, s), 7.95-8.10 (1H, m), 8.17 (1H, d, J=8.8Hz), 8.30 (1H, d, J=2.4Hz), 9.74 (1H, s)
MS(ESI)m/z：464(M+H)+.
[reference example 569] (1S, 2R, 4S) -4- (amino carbonyl) -2- [(tert-butoxycarbonyl) amino] Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
It is same with reference example 143, make compound and ammonium chloride condensation that reference example 557 is obtained, obtain title compound.
1H-NMR(CDCl3)δ：0.04 (9H, s), 0.97 (2H, t, J=8.3Hz), 1.45 (9H, s), 1.62-2.07 (6H, m), 2.33 (1H, br.s), 3.69 (1H, br.s), 4.00-4.21 (3H, m), 4.93 (1H, br.s), 5.15 (1H, br.s), 5.60 (1H, br.s), 5.75 (1H, br.s)
MS(ESI)m/z：302(M-Boc)+.
[reference example 570] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- cyanocyclohexanoic aminocarbamic acids 2- (trimethyl silyl) ethyl ester
Figure G2003801097466D03261
The compound (1.48g) and triethylamine (1.04ml) that reference example 569 is obtained, which are dissolved under dichloromethane (25ml), ice cooling in the solution, adds TFAA (0.790ml).After stirring 1 hour at room temperature, saturated sodium bicarbonate aqueous solution is added in the solution and dichloromethane carries out a point liquid.Gained organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.Hexane solidification is added in residue, title compound (1.18g) is obtained.
1H-NMR(DMSO-d6)δ：0.01 (9H, s), 0.91 (2H, dd, J=9.0,7.1Hz), 1.38 (9H, s), 1.48-1.64 (3H, m), 1.65-1.77 (1H, m), (1.81 2H, t, J=5.9Hz), 3.03 (1H, br.s), 3.62 (1H, br.s), 3.78 (1H, br.s), 4.02 (2H, dd, J=9.0,7.1Hz), 6.54 (1H, br.s), 6.74 (1H, br.s)
MS(ESI)m/z：406(M+Na)+, 328 (M-tBu)+, 284 (M-Boc)+.
[reference example 571] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Using the method same with reference example 550, make compound and azanol reaction that reference example 570 is obtained, cyclization is then carried out with trimethyl orthoacetate, title compound is obtained.
1H-NMR(CDCl3)δ：0.03 (9H, s), 0.98 (2H, t, J=8.4Hz), 1.35-2.18 (6H, m), 1.45 (9H, s), 2.56 (3H, s), 2.81-2.96 (1H, m), 3.65-3.79 (1H, m), 4.05-4.23 (3H, m), 4.65-4.83 (1H, m), 5.10-5.30 (1H, m)
[reference example 572] (1S, 2R, 4S) -4- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Using the method same with reference example 560, the compound obtained with p-methyl benzenesulfonic acid to reference example 571 is handled, after deprotection, the compound condensation obtained with reference example 10, obtains title compound.
1H-NMR(CDCl3)δ：0.02 (9H, s), 0.96 (2H, t, J=8.4Hz), 1.52-1.66 (1H, m), 1.73-1.90 (1H, m), 2.00-2.29 (4H, m), 2.56 (3H, s), 2.58 (3H, s), 2.85-3.11 (5H, m), 3.73-3.93 (3H, m), 4.13 (2H, t, J=8.4Hz), 4.59-4.68 (1H, m), 5.15-5.26 (1H, m), 7.34-7.45 (1H, m)
MS(ESI)m/z：521(M+H)+.
[reference example 573] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- ({ [2- (trimethyl silyl) ethyoxyl] carbonyl } amino) Cyclohexylamino benzyl formate
Triethylamine (1.67ml) and diphenylphosphoryl azide (2.06ml) are added in toluene (60ml) solution for the compound (3.14g) that reference example 142 is obtained, is stirred 2 hours in 80 DEG C.It is cooled to after room temperature and adds Trimethylsilylethanol (4.59ml), is stirred 16 hours in 90 DEG C.Reaction solution, which is cooled to after room temperature, depressurizes lower concentration, is dissolved in ethyl acetate.The solution with 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, is concentrated with decompression after anhydrous sodium sulfate drying is lower successively.Residue (dichloromethane: methanol=50: 1) is refined with silica gel column chromatography, hexane leaching is added in gained solid, obtain title compound (2.72g).
1H-NMR(CDCl3)δ：0.03 (9H, s), 0.91-1.01 (2H, m), 1.23-1.64 (3H, m), 1.44 (9H, s), 1.90-2.08 (3H, m), 3.51-3.75 (2H, m), 4.04-4.18 (3H, m), 4.49 (1H, br.s), 4.78 (1H, br.s), 5.03-5.14 (2H, m), 5.36 (1H, br.s), 7.28-7.38 (5H, m)
MS(ESI)m/z：508(M+H)+.
[reference example 574] (1S, 2R, 4S) -4- amino -2- [(tert-butoxycarbonyl) amino] Cyclohexylamino benzyl formate
Figure G2003801097466D03281
The tetrahydrofuran solution (6.0ml) of 1N tetrabutylammonium is added in tetrahydrofuran (6.0ml) solution for the compound (1.02g) that reference example 573 is obtained, is stirred 3 days at room temperature.Ethyl acetate is added in reaction solution, successively with saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing.Lower concentrate is depressurized after organic layer anhydrous sodium sulfate drying.Residue (dichloromethane: methanol: concentrated ammonia liquor=100: 10: 1) is refined with silica gel column chromatography, obtains title compound (660mg).
1H-NMR(CDCl3)δ：1.19-1.63 (3H, m), 1.44 (9H, s), 1.80-2.06 (3H, m), 2.79-2.91 (1H, m), 3.63-3.72 (1H, m), 4.11 (1H, br.s), 4.68 (1H, br.s), 5.03-5.14 (2H, m), 5.27 (1H, br.s), 7.28-7.38 (5H, m)
MS(ESI)m/z：363(M+H)+.
[reference example 575] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) -4- (4H-1,2,4- triazole-4-yls) amino] Cyclohexylamino benzyl formate
1 is added in pyridine (3.0ml) solution for the compound (182mg) that reference example 574 is obtained, 2- diformylhydrazines (154mg), triethylamine (0.464ml) and chlorine trimethyl silane (0.952ml), in 80 DEG C of heating stirrings 6 hours.Reaction solution is cooled to after room temperature, adds saturated sodium bicarbonate aqueous solution and dichloromethane point liquid, organic layer saturated common salt water washing.Lower concentration is depressurized after organic layer anhydrous sodium sulfate drying, residue is refined to silica gel for the flash column chromatography (dichloromethane: methanol 30: 1 → 10: 1) of carrier, obtains title compound (127mg).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.54-1.91 (3H, m), 1.91-2.15 (2H, m), 2.21 (1H, d, J=12.5Hz), 2.37 (1H, d, J=12.9Hz), 3.82 (1H, br.s), 4.24 (1H, br.s), 4.36 (1H, br.s), 5.05-5.16 (2H, m), 5.35 (1H, d, J=7.6Hz), 7.30-7.40 (5H, m), 8.26 (2H, s)
MS(ESI)m/z：416(M+H)+.
[reference example 576] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (4H-1,2,4- triazole-4-yls) Cyclohexylamino t-butyl formate
Using the method same with reference example 552, after the compound deprotection obtained to reference example 575, the compound condensation obtained with reference example 266 prepares title compound.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.60-1.98 (2H, m), 2.05-2.20 (2H, m), 2.25-2.35 (1H, m), 2.36-2.45 (1H, m), 4.03-4.13 (1H, m), 4.37 (1H, br.s), 4.47 (1H, br.s), 5.42 (1H, br.s), 7.71 (1H, dd, J=8.8,2.4Hz), 8.04 (1H, br.s), 8.17 (1H, d, J=8.8Hz), 8.31-8.33 (3H, m), 9.71 (1H, s)
MS(ESI)m/z：464(M+H)+.
[reference example 577] (1R, 2S, 5S) -2- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) Cyclohexylamino t-butyl formate
Figure G2003801097466D03292
The compound (5.74g) that reference example 551 is obtained is dissolved in methanol (110ml), adds 10% palladium-carbon catalyst (1.22g), is stirred at room temperature in nitrogen atmosphere 17 hours.Filter off and solvent is boiled off under being depressurized after catalyst, obtain title compound (3.95g).
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.65-2.45 (6H, m), 2.51 (3H, s), 3.03-3.60 (3H, m), 4.12-4.35 (1H, m), 5.45-5.76 (1H, m), 6.86-7.17 (1H, m)
MS(ESI)m/z：297(M+H)+.
[reference example 578] 2- [(5- bromopyridine -2- bases) amino] -2- Oxoacetic Acid lithium salts
Using the method same with reference example 266, the compound obtained by reference example 262 prepares title compound.
1H-NMR(DMSO-d6)δ：8.03 (1H, dd, J=8.8,2.4Hz), 8.09 (1H, d, J=8.8Hz), 8.44 (1H, d, J=2.4Hz), 10.18 (1H, s)
[reference example 579] (1R; 2S; 5S) -2- ({ 2- [(5- bromopyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) Cyclohexylamino t-butyl formate
Figure G2003801097466D03301
The N of the compound (900mg) obtained in reference example 577, compound (1.24g), 3- (3- dimethylaminopropyls) -1- ethyl-carbodiimide hydrochlorides (1.17g) and I-hydroxybenzotriazole (205mg) that reference example 578 is obtained are added in dinethylformamide (40ml) solution, is stirred 7 hours in 40 DEG C.Ethyl acetate and moisture liquid are added in reaction solution, organic layer is washed with water, and with anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: methanol=19: 1) refines for the flash column chromatography of carrier to silica gel, obtains title compound (1.51g).
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.56-2.31 (6H, m), 2.52 (3H, s), 3.01-3.12 (1H, m), 4.00-4.08 (1H, m), 4.26 (1H, br.s), 4.92 (1H, br.s), 7.84 (1H, dd, J=8.8,2.5Hz), (8.03 1H, d, J=2.9Hz), (8.14 1H, d, J=8.8Hz), (8.41 1H, d, J=2.5Hz), 9.72 (1H, s)
[reference example 580] (1R, 2S, 5S) -2- { [(7- chlorine cinnolines -3- bases) carbonyl] amino } -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) Cyclohexylamino t-butyl formate
Figure G2003801097466D03302
Using the method same with reference example 579, the compound that reference example 297 is obtained is hydrolyzed, the compound condensation for obtaining gained carboxylic acid lithium salt and reference example 577 obtains title compound.
1H-NMR(CDCl3)δ：1.37 (9H, s), 1.68-1.82 (1H, m), 1.82-1.99 (1H, m), 2.01-2.37 (4H, m), 2.53 (3H, s), 3.12 (1H, br.s), 4.40 (2H, br.s), 4.96 (1H, br.s), 7.79 (1H, dd, J=8.8,1.8Hz), 7.98 (1H, d, J=8.8Hz), 8.61 (1H, s), 8.69 (1H, d, J=7.8Hz), 8.74 (1H, s)
MS(ESI)m/z：487(M+H)+.
[reference example 581] (1R, 2S, 5S) -2- { [(7- chlorine isoquinolin -3- bases) carbonyl] amino } -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) Cyclohexylamino t-butyl formate
Figure G2003801097466D03311
Using the method same with reference example 579, make the compound that reference example 577 is obtained and the compound condensation that reference example 57 is obtained, obtain title compound.
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.57-1.74 (1H, m), 1.79-2.49 (5H, m), 2.53 (3H, s), 3.00-3.16 (1H, m), 4.24-4.38 (2H, m), 5.00 (1H, br.s), 7.71 (1H, dd, J=8.8,1.7Hz), 7.90-7.97 (1H, m), 8.02 (1H, d, J=1.7Hz), 8.45-8.62 (2H, m), 9.05 (1H, s)
MS(ESI)m/z：486(M+H)+.
[reference example 582] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (1,2,4- oxadiazole -5- bases) Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Stirred 2 hours in the mixture of 120 DEG C of compounds (994mg) obtained to reference example 569 and the dimethylacetal (10ml) of DMF.Place to room temperature and depressurize lower concentration of reaction solution, adding hexane in residue obtains colourless powder.70% acetic acid aqueous solution (10ml) and azanol (aqueous 50%, 197mg) are added in the powder, is stirred all night at room temperature.Decompression boils off solvent, in residue obtained middle addition ethyl acetate and saturated sodium bicarbonate aqueous solution point liquid.Decompression boils off solvent after organic layer anhydrous sodium sulfate drying, and residue (hexane: ethyl acetate=2: 1) is refined with silica gel column chromatography, obtains title compound (759mg).
1H-NMR(CDCl3)δ：0.04 (9H, s), 0.91-1.04 (2H, m), 1.46 (9H, s), 1.61-2.44 (6H, m), 2.98-3.49 (1H, m), 3.73 (1H, br.s), 4.03-4.25 (2H, m), 4.85 (1H, br.s), 5.30 (1H, br.s), 6.70 (1H, br.s), 8.34 (1H, s)
MS(ESI)m/z：449(M+Na)+, 327 (M-Boc)+.
[reference example 583] (1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,2,4- oxadiazole -5- bases) Cyclohexylamino formic acid 2- (trimethyl silyl) ethyl ester
Figure G2003801097466D03321
Using the method same with reference example 560, the compound obtained with p-methyl benzenesulfonic acid to reference example 583 is carried out after processing deprotection, the compound condensation obtained with reference example 564, obtains title compound.
1H-NMR(CDCl3)δ：0.02 (9H, s), 0.97 (2H, dd, J=9.9, 7.0Hz), 1.58-1.94 (2H, m), 2.07-2.20 (2H, m), 2.21-2.30 (1H, m), 2.35-2.44 (1H, m), 2.53 (3H, s), 2.85 (2H, t, J=5.6Hz), 2.95 (2H, t, J=5.6Hz), 3.20-3.32 (1H, m), 3.74 (2H, s), 3.90 (1H, br.s), 4.14 (2H, dd, J=9.9, 7.0Hz), 4.62-4.69 (1H, m), 5.19 (1H, br.s), 7.39 (1H, d, J=8.1Hz), 8.35 (1H, s)
MS(ESI)m/z：507(M+H)+.
[reference example 584] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- { [2- (2,2,2- trifluoroacetyl group) diazanyl] carbonyl } Cyclohexylamino benzyl formate
The N of the compound (4.00g) obtained in reference example 142,1 hydrate (765mg), I-hydroxybenzotriazole (1.38g), 1- (the dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (2.93g) of hydrazine are added in dinethylformamide (100ml) solution, is stirred all night at room temperature.The lower concentration of reaction solution of decompression, adds dichloromethane and sodium bicarbonate aqueous solution point liquid in residue.Water layer is extracted with dichloromethane, is merged gained organic layer, is used anhydrous sodium sulfate drying.Filter off after anhydrous sodium sulfate, add silica gel (25g) in gained filtrate and methanol (15ml) is stirred, filter off insoluble matter.Solvent is boiled off under decompression, rough (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (Hydrazinocarbonyl) Cyclohexylamino benzyl formates (3.71g) in colourless oily mater are obtained.Added in gained colourless oily mater (306mg) under dichloromethane (10ml) and triethylamine (115 μ l), ice cooling and add TFAA (116 μ l) in the mixture, stirred 5 hours at room temperature.Then, additional triethylamine (115 μ l) and TFAA (116 μ l), are stirred 1 hour at room temperature.Dichloromethane and moisture liquid are added in reaction solution, after water layer is extracted with dichloromethane, merges gained organic layer, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 19) is refined with silica gel column chromatography, obtains title compound (283mg).
1H-NMR(CDCl3)δ：1.41 (9H, s), 1.52-2.06 (6H, m), 2.53 (1H, br.s), 3.73 (1H, br.s), 4.09 (1H, br.s), 4.99-5.15 (3H, m), 5.34 (1H, d, J=7.3Hz), 7.27-7.36 (5H, m), 8.92-9.36 (1H, m)
MS(ESI)m/z：525(M+Na)+, 403 (M-Boc)+.
[reference example 585] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- [5- (trifluoromethyl) -1,3,4- oxadiazole -2- bases] Cyclohexylamino benzyl formate
Figure G2003801097466D03331
Triphenyl phasphine (392mg) is dissolved in the dichloromethane (5ml) for sequentially adding the compound (250mg) that carbon trichloride (296mg) and triethylamine (416 μ l) and reference example 584 are obtained under dichloromethane (10ml), ice cooling in the solution.Stir at room temperature all night after, dichloromethane and 10% aqueous citric acid solution point liquid are added in reaction solution.Organic layer saturated aqueous common salt, sodium bicarbonate aqueous solution and saturated common salt water washing.With after anhydrous sodium sulfate drying depressurize under boil off solvent.Residue (hexane: ethyl acetate=1: 1) is refined with silica gel column chromatography, obtains title compound (204mg).
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.51-1.62 (1H, m), 1.71-1.90 (1H, m), 1.92-2.16 (2H, m), 2.16-2.25 (1H, m), 2.28-2.38 (1H, m), 3.16 (1H, br.s), 3.81 (1H, br.s), 4.20 (1H, br.s), 4.56-4.84 (1H, m), 5.04-5.16 (2H, m), 5.20-5.28 (1H, m), 7.29-7.39 (5H, m)
MS(ESI)m/z：429(M-tBu)+, 385 (M-Boc)+.
[reference example 586] (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [5- (trifluoromethyl) -1,3,4- oxadiazole -2- bases] Cyclohexylamino t-butyl formate
Using the method same with reference example 552, after the compound deprotection obtained to reference example 585, the compound condensation obtained with reference example 266 obtains title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.55-1.66 (1H, m), 1.79-1.94 (1H, m), 1.98-2.19 (2H, m), 2.23-2.32 (1H, m), 2.32-2.41 (1H, m), 3.18 (1H, br.s), 4.00-4.10 (1H, m), 4.29 (1H, br.s), 4.86 (1H, br.s), 7.71 (1H, dd, J=8.8,2.4Hz), 7.98 (1H, br.s), 8.18 (1H, d, J=8.8Hz), 8.32 (1H, d, J=2.4Hz), 9.72 (1H, s)
MS(ESI)m/z：477(M-tBu)+, 433 (M-Boc)+.
[reference example 587] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- { [(2- chloroethoxies) carbonyl] amino } Cyclohexylamino benzyl formate
Under ice cooling, ethyl chloroformate (323 μ l) and triethylamine (499 μ l) are added in dichloromethane (30ml) solution for the compound (872mg) that reference example 574 is obtained, is stirred 1 hour in 0 DEG C.Add water a point liquid in reaction solution, and organic layer is washed with water, and uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=3: 2) refines for the flash column chromatography of carrier to silica gel, obtains title compound (1.03g).
1H-NMR(CDCl3)δ：1.24-1.70 (12H, m), 1.99-2.03 (3H, m), 3.59-3.73 (4H, m), 4.06-4.13 (1H, m), 4.29 (2H, t, J=5.5Hz), 4.82 (1H, br.s), 4.86 (1H, br.s), 5.05-5.12 (2H, m), 5.41 (1H, br.s), 7.28-7.36 (5H, m)
MS(ESI)m/z：492(M+Na)+.
[reference example 588] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (2- oxo -1,3- oxazolidine -3- bases) Cyclohexylamino benzyl formate
Figure G2003801097466D03342
In 60% sodium hydride (87mg) N, the N for the compound (926mg) that reference example 587 is obtained is added in dinethylformamide (5.0ml) suspension, dinethylformamide (5.0ml) solution, is stirred 1 hour at room temperature.Water and ethyl acetate point liquid, organic layer water and saturated common salt water washing are added in reaction solution.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression, it is residue obtained (hexane: ethyl acetate=2: 3) to refine for the flash column chromatography of carrier to silica gel, obtain title compound (680mg).
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.45-2.08 (6H, m), 3.44-3.54 (2H, m), 3.64 (1H, br.s), 3.77-3.87 (1H, m), 4.20 (1H, br.s), 4.29-4.36 (2H, m), 4.84 (1H, br.s), 5.05-5.13 (2H, m), 5.37 (1H, br.s), 7.27-7.36 (5H, m)
MS(ESI)m/z：434(M+H)+.
[reference example 589] (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (2- oxo -1,3- oxazolidine -3- bases) Cyclohexylamino t-butyl formate
Using the method same with reference example 552, after the compound deprotection of the gained of reference example 588, the compound condensation obtained with reference example 266 prepares title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.58-1.65 (2H, m), 1.79-2.05 (4H, m), 3.47-3.55 (2H, m), 3.84-3.93 (2H, m), 4.29 (1H, br.s), 4.33-4.39 (2H, m), 5.08 (1H, br.s), 7.70 (1H, dd, J=8.8,2.5Hz), 8.10 (1H, br.s), 8.19 (1H, dd, J=8.8,0.7Hz), 8.31 (1H, dd, J=2.5,0.7Hz), 9.71 (1H, s)
MS(ESI)m/z：504(M+Na)+.
[reference example 590] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (Formylamino) Cyclohexylamino benzyl formate
Figure G2003801097466D03352
Formic acid (31.1 μ l), I-hydroxybenzotriazole (108mg), triethylamine (115 μ l) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (210mg) are added in dichloromethane (5ml) solution for the compound (200mg) that reference example 574 is obtained, is stirred 22 hours at room temperature.Solvent is boiled off under decompression, saturated sodium bicarbonate aqueous solution is added in residue, is extracted with dichloromethane, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (dichloromethane: methanol=49: 1 → 97: 3) is refined with silica gel column chromatography, obtains title compound (100mg).
1H-NMR(CDCl3)δ：1.27-1.50 (2H, m), 1.44 (9H, s), 1.94-2.07 (4H, m), 3.66-3.74 (1H, m), 3.97-4.07 (1H, m), 4.08-4.15 (1H, m), 4.80-4.88 (1H, m), 5.05 (1H, d, J=12.2Hz), 5.10 (1H, d, J=12.0Hz), 5.33-5.41 (1H, m), 5.43-5.50 (1H, m), 7.30-7.37 (5H, m), 8.12 (1H, s)
MS(ESI)m/z：392(M+H)+.
[reference example 591] (1R, 2S, 5S) -2- [(benzyloxycarbonyl) amino] -5- (tetrazolium -1- bases) Cyclohexylamino t-butyl formate
Under ice cooling, trichloromethyl chloroformate (268 μ l) is instilled in the compound (792mg) and dichloromethane (10ml) solution of pyridine (1.63ml) that reference example 590 is obtained, is stirred 10 minutes at the same temperature.Reactant mixture is returned back to after room temperature and stirred 15 minutes, adds Azide trimethyl silyl (295 μ l), continues to stir 22 hours.Solvent is boiled off under decompression, sodium bicarbonate aqueous solution is added in residue, leaching insoluble matter is washed with water, gained solid (dichloromethane: methanol=199: 1 → 49: 1) is refined with silica gel column chromatography, obtains title compound (60mg).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.55-1.59 (1H, m), 2.02-2.14 (2H, m), 2.21-2.32 (2H, m), 2.41-2.49 (1H, m), 3.84-3.92 (1H, m), 4.20-4.25 (1H, m), 4.65-4.76 (1H, m), 5.07-5.16 (3H, m), 5.21-5.28 (1H, m), 7.32-7.38 (5H, m), 8.68 (1H, s)
MS(ESI)m/z：417(M+H)+.
[reference example 592] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (tetrazolium -1- bases) Cyclohexylamino t-butyl formate
Using the method same with reference example 552, after the compound deprotection obtained to reference example 591, the compound condensation obtained with reference example 266 obtains title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.73-1.92 (1H, m), 2.07-2.21 (2H, m), 2.28-2.41 (2H, m), 2.45-2.53 (1H, m), 4.10-4.19 (1H, m), 4.33-4.40 (1H, m), 4.71-4.89 (1H, m), 4.99-5.14 (1H, m), 7.71 (1H, dd, J=8.8,2.4Hz), 7.96-8.04 (1H, m), 8.17 (1H, d, J=8.8Hz), 8.32 (1H, d, J=2.4Hz), 8.69 (1H, s), 9.71 (1H, s)
MS(ESI)m/z：465(M+H)+.
[reference example 593] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (1H- pyrroles -1- bases) Cyclohexylamino benzyl formate
Reference example 574 obtain compound (200mg), 2,5- dimethoxy-tetrahydrofurans (71.3 μ l), water (10ml) and 1,1N hydrochloric acid (550 μ l) is added in the mixture of 2- dichloroethanes (10ml), is stirred 2.5 hours in 80 DEG C.Place to room temperature, saturated sodium bicarbonate aqueous solution and dichloromethane point liquid are added in reaction solution.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, (hexane: ethyl acetate=4: 1 → 1: 1) is refined with silica gel column chromatography, obtains title compound (84mg).
1H-NMR(CDCl3)δ：1.45 (9H, s), 1.71-2.20 (5H, m), 2.22-2.31 (1H, m), 3.78 (1H, br.s), 3.99 (1H, br.s), 4.22 (1H, br.s), 4.73 (1H, br.s), 5.04-5.16 (2H, m), 5.29 (1H, br.s), 6.15 (2H, t, J=2.2Hz), 6.70 (2H, t, J=2.2Hz), 7.29-7.39 (5H, m)
MS(ESI)m/z：436(M+Na)+.
[reference example 594] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (1H- pyrroles -1- bases) Cyclohexylamino t-butyl formate
Figure G2003801097466D03372
Using the method same with reference example 552, after the compound deprotection obtained to reference example 593, the compound condensation obtained with reference example 266 obtains title compound.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.80-2.33 (6H, m), 3.92-4.08 (2H, m), 4.31 (1H, br.s), 4.89 (1H, br.s), 6.17 (2H, t, J=2.0Hz), 6.71 (2H, t, J=2.0Hz), 7.69 (1H, dd, J=8.8,2.2Hz), 8.02 (1H, br.s), 8.17 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.2Hz), 9.72 (1H, br.s)
MS(ESI)m/z：462(M+H)+.
[reference example 595] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- ({ [(dimethylamino) methylene] amino } carbonyl) Cyclohexylamino benzyl formate
The N of the compound (1.50g) obtained in reference example 142, ammonium chloride (409mg), I-hydroxybenzotriazole (516mg), 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (1.03g) and triethylamine (1.06ml) are added in dinethylformamide (100ml) solution, is stirred all night at room temperature.The lower concentration of reaction solution of decompression, adds ethyl acetate and 10% aqueous citric acid solution point liquid in residue.Organic layer saturated aqueous common salt, sodium bicarbonate aqueous solution and saturated common salt water washing.After being dried with anhydrous magnesium sulfate, solvent is boiled off under decompression.Gained powder is suspended in the dimethylacetal (30ml) of DMF, stirred 2 hours in 120 DEG C.The colourless powder separated out to leaching after room temperature is placed, is washed with ether, title compound (957mg) is obtained.
1H-NMR(CDCl3)δ：1.25-1.40 (1H, m), 1.44 (9H, s), 1.53-1.66 (1H, m), 1.73-2.08 (4H, m), 2.32-2.46 (1H, m), 3.07 (3H, s), 3.11 (3H, s), 3.63-3.75 (1H, m), 4.13 (1H, br.s), 4.59-4.75 (1H, m), (5.07 1H, d, J=12.2Hz), (5.12 1H, d, J=12.2Hz), 5.30-5.45 (1H, m), 7.28-7.37 (5H, m), 8.40 (1H, s)
MS(ESI)m/z：447(M+H)+.
[reference example 596] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (1,2,4- triazole -5- bases) Cyclohexylamino benzyl formate
1 hydrate (51.9 μ l) of hydrazine is added in acetic acid (10ml) solution for the compound (400mg) that reference example 595 is obtained, is stirred 2 hours at room temperature.Solvent is boiled off under decompression, in residue obtained middle addition sodium bicarbonate aqueous solution and ethyl acetate point liquid.Organic layer saturated common salt water washing, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, title compound (370mg) is obtained.
1H-NMR(DMSO-d6)δ：1.39 (9H, s), 1.48-1.62 (2H, m), 1.62-1.75 (2H, m), 1.88-2.06 (2H, m), 3.06 (1H, br.s), 3.56 (1H, br.s), 3.95 (1H, br.s), 4.95-5.10 (2H, m), 6.62 (1H, br.s), 7.00 (1H, br.s), 7.27-7.38 (5H, m), 13.59 (1H, br.s)
MS(ESI)m/z：416(M+H)+.
[reference example 597] (1R, 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (1,2,4- triazole -5- bases) Cyclohexylamino t-butyl formate
Figure G2003801097466D03391
Using the method same with reference example 552, after the compound deprotection obtained to reference example 596, title compound is made in the compound condensation obtained with reference example 266.
1H-NMR(DMSO-d6)δ：1.39 (9H, s), 1.50-2.03 (5H, m), 2.05-2.17 (1H, m), 2.94-3.20 (1H, m), 3.85-3.99 (2H, m), 7.06 (1H, br.s), 7.80 (0.5H, br.s), 8.03 (1H, dd, J=8.8,2.2Hz), 8.06 (1H, d, J=8.8Hz), 8.39 (0.5H, s), (8.47 1H, d, J=2.2Hz), 8.56-8.69 (1H, m), 10.27 (1H, s), 13.59-13.66 (1H, m)
MS(ESI)m/z：464(M+H)+.
[reference example 598] (1S, 2R, 4S) -2- [(tert-butoxycarbonyl) amino] -4- (1- methyl isophthalic acids H-1,2,4- triazole -5- bases) Cyclohexylamino benzyl formate
Figure G2003801097466D03392
Methyl hydrazine (56.9 μ l) is added in acetic acid (10ml) solution for the compound (400mg) that reference example 595 is obtained, is stirred all night at room temperature.Solvent is boiled off under decompression, in residue obtained middle addition saturated sodium bicarbonate aqueous solution and ethyl acetate point liquid.Organic layer saturated common salt water washing, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, (methanol: dichloromethane=1: 19) is refined with silica gel column chromatography, obtains title compound (224mg).
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.53-1.80 (2H, m), 1.88-2.18 (4H, m), 2.77-2.89 (1H, m), 3.71-3.83 (1H, m), 3.86 (3H, s), 4.17 (1H, br.s), 4.74 (1H, br.s), 5.08 (1H, d, J=12.2Hz), 5.12 (1H, d, J=12.2Hz), 5.25-5.42 (1H, m), 7.29-7.39 (5H, m), 7.91 (1H, s)
MS(ESI)m/z：430(M+H)+.
[reference example 599] (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- (1- methyl isophthalic acids H-1,2,4- triazole -5- bases) Cyclohexylamino t-butyl formate
Figure G2003801097466D03401
Using the method same with reference example 552, after the compound deprotection obtained to reference example 598, title compound is made in the compound condensation obtained with reference example 266.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.50-1.65 (1H, m), 1.72-1.87 (1H, m), 1.95-2.22 (4H, m), 2.81-2.94 (1H, m), 3.87 (3H, s), 3.97-4.06 (1H, m), 4.25 (1H, br.s), 4.91 (1H, d, J=8.8Hz), 7.70 (1H, dd, J=8.8,2.4Hz), 7.93 (1H, s), 8.06 (1H, br.s), 8.20 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.4Hz), 9.74 (1H, s)
MS(ESI)m/z：478(M+H)+.
[reference example 600] (3R, 4S) -4- [(benzyloxycarbonyl) amino] -3- [(tert-butoxycarbonyl) amino] piperidines -1- carbamic acid 2- trimethylsilylethyls
Figure G2003801097466D03402
The compound obtained in reference example 212 (adds 9% sodium bicarbonate aqueous solution (150ml) in 5.98g) dioxanes (50ml) solution, it is cooled to after 0 DEG C, add 1- [(2- trimethyl silyls) ethoxy carbonyl epoxide] pyrrolidines -2, (4.83g) dioxanes (20ml) solution is stirred 20 hours 5- diketone at room temperature.Ethyl acetate and water are added in reaction solution, after organic layer is washed with saturated sodium bicarbonate aqueous solution, 10% aqueous citric acid solution, saturated sodium-chloride water solution, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue (hexane: ethyl acetate=4: 1 → 2: 1) is refined with silica gel column chromatography, obtains title compound.
1H-NMR(CDCl3)δ：0.00 (9H, s), 0.96 (2H, t, J=8.3Hz), 1.36-1.53 (1H, m), 1.41 (9H, s), 1.82-2.00 (1H, m), 2.85 (1H, t, J=12.1Hz), 3.01 (1H, d, J=13.4Hz), 3.66-3.81 (1H, m), 3.87-4.25 (5H, m), 4.63-4.81 (1H, m), 5.06 (2H, br.s), 5.22-5.69 (1H, br), 7.23-7.40 (5H, m)
ESI-MSm/z：394(M-Boc)+.
[reference example 601] (3R, 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -3- [(tert-butoxycarbonyl) amino] piperidines -1- carbamic acid 2- trimethylsilylethyls
Using the method same with reference example 552, after the compound deprotection obtained to reference example 600, the compound condensation obtained with reference example 266 obtains title compound.
1H-NMR(CDCl3)δ：0.05 (9H, s), 0.84-0.92 (2H, m), 1.47 (9H, s), 1.51-1.70 (1H, m), 1.98 (1H, d, J=11.2Hz), 2.84-2.98 (1H, m), 3.07 (1H, d, J=13.9Hz), 3.94-4.29 (6H, m), 4.81-4.95 (1H, br), (7.70 1H, d, J=9.0Hz), 8.09-8.34 (1H, br), 8.20 (1H, d, J=9.0Hz), 8.31 (1H, s), 9.69 (1H, s)
MS(ESI)m/z：442(M-Boc)+, 486 (M-tBu)+.
[reference example 602] (3R, 4S)-[4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) piperidines -3- bases] t-butyl carbamate
The tetrahydrofuran solution (40ml) of 1.0mmol/l tetrabutylammoniums is added in tetrahydrofuran (90ml) solution for the compound (6.92g) that reference example 601 is obtained, is stirred 5 days at room temperature.Ethyl acetate, saturated sodium-chloride water solution are added in reaction solution.Aqueous layer with ethyl acetate and dichloromethane extraction, after being washed with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution to the organic layer of merging, use anhydrous sodium sulfate drying.Boiled off under decompression after solvent, residue (dichloromethane: methanol=30: 1 → 20: 1 → 10: 1) is refined with silica gel column chromatography, obtains the thing (7.96g) that is roughly refined.Ethyl acetate is added being roughly refined in thing, leaching insoluble matter obtains title compound (466mg).In addition, being added water in filtrate, extracted with ethyl acetate and dichloromethane, after being washed respectively with saturated sodium-chloride, use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, the mixture (4.86g) of the title compound containing about 30% tetrabutylammonium is obtained.
1H-NMR(CDCl3)δ：1.47 (9H, s), 1.55-1.72 (2H, m), 1.84-1.99 (1H, m), 2.71 (1H, t, J=10.7Hz), 2.85 (1H, d, J=11.2Hz), 3.03 (2H, t, J=12.7Hz), 3.85-3.98 (1H, m), 3.98-4.09 (1H, m), 5.40-5.71 (1H, m), 7.70 (1H, dd, J=8.8,2.4Hz), 8.13 (1H, br.s), 8.21 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.4Hz), 9.75 (1H, s)
MS(ESI)m/z：398(M+H)+.
[reference example 603] (3R, 4S)-[4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -1- (thiazol-2-yl) piperidines -3- bases] t-butyl carbamate
2- bromo thiazoles (115 μ l), sodium tert-butoxide (91mg), (S)-(-) -2 are added in toluene (4ml) solution of the mixture (401mg) for the tetrabutylammonium that reference example 602 is obtained, 2 '-bis- (diphenylphosphinos) -1,1 '-dinaphthalene (65mg) and three (dibenzylideneacetone) two palladium (0) (28mg), are stirred 3 days in 80 DEG C under an argon.Ethyl acetate is added after cooling reaction solution, insoluble matter is filtered off by diatomite, saturated sodium-chloride water solution is added in filtrate.After being extracted with ethyl acetate, the organic layer merged is washed with saturated sodium-chloride water solution.With anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (hexane: ethyl acetate=2: 1 → 1: 1) is refined with silica gel column chromatography, obtains title compound (169mg).
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.78-1.93 (1H, m), 2.07-2.18 (1H, m), 3.05-3.19 (1H, m), 3.27 (1H, dd, J=13.2, 1.7Hz), 3.98 (1H, br.d, J=12.9Hz), 4.04-4.15 (2H, m), 4.18-4.29 (1H, br), 5.04-5.34 (1H, m), 6.65 (1H, d, J=3.7Hz), 7.21 (1H, d, J=3.7Hz), 7.70 (1H, dd, J=8.8, 2.4Hz), 8.21 (1H, d, J=8.8Hz), 8.23-8.33 (1H, br), 8.31 (1H, d, J=2.4Hz), 9.73 (1H, br.s)
MS(ESI)m/z：481(M+H)+.
[embodiment 1] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclopropyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03422
At room temperature, the compound (124mg) that the compound (108mg) and reference example 10 obtained in reference example 59 is obtained is dissolved in N, the hydrate of I-hydroxybenzotriazole 1 (71mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (100mg) are added in solution formed by dinethylformamide (3ml), are stirred 8 days.After concentration of reaction solution under vacuum pump pressure, water (50ml) and saturated sodium bicarbonate aqueous solution (50ml) are added, is extracted with dichloromethane.Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue (dichloromethane: methanol=10: 1) is refined with silica gel thin-layer chromatography is prepared.Concentrated after ethanol solution hydrochloride, dichloromethane and methanol that 1N is added in gained amorphous substance, obtain title compound (72mg).
1H-NMR(DMSO-d6)δ：1.15-1.35 (2H, m), 2.88 (3H, s), 2.95-3.25 (4H, m), 3.35-3.75 (2H, m), 4.32-4.45 (1H, m), 4.68 (1H, br, J=15.4Hz), 7.08 (1H, s), 7.17 (1H, dd, J=8.6,2.1Hz), 7.41 (1H, d, J=8.6Hz), 7.70 (1H, s), 8.50 (1H, br, J=11.0Hz), 8.56 (1H, br.s), 11.56 (1H, br, J=19.3Hz), 11.86 (1H, s)
MS(FAB)m/z：430(M+H)+.
[embodiment 2] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclobutyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (117mg) that reference example 60 is obtained is dissolved in N, dinethylformamide (5ml), compound (136mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (255mg) and the hydrate of I-hydroxybenzotriazole 1 (90mg) that reference example 10 is obtained are added, an evening is stirred at room temperature.With solvent is boiled off under vacuum pump pressure, dichloromethane and saturated sodium bicarbonate aqueous solution point liquid are added in residue.Organic layer saturated common salt water washing, after anhydrous sodium sulfate drying, boils off solvent, residue (methanol: dichloromethane=7: 93) is refined with silica gel column chromatography under decompression.The ethanol solution hydrochloride of ethyl acetate and 1N is added in gained compound makes reaction solution in acidity, the lower concentrated solvent of decompression.Ethyl acetate is added again, and the precipitation of leaching generation obtains title compound (56mg) after drying.
1H-NMR(DMSO-d6)δ：2.00-2.35 (4H, m), 2.88 (3H, s), 3.10 (2H, br.s), 3.20-3.75 (3H, m), 4.20-4.85 (3H, m), 7.09 (1H, s), (7.16 1H, d, J=8.8Hz), (7.38 1H, d, J=8.8Hz), 7.71 (1H, s), 8.63 (1H, d, J=8.3Hz), 8.85 (1H, d, J=8.6Hz), 10.85-11.20 (1H, br), 11.81 (1H, s)
MS(FAB)m/z：444(M+H)+.
[embodiment 3] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclopenta) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (120mg) that reference example 62 is obtained is dissolved in N, dinethylformamide (5ml), 5- chloro-indole -2- carboxylic acids (80mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (98mg) and the hydrate of I-hydroxybenzotriazole 1 (23mg) and triethylamine (141 μ l) are added, is stirred 3 days at room temperature.Solvent is boiled off under decompression, dichloromethane and saturated sodium bicarbonate aqueous solution point liquid are added in residue.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue (dichloromethane: methanol=93: 7) is refined with silica gel column chromatography.Dichloromethane (5ml) and 1N ethanol solution hydrochloride (282 μ l) are added in gained faint yellow solid.Then, ethyl acetate is added, the lower concentrated solvent of decompression, the precipitation of leaching generation obtains title compound (109mg).
1H-NMR(DMS0-d6)δ：1.64-1.74 (4H, m), 1.98-2.02 (2H, m), 2.89 (3H, s), 3.14 (2H, br.s), 3.47-3.65 (2H, m), 4.29-4.63 (4H, m), 7.10 (1H, d, J=1.5Hz), 7.14 (1H, dd, J=8.5,2.0Hz), 7.38 (1H, d, J=8.5Hz), 7.68 (1H, d, J=2.0Hz), 8.55 (1H, d, J=8.5Hz), 8.91 (1H, d, J=8.5Hz), 11.49 (1H, br.s), 11.76 (1H, s)
MS(ESI)m/z：458(M+H)+.
[embodiment 4] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) sulfonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (400mg) that reference example 67 is obtained is suspended in dichloromethane (10ml); triethylamine (0.514ml) and 5- chloro-1-phenyl sulfonyl indole -2- sulfonic acid chlorides (Japanese Patent Laid-Open 2000-119253) (319mg) are added, is stirred 15 minutes at room temperature.After the progress point liquid that added water in reaction solution is operated, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtains faint yellow blister material.The material is dissolved in tetrahydrofuran (3ml), methanol (2ml) and 1N sodium hydrate aqueous solution (1.5ml) is added, is heated to reflux 2 hours.The lower concentration of reaction solution of decompression, the aqueous hydrochloric acid solution that dichloromethane and 1N are added in residue carries out a point liquid operation.Organic layer with after anhydrous sodium sulfate drying depressurize under boil off solvent.Residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography.Concentrated under hydrochloric acid (1ml) decompression that 1N is added in gained product, obtain title compound (108mg).
1H-NMR(DMSO-d6)δ：1.20-1.78 (8H, m), 2.94 (3H, s), 3.13 (2H, br.s), 3.22-3.40 (1H, m), 3.44-3.70 (3H, m), 3.83-3.95 (1H, m), 4.20-4.70 (1H, m), 6.78 (1H, s), 7.18-7.30 (2H, m), 7.44 (1H, s), 7.69 (1H, br.s), 8.09 (1H, br.s), 11.92 (1H, s)
MS(FAB)m/z：508(M+H)+.
[embodiment 5] N- ((1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03451
The compound (300mg) that reference example 65 is obtained is dissolved in N, dinethylformamide (20ml), 5- chloro-indole -2- carboxylic acids (109mg), the hydrate of I-hydroxybenzotriazole 1 (9mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (321mg) and triethylamine (0.232ml) are added, an evening is stirred at room temperature.With concentration of reaction solution under vacuum pump pressure, dichloromethane is added in residue and water is carried out after point liquid operation after organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue (dichloromethane: methanol=25: 1) is refined with silica gel column chromatography, obtains colourless blister material.1N hydrochloric acid (1ml) is added wherein, and decompression is lower to be concentrated, and obtains title compound (203mg).
1H-NMR(DMSO-d6)δ：1.25-1.40 (2H, m), 1.46-1.81 (4H, m), 1.88-1.98 (2H, m), 2.89 (3H, s), 3.00-3.76 (5H, m), 3.86-3.97 (1H, m), 4.00-4.10 (1H, m), 4.25-4.72 (1H, m), 7.03 (1H, s), 7.12 (1H, dd, J=8.5,1.2Hz), 7.38 (1H, d, J=8.5Hz), 7.64 (1H, s), 8.28 (1H, d, J=8.5Hz), 8.54 (1H, d, J=8.5Hz), 11.70 (1H, s)
MS(FAB)m/z：472(M+H)+.
[embodiment 6] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03461
Using method similarly to Example 5, the compound obtained by reference example 67 and 5- chloro-indole -2- carboxylic acids prepare title compound.
1H-NMR(DMSO-d6)δ：1.35-1.70 (6H, m), 1.80-2.06 (2H, m), 2.89 (3H, s), 3.00-3.27 (2H, m), 3.35-3.51 (1H, m), 3.57-3.82 (1H, m), 4.15-4.30 (2H, m), 4.32-4.48 (1H, m), 4.60-4.74 (1H, m), 7.15 (1H, s), 7.17 (1H, dd, J=8.8, 2.0Hz), 7.41 (1H, d, J=8.6Hz), 7.70 (1H, d, J=2.0Hz), 8.14 (1H, br.s), 8.36-8.48 (1H, m), 11.51 (1H, br.s), 11.86 (1H, s)
MS(FAB)m/z：472(M+H)+.
[embodiment 7] N- { (1R*, 2S*) -2- [(the chloro- 2- naphthoyls of 6-) amino] cyclohexyl -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03462
Using method similarly to Example 5, compound (275mg) that reference example 67 is obtained, 6- chloronaphthalene -2- carboxylic acids (Eur.J.Chem.Chim.Ther., 1984, volume 19,205-214 pages) (148mg), triethylamine (0.298ml) and the hydrate of I-hydroxybenzotriazole 1 (11mg) be dissolved in N, dinethylformamide (20ml), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (412mg) are added, them is reacted and is obtained title compound (186mg).
1H-NMR(DMSO-d6)δ：1.40-1.56 (2H, m), 1.57-1.77 (4H, m), 1.90-2.10 (2H, m), 2.90 (3H, s), 3.13 (2H, br.s), 3.28-3.74 (2H, m), 4.26 (2H, br.s), 4.30-4.74 (2H, m), (7.59 1H, d, J=8.6Hz), (7.90 1H, d, J=8.6Hz), (7.98 1H, d, J=8.3Hz), 8.03-8.11 (2H, m), 8.25-8.58 (3H, m), 11.52 (1H, br.s)
MS(FAB)m/z：483(M+H)+.
[embodiment 8] N- ((1R*, 2R*) -2- { [(the chloro- 1- benzothiophenes -2- bases of 6-) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03471
Using method similarly to Example 5, compound (255mg) that reference example 65 is obtained, simultaneously [b] thiophene-2-carboxylic acid (Japanese Patent Laid-Open 2000-119253) (141mg), triethylamine (0.276ml) and the hydrate of I-hydroxybenzotriazole 1 (10mg) are dissolved in N to 6- chlorobenzenes, dinethylformamide (20ml), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (382mg) are added, them is reacted and is obtained title compound (239mg).
1H-NMR(DMSO-d6)δ：1.20-1.98 (8H, m), 2.88 (3H, s), 3.00-3.72 (4H, m), 3.84-4.09 (2H, m), 4.20-4.75 (2H, m), 7.41 (1H, dd, J=8.6,1.7Hz), 7.91 (1H, d, J=8.6Hz), 7.99 (1H, s), 8.12 (1H, s), 8.54-8.67 (2H, m), 11.53 (1H, br.s)
MS(FAB)m/z：489(M+H)+.
[embodiment 9] N- ((1R*, 2R*) -2- { [(5- fluoro indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 5, the compound obtained by reference example 65 and 5- fluoro indole -2- carboxylic acids prepare title compound.
1H-NMR(DMSO-d6)δ：1.20-1.38 (2H, m), 1.40-1.57 (1H, m), 1.54-1.68 (1H, m), 1.71 (2H, d, J=7.3Hz), 1.88 (2H, d, J=12.0Hz), 2.86 (3H, s), 2.95-3.24 (2H, m), 3.40 (1H, br.s), 3.63 (1H, br.s), 3.90 (1H, br.s), 3.97-4.10 (1H, m), 4.20-4.44 (1H, m), 4.53-4.70 (1H, m), 6.98 (1H, dd, J=9.2, 2.3Hz), 7.01 (1H, s), 7.31-7.39 (2H, m), 8.26 (1H, d, J=8.6Hz), 8.59 (1H, d, J=8.4Hz), 11.21 (1/2H, br.s), 11.42 (1/2H, br.s), 11.60 (1H, s)
MS(ESI)m/z：456(M+H)+.
[embodiment 10] N- ((1R*, 2R*) -2- { [(the fluoro- 6- fluoro indoles -2- bases of 5-) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 5, the compound that the compound obtained by reference example 65 and reference example 23 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.20-1.40 (2H, m), 1.40-1.80 (4H, m), 1.80-2.00 (2H, m), 2.87 (3H, s), 3.01 (2H, br.s), 3.30-3.80 (2H, m), 3.81-3.97 (2H, m), 4.20-4.80 (2H, m), 7.06 (1H, s), 7.28 (1H, d, J=10.0Hz), 7.86 (1H, d, J=7.3Hz), 8.32 (1H, d, J=8.5Hz), 8.59 (1H, d, J=8.5Hz), 11.77 (1H, s)
MS(FAB)m/z：490(M+H)+.
[embodiment 11] N- ((1R*, 2S*) -2- { [(5- bromo indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03482
Using method similarly to Example 5, the compound obtained by reference example 67 and 5- bromo indole -2- carboxylic acids prepare title compound.
1H-NMR(DMSO-d6)δ：1.43 (2H, br.s), 1.61 (4H, br.s), 1.80-2.10 (2H, m), 2.88 (3H, s), 3.00-3.26 (2H, m), 3.40 (1H, br.s), 3.65 (1H, br.s), 4.22 (1H, br.s), 4.26 (1H, br.s), 4.41 (1H, br.s), 4.67 (1H, d, J=15.6Hz), 7.14 (1H, s), 7.28 (1H, d, J=8.7Hz), 7.37 (1H, d, J=8.7Hz), 7.84 (1H, s), 8.13 (1H, br.s), 8.33-8.52 (1H, m), 11.51 (1H, br.s), 11.86 (1H, s)
MS(ESI)m/z：515(M+).
[embodiment 12] N- ((1R*, 2S*) -2- { [(5- Ethynylindole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
At room temperature triethylamine (6ml), DMF (5ml), trimethylsilyl acetylene (0.250ml) and acid chloride (20mg) are added in the compound (300mg) and the tetrahydrofuran solution (2ml) of triphenyl phasphine (70mg) that embodiment 11 is obtained.Reaction solution is naturally cooled into room temperature after being stirred 2 hours in 90 DEG C, dichloromethane (20ml) and saturated sodium bicarbonate aqueous solution (30ml) point liquid is added.Water layer is extracted with dichloromethane (3 × 10ml), merges organic layer, and residue is obtained with solvent is boiled off under decompression after anhydrous sodium sulfate drying.With preparation silica gel thin-layer chromatography (dichloromethane: acetone: methanol=10；10: 1) refined to residue obtained, obtain colorless solid.The solid is dissolved in methanol (6ml), potassium carbonate (120mg) is added and stirs 1 hour.Dichloromethane (20ml) and water (20ml) point liquid are added in reaction solution, water layer is extracted with dichloromethane (2 × 15ml).Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue preparation silica gel thin-layer chromatography (dichloromethane: acetone: methanol=10；10: 1) refined, be dissolved in concentrating after water-methanol-dichloromethane, obtain title compound (72mg).
1H-NMR(CDCl3)δ：1.50-2.25 (8H, m), 2.53 (3H, s), 2.85 (2H, br.s), (2.93 2H, br.s), 3.01 (1H, s), 3.74 (1H, d, J=14.1Hz), 3.77 (1H, d, J=14.1Hz), 4.21 (1H, br.s), (4.45 1H, br.s), 6.91 (1H, s), 7.25-7.42 (2H, m), (7.61 1H, br.s), 7.80-7.97 (2H, m), 9.72 (1H, s)
MS(FAB)m/z：462(M+H)+.
[embodiment 13] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5,6- dimethyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-d] pyridazine -2- carboxamide hydrochlorides
Using method similarly to Example 2, the compound that the compound obtained by reference example 71 and reference example 51 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.35-1.50 (2H, m), 1.50-1.75 (4H, m), 1.80-2.10 (2H, m), 2.70 (3H, br.s), 2.79 (3H, br.s), 4.10-4.70 (6H, m), 7.10-7.27 (2H, m), 7.41 (1H, d, J=8.8Hz), 7.70 (1H, s), 8.12 (1H, d, J=6.8Hz), 8.47 (1H, d, J=7.6Hz), 11.85 (1H, s)
MS(FAB)m/z：487(M+H)+.
[embodiment 14] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazole -2- formamides
Figure G2003801097466D03501
Using method similarly to Example 2, the compound that the compound obtained by reference example 71 and reference example 26 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.36-1.72 (6H, m), 1.90-2.10 (2H, m), 2.80-2.87 (2H, m), 3.93 (2H, t, J=5.6Hz), 4.20-4.32 (2H, m), 4.81 (2H, s), 7.12 (1H, s), 7.15 (1H, dd, J=8.8,2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.67 (1H, d, J=1.7Hz), 8.11 (1H, d, J=6.6Hz), 8.36 (1H, d, J=8.3Hz), 11.78 (1H, s)
MS(FAB)m/z：459(M+H)+.
[embodiment 15] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 2, the compound that the compound obtained by reference example 71 and reference example 29 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.32-1.74 (6H, m), 1.82-2.10 (2H, m), 2.92 (3H, s), 3.12-3.50 (3H, m), 3.69 (1H, br.s), 4.13-4.39 (3H, m), 4.51 (1H, br.s), 7.10-7.19 (2H, m), 7.41 (1H, d, J=8.6Hz), 7.68 (1H, s), 8.10 (1H, br.s), 8.40 (1H, br.s), 11.41 (1H, br.s), 11.87 (1H, s)
MS(FAB)m/z：472(M+H)+.
[embodiment 16] N- ((1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetra- Qing oxazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 2, the compound that the compound obtained by reference example 69 and reference example 21 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.23-1.39 (2H, m), 1.40-1.81 (4H, m), 1.82-1.98 (2H, m), 2.60-3.00 (5H, m), 3.20-3.70 (2H, m), 3.87-3.96 (1H, m), 3.98-4.10 (1H, m), 4.12-4.70 (2H, m), 7.04 (1H, d, J=1.5Hz), 7.12 (1H, dd, J=8.8, 2.0Hz), 7.38 (1H, d, J=8.8Hz), 7.65 (1H, d, J=2.0Hz), 8.33 (1H, d, J=8.6Hz), 8.72 (1H, d, J=8.6Hz), 11.61 (1H, br.s), 11.72 (1H, s)
MS(FAB)m/z：456(M+H)+.
[embodiment 17] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03512
Using method similarly to Example 2, make compound and 5- (tert-butoxycarbonyl) -4,5 that reference example 71 is obtained; simultaneously [3,2-c] pyridine-2-carboxylic acids (WO 94/21599) are condensed 6,7- thiophanes; processing deprotection is carried out with hydrochloric acid, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.42 (2H, br.s), 1.56-1.76 (4H, m), 1.98-2.11 (2H, m), 3.04 (2H, br.s), 3.32-3.45 (2H, m), 4.15 (3H, br.s), 4.26 (1H, br.s), 7.14 (1H, dd, J=8.8,2.0Hz), 7.23 (1H, s), 7.41 (1H, d, J=8.8Hz), 7.62 (1H, s), 7.77 (1H, s), 8.18-8.30 (2H, m), 9.42 (2H, br.s), 11.92 (1H, s)
MS(FAB)m/z：457(M+H)+.
[embodiment 18] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine-2-carboxamide hydrochloride
The compound (171mg) that embodiment 17 is obtained is suspended in dichloromethane (10ml), adds triethylamine (0.104ml) and stirs 10 minutes at room temperature.Added in reaction solution after acetic acid (0.059m1), add 35% formalin (0.070ml), sodium triacetoxy borohydride (118mg), stirred 30 minutes at room temperature.Add water progress point liquid operation after the sodium hydrate aqueous solution (3ml) that 1N is added in reaction solution.Organic layer (dichloromethane: methanol=50: 3) is refined with silica gel column chromatography with solvent, residue is boiled off under decompression after anhydrous sodium sulfate drying, obtains colourless blister material.Adding 1N hydrochloric acid wherein makes after its suspension, and the lower concentration of decompression obtains title compound (85mg).
1H-NMR(DMSO-d6)δ：1.40 (2H, br.s), 1.50-1.71 (4H, m), 1.97-2.05 (2H, m), 2.87 (3H, s), 2.98-3.20 (1H, m), 3.30-3.38 (2H, m), 3.54-3.70 (1H, m), 4.05-4.42 (4H, m), (7.14 1H, d, J=8.6Hz), 7.23 (1H, s), 7.40 (1H, d, J=8.6Hz), 7.63 (1H, s), 7.77 (1H, s), 8.17-8.27 (2H, m), 10.83 (1H, br.s), 11.92 (1H, s)
MS(FAB)m/z：471(M+H)+.
[embodiment 19] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -6- (dimethylamino) -4,5,6,7- tetrahydro benzothiazol -2- carboxamide hydrochlorides
Using method similarly to Example 2, the compound that the compound obtained by reference example 71 and reference example 31 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.44 (2H, br.s), 1.52-1.68 (4H, m), 1.87-2.08 (3H, m), 2.30-2.40 (1H, m), 2.65-2.75 (1H, m), 2.77 (6H, s), 2.95-3.17 (2H, m), 3.30-3.70 (2H, m), 4.15-4.30 (2H, m), 7.10-7.20 (2H, m), (7.41 1H, d, J=8.6Hz), 7.69 (1H, s), 8.11 (1H, d, J=5.1Hz), 8.34 (1H, d, J=8.1Hz), 10.95 (1H, br.s), 11.83 (1H, s)
MS(FAB)m/z：500(M+H)+.
[embodiment 20] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- (pyridin-4-yl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Instill after n-BuLi (1.60N hexane solution, 0.704ml), stirred 30 minutes in 0 DEG C in tetrahydrofuran (3ml) solution for the compound (204mg) that reference example 24 is obtained in -78 DEG C.It is cooled to again after -78 DEG C, room temperature, the lower concentration of reaction solution of decompression was warming up to 20 minutes while introducing carbon dioxide gas.Compound (400mg), the hydrate of I-hydroxybenzotriazole 1 (254mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (360mg) and diisopropylamine (0.491ml) that reference example 71 is obtained are added in residue obtained DMF (6ml) solution at room temperature.Lower concentration reaction mixture is depressurized in stirring after 3 days, added in residue after dichloromethane (30ml), saturated sodium bicarbonate aqueous solution (100ml) and water (100ml) point liquid, water layer is extracted with dichloromethane (4 × 15ml).Merge organic layer, with after anhydrous sodium sulfate drying depressurize under boil off solvent.Residue (dichloromethane: methanol=20: 1 → 10: 1) is refined with silica gel column chromatography, is dissolved in concentrating after 1N aqueous hydrochloric acid solution-methanol dichloromethane, obtains title compound (245mg).
1H-NMR(DMSO-d6)δ：1.42 (2H, br.s), 1.60 (4H, br.s), 1.84-1.94 (1H, m), 1.94-2.08 (1H, m), 2.97 (2H, br.s), 3.97-4.13 (2H, m), 4.19 (1H, br.s), 4.27 (1H, br.s), 5.03 (2H, s), 7.13 (1H, br.s), 7.16 (1H, dd, J=8.8, 2.0Hz), 7.32 (2H, br.s), 7.40 (1H, d, J=8.8Hz), 7.68 (1H, d, J=2.0Hz), 8.15 (1H, br, J=7.3Hz), 8.31 (2H, d, J=5.9Hz), 8.39 (1H, d, J=8.1Hz), 11.90 (1H, s), 14.03 (1H, br.s)
MS(ESI)m/z：535(M+H)+.
[embodiment 21] N- ((1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } suberyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03532
Using method similarly to Example 2, the compound that the compound obtained by reference example 74 and reference example 10 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.51-1.55 (4H, m), 1.75-1.80 (6H, m), 2.88 (3H, s), 3.12 (1H, br.s), 3.35-3.63 (4H, m), 4.10-4.13 (1H, m), 4.29-4.61 (2H, m), 7.06 (1H, s), 7.14 (1H, dd, J=8.8,2.0Hz), 7.39 (1H, d, J=8.8Hz), 7.67 (1H, d, J=2.0Hz), 8.46 (1H, d, J=8.3Hz), 8.77 (1H, d, J=8.3Hz), 11.21-11.35 (1H, m), 11.71 (1H, s)
MS(ESI)m/z：486(M+H)+.
[embodiment 22] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclooctyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 2, the compound that the compound obtained by reference example 78 and reference example 10 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.61-2.06 (12H, m), 2.90 (3H, s), 3.08-3.17 (2H, m), 3.43-3.45 (1H, m), 3.67 (1H, br.s), 4.43 (3H, br.s), 4.67 (1H, br.s), 7.16-7.18 (2H, m), (7.42 1H, d, J=8.8Hz), 7.70 (1H, s), 8.24 (1H, br.s), 8.58 (1H, d, J=8.3Hz), 11.43,11.63 (1H, each br.s), 11.80 (1H, s)
MS(ESI)m/z：500(M+H)+.
[embodiment 23] N- ((1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclopenta) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03542
Similarly to Example 2, the reaction product for the compound that the compound and reference example 34 obtained to reference example 63 is obtained is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.60-1.82 (4H, m), 1.91-2.15 (2H, m), 3.08 (2H, s), 3.37-3.49 (2H, m), 4.28-4.56 (4H, m), 7.13 (1H, s), (7.15 1H, d, J=8.8Hz), (7.40 1H, d, J=8.8Hz), 7.69 (1H, s), 8.61 (1H, d, J=8.3Hz), 8.88 (1H, d, J=8.3Hz), 10.05 (2H, br.s), 11.82 (1H, s)
MS(FAB)m/z：444(M+H)+.
[embodiment 24] N- ((1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclopenta) -5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (30mg) that embodiment 23 is obtained is suspended in dichloromethane (20ml), adds triethylamine (260 μ l) and stirs 15 minutes at room temperature.Acetic acid (179 μ l) is added in reaction solution and acetone (920 μ l) is stirred 2 minutes at room temperature.Sodium triacetoxy borohydride (796mg) is added in reaction solution, is stirred 5 hours at room temperature.The sodium hydrate aqueous solution (10ml) that 1N is added in reaction solution carries out a point liquid operation.Organic layer with after anhydrous sodium sulfate drying depressurize under boil off solvent.Residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtains colourless blister material.Dichloromethane is dissolved in, 1N ethanol solution hydrochloride (1ml) is added.The lower concentrate solution of decompression obtains title compound (205mg).
1H-NMR(DMSO-d6)δ：1.27-1.39 (6H, m), 1.58-1.80 (4H, m), 1.95-2.10 (2H, m), 3.00-3.12 (1H, m), 3.25-3.45 (2H, m), 3.59-3.77 (2H, m), 4.25-4.39 (1H, m), 4.40-4.55 (2H, m), 4.57-4.65 (1H, m), 7.10 (1H, s), 7.14 (1H, d, J=8.8Hz), 7.38 (1H, d, J=8.8Hz), 7.68 (1H, s), 8.56 (1H, d, J=8.8Hz), 8.90 (1H, d, J=8.8Hz), 11.39 (1H, br.s), 11.76 (0.5H, s), 11.80 (0.5H, s)
MS(FAB)m/z：486(M+H)+.
[embodiment 25] N- ((1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclopenta) -5- ethyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03552
The compound (500mg) that embodiment 23 is obtained is dissolved in DMF (10ml), adds and stirs an evening after triethylamine (576 μ l) and ethyl iodide (329 μ l) at room temperature.The lower concentration of reaction solution of decompression, add water leaching insoluble matter in residue.It (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtain filbert blister material.1N hydrochloric acid (2ml) is suspended in, the lower concentrate solution of decompression obtains title compound (180mg).
1H-NMR(DMSO-d6)δ：1.32 (3H, t, J=7.1Hz), 1.60-1.80 (4H, m), 1.96-2.10 (2H, m), 3.20-3.39 (5H, m), 3.70-3.80 (1H, m), 4.26-4.58 (3H, m), 4.68-4.79 (1H, m), 7.11 (1H, s), 7.15 (1H, dd, J=8.8, 2.0Hz), 7.39 (1H, d, J=8.8Hz), 7.69 (1H, d, J=1.5Hz), 8.55 (1H, d, J=8.5Hz), 8.92 (1H, d, J=8.5Hz), 11.38 (1H, br.s), 11.70-11.80 (1H, m)
MS(FAB)m/z：472(M+H)+.
[reference example 26] N- ((1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclopenta) -5- (1- methylcyclopropyl groups) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03561
Using method similarly to Example 2, the compound that the compound obtained by reference example 63 and reference example 39 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：0.81 (2H, br.s), 1.20-1.55 (5H, br), 1.55-1.80 (4H, m), 1.95-2.12 (2H, m), 3.05-3.40 (2H, br), 3.60-3.80 (2H, br), 4.25-4.80 (4H, m), 7.10 (1H, s), 7.16 (1H, d, J=8.8Hz), 7.39 (1H, d, J=8.8Hz), 7.69 (1H, s), (8.53 1H, d, J=8.6Hz), 8.85-8.95 (1H, m), 10.60-10.90 (1H, br), 11.73 (1H, br.s)
MS(FAB)m/z：498(M+H)+.
[embodiment 27] N- ((1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- methoxies cyclopentyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride (stereoisomer A and stereoisomer B)
Figure G2003801097466D03562
The compound (mixture of the stereoisomer of 4) (268mg) obtained by reference example 82, using method similarly to Example 2, the compound condensation obtained with reference example 10, the stereoisomer A and B of synthesising title compound mixture, after being separated by silica gel column chromatography, hydrochloride is formed, the stereoisomer A (75mg) and stereoisomer B (70mg) of title compound is obtained.
Stereoisomer A：
1H-NMR(DMSO-d6)δ：1.70-2.15 (4H, m), 2.90 (3H, s), 3.00-3.90 (8H, m), 4.10-4.80 (4H, m), 7.08 (1H, s), 7.16 (1H, d, J=8.8Hz), 7.38 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.56 (1H, d, J=8.8Hz), 8.88 (1H, d, J=8.3Hz), 10.96 (1H, br.s), 11.75 (1H, br.s)
MS(FAB)m/z：488(M+H)+.
Stereoisomer B：
1H-NMR(DMSO-d6)δ：1.60-2.10 (4H, m), 2.89 (3H, s), 3.00-3.70 (7H, m), 3.70-3.90 (1H, m), 4.20-4.80 (4H, m), 7.05-7.20 (2H, m), (7.38 1H, d, J=8.8Hz), 7.68 (1H, s), 8.59 (1H, d, J=8.3Hz), 8.90 (1H, d, J=8.5Hz), 11.26 (1H, br.s), 11.74 (1H, br.s)
MS(FAB)m/z：488(M+H)+.
[embodiment 28] N- [(1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- (hydroxymethyl) cyclopenta] -5- (1,1- dimethyl -2- hydroxyethyls) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride (stereoisomer A)
Figure G2003801097466D03571
1) using method similarly to Example 2, the compound that the compound obtained by reference example 85 and reference example 42 are obtained prepares N- ((1R*, 2R*) -4- [(benzyloxy) methyl] -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclopenta) -5- (2- { [tert-butyl group (diphenyl) silicyl] epoxide } -1,1- dimethyl ethyls) -4,5,6, the stereoisomer A and stereoisomer B of 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide.
Stereoisomer A：
1H-NMR(CDCl3)δ：1.05 (9H, s), 1.168, 1.171 (6H, each s), 1.53-1.61 (1H, m), 1.76-1.88 (1H, m), 2.30-2.37 (2H, m), 2.78-2.79 (2H, m), 2.87-2.90 (1H, m), 2.96-3.00 (1H, m), 3.37-3.47 (2H, m), 3.58 (2H, s), 3.96 (1H, q, J=13.1Hz), 4.41-4.45 (1H, m), 4.51-4.57 (2H, m), 6.88 (1H, d, J=1.5Hz), 7.17 (1H, dd, J=8.8, 2.0Hz), 7.23-7.43 (12H, m), 7.52 (1H, d, J=7.6Hz), 9.37 (1H, br.s)
Stereoisomer B：
1H-NMR(CDCl3)δ：1.05 (9H, s), 1.17 (6H, s), 1.43-1.47 (1H, m), 1.85-1.88 (1H, m), 2.09-2.14 (1H, m), 2.58-2.63 (1H, m), 2.78-2.79 (2H, m), 2.86-2.90 (1H, m), 2.96-3.00 (1H, m), 3.38-3.46 (2H, m), 3.59 (2H, s), 3.95 (1H, q, J=13.3Hz), 4.15-4.20 (1H, m), 4.45-4.56 (3H, m), 6.74 (1H, d, J=2.0Hz), 7.16 (1H, dd, J=8.8, 2.0Hz), 7.27-7.43 (12H, m), 7.57 (1H, d, J=2.0Hz), 9.48 (1H, br.s)
2) aforementioned stereoisomers A (288mg) is suspended in dichloromethane (20ml), adds dimethyl sulfide (1.15ml), anhydrous Aluminum chloride (350mg), stirred 1 hour at room temperature.1N sodium hydrate aqueous solution (10ml) is added in reaction solution, is extracted with dichloromethane, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=9: 1) is refined with silica gel column chromatography, obtain 5- (2- { [tert-butyl group (diphenyl) silicyl] epoxide } -1,1- dimethyl ethyls)-N- [(1R*, 2R*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- (hydroxymethyl) cyclopenta] -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (stereoisomer A) (184mg).
1H-NMR(CDCl3)δ：1.04 (9H, s), 1.15 (6H, s), 1.54-1.62 (1H, m), 1.73-1.81 (1H, m), 1.99-2.25 (2H, m), 2.34-2.38 (2H, m), 2.67-2.85 (3H, m), 2.92-2.97 (1H, m), 3.48-3.62 (4H, m), 3.93 (1H, q, J=15.6Hz), 4.20-4.28 (1H, m), 4.47-4.56 (1H, m), 6.89 (1H, s), 7.11-7.18 (1H, m), 7.24-7.27 (1H, m), 7.32-7.43 (6H, m), 7.54 (1H, d, J=1.7Hz), 7.63 (4H, dd, J=7.8, 1.5Hz), 7.90-7.92 (2H, m), 10.13 (1H, br.s)
MS(FAB)m/z：784(M+H)+.
3) the above-mentioned stereoisomer (A) (180mg) 2) obtained is dissolved in the tetrahydrofuran solution of 1N tetrabutylammonium (2ml), an evening is stirred at room temperature.Dichloromethane, 1N sodium hydrate aqueous solution and sodium chloride are added in reaction solution and carries out point a liquid operation, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=19: 1) is refined with silica gel column chromatography, gained powder is dissolved in methanol, add 1N ethanol solution hydrochloride (229 μ l), the lower concentrated solvent of ethyl acetate decompression is added, title compound (63mg) is obtained.
1H-NMR(DMSO-d6)δ：1.33-1.50 (8H, m), 1.70-1.91 (2H, m), 2.07-2.14 (1H, m), 2.23-2.24 (1H, m), 3.04-3.10 (1H, m), 3.27-3.44 (4H, m), 3.57-3.70 (2H, m), 3.92-3.95 (1H, m), 4.29-4.72 (4H, m), 5.81 (1H, br.s), 7.11 (1H, s), 7.15 (1H, dd, J=8.6, 2.0Hz), 7.39 (1H, d, J=8.6Hz), 7.68 (1H, d, J=2.0Hz), 8.53-8.56 (1H, m), 8.83 (1H, d, J=8.3Hz), 10.36 (1H, br.s), 11.75, 11.77 (1H, each s)
MS(ESI)m/z：546(M+H)+.
[embodiment 29] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -4,7,8,10- tetrahydrochysene -6H- pyrazolos [1,2-a] thiazoles simultaneously [4,5-d] pyridazine -2- carboxamide hydrochlorides
Using method similarly to Example 2, the compound that the compound obtained by reference example 71 and reference example 44 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.35-1.50 (2H, m), 1.61 (4H, br.s), 1.80-2.00 (2H, m), 2.27 (2H, br.s), 2.80-4.80 (10H, m), 7.14 (1H, d, J=1.5Hz), 7.17 (1H, dd, J=8.5,2.0Hz), 7.41 (1H, d, J=8.5Hz), 7.70 (1H, d, J=2.0Hz), 8.09 (1H, d, J=7.3Hz), 8.44 (1H, br.s), 11.81 (1H, br.s)
MS(FAB)m/z：499(M+H)+.
[embodiment 30] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -4,6,7,8,9,11- hexahydro-pyridazines simultaneously [1,2-a] thiazole simultaneously [4,5-d] pyridazine -2- carboxamide hydrochlorides
Using method similarly to Example 2, the compound that the compound obtained by reference example 46 and reference example 71 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.35-1.55 (2H, m), 1.55-2.10 (10H, m), 2.80-4.80 (10H, m), 7.10-7.25 (2H, m), (7.42 1H, d, J=8.8Hz), (7.72 1H, d, J=1.7Hz), 8.12 (1H, br.s), 8.41 (1H, br.s), 11.83 (1H, br.s)
MS(FAB)m/z：513(M+H)+.
Chloro- the N- { (1R of [embodiment 31] 5-*, 2S*) -2- [(5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl carbonyl) amino] cyclohexyl indole 2-carboxamides hydrochloride
Under argon atmospher, the compound (171mg) that reference example 33 is obtained is dissolved in ether (5ml), n-BuLi (1.60N hexane solution, 385 μ l) is instilled in -78 DEG C.With after 20 minutes introducing carbon dioxide gas after being stirred 10 minutes in -78 DEG C, room temperature is warming up to.The lower concentration of reaction solution of decompression, N is dissolved in by residue obtained, dinethylformamide (10ml), compound (184mg), the hydrate of I-hydroxybenzotriazole 1 (76mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (215mg) that reference example 71 is obtained are added, is stirred 3 days at room temperature.Dichloromethane and saturated sodium bicarbonate aqueous solution are added after concentration of reaction solution, organic layer is separated, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: dichloromethane=3: 97) is refined with silica gel column chromatography, ethanol solution hydrochloride (5ml) is added in gained product, stirred 1 hour at room temperature, concentration of reaction solution.Ethyl acetate solidification is added in gained residue, leaching powder obtains title compound (31mg).
1H-NMR(DMSO-d6)δ：1.35-1.52 (2H, m), 1.55-1.80 (4H, m), 1.82-2.05 (2H, m), 4.22 (1H, br.s), 4.28 (1H, br.s), 4.38 (2H, s), 4.56 (2H, s), 7.14-7.20 (2H, m), 7.42 (1H, d, J=8.6Hz), 7.71 (1H, d, J=1.7Hz), 8.10 (1H, d, J=7.1Hz), 8.45 (1H, d, J=7.8Hz), 10.10-10.50 (2H, br), 11.83 (1H, br.s) .MS (FAB) m/z：444(M+H)+.
[embodiment 32] 2- { [((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl -5,7- dihydro -6H- pyrrolo-es [3,4-d] pyrimidine -6- carboxylic acid tert-butyl esters
After compound with the acquisition of lithium hydrate reference example 50, using method similarly to Example 2, the compound that itself and reference example 71 are obtained is reacted, title compound is obtained.
1H-NMR(CDCl3)δ：1.54 (9H, s), 1.55-2.30 (8H, m), 4.23 (1H, br.s), 4.53 (1H, br.s), 4.74-4.83 (4H, m), 6.99 (1H, d, J=1.5Hz), 7.19 (1H, dd, J=8.8,2.1Hz), 7.34 (1H, d, J=8.8Hz), 7.62 (1H, d, J=2.1Hz), 8.11 (1H, br.s), 8.48-8.53 (1H, br), 8.70-8.76 (1H, br), 9.60-9.70 (1H, br)
MS(ESI)m/z：539(M+H)+.
[embodiment 33] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -6- methyl -6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine -2- carboxamide hydrochlorides
It is dissolved at room temperature in the compound (34.0mg) for obtaining embodiment 32 in solution formed by dichloromethane (1ml) and adds trifluoroacetic acid (1ml) stirring 1 hour.Decompression is lower to be concentrated, residue is dissolved in dichloromethane (1ml), triethylamine (17.6 μ l), acetic acid (7.21 μ l), 35% formalin (8.13 μ l) and sodium triacetoxy borohydride (20.1mg) are added at room temperature, are stirred 1 hour.Dichloromethane (10ml) and saturated sodium bicarbonate aqueous solution are added in reaction solution, organic layer is separated, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: dichloromethane=7: 93) is refined, adding 1N ethanol solution hydrochloride and ethyl acetate solidifies it, leaching obtains title compound (8.00mg) with silica gel column chromatography.
1H-NMR(DMSO-d6)δ：1.40-1.55 (2H, m), 1.55-1.75 (4H, m), 1.80-2.05 (2H, m), 2.98 (3H, br.s), (4.28 2H, br.s), 4.65 (4H, br.s), 7.14-7.20 (2H, m), (7.41 1H, d, J=8.8Hz), (7.69 1H, d, J=2.0Hz), (8.17 1H, d, J=6.9Hz), (8.65 1H, d, J=8.3Hz), 8.93 (1H, s), 11.73 (1H, br.s), 11.82 (1H, br.s)
MS(FAB)m/z：453(M+H)+.
[embodiment 34] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 2, the reaction product for the compound that the compound obtained to reference example 71 and reference example 34 are obtained is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.39-1.52 (2H, m), 1.62 (4H, br.s), 1.86-2.09 (2H, m), 3.03 (2H, br.s), 3.40-3.47 (2H, m), 4.17-4.32 (2H, m), 4.44 (2H, s), 7.15 (1H, s), 7.17 (1H, dd, J=8.6,2.0Hz), 7.41 (1H, d, J=8.6Hz), 7.71 (1H, s), 8.10-8.15 (1H, m), 8.40-8.47 (1H, m), 9.69 (2H, br.s), 11.85 (1H, s)
MS(FAB)m/z：458(M+H)+.
[embodiment 35] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- (2- methoxy ethyls) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03621
Using method similarly to Example 25, the compound obtained by embodiment 34 and 2- methoxy ethyl bromines prepare title compound.
1H-NMR(DMSO-d6)δ：1.44 (2H, br.s), 1.62 (4H, br.s), 1.85-2.10 (2H, m), 2.76-3.21 (6H, m), 3.28 (3H, s), 3.64 (2H, br.s), 4.00-4.52 (4H, m), 7.14 (1H, s), 7.17 (1H, dd, J=8.8,2.0Hz), (7.41 1H, d, J=8.8Hz), (7.70 1H, d, J=2.0Hz), 8.08-8.20 (1H, m), 8.36-8.48 (1H, m), 11.84 (1H, s)
MS(FAB)m/z：516(M+H)+.
[embodiment 36] 2- [2- { [((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-yl] acetate hydrochloride
Figure G2003801097466D03622
Using method similarly to Example 25, the compound obtained by embodiment 34 and methyl bromoacetate obtain title compound.
1H-NMR(CDCl3)δ：1.52-1.98 (7H, m), 2.17 (1H, br.s), 2.87-3.10 (4H, m), 3.49 (2H, s), 3.76 (3H, s), 3.93 (1H, d, J=15.4Hz), 3.99 (1H, d, J=15.4Hz), 4.22 (1H, br.s), 4.45 (1H, br.s), 6.86 (1H, d, J=1.2Hz), 7.18 (1H, dd, J=8.8,2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.58-7.63 (2H, m), 7.87 (1H, br.s), 9.88 (1H, br.s)
MS(FAB)m/z：530(M+H)+.
[embodiment 37] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03631
Using method similarly to Example 24, the compound and acetone obtained by embodiment 34 prepares title compound.
1H-NMR(DMSO-d6)δ：1.18-1.73 (8H, m), 1.81-2.10 (2H, m), 2.97-3.16 (1H, m), 3.20-3.41 (2H, m), 3.52-3.80 (2H, m), 4.19-4.31 (2H, m), 4.34-4.77 (2H, m), 7.17 (1H, s), 7.18 (1H, dd, J=8.8,2.0Hz), 7.42 (1H, d, J=8.8Hz), 7.71 (1H, d, J=2.0Hz), 8.15 (1H, br.s), 8.28-8.51 (1H, m), 11.31 (1H, br.s), 11.86 (1H, s)
MS(FAB)m/z：500(M+H)+.
[embodiment 38] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- (tetrahydrochysene -2H- pyrans -4- bases) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 24, the compound obtained by embodiment 34 and tetrahydrochysene -4H- pyrans -4- ketone prepare title compound.
1H-NMR(DMSO-d6)δ：1.30-3.56 (19H, m), 3.70-4.01 (3H, m), 4.17-4.30 (2H, m), 4.32-4.80 (1H, m), 7.15 (1H, s), 7.17 (1H, dd, J=8.6,2.0Hz), 7.41 (1H, d, J=8.6Hz), 7.71 (1H, d, J=2.0Hz), 8.14 (1H, br.s), 8.39 (1H, br.s), 11.84 (1H, s)
MS(FAB)m/z：542(M+H)+.
[embodiment 39] 2- [2- { [((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-yl] ethylcarbamate
Figure G2003801097466D03641
Using method similarly to Example 24, the compound obtained by embodiment 34 and N- (tert-butoxycarbonyl) aminoacetaldehyde (J.Org.Chem., 1988, volume 53, page 3457) prepare title compound.
1H-NMR(CDCl3)δ：1.44 (9H, s), 1.54-1.98 (7H, m), 2.10-2.20 (1H, m), 2.74 (2H, br.s), 2.92 (4H, br.s), 3.34 (2H, br.s), 3.84 (2H, br.s), 4.21 (1H, br.s), 4.45 (1H, br.s), 6.86 (1H, s), 7.19 (1H, dd, J=8.8,2.0Hz), (7.33 1H, d, J=8.8Hz), 7.57-7.63 (2H, m), 7.81 (1H, br.s), 9.66 (1H, br.s)
MS(FAB)m/z：601(M+H)+.
[embodiment 40] 5- (2- amino-ethyls)-N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03642
The compound (450mg) that embodiment 39 is obtained is dissolved in dichloromethane (5ml), adds ethanol solution hydrochloride (30ml) and is stirred at room temperature 1 minute.The lower concentration of reaction solution of decompression, adds ethyl acetate in residue, and the solid that leaching is separated out obtains title compound (367mg).
1H-NMR(DMSO-d6)δ：1.38-1.50 (2H, m), 1.61 (4H, br.s), 1.85-2.08 (2H, m), 3.00-4.62 (12H, m), 7.14 (1H, s), 7.16 (1H, dd, J=8.8,2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, d, J=2.0Hz), 8.12 (1H, d, J=6.6Hz), 8.15-8.68 (4H, m), 11.85 (1H, s)
MS(FAB)m/z：501(M+H)+.
[embodiment 41] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- { 2- [(methyl sulphonyl) amino] ethyl } -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (110mg) that embodiment 40 is obtained is dissolved in pyridine (3ml), adds after mesyl chloride (30 μ l), at room temperature stirring-evening.The lower concentration of reaction solution of decompression, adds dichloromethane in residue: methanol=85: 15 solution and water is carried out after point liquid operation, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtains faint yellow blister material.It is suspended in 1N hydrochloric acid (0.3ml), the lower concentrate solution of decompression obtains title compound (63mg).
1H-NMR(DMSO-d6)δ：1.38-1.50 (2H, m), 1.55-1.70 (4H, m), 1.86-2.05 (2H, m), 2.97 (3H, s), 3.02-3.25 (2H, m), 3.30-3.60 (5H, m), 3.78 (1H, br.s), 4.18-4.30 (2H, m), 4.45-4.86 (2H, m), 7.14 (1H, s), 7.16 (1H, dd, J=8.8, 2.0Hz), 7.40 (1H, d, J=8.8Hz), 7.41 (1H, br.s), 7.69 (1H, d, J=2.0Hz), 8.09 (1H, br.s), 8.43 (1H, br.s), 11.18 (1H, br.s), 11.82 (1H, s)
MS(FAB)m/z：579(M+H)+.
[embodiment 42] 2- [2- { [((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-yl] ethylidene dicarbamate hydrochloride
The compound (144mg) that embodiment 40 is obtained is dissolved in pyridine (3ml), is stirred at room temperature 5 minutes after adding triethylamine (138 μ l).At room temperature, instilled in the solution and the solution after triphosgene (49mg) is adjusted is added in the tetrahydrofuran (1ml) containing methanol (20 μ l), stirred 1 hour.The lower concentration of reaction solution of decompression, dichloromethane is dissolved in by residue: methanol=9: 1, the progress that adds water, which divides to divide after liquid, takes organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtains colourless blister material.1N hydrochloric acid (0.2ml) is suspended in, the lower concentrate solution of decompression obtains title compound (60mg).
1H-NMR(DMSO-d6)δ：1.38-1.50 (2H, m), 1.61 (4H, br.s), 1.85-2.04 (2H, m), 2.80-3.49 (8H, m), 3.52 (3H, s), 3.62-4.91 (4H, m), 7.14 (1H, s), 7.16 (1H, dd, J=8.8,2.0Hz), 7.37 (1H, br.s), 7.40 (1H, d, J=8.8Hz), 7.70 (1H, s), (8.11 1H, d, J=6.8Hz), 8.40 (1H, br.s), 11.05 (1H, br.s), 11.82 (1H, br.s)
MS(FAB)m/z：559(M+H)+.
[embodiment 43] 5- [2- (acetyl-amino) ethyl]-N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (90mg) that embodiment 40 is obtained is dissolved in DMF (3ml), adds and stirs an evening after triethylamine (65 μ l) and acetic anhydride (22 μ l) at room temperature.The lower concentration of reaction solution of decompression, the sodium hydrate aqueous solution that dichloromethane and 0.3N are added in residue carries out organic layer anhydrous sodium sulfate drying after point liquid operation.Solvent is boiled off under decompression, residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtains colourless blister material.1N hydrochloric acid (0.3ml) is suspended in, the lower concentrate solution of decompression obtains title compound (73mg).
1H-NMR(DMSO-d6)δ：1.39-1.52 (2H, m), 1.54-1.70 (4H, m), 1.83 (3H, s), 1.84-2.06 (2H, m), 3.02-3.87 (8H, m), 4.16-4.32 (2H, m), 4.40-4.52 (1H, m), 4.78-4.88 (1H, m), 7.14 (1H, s), 7.16 (1H, d, J=8.6Hz), 7.40 (1H, d, J=8.6Hz), 7.70 (1H, s), 8.07-8.17 (1H, m), 8.22-8.30 (1H, m), 8.38-8.52 (1H, m), 11.14 (1H, br.s), 11.83 (1H, s)
MS(FAB)m/z：543(M+H)+.
[embodiment 44] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- (2- hydroxyethyls) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Using method similarly to Example 25, the compound and ethylene bromohyrin obtained by embodiment 34 prepares title compound.
1H-NMR(DMSO-d6)δ：1.37-1.69 (6H, m), 1.86-2.03 (2H, m), 2.54-2.61 (2H, m), 2.75-2.86 (4H, m), 3.52-3.59 (2H, m), 3.75 (2H, s), 4.47 (1H, t, J=5.4Hz), 7.12 (1H, s), 7.16 (1H, dd, J=8.8,2.0Hz), 7.40 (1H, d, J=8.8Hz), 7.70 (1H, s), 8.05-8.13 (1H, m), 8.28-8.35 (1H, m), 11.78 (1H, s)
MS(FAB)m/z：502(M+H)+.
[embodiment 45] 5- butyl-N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 25, the compound obtained by embodiment 34 and 1- NBBs prepare title compound.
1H-NMR(DMSO-d6)δ：0.88 (3H, t, J=7.2Hz), 1.20-1.70 (10H, m), 1.87-2.05 (2H, m), 2.55-3.40 (8H, m), 4.16-4.30 (2H, m), 7.13 (1H, s), 7.16 (1H, d, J=8.8Hz), 7.40 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.05-8.14 (1H, m), 8.35 (1H, br.s), 11.81 (1H, s)
MS(FAB)m/z：514(M+H)+.
[embodiment 46] 5- acetyl group-N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The compound (100mg) that embodiment 34 is obtained is dissolved in DMF (3ml), is stirred at room temperature 3 hours after adding triethylamine (84 μ l), acetic anhydride (29 μ l).The lower concentration of reaction solution of decompression, the hydrochloric acid that dichloromethane and 1N are added in residue is carried out after point liquid operation, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtains title compound (86mg).
1H-NMR(CDCl3)δ：1.52-1.85 (5H, m), 1.91 (2H, br.s), 2.10-2.28 (4H, m), 2.77-3.00 (2H, m), 3.70-4.00 (2H, m), 4.19-4.38 (1H, m), 4.45 (1H, br.s), 4.68-4.99 (2H, m), 6.85 (1H, s), 7.17-7.22 (1H, m), 7.30-7.39 (1H, m), 7.50-7.84 (3H, m), 9.7
2-10.05 (1H, m)
MS(FAB)m/z：500(M+H)+.
[embodiment 47] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- (methyl sulphonyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D03681
The compound (100mg) that embodiment 34 is obtained is dissolved in pyridine (3ml), is added and is stirred an evening after triethylamine (168 μ l), mesyl chloride (48 μ l) at room temperature.The lower concentration of reaction solution of decompression, dichloromethane and 1N hydrochloric acid are added in residue, divides to take and anhydrous sodium sulfate drying is used after organic layer.Solvent is boiled off under decompression, residue (dichloromethane: methanol=100: 1) is refined with silica gel column chromatography, obtains title compound (79mg).
1H-NMR(CDCl3)δ：1.50-1.82 (5H, m), 1.90 (2H, br.s), 2.13 (1H, br.s), 2.89 (3H, s), 2.91-2.98 (2H, m), 3.60-3.70 (2H, m), 4.30 (1H, br.s), 4.44 (1H, br.s), 4.58 (2H, s), 6.87 (1H, s), 7.19 (1H, d, J=8.8Hz), 7.34 (1H, d, J=8.8Hz), 7.61 (3H, br.s), 9.91 (1H, br.s)
MS(FAB)m/z：536(M+H)+.
[embodiment 48] 5- methyl-N- ((1R*, 2S*) -2- { [(5- methyl indol -2- bases) carbonyl] amino } cyclohexyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using method similarly to Example 5, the compound obtained by reference example 67 and 5- methyl indol -2- carboxylic acids prepare title compound.
1H-NMR(DMSO-d6)δ：1.35-1.50 (2H, m), 1.50-1.80 (4H, m), 1.85-2.07 (2H, m), 2.36 (3H, s), 2.88 (3H, s), 3.12 (2H, br.s), 3.53 (2H, br.s), 4.15-4.30 (2H, m), 4.30-4.80 (2H, br), 7.00 (1H, dd, J=8.4, 1.5Hz), 7.05 (1H, d, J=1.5Hz), 7.30 (1H, d, J=8.4Hz), 7.38 (1H, s), 8.00 (1H, d, J=7.3Hz), 8.43 (1H, br.s), 11.45 (1H, br.s), 11.49 (1H, br.s)
MS(FAB)m/z：452(M+H)+.
[embodiment 49] (1R*, 3S*, 4R*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexanecarboxylate
Figure G2003801097466D03691
The compound (1.40g) that reference example 91 is obtained is suspended in ethanol (8ml), and ethanol solution hydrochloride (10ml) is added at room temperature and is stirred 12 hours.Solvent is boiled off under decompression, (1R is obtained*, 3S*, 4R*) -3- amino -4- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexanecarboxylate's hydrochloride (1.25g).
Using method similarly to Example 2, the compound obtained by above-mentioned product and reference example 10 prepares title compound.
1H-NMR(CDCl3)δ：1.29 (3H, t, J=7.1Hz), 1.52-1.80 (2H, m), 2.03-2.37 (4H, m), 2.53 (3H, s), 2.57-2.71 (1H, m), (each 1H of 3.73 and 3.78, each d, J=14.4Hz), 4.08-4.17 (1H, m), 4.18 (2H, q, J=7.2Hz), 4.55-4.65 (1H, m), 6.85 (1H, br.s), 7.21 (1H, dd, J=8.8, 2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.48 (1H, d, J=7.6Hz), 7.63 (1H, d, J=2.0Hz), 7.98 (1H, d, J=7.6Hz), 9.30 (1H, s)
MS(ESI)m/z：544(M+H)+.
[embodiment 50] (1R, 3R, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexanecarboxylate
Figure G2003801097466D03692
The compound (4.2g) that reference example 97 is obtained is suspended in ethanol (25ml), and ethanol solution hydrochloride (55ml) is added at room temperature and is stirred 11 hours.Solvent is boiled off under decompression, colorless solid (4.15g) is obtained.
Above-mentioned product (4.15g) is dissolved in N, dinethylformamide (40ml), the compound (2.86g) of addition reference example 10 acquisition, the hydrate of I-hydroxybenzotriazole 1 (1.72g), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (2.15g), are stirred 39 hours at room temperature.The lower concentration of reaction solution of decompression, add water organic layer saturated common salt water washing after being extracted with chloroform in residue, then is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (chloroform: methanol=100: 1) is refined with silica gel column chromatography, obtains title compound (1.71g).
[d]D- 94 ° (c=1.0, chloroform)
[embodiment 51] (1R*, 3R*, 4S*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid methyl esters
Figure G2003801097466D03701
Using the method same with embodiment 49, after the compound obtained with ethanol solution hydrochloride to reference example 107 is handled, the compound condensation for making it be obtained with reference example 10 obtains title compound.
1H-NMR(DMSO-d6)δ：1.55-1.80 (3H, m), 1.80-2.20 (3H, m), 2.60-2.75 (1H, m), 2.92 (3H, s), 3.15-3.30 (1H, m), 3.30-3.50 (4H, m), 3.57 (3H, s), 3.55-3.70 (1H, m), 4.20-4.30 (1H, m), 4.30-4.40 (1H, m), 7.02 (1H, s), 7.17 (1H, dd, J=8.5, 2.0Hz), 7.41 (1H, d, J=8.5Hz), 7.71 (1H, s), 8.20-8.35 (1H, m), 8.35-8.45 (1H, m), 11.82 (1H, br)
MS(FAB)m/z：530(M+H)+.
[embodiment 52] (1R*, 3S*, 4R*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexanecarboxylate
Figure G2003801097466D03702
Using the method same with embodiment 49, after the compound obtained with ethanol solution hydrochloride to reference example 98 is handled, it is condensed with 5- chloro-indole -2- carboxylic acids, obtain title compound.
1H-NMR(CDCl3)δ：1.29 (3H, t, J=7.1Hz), 1.82-2.30 (6H, m), 2.49 (3H, s), 2.62-2.73 (1H, m), 3.74-3.85 (2H, m), 3.85-3.93 (2H, m), 3.71 (2H, s), 4.12-4.29 (3H, m), 4.49-4.59 (1H, m), 6.89 (1H, br.s), 7.21 (1H, dd, J=8.8,2.0Hz), 7.32 (1H, d, J=8.8Hz), 7.33 (1H, br.s), 7.41 (1H, br.s), 7.62 (1H, br.s), 9.37 (1H, s)
MS(ESI)m/z：544(M+H)+.
[embodiment 53] (1R*, 3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid methyl ester hydrochloride
Using the method same with embodiment 49, after the compound obtained with 4N Yan Suan dioxane solutions to reference example 106 is handled, it is condensed with 5- chloro-indole -2- carboxylic acids, obtain title compound.
1H-NMR(DMSO-d6)δ：1.65-1.80 (3H, m), 1.80-2.10 (2H, m), 2.15-2.25 (1H, m), 2.55-2.70 (1H, m), 2.89 (3H, s), 3.05-3.20 (1H, m), 3.30-3.50 (4H, m), 3.55-3.65 (1H, m), 3.62 (3H, s), 4.20-4.30 (1H, m), 4.35-4.45 (1H, m), 7.19 (1H, dd, J=8.8, 1.2Hz), 7.23 (1H, s), 7.43 (1H, d, J=8.8Hz), 7.73 (1H, s), 8.03 (1H, d, J=6.8Hz), 8.73 (1H, d, J=8.5Hz), 11.15-11.38 (1H, br), 11.85 (1H, s)
MS(FAB)m/z：530(M+H)+.
[embodiment 54] (1R, 3R, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid methyl esters
Figure G2003801097466D03712
Using the method same with embodiment 49, after the compound obtained with 4N Yan Suan dioxane solutions to reference example 112 is handled, it is condensed with 5- chloro-indole -2- carboxylic acids, obtain title compound.
1H-NMR(DMSO-d6)δ：1.67-1.76 (3H, m), 1.88-1.91 (1H, m), 2.01 (1H, br.s), 2.13-2.22 (1H, m), 2.52-2.67 (4H, m), 2.86 (2H, br.s), 3.04 (2H, br.s), 3.33-3.41 (1H, m), 3.61 (3H, s), 4.22-4.36 (3H, m), 7.17-7.22 (2H, m), 7.42 (1H, d, J=8.8Hz), 7.72 (1H, s), 8.00 (1H, d, J=6.9Hz), 8.68 (1H, d, J=8.6Hz), 11.80 (1H, s)
MS(FAB)m/z：530(M+H)+.
[embodiment 55] N- ((1R*, 2S*, 5S*) -5- (amino carbonyl) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Using the method same with embodiment 49, after the compound obtained with 4N Yan Suan dioxane solutions to reference example 113 is handled, the compound condensation for making it be obtained with reference example 10 obtains title compound.
1H-NMR(CDCl3)δ：0.78-2.40 (7H, m), 2.53 (3H, s), 2.80-2.89 (1H, m), 2.91-3.00 (1H, m), 3.68-3.76 (2H, m), 4.08-4.19 (1H, m), 4.54-4.65 (1H, m), 6.80 (1H, br.s), 7.21 (1H, dd, J=8.4,1.6Hz), 7.33 (1H, d, J=8.4Hz), 7.38-7.43 (1H, m), 7.49-7.55 (1H, m), 7.63 (1H, br.s), 9.14 (1H, br.s)
MS(ESI)m/z：515(M+H)+.
[embodiment 56] (1R*, 3S*, 4R*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid
The compound (916mg) that embodiment 49 is obtained is suspended in the mixed solvent of ethanol (10ml) and tetrahydrofuran (8ml), adds under 1N sodium hydrate aqueous solution (3.3ml), equality of temperature and stirs 12 hours at room temperature.After the ethanol solution hydrochloride (3.3ml) for adding 1N, solvent is boiled off under decompression, residue obtains title compound (712mg) after being washed with water and ether.
[embodiment 57] N- { (1R*, 2S*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Triethylamine (0.25ml), dimethylamine hydrochloride (133mg), the hydrate of I-hydroxybenzotriazole 1 (53mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (75mg) are added in the chloroform suspension (10ml) for the compound (168mg) that embodiment 56 is obtained, is stirred 72 hours.Solvent is boiled off under decompression, added water in residue is extracted with chloroform, organic layer after saturated common salt water washing with anhydrous magnesium sulfate with being dried.Solvent is boiled off under decompression, residue (dichloromethane: methanol=93: 7) is refined with silica gel column chromatography, the colorless solid (135mg) of gained is set to be suspended in ethanol (5ml), the ethanol solution hydrochloride (0.5ml) for adding 1N is stirred 2 hours.Solvent is boiled off, title compound (112mg) is obtained.
1H-NMR(DMSO-d6)δ：1.42-2.07 (6H, m), 2.73-3.70 (10H, m), 2.88 (3H, s), 2.97 (3H, s), 4.03-4.20 (1H, m), 4.51-4.67 (1H, m), 7.04 (1H, br.s), 7.16 (1H, br, J=8.8Hz), 7.41 (1H, d, J=8.8Hz), 7.68 (1H, br.s), 8.32-8.47 (2H, m), 10.76 (1H, br.s)
MS(ESI)m/z：543(M+H)+.
[embodiment 58] (1S, 3R, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid
The compound (1.6g) for obtaining embodiment 50 is suspended in the in the mixed solvent of ethanol (20ml) and tetrahydrofuran (15ml), add and stirred 12 hours under 1N sodium hydrate aqueous solution (5.9ml), equality of temperature at room temperature.Addition 1N hydrochloric acid (5.9ml) boils off solvent under depressurizing afterwards, and residue is washed with water and ether, obtains title compound (1.19g).
Fusing point：234~236 DEG C
[α]D- 57 ° (c=1.0, methanol)
[embodiment 59] N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(cyclopropylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03732
Using the method same with embodiment 57, the compound and cyclopropylamine obtained by embodiment 58 prepares title compound.
1H-NMR(DMSO-d6)δ：0.32-0.40 (2H, m), 0.53-0.63 (2H, m), 1.50-2.10 (6H, m), 2.25-2.40 (1H, m), 2.45-2.70 (2H, m), 2.91 (3H, s), 3.05-3.80 (3H, m), 4.05-4.17 (1H, m), 4.30-4.55 (2H, m), 4.55-4.80 (1H, m), 7.03 (1H, d, J=1.5Hz), 7.16 (1H, dd, J=8.8, 2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.68 (1H, d, J=2.0Hz), 7.86 (1H, br, J=3.4Hz), 8.06 (1H, br.s), 8.40 (1H, br, J=7.6Hz), 11.20-11.60 (1H, br), 11.79 (1H, s)
MS(FAB)m/z：555(M+H)+.
[embodiment 60] N- [(1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (pyrrolidin-1-yl carbonyl) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03741
Using the method same with embodiment 57, the compound and pyrrolidines obtained by embodiment 58 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-2.10 (10H, m), 2.75-2.90 (2H, m), 2.90 (3H, s), 3.10-3.70 (H, m), 4.05-4.20 (1H, m), 4.25-4.80 (3H, m), 7.05 (1H, s), (7.17 1H, d, J=8.7Hz), (7.41 1H, d, J=8.7Hz), 7.69 (1H, s), 8.32 (1H, br, J=7.6Hz), 8.38 (1H, br, J=7.1Hz), 11.22 (1H, br.s), 11.78 (1H, s)
MS(FAB)m/z：569(M+H)+.
[embodiment 61] N- [(1R*, 2S*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (4- morpholinyl carbonyls) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 57, the compound and morpholine obtained by embodiment 56 prepares title compound.
1H-NMR(DMSO-d6)δ：1.40-2.05 (6H, m), 2.75-3.70 (18H, m), 4.02-4.17 (1H, m), 4.55-4.69 (1H, m), 7.05 (1H, br.s), 7.17 (1H, br, J=8.8Hz), 7.41 (1H, d, J=8.8Hz), 7.67 (1H, br.s), 8.35 (1H, d, J=7.6Hz), 8.40 (1H, d, J=7.6Hz), 10.79 (1H, br.s)
MS(ESI)m/z：585(M+H)+.
[embodiment 62] N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(ethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (150mg) that embodiment 58 is obtained is dissolved in N, dinethylformamide (3ml), N- ethylamine hydrochlorides (119mg), the hydrate of I-hydroxybenzotriazole 1 (79mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (112mg) and triethylamine (326 μ l) are added, is stirred 4 days at room temperature.Solvent is boiled off under decompression, after addition saturated sodium bicarbonate aqueous solution is extracted with dichloromethane in residue, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=47: 3) is refined with silica gel column chromatography.Gained solid is dissolved in dichloromethane, 1N ethanol solution hydrochloride (171 μ l) is added, solvent is boiled off under decompression.Methanol and ether are added in residue, the precipitation of leaching generation obtains title compound (74mg).
1H-NMR(DMSO-d6)δ：0.99 (3H, t, J=7.2Hz), 1.57-2.02 (6H, m), 2.33-2.38 (1H, m), 2.92 (3H, s), 3.01-3.08 (2H, m), 3.17-3.20 (2H, s), 3.45-3.70 (2H, m), 4.10-4.17 (1H, m), 4.40-4.69 (3H, m), 7.04 (1H, d, J=2.0Hz), 7.17 (1H, dd, J=8.8, 2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, d, J=2.0Hz), 7.78-7.81 (1H, m), 8.08-8.12 (1H, m), 8.40 (1H, d, J=8.1Hz), 11.23 (1H, br.s), 11.79 (1H, br.s)
MS(FAB)m/z：543(M+H)+.
[embodiment 63] N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (900mg) that embodiment 58 is obtained is dissolved in N, dinethylformamide (50ml), dimethylamine hydrochloride (304mg), the hydrate of I-hydroxybenzotriazole 1 (262mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (369mg), diisopropylethylamine (1.83ml) are added, is stirred 12 hours at room temperature.Solvent is boiled off under decompression, saturated sodium bicarbonate aqueous solution is added in residue, organic layer anhydrous sodium sulfate drying after being extracted with dichloromethane.Solvent is boiled off under decompression, residue obtained use silica gel column chromatography (dichloromethane: methanol=47: 3) refines, gained white solid is dissolved in into dichloromethane, add 1N ethanol solution hydrochloride (1.49ml), solvent is boiled off under decompression.Methanol and ether are added in residue, the precipitation of leaching generation obtains title compound (777mg).
[α]D- 53.9 ° (18 °, c=0.505, methanol)
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.70-1.85 (3H, m), 1.90-2.05 (2H, m), 2.80 (3H, s), 2.91 (3H, s), 2.95-3.10 (1H, m), 2.97 (3H, s), 3.10-3.75 (4H, m), 4.05-4.15 (1H, m), 4.35-4.75 (3H, m), 7.05 (1H, s), 7.16 (1H, dd, J=8.7, 2.1Hz), 7.41 (1H, d, J=8.6Hz), 7.67 (1H, s), 8.30-8.45 (2H, m), 11.63 (1H, br), 11.78 (1H, s)
MS(FAB)m/z：543(M+H)+.
[embodiment 64] N- ((1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- { [(2- methoxy ethyls) (methyl) amino] carbonyl } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 57, the compound obtained by embodiment 58 prepares title compound.
1H-NMR(DMSO-d6)δ：1.50-1.99 (6H, m), 2.80, 3.01 (3H, each s), 2.91 (3H, s), 3.03 (1H, br.s), 3.16 (2H, s), 3.23 (3H, s), 3.35-3.67 (6H, m), 4.09-4.16 (1H, m), 4.43-4.67 (3H, m), 7.04-7.06 (1H, m), 7.16 (1H, dd, J=8.8, 2.0Hz), 7.42 (1H, d, J=8.8Hz), 7.69 (1H, br.s), 8.29-8.41 (2H, m), 11.59 (1H, br.s), 11.80 (1H, br.s)
MS(FAB)m/z：587(M+H)+.
[embodiment 65] N- ((1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- { [(2- hydroxyethyls) (methyl) amino] carbonyl } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03772
Using the method same with embodiment 57, the compound obtained by embodiment 58 prepares title compound.
1H-NMR(DMSO-d6)δ：1.50-1.55 (1H, m), 1.74-1.84 (3H, m), 1.94-1.97 (2H, m), 2.67,3.02 (3H, each s), 2.91 (3H, s), 3.10-3.68 (9H, m), 4.11-4.13 (1H, m), 4.43-4.66 (4H, m), 7.05 (1H, s), 7.16 (1H, dd, J=8.7,2.0Hz), 7.41 (1H, d, J=8.7Hz), 7.68 (1H, s), 8.34-8.40 (2H, m), 11.47 (1H, br.s), 11.79 (1H, s)
MS(FAB)m/z：573(M+H)+.
[embodiment 66] N- ((1R, 2S, 5S) -5- (1- azetidinyl carbonyls) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 57, the compound and azetidine hydrochloride obtained by embodiment 58 prepares title compound.
1H-NMR(DMSO-d6)δ：1.47-1.55 (1H, m), 1.65-1.82 (3H, m), 1.88-2.01 (2H, m), 2.16 (2H, quint., J=7.6Hz), 3.17-3.67 (5H, m), 3.82 (2H, t, J=7.6Hz), 4.02-4.14 (3H, m), 4.43-4.67 (3H, m), 7.06 (1H, s), 7.17 (1H, dd, J=8.7, 1.7Hz), 7.41 (1H, d, J=8.7Hz), 7.69 (1H, br.s), 8.31 (1H, d, J=7.6Hz), 8.38 (1H, d, J=7.6Hz), 11.41 (1H, br.s), 11.80 (1H, s)
MS(FAB)m/z：555(M+H)+.
[embodiment 67] N- ((1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- { [(3S) -3- fluoropyrrolidines base] carbonyl } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 57, the compound obtained by embodiment 58 and (S) -3- fluoropyrrolidines (Synlett., nineteen ninety-five, page 55) obtain title compound.
1H-NMR(DMSO-d6)δ：1.23-3.77 (22H, m), 4.11-4.16 (1H, m), 4.58-4.51 (1H, m), 5.23-5.42 (1H, m), 7.05 (1H, s), 7.16 (1H, d, J=8.3Hz), 7.42 (1H, d, J=8.3Hz), 7.68 (1H, s), 8.34-8.37 (2H, m), 11.78 (1H, s)
MS(FAB)m/z：587(M+H)+.
[embodiment 68] (1R*, 3R*, 4S*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid lithium salts
Figure G2003801097466D03791
The compound (1.20g) that embodiment 51 is obtained, which is dissolved under tetrahydrofuran (32ml), ice cooling, sequentially adds lithium hydroxide (60.8mg) and water (4ml), stirs 14 hours at room temperature.Solvent is boiled off under decompression, title compound (1.12g) is obtained.
1H-NMR(DMSO-d6)δ：1.55-1.70 (2H, m), 1.70-2.05 (4H, m), 2.10-2.20 (1H, m), 2.25-2.40 (4H, m), 2.50-2.80 (4H, m), 3.45-3.65 (3H, m), 4.10-4.30 (2H, m), 7.00-7.20 (2H, m), 7.50-7.65 (2H, m)
[embodiment 69] N- { (1R*, 2S*, 4S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- [(dimethylamino) carbonyl] cyclohexyl -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 57, the compound and dimethylamine hydrochloride obtained by embodiment 68 prepares title compound.
1H-NMR(DMSO-d6)δ：1.40-1.60 (2H, m), 1.65-1.80 (2H, m), 1.95-2.10 (2H, m), 2.84 (3H, s), 2.90-3.05 (1H, m), 2.92 (3H, s), 3.06 (3H, s), 3.15-3.75 (4H, m), 4.25-4.75 (4H, m), 7.02 (1H, d, J=1.5Hz), 7.15 (1H, dd, J=8.8, 2.1Hz), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, d, J=2.1Hz), 8.05 (1H, d, J=7.7Hz), 8.63 (1H, d, J=7.7Hz), 11.20 (1H, br), 11.79 (1H, s)
MS(FAB)m/z：543(M+H)+.
[embodiment 70] N- ((1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- { [(3R) -3- hydroxypyrroles alkyl] carbonyl } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
1) compound (1.18g) obtained reference example 58 is dissolved in methanol (12ml), add 1N hydrochloric acid (240 μ l) and palladium dydroxide (221mg), hydrogen is imported, catalytic reduction reaction is carried out with normal pressure with 4.5 hours at room temperature.Catalyst is filtered off, it is solid that the filtrate was concentrated to dryness under decompression, obtains rough (3R) -3- { [tert-butyl group (diphenyl) silicyl] epoxide } pyrrolidine hydrochloride (984mg).
Compound (295mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (126mg) and the hydrate of I-hydroxybenzotriazole 1 (87mg) that gained product (249mg), embodiment 58 are obtained are dissolved in DMF (10ml).Under ice cooling, diisopropylethylamine (450 μ l) is instilled, is stirred 12 hours at room temperature.Solvent is boiled off under decompression, dichloromethane is added in residue and saturated sodium bicarbonate aqueous solution is carried out after point liquid operation, organic layer anhydrous sodium sulfate drying boils off solvent under decompression.Residue (methanol: dichloromethane=3: 97) is refined with silica gel column chromatography, obtain N- ((1R, 2S, 5S) -5- [((3R) -3- { [tert-butyl group (diphenyl) silicyl] epoxide } pyrrolidinyl) carbonyl] -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (248mg).
1H-NMR(CDCl3)δ：1.06 (9H, s), 1.50-1.60 (1H, m), 1.75-2.10 (5H, m), 2.20-2.50 (2H, m), 2.54 (3H, d, J=2.8Hz), 2.60-3.00 (5H, m), 3.30-3.80 (6H, m), 4.10-4.20 (1H, m), 4.40-4.70 (2H, m), 6.85 (1H, s), 7.15-7.25 (1H, m), 7.30-7.50 (8H, m), 7.60-7.70 (5H, m), 7.90-8.00 (1H, m), 9.38 (1H, s)
MS(FAB)m/z：823(M+H)+.
2) above-mentioned product (240mg) is dissolved under pyridine (10ml), ice cooling, instills hydrogen fluoride pyridine (3.0ml), stirred 4.5 hours in 0 DEG C.Under ice cooling, addition ethyl acetate (80ml) is diluted in reaction solution, and the reaction solution after dilution is injected in frozen water.Sodium acid carbonate is added in the solution makes it in the operation of progress point liquid, organic layer anhydrous sodium sulfate drying after alkalescence.Solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 19 → 1: 9) is refined with silica gel column chromatography.The gained thing that is roughly refined is dissolved in dichloromethane and methanol, 1N ethanol solution hydrochloride (225 μ l) flush distillation is added to solid, in residue plus methanol-diethyl ether, is allowed to solidify, obtains title compound (114mg).
1H-NMR(DMSO-d6)δ：1.50-1.60 (1H, m), 1.70-2.10 (6H, m), 2.75-2.85 (1H, m), 2.92 (3H, s), 3.10-3.80 (8H, m), 4.10-5.10 (6H, m), (7.05 1H, d, J=1.7Hz), 7.16 (1H, dd, J=8.8,1.7Hz), 7.42 (1H, d, J=8.8Hz), 7.68 (1H, s), 8.30-8.45 (2H, m), 11.10-11.40 (1H, m), 11.78 (1H, s)
MS(FAB)m/z：585(M+H)+.
[embodiment 71] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5,5- dimethoxycyclohexyls) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide or N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4,4- dimethoxycyclohexyls) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Using method similarly to Example 2, the compound obtained by reference example 118 prepares title compound with the compound that reference example 10 is obtained.
1H-NMR(CDCl3)δ：2.11-2.15 (1H, m), 2.21-2.25 (1H, m), 2.41-2.43 (1H, m), 2.46 (3H, s), 2.70-2.75 (1H, m), 2.81-2.88 (1H, m), 3.21 (3H, s), 3.24 (3H, s), 3.49 (1H, s), 3.58 (1H, d, J=15.6Hz), 3.71 (1H, d, J=15.6Hz), 3.87-3.93 (1H, m), 4.26-4.29 (1H, m), 6.85 (1H, d, J=2.0Hz), 7.19 (1H, dd, J=8.5, 2.0Hz), 7.30 (1H, d, J=8.5Hz), 7.62 (1H, s), 9.21 (1H, s)
[embodiment 72] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- oxocyclohexyls) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide or N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- oxocyclohexyls) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The compound (100mg) that embodiment 71 is obtained is dissolved in chloroform (2ml), adds trifluoroacetic acid (0.5ml) and water (0.5ml), is stirred 3.5 hours at room temperature.Saturated sodium bicarbonate aqueous solution is added in reaction solution, is extracted with ethyl acetate, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (dichloromethane: methanol=19: 1) is refined with silica gel thin-layer chromatography is prepared.Gained colorless solid is dissolved in methanol (4ml), 1N ethanol solution hydrochloride (0.38ml) is added, solvent is boiled off under decompression, title compound (35mg) is obtained.
1H-NMR(DMSO-d6)δ：1.83-1.90 (1H, m), 2.08-2.10 (1H, m), 2.28-2.32 (1H, m), 2.50-2.59 (1H, m), 2.87 (3H, s), 2.96 (1H, t, J=13.0Hz), 3.06-3.10 (2H, m), 3.33-3.36 (3H, m), 4.02-4.04 (2H, m), 4.55-4.57 (2H, m), 7.03 (1H, s), 7.15 (1H, d, J=8.8Hz), 7.38 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.43 (1H, d, J=8.8Hz), 8.91 (1H, d, J=8.8Hz), 11.75 (1H, s)
[embodiment 73] N- [(1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (oxyimino) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide or N- [(1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- (oxyimino) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The compound (133mg) that embodiment 72 is obtained is dissolved in the in the mixed solvent of pyridine (8ml) and methanol (8ml), adds hydroxylamine hydrochloride (30mg), stirs 3 days at room temperature.Concentration of reaction solution adds water in residue, is extracted with ethyl acetate, and organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (dichloromethane: methanol=97: 3 → 17: 3) is refined with silica gel column chromatography, obtains title compound (131mg).
1H-NMR(CDCl3)δ：1.43-1.86 (3H, m), 1.98-2.03 (1H, m), 2.26-2.30 (1H, m), 2.45 (3H, s), 2.47-2.51 (1H, m), 2.67-2.71 (1H, m), 2.78-2.86 (3H, m), 3.86-3.43 (2H, m), 4.16-4.24 (2H, m), 6.85 (1H, s), 7.13-7.16 (1H, m), 7.20-7.24 (1H, m), 7.46,7.50 (whole 1H, s), 7.56-7.64 (2H, m), 9.59,9.62 (whole 1H, s)
[embodiment 74] N- ((7R*, 8S*) -8- { [(5- chloro-indole -2- bases) carbonyl] amino }-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 7- yls) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide or N- ((7R*, 8S*) -7- ([(5- chloro-indole -2- bases) carbonyl] amino }-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl- 8- yls) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Using method similarly to Example 2, the compound that the compound obtained by reference example 120 and reference example 10 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.69-1.87 (6H, m), 2.14-2.17 (1H, m), 2.30-2.32 (1H, m), 2.47 (3H, s), 2.70-2.75 (1H, m), 2.81-2.89 (2H, m), 3.58 (1H, d, J=15.4Hz), 3.72 (1H, d, J=15.4Hz), 3.89-3.91 (1H, m), 3.99 (4H, s), 4.37-4.40 (1H, m), 6.86 (1H, d, J=2.0Hz), 7.19 (1H, dd, J=8.8, 2.0Hz), 7.30 (1H, d, J=8.8Hz), 7.38 (1H, d, J=7.3Hz), 7.62 (1H, d, J=2.0Hz), 9.15 (1H, s)
[embodiment 75] N- [(1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (methoxyimino) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide or N- [(1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- (methoxyimino) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
1) compound (2.21g) obtained reference example 124 is dissolved in dichloromethane (30ml), adds trifluoroacetic acid (6ml), stirs 1.5 hours at room temperature.After concentration of reaction solution is dried with vavuum pump, it is dissolved in N, dinethylformamide (20ml), 5- chloro-indole -2- carboxylic acids (500mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (593mg), the hydrate of I-hydroxybenzotriazole 1 (473mg) and N-methylmorpholine (2.8ml) are added, is stirred 10 hours at room temperature.Then, 5- chloro-indole -2- carboxylic acids (242mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (237mg) and the hydrate of I-hydroxybenzotriazole 1 (189mg) are added, is stirred 4 hours.Saturated sodium bicarbonate aqueous solution is added in reaction solution, with ethyl acetate and the mixed extractant solvent of ethyl acetate and tetrahydrofuran.Organic layer saturated common salt water washing, after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: methanol=97: 3 → 4: 1) is refined with silica gel column chromatography, obtains N- [(1R*, 2S*) -2- amino -5- (methoxyimino) cyclohexyl] -5- chloro-indole -2- formamides (368mg) and N- [(1R*, 2S*) -2- amino -4- (methoxyimino) cyclohexyl] -5- chloro-indole -2- formamides (300mg).
2) the N- [(1R of one of product obtained by above-mentioned reaction*, 2S*) -2- amino -5- (methoxyimino) cyclohexyl] -5- chloro-indole -2- formamides or N- [(1R*, 2S*) -2- amino -4- (methoxyimino) cyclohexyl] compound that obtains of -5- chloro-indole -2- formamides and reference example 10, by method similarly to Example 2, title compound (syn the and anti isomer mixtures of methoxyimino part) is prepared.
1H-NMR(CDCl3)δ：1.84-2.00 (3H, m), 2.26-2.56 (3H, m), 2.46 (3H, s), 2.80-2.83 (4H, m), 3.57 (1H, q, J=15.4Hz), 3.70 (1H, q, J=15.4Hz), 3.84,3.85 (whole 3H, s), 4.08-4.14 (1H, m), 4.26-4.30 (1H, m), 6.84 (1H, s), 7.17 (1H, d, J=8.8Hz), 7.27 (1H, d, J=8.8Hz), 7.46-7.48 (2H, m), 7.56 (1H, m), 9.42,9.55 (whole 1H, s)
[embodiment 76] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- hydroxy-cyclohexyls) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (stereoisomer A) or N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- hydroxy-cyclohexyls) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (stereoisomer A)
1) using 1) the same method with embodiment 75, (the 1R that reference example 125 is obtained is removed*, 2S*) body (stereoisomer A) tert-butoxycarbonyl after, by with 5- chloro-indole -2- carboxylic acid reactions, obtain N- ((1R*, 2S*) -2- amino -4- { [tert-butyl group (diphenyl) silicyl] epoxide } cyclohexyl) -5- chloro-indole -2- formamides (stereoisomer A) and N- ((1R*, 2S*) -2- amino -5- { [tert-butyl group (diphenyl) silicyl] epoxide } cyclohexyl) -5- chloro-indole -2- formamides (stereoisomer A).
2) mixture obtained by above-mentioned product and reference example 10, using method similarly to Example 2, obtains N- ((1R*, 2S*) -5- { [tert-butyl group (diphenyl) silicyl] epoxide } -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (stereoisomer A) or N- ((1R*, 2S*) -4- { [tert-butyl group (diphenyl) silicyl] epoxide } -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (stereoisomer A).
1H-NMR(CDCl3)δ：1.06 (9H, s), 1.55-1.61 (1H, m), 1.85-1.90 (1H, m), 2.18-2.25 (1H, m), 2.46 (3H, s), 2.51 (2H, d, J=7.6Hz), 2.68-2.76 (1H, m), 3.56 (1H, s), 3.57 (1H, d, J=15.3Hz), 3.72 (1H, d, J=15.3Hz), 3.71-3.81 (1H, m), 3.88-3.95 (1H, m), 6.78 (1H, s), 7.17 (1H, dd, J=2.0, 8.8Hz), 7.37-7.44 (7H, m), 7.59 (1H, s), 7.65-7.68 (6H, m), 9.30 (1H, s)
3) compound obtained by above-mentioned reaction, title compound is prepared by 3) the same method with embodiment 28.
1H-NMR(DMSO-d6)δ：1.25-1.30 (2H, m), 1.45-1.64 (2H, m), 1.86 (1H, d, J=9.0Hz), 1.98-2.03 (1H, m), 2.33 (3H, s), 2.66-2.73 (2H, m), 2.75-2.79 (2H, m), 3.54 (1H, d, J=15.6Hz), 3.62 (1H, d, J=15.6Hz), 3.96-4.02 (2H, m), 4.78 (1H, d, J=4.2Hz), 7.00 (1H, s), 7.14 (1H, dd, J=2.0, 8.8Hz), 7.38 (1H, d, J=8.8Hz), 7.66 (1H, s), 8.20 (1H, d, J=7.8Hz), 8.54 (1H, d, J=7.8Hz), 11.69 (1H, s)
[embodiment 77] N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- hydroxy-5-methyls butylcyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (isomers A1) or N- ((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- hydroxy-4-methyls cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (isomers A2)
Using method similarly to Example 2, the compound that reference example 128 is obtained is reacted with the compound that reference example 10 is obtained, obtain title compound.
Isomers A1：
1H-NMR(DMSO-d6)δ：1.24 (3H, s), 1.33-1.82 (4H, m), 2.34 (3H, s), 2.67-3.64 (8H, m), 4.02-4.10 (2H, m), 4.67 (1H, br.s), 7.02 (1H, s), 7.13 (1H, d, J=8.6Hz), 7.38 (1H, d, J=8.6Hz), 7.66 (1H, d, J=2.0Hz), 8.21-8.26 (1H, m), 8.59 (1H, d, J=8.1Hz), 11.73 (1H, br.s)
MS(FAB)m/z：502(M+H)+.
Isomers A2：
1H-NMR(DMSO-d6) δ 1.25 (3H, s), 1.33-1.79 (4H, m), 2.33 (3H, s), 2.65-3.63 (8H, m), 3.88-3.94 (1H, m), 4.20-4.25 (1H, m), 4.59 (1H, br), 7.01 (1H, s), (7.13 1H, d, J=7.8Hz), (7.38 1H, d, J=8.6Hz), 7.67 (1H, s), 8.29 (1H, br), 8.43 (1H, d, J=9.3Hz), 11.67 (1H, br)
MS(FAB)m/z：502(M+H)+.
[embodiment 78] N- [(1R*, 2R*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (hydroxymethyl) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Same with embodiment 49, after the compound obtained with ethanol solution hydrochloride to reference example 129 is handled, the compound condensation for making it be obtained with reference example 10 prepares title compound.
1H-NMR(DMSO-d6)δ：1.42-1.90 (5H, m), 2.07-2.26 (3H, m), 2.46 (3H, s), 2.67-2.95 (4H, m), 3.55-3.80 (4H, m), 3.80-3.95 (1H, m), 4.13-4.25 (1H, m), 6.84 (1H, br.s), 7.17 (1H, dd, J=8.8,2.0Hz), 7.23-7.35 (2H, m), 7.43 (1H, d, J=7.2Hz), 7.58 (1H, br.s), 9.29 (1H, s)
MS(ESI)m/z：502(M+H)+.
[embodiment 79] N- [(1R*, 2S*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- (methoxy) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D03851
Same with embodiment 49, after the compound obtained with ethanol solution hydrochloride to reference example 135 is handled, the compound condensation for making it be obtained with reference example 10 prepares title compound.
1H-NMR(CDCl3)δ：1.20-1.38 (1H, m), 1.50-1.67 (2H, m), 1.88-2.03 (2H, m), 2.03-2.14 (1H, m), 2.21-2.32 (1H, m), 2.53 (3H, s), 2.75-2.95 (2H, m), 3.20-3.35 (2H, m), 3.37 (3H, s), 3.73 (1H, d, J=16.0Hz), 3.76 (1H, d, J=16.0Hz), 4.04-4.13 (1H, m), 4.53-4.62 (1H, m), 6.85 (1H, d, J=2.0Hz), 7.19 (1H, dd, J=8.8, 2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.54 (1H, d, J=7.2Hz), 7.63 (1H, d, J=2.0Hz), 8.07 (1H, d, J=5.6Hz), 9.49 (1H, br.s)
[embodiment 80] N- ((1R*, 2S*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- { [(methyl sulphonyl) amino] methyl } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
1) compound (437mg) obtained reference example 137 is dissolved in ethanol (5ml), and 4N Yan Suan dioxane solutions (5ml) are added at room temperature, stirs 13 hours.Boil off solvent, residue is dissolved in N, dinethylformamide (10ml), compound (300mg), the hydrate of I-hydroxybenzotriazole 1 (162mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (230mg) that triethylamine (0.7ml), reference example 10 are obtained are added, is stirred 13 hours.Solvent is boiled off under decompression, adds water and is extracted with chloroform, after organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (dichloromethane: methanol=97: 3) is refined with silica gel column chromatography, obtains N- ((1R*, 2S*, 5S*) -5- (azido methyl) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (330mg).
1H-NMR(DMSO-d6)δ：1.15-2.08 (7H, m), 2.33 (3H, s), 2.34-2.95 (6H, m), 3.64 (2H, s), 4.05-4.17 (1H, m), 4.36-4.47 (1H, m), 7.02 (1H, s), 7.15 (1H, dd, J=8.8,2.0Hz), 7.40 (1H, d, J=8.8Hz), 7.67 (1H, d, J=2.0Hz), 8.02 (1H, d, J=7.6Hz), 8.44 (1H, d, J=7.6Hz), 11.8 (1H, s)
2) compound (300mg) obtained above-mentioned reaction is dissolved in ethanol (8ml), adds and is stirred at room temperature 168 hours under 10% palladium carbon of catalytic amount, hydrogen stream.Insoluble matter is filtered, solvent is boiled off, by rough N- ((1R*, 2S*, 5S*) -5- (amino methyl) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (150mg) be dissolved under chloroform (6ml), ice cooling add triethylamine (0.2ml) and mesyl chloride (0.035ml) stirring 13 hours.Solvent is boiled off under decompression, adds water and is extracted with chloroform, after organic layer saturated sodium bicarbonate aqueous solution and saturated common salt water washing, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (dichloromethane: methanol=24: 1) is refined with silica gel column chromatography, obtains title compound (56mg).
1H-NMR(CDCl3)δ：1.18-1.34 (2H, m), 1.50-1.75 (4H, m), 1.90-2.30 (4H, m), 2.53 (3H, s), 2.78-2.90 (2H, m), 2.90-3.05 (6H, m), 3.20-3.30 (1H, m), 3.68-3.81 (2H, m), 3.98-4.08 (1H, m), 4.54-4.62 (1H, m), 6.10-6.19 (1H, m), 6.86 (1H, s), 7.19 (1H, dd, J=8.8, 2.0Hz), 7.35 (1H, d, J=8.8Hz), 7.52 (1H, d, J=7.6Hz), 7.62 (1H, d, J=2.0Hz), 8.21 (1H, d, J=5.6Hz), 9.89 (1H, s)
MS(ESI)m/z：579(M+H)+.
[embodiment 81] N- { (1R*, 2S*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) methyl] cyclohexyl -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide trifluoroacetate
Using method similarly to Example 24, title compound is prepared by the amine 2) obtained of embodiment 80.
1H-NMR(DMSO-d6)δ：1.15-2.22 (7H, m), 2.40-2.65 (2H, m), 2.68-2.85 (6H, m), 2.92-3.08 (5H, m), 3.10-3.18 (2H, m), 4.08-4.20 (1H, m), 4.35-4.51 (2H, m), 7.04 (1H, s), 7.14-7.20 (1H, m), (7.41 1H, d, J=8.8Hz), 7.67 (1H, s), 8.25-8.42 (2H, m), 9.11 (1H, br.s), 9.89 (1H, s)
MS(ESI)m/z：529(M+H)+.
[embodiment 82] (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate (isomers B) and (3R*, 4S*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate (isomers B)
Figure G2003801097466D03871
The compound (stereoisomer B) (1.79g) that reference example 140 is obtained is dissolved in tetrahydrofuran (36ml), adds and is stirred at room temperature 20 hours under 10% palladium carbon (0.40g), hydrogen stream.Filter off and lower concentration filtrate is depressurized after catalyst, residue is dissolved in DMF (36ml), add 5- chloro-indole -2- carboxylic acid p-nitrophenyl phenolic esters (2.02g) and stir 16 hours.Be concentrated under reduced pressure reaction solution, adds ethyl acetate and water leaching insoluble matter, is washed with ethyl acetate, obtains rough (3R*, 4S*) -3- amino -4- { [(5- chloro-indole -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate (or (3R*, 4S*) -4- amino -3- { [(5- chloro-indole -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate) (isomers B1) (1.49g).The organic layer of filtrate is washed, anhydrous sodium sulfate drying is used.Decompression boils off solvent, and residue (dichloromethane: methanol=30: 1 → 10: 1) is refined with silica gel column chromatography, obtains (3R*, 4S*) -4- amino -3- { [(5- chloro-indole -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate (or (3R*, 4S*) -3- amino -4- { [(5- chloro-indole -2- bases) carbonyl] amino } Cyclohexylamino t-butyl formate) (isomers B2) (0.37g).
Using method similarly to Example 2, the compound obtained by above-mentioned isomers B1 and reference example 10 prepares one of title compound.
1H-NMR(DMSO-d6)δ：1.25-1.50 (1H, m), 1.37 (9H, s), 1.50-1.65 (1H, m), 1.75-2.20 (4H, m), 2.37 (3H, s), 2.70-3.00 (4H, m), 3.60-3.80 (3H, m), 4.13 (1H, br.s), 4.43 (1H, br.s), 6.92 (1H, d, J=7.1Hz), 7.05 (1H, s), 7.17 (1H, dd, J=8.8, 2.2Hz), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.15 (1H, d, J=7.8Hz), 8.37 (1H, d, J=7.1Hz), 11.78 (1H, s)
MS(FAB)m/z：587(M+H)+.
In addition, another title compound is made by above-mentioned isomers B2 with same method.
1H-NMR(DMSO-d6)δ：1.15-1.30 (1H, m), 1.35 (9H, s), 1.45-1.60 (1H, m), 1.65-1.75 (1H, m), 1.85-1.95 (1H, m), 2.05-2.20 (2H, m), 2.34 (3H, s), 2.65-2.85 (4H, m), 3.55-3.70 (3H, m), 4.05-4.14 (1H, m), 4.40 (1H, br.s), 6.80 (1H, d, J=7.3Hz), 7.15-7.25 (2H, m), 7.43 (1H, d, J=8.8Hz), 7.73 (1H, d, J=2.0Hz), 8.05 (1H, d, J=6.6Hz), 8.51 (1H, d, J=8.8Hz), 11.82 (1H, s)
MS(FAB)m/z：587(M+H)+.
[embodiment 83] N- ((1R*, 2S*) -5- amino -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (or N- ((1R*, 2S*) -4- amino -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide) hydrochloride (stereoisomer B)
The compound (stereoisomer B) (1.11g) synthesized in embodiment 82 by isomers B1 is suspended in dichloromethane (20ml), ethanol solution hydrochloride (20ml) is added and stirs 2 hours at room temperature.Decompression boils off solvent, and residue filters (Sephadex LH-20, methanol) through silica gel and refined, and obtains title compound (1.05g).
1H-NMR(DMSO-d6)δ：1.55-1.65 (1H, m), 1.75-1.90 (2H, m), 1.95-2.20 (2H, m), 2.20-2.40 (1H, m), 2.90 (3H, s), 3.10-3.20 (1H, m), 3.20-3.50 (3H, m), 3.65-3.75 (1H, m), 4.10-4.20 (1H, m), 4.35-4.50 (1H, m), 4.55-4.65 (1H, m), 4.65-4.75 (1H, m), 7.07 (1H, s), 7.17 (1H, dd, J=8.8, 2.0Hz), 7.42 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.05-8.30 (3H, br), 8.40-8.50 (2H, m), 11.70-11.90 (2H, m)
MS(FAB)m/z：487(M+H)+.
[embodiment 84] N- [(1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(methyl sulphonyl) amino] cyclohexyl -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide or N- [(1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- [(methyl sulphonyl) amino] cyclohexyl -5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (stereoisomer B)
The compound (0.20g) for obtaining embodiment 83 is suspended in dichloromethane (7ml), adds triethylamine (0.16ml) and mesyl chloride (28 μ l), stirs 20 hours at room temperature.After reaction solution dchloromethane, washed with sodium hydrate aqueous solution, then use anhydrous sodium sulfate drying.Decompression boils off solvent, and residue (dichloromethane: methanol=30: 1 → 15: 1) is refined with silica gel column chromatography, obtains title compound (67.9mg).
1H-NMR(DMSO-d6)δ：1.40-1.55 (1H, m), 1.65-1.85 (2H, m), 1.90-2.05 (2H, m), 2.15-2.25 (1H, m), 2.41 (3H, s), 2.75-2.95 (4H, m), 2.92 (3H, s), 3.55-3.80 (3H, m), 4.10-4.20 (1H, m), 4.45-4.55 (1H, m), 7.08 (1H, s), 7.15-7.20 (2H, m), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.27 (1H, d, J=7.3Hz), 8.33 (1H, d, J=8.1Hz), 11.77 (1H, s)
MS(FAB)m/z：565(M+H)+.
[embodiment 85] N- ((1R*, 2S*) -5- (acetyl-amino) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide or N- ((1R*, 2S*) -4- (acetyl-amino) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (stereoisomer B)
The compound (stereoisomer B) (0.20g) that embodiment 83 is obtained is suspended in dichloromethane (7ml), adds triethylamine (0.16ml) at room temperature and acetic anhydride (34 μ l) is stirred 20 hours at room temperature.Dichloromethane and sodium hydrate aqueous solution, leaching insoluble matter are added in reaction solution.After the organic layer anhydrous sodium sulfate drying of separating filtrate, decompression boils off solvent, and residue (dichloromethane: methanol=15: 1 → 10: 1) is refined with silica gel column chromatography, obtains title compound (0.12g).
1H-NMR(DMSO-d6)δ：1.35-1.50 (1H, m), 1.55-1.70 (1H, m), 1.80 (3H, s), 1.80-2.05 (3H, m), 2.05-2.20 (1H, m), 2.47 (3H, s), 2.80-3.00 (4H, m), 3.75-4.00 (3H, m), 4.15-4.30 (1H, m), 4.45-4.55 (1H, m), 7.07 (1H, s), 7.17 (1H, dd, J=8.8, 1.0Hz), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, s), 7.89 (1H, d, J=7.3Hz), 8.24 (1H, d, J=8.1Hz), 8.31 (1H, d, J=7.3Hz), 11.77 (1H, s)
MS(FAB)m/z：528(M+H)+.
[embodiment 86] N- ((1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- { [methoxyl group (methyl) amino] carbonyl } cyclohexyl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03901
The compound (250mg) that embodiment 58 is obtained is dissolved in N, dinethylformamide (5ml), add N, O- dimethyl hydroxylamine hydrochlorides (142mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (111mg), the hydrate of I-hydroxybenzotriazole 1 (89mg), N-methylmorpholine (213ml), are stirred 19 hours at room temperature.Saturated sodium bicarbonate aqueous solution is added after reaction solution concentration, is extracted with ethyl acetate.Organic layer saturated common salt water washing, after anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (dichloromethane: methanol=47: 3 → 23: 2) is refined with silica gel column chromatography, obtains colourless non-crystalline solids (179mg).The solid is dissolved in methanol-tetrahydrofuran, 1N ethanol solution hydrochloride (960ml) is added, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.57-1.91 (4H, m), 1.96-2.00 (1H, m), 2.10-2.21 (1H, m), 2.92 (3H, s), 2.93-3.03 (2H, m), 3.08 (3H, s), 3.10-3.28 (2H, m), 4.16-4.19 (1H, m), 4.50-4.52 (1H, m), 4.69 (1H, br.s), 7.06 (1H, s), 7.17 (1H, dd, J=8.8, 1.5Hz), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, s), 8.33 (1H, br.s), 8.41 (1H, d, J=7.8Hz), 11.81 (1H, br.s)
MS(ESI)m/z：559(M+H)+.
[embodiment 87] N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(2,2- dimethyl diazanyl) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03902
Using the method same with embodiment 57, the compound obtained by embodiment 58 and N, N- dimethylhydrazine obtain title compound.
1H-NMR(DMSO-d6)δ：1.49-1.54 (1H, m), 1.76-1.81 (2H, m), 1.89-1.93 (2H, m), 2.07-2.17 (1H, m), 2.33-3.60 (14H, m), 4.15-4.19 (1H, m), 4.40-4.47 (2H, m), 4.70-4.72 (1H, m), 7.04 (1H, s), 7.17 (1H, dd, J=8.5,2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.70 (1H, s), 8.17-8.22 (1H, m), 8.41-8.43 (1H, m), 11.80 (1H, br.s)
MS(ESI)m/z：558(M+H)+.
Chloro- the N- ((1S of [embodiment 88] 6-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -2- quinoline formyl amine hydrochlorates
Figure G2003801097466D03911
Using the method same with embodiment 49, after the compound obtained with ethanol solution hydrochloride to reference example 145 is handled, the compound condensation for making it be obtained with reference example 10 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.75-1.90 (3H, m), 1.90-2.00 (1H, m), 2.00-2.20 (1H, m), 2.80 (3H, s), 2.90 (3H, s), 2.99 (3H, s), 3.10-3.30 (5H, m), 3.56 (1H, br), 4.10-4.20 (1H, m), 4.40-4.70 (2H, m), 7.88 (2H, s), 8.15 (1H, d, J=8.6Hz), 8.22 (1H, s), 8.52 (1H, d, J=8.6Hz), 8.72 (1H, d, J=8.3Hz), 8.89 (1H, d, J=8.3Hz)
MS(FAB)m/z：555(M+H)+.
[embodiment 89] N- { (1R, 2S, 5S) -2- { [(the chloro- 4- fluoro indoles -2- bases of 5-) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with reference example 91, make the compound that reference example 144 is obtained and the compound condensation that reference example 274 is obtained, gained compound is handled with 4N Yan Suan dioxane solutions again, the compound condensation for then making it be obtained with reference example 10 obtains title compound.
1H-NMR(DMSO-d6)δ：1.24-1.98 (6H, m), 2.33-3.33 (6H, m), 2.81 (3H, s), 2.90 (3H, s), 2.99 (3H, s), 4.12 (1H, br.s), 4.30-4.70 (1H, m), 4.60 (1H, br.s), 7.21 (1H, s), 7.27 (2H, br.s), 8.37 (1H, d, J=8.1Hz), 8.43 (1H, d, J=7.6Hz) .12.11 (1H, s)
MS(FAB)m/z：561(M+H)+.
Chloro- the N- ((1S of [embodiment 90] 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) isoquinolin -3- carboxamide hydrochlorides
Figure G2003801097466D03921
Using the method same with embodiment 49, after the compound obtained with ethanol solution hydrochloride to reference example 146 is handled, title compound is made in the compound condensation for making it be obtained with reference example 10.
1H-NMR(DMSO-d6)δ：1.45-1.65 (1H, m), 1.70-1.85 (3H, m), 1.95-2.10 (1H, m), 2.10-2.20 (1H, m), 2.80 (3H, s), 2.92 (3H, s), 2.96 (3H, s), 2.95-3.10 (1H, m), 3.10-3.40 (3H, m), 3.70-3.80 (1H, m), 4.20-4.30 (1H, m), 4.40-4.60 (2H, m), 4.65-4.80 (1H, m), 7.83-7.93 (1H, m), 8.26 (1H, d, J=8.8Hz), 8.38 (1H, s), 8.60 (1H, s), 8.85-9.00 (2H, m), 9.30-9.40 (1H, m)
MS(FAB)m/z：555(M+H)+.
[embodiment 91] N- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } tetrahydrofuran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03922
The N of the compound (0.12g) obtained in reference example 172, compound (0.1g), the hydrate of I-hydroxybenzotriazole 1 (78mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (0.2g) of the acquisition of reference example 10 are sequentially added in dinethylformamide (20ml) solution, is stirred 1 day at room temperature.Concentration of reaction solution, residue obtained use chloroform: methanol (9: 1) dilution, after saturated sodium bicarbonate aqueous solution and saturated common salt water washing, organic layer anhydrous sodium sulfate drying boils off solvent under decompression.Residue obtained use silica gel column chromatography (chloroform: methanol=95: 5) refines, obtains the free alkali of title compound, handled with ethanol solution hydrochloride, obtain title compound (0.1g).
1H-NMR(CDCl3)δ：2.50 (3H, s), 2.70-2.90 (4H, m), 3.67 (1H, s), 3.70 (1H, s), 3.86 (1H, dd, J=9.2, 6.3Hz), 3.97 (1H, dd, J=9.7, 4.1Hz), 4.15 (1H, dd, J=9.7, 5.8Hz), 4.24 (1H, dd, J=9.2, 7.0Hz), 4.75-4.89 (1H, m), 4.92-5.03 (1H, m), 6.88 (1H, s), 7.20 (1H, dd, J=8.8, 2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.35-7.43 (1H, m), 7.58 (1H, d, J=2.0Hz), 7.64 (1H, d, J=7.1Hz), 9.38 (1H, s)
MS(FAB)m/z：460(M+H+).
[embodiment 92] N- ((3S, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } tetrahydrofuran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The compound obtained by reference example 183, title compound is obtained according to the method for reference example 172 and embodiment 91.
1H-NMR(CDCl3)δ：2.51 (3H, s), 2.83 (2H, t, J=5.3Hz), 2.93 (2H, t, J=5.3Hz), 3.72 (2H, s), 3.78-3.89 (2H, m), 4.31 (1H, dd, J=9.2, 7.3Hz), 4.41-4.56 (2H, m), 4.63-4.75 (1H, m), 6.88 (1H, s), 7.22 (1H, dd, J=8.8, 2.0Hz), 7.32 (1H, d, J=8.8Hz), 7.35-7.46 (1H, m), 7.55 (1H, d, J=7.1Hz), 7.60 (1H, d, J=2.0Hz), 9.38 (1H, s)
MS(FAB)m/z：460(M+H+).
[embodiment 93] N- ((3R, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } tetrahydrofuran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound obtained by reference example 187, title compound is prepared according to the method for reference example 172 and embodiment 91.
1H-NMR and MS (FAB)：It is consistent with as the embodiment 92 of enantiomer.
[embodiment 94] (3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidines -1- carboxylic acid tert-butyl esters
The compound that the compound obtained by reference example 193 is obtained with reference example 10, title compound is prepared according to the method for embodiment 91.
Fusing point：190~192 DEG C
1H-NMR(CDCl3)δ：1.45 (9H, s), 2.46 (3H, s), 2.74-2.81 (4H, m), 3.24-3.37 (2H, m), 3.54-3.70 (2H, m), 3.96-4.00 (1H, m), 4.15-4.23 (1H, m), 4.50-4.65 (1H, m), 4.77-4.82 (1H, m), 6.79,6.87 (whole 1H, it is each s), 7.12-7.95 (5H, m), 9.91,9.97 (whole 1H, each s)
MS(FAB)m/z：559(M+H+).
[embodiment 95] N- ((3R, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } pyrrolidin-3-yl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (170mg) that embodiment 94 is obtained is dissolved in dichloromethane (3ml), and trifluoroacetic acid (2ml) is added at room temperature and is stirred 1 hour.Chloroform and saturated sodium bicarbonate aqueous solution, organic layer anhydrous sodium sulfate drying are added after concentration, solvent is boiled off under decompression.Residue obtained use prepares silica gel thin-layer chromatography (chloroform: methanol: water=7: 3: 1, lower floor) it is refined, hydrochloric acid methanol is added in purpose thing and forms it into hydrochloride, title compound (90mg) (NMR is determined with free alkali) is obtained.
Fusing point：248~250 DEG C (decomposition)
1H-NMR(CDCl3)δ：2.44 (3H, s), 2.70-2.80 (4H, m), 2.97-3.05 (2H, m), 3.46-3.68 (4H, m), 4.49-4.52 (1H, m), 4.60-4.65 (1H, m), 6.86 (1H, s), 7.05-7.08 (1H, m), 7.20 (1H, d, J=8.5Hz), 7.44 (1H, s), 7.89 (2H, br), 10.51 (1H, br)
MS(FAB)m/z：459(M+H+).
[embodiment 96] N- ((3S, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- oxo-tetrahydrofuran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D03951
It is same with reference example 69, it is same with embodiment 91 after the tert-butoxycarbonyl for removing the compound that reference example 196 is obtained, it is reacted with the compound that reference example 10 is obtained, obtain title compound.
1H-NMR(DMSO-d6)δ：2.90 (3H, s), 3.02-3.17 (2H, m), 3.23-3.34 (4H, m), 4.20 (1H, t, J=8.6Hz), 4.61 (1H, t, J=8.6Hz), 4.92-5.01 (1H, m), 5.14-5.26 (1H, m), 7.09 (1H, s), 7.19 (1H, dd, J=8.8, 2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.73 (1H, d, J=2.0Hz), 9.27 (1H, d, J=6.8Hz), 9.35 (1H, d, J=6.8Hz), 11.22-11.33 (1H, m), 11.89 (1H, s)
MS(FAB)m/z：474(M+H+).
[embodiment 97] N- ((3S, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -2- oxo-tetrahydrofuran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
It is same with reference example 69, it is same with embodiment 91 after the tert-butoxycarbonyl for removing the compound that reference example 197 is obtained, make itself and 5- chloro-indole -2- carboxylic acid reactions, obtain title compound.
1H-NMR(DMSO-d6)δ：2.52 (3H, s), 2.83 (2H, t, J=5.9Hz), 2.91-3.00 (2H, m), 3.73 (2H, s), 4.23 (1H, t, J=8.6Hz), 4.40-4.53 (1H, m), 4.96 (1H, dd, J=10.8, 5.2Hz), 5.16 (1H, dd, J=9.2, 7.3Hz), 7.01 (1H, s), 7.25 (1H, dd, J=8.8, 2.0Hz), 7.34 (1H, d, J=8.8Hz), 7.52 (1H, d, J=2.0Hz), 8.01 (1H, d, J=5.4Hz), 8.51-8.63 (1H, m), 9.22 (1H, s)
MS(FAB)m/z：474(M+H+).
[embodiment 98] (3S, 4R) -2- (3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -2- oxo-pyrrolidine -1- bases) ethyl acetate hydrochloride
Figure G2003801097466D03961
The compound that the compound and reference example 10 obtained by reference example 199 is obtained, it is same with embodiment 91, obtain title compound (NMR is determined with free alkali).
1H-NMR(DMSO-d6)δ：1.19 (3H, t, J=7.1Hz), 2.35 (3H, s), 2.71-2.84 (2H, m), 2.80-2.90 (2H, m), 3.40 (1H, d, J=10.3Hz), 3.61 (2H, d, J=10.8Hz), 3.84 (1H, dd, J=10.3, 5.6Hz), 4.01-4.23 (4H, m), 4.80-4.94 (1H, m), 5.04 (1H, t, J=8.6Hz), 7.01 (1H, s), 7.16 (1H, dd, J=8.8, 2.0Hz), 7.40 (1H, d, J=8.8Hz), 7.69 (1H, d, J=2.0Hz), 8.73 (1H, d, J=8.6Hz), 8.90 (1H, d, J=8.8Hz), 11.86 (1H, s)
MS(FAB)m/z：559(M+H+).
[embodiment 99] N- ((3R, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- methyl -5- oxo-pyrrolidine -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D03962
The compound that the compound and reference example 10 obtained by reference example 201 is obtained, title compound is equally obtained with embodiment 91.
1H-NMR(CDCl3)δ：2.49 (3H, s), 2.77-2.82 (2H, m), 2.86-2.91 (5H, m), 3.69 (2H, d, J=1.2Hz), 4.39-4.54 (3H, m), 4.93-4.98 (1H, m), 6.98 (1H, d, J=1.2Hz), and 7.05-7.34 (3H, m), 7.63 (1H, d, J=2.0Hz), 8.11 (1H, d, J=7.8Hz), 9.00 (1H, s)
MS(FAB)m/z：487(M+H+).
[embodiment 100] 2- [((3R; 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) sulfonyl] methyl acetate
The compound (230mg) and triethylamine (0.10ml) that embodiment 95 is obtained are dissolved in dichloromethane (6.9ml), are cooled with ice.Then, methoxycarbonyl mesyl chloride (Synthesis, page 321,1975) (105mg) is added, temperature is returned to room temperature, the evening of stirring one.Water and saturated common salt water washing are used after being diluted with chloroform, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.It is residue obtained (chloroform: methanol=20: after 1) refining, to be used methanol-water powdered with preparation silica gel thin-layer chromatography, obtain title compound (150mg).
1H-NMR(CDCl3)δ：2.48 (3H, s), 2.76-2.86 (4H, m), 3.49-3.73 (4H, m), 3.87 (3H, s), 3.94-3.98 (1H, m), 4.08-4.11 (1H, m), 4.13 (2H, s), 4.69-4.72 (1H, m), 4.88-4.91 (1H, m), 6.89 (1H, s), 7.12-7.15 (1H, m), 7.27-7.28 (1H, m), 7.50 (1H, s), 7.81-7.86 (2H, m), 9.92 (1H, s)
MS(FAB)m/z：595(M+H+).
[embodiment 101] 2- [((3R; 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) sulfonyl] acetic acid
The compound (100mg) that embodiment 100 is obtained is dissolved in tetrahydrofuran (4ml)-water (1ml), is cooled with ice.Then, the hydrate of lithium hydroxide 1 (7.8ml) is added, temperature is returned to after room temperature and stirred 4 hours.Concentrated after being neutralized with 1N aqueous hydrochloric acid solution, leaching precipitate is washed with water and 50% ethanol, an evening is dried under reduced pressure in 50 DEG C, title compound (87mg) is obtained.
1H-NMR(DMSO-d6)δ：2.50 (3H, s), 2.92 (4H, s), 3.34-3.43 (4H, m), 3.76-3.85 (2H, m), 4.27 (each 1H, AB type d, J=14.5Hz), 4.65-4.71 (1H, m), 4.78-4.84 (1H, m), 7.14 (1H, s), 7.18 (1H, d, J=8.8Hz), 7.40 (1H, d, J=8.8Hz), 7.72 (1H, s), 8.87 (1H, d, J=7.8Hz), 9.12 (1H, d, J=8.2Hz), 11.83 (1H, s)
[embodiment 102] 2- ((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) methyl acetate
The compound (230mg) and potassium carbonate (90mg) that embodiment 95 is obtained are dissolved in DMF (4.6ml), are cooled with ice.Then, methyl bromoacetate (0.062ml) is added to stir 45 minutes.After reaction solution ethyl acetate dilutes, with water and saturated common salt water washing, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.It is residue obtained (chloroform: methanol=10: after 1) refining, to be used methanol-water powdered with preparation silica gel thin-layer chromatography, obtain title compound (190mg).
1H-NMR(CDCl3)δ：2.35 (2H, s), 2.48 (3H, s), 2.73-2.95 (4H, m), 3.34-3.42 (2H, m), 3.46 (2H, q, J=6.5Hz), 3.67 (2H, q, J=6.5Hz), 3.75 (3H, s), 4.57-4.71 (2H, m), 6.91 (1H, s), 7.10-7.13 (1H, m), 7-31 (1H, d, J=9.0Hz), 7.53 (1H, s), 7.77 (1H, d, J=8.0Hz), 7.87 (1H, d, J=6.8Hz), 10.22 (1H, s) .MS (FAB) m/z：531(M+H+).
[embodiment 103] 2- ((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) acetic acid
Figure G2003801097466D03991
The compound obtained by embodiment 102, title compound is equally prepared with embodiment 101.
1H-NMR(DMSO-d6)δ：2.42 (3H, s), 2.69-2.87 (6H, m), 3.13 (1H, t, J=9.0Hz), 3.22 (1H, t, J=9.0Hz), 3.33 (each 1H, AB type d, J=6.8Hz), 3.72 (2H, s), 4.53-4.60 (1H, m), 4.65-4.72 (1H, m), 7.16-7.20 (2H, m), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, s), 8.85 (1H, d, J=7.5Hz), 9.00 (1H, d, J=8.3Hz), 11.79 (1H, s)
[embodiment 104] 3- ((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) methyl propionate
Figure G2003801097466D03992
The compound and 3- methyl bromide cs obtained by embodiment 95, it is same with embodiment 102, obtain title compound.
1H-NMR(CDCl3)δ：1.96-2.20 (2H, m), 2.49 (3H, s), 2.61-2.96 (8H, m), 3.17-3.21 (2H, m), 3.62-3.72 (2H, m), 3.69 (3H, s), 4.46-4.49 (1H, m), 4.56-4.61 (1H, m), 6.87 (1H, s), 7.05-7.14 (1H, m), 7.32 (1H, d, J=9.2Hz), 7.53 (1H, s), 7.65-7.71 (2H, m), 10.02 (1H, s)
MS(FAB)m/z：545(M+H+).
[embodiment 105] 3- ((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) propionic acid
The compound obtained by embodiment 104, title compound is equally obtained with embodiment 101.
1H-NMR(DMSO-d6)δ：2.38 (3H, s), 2.39-2.84 (10H, m), 2.93 (1H, t, J=8.8Hz), 3.05 (1H, t, J=8.8Hz), 3.65 (2H, s), 4.51-4.56 (1H, m), 4.63-4.68 (1H, m), 7.16-7.19 (2H, m), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.81 (1H, d, J=7.8Hz), 8.97 (1H, d, J=8.3Hz), 11.75 (1H, s)
[embodiment 106] 3- ((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) -3- oxopropanoates
The compound and ethyl maloyl chloride obtained by embodiment 95, with the same operation preparation title compound of embodiment 100.
1H-NMR(DMSO-d6)δ：1.20 (3H, t, J=7.0Hz), 2.37 (3H, s), 2.73-2.75 (2H, m), 2.82-2.84 (2H, m), 3.35-3.38 (2H, m), 3.64 (2H, s), 3.68-3.83 (2H, m), 3.91-4.00 (2H, m), 4.10 (2H, q, J=7.0Hz), 4.61-4.84 (2H, m), 7.13 (1H, s), 7.18 (1H, dd, J=8.5, 2.0Hz), 7.41 (1H, d, J=8.5Hz), 7.72 (1H, s), 8.73 (1H, t, J=9.0Hz), 9.10 (1H, d, J=9.0Hz), 11.79 (1H, s)
[embodiment 107] 3- ((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) -3- oxopropanoic acids
The compound obtained by embodiment 106, with the same operation preparation title compound of embodiment 101.
1H-NMR(DMSO-d6)δ：2.39 (3H, s), 2.77 (2H, s), 2.85 (2H, s), 3.29-3.55 (4H, m), 3.68 (2H, s), 3.82-4.01 (2H, m), 4.62-4.68 (1H, m), 4.77-4.86 (1H, m), 7.14 (1H, s), 7.18 (1H, d, J=8.8Hz), 7.41 (1H, d, J=8.8Hz), 7.72 (1H, s), 8.75 (1H, t, J=8.8Hz), 9.12 (1H, d, J=7.8Hz), 11.81 (1H, s)
[embodiment 108] 1- [((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) methyl] methyl cyclopropanecarboxylate
The compound obtained by embodiment 95 and 1- (bromomethyl) methyl cyclopropanecarboxylate, title compound is obtained with the equally operation of embodiment 102.
1H-NMR(CDCl3)δ：0.78-0.79 (2H, m), 1.24-1.26 (2H, m), 2.49 (3H, s), 2.62-2.88 (6H, m), 3.20-3.28 (2H, m), 3.66 (3H, s), 3.61-3.75 (4H, m), 4.45-4.62 (2H, m), 6.86 (1H, s), 7.12-7.15 (1H, m), 7.24-7.28 (1H, m), 7.52 (1H, d, J=8.5Hz), 7.54 (1H, s), 7.69 (1H, d, J=8.0Hz), 10.00 (1H, s)
MS(ESI)m/z：571(M+H+).
[embodiment 109] 1- [((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) methyl] cyclopropane-carboxylic acid
Figure G2003801097466D04021
The compound obtained by embodiment 108, embodiment 101 is equally operated, and obtains title compound.
1H-NMR(DMSO-d6)δ：0.73-0.78 (2H, m), 1.04-1.07 (2H, m), 2.37 (3H, s), 2.65-2.84 (6H, m), 3.11-3.20 (4H, m), 3.64 (2H, s), 4.59-4.74 (2H, m), 7.16 (1H, s), 7.17 (1H, d, J=8.5Hz), 7.40 (1H, d, J=8.5Hz), 7.70 (1H, s), 8.84 (1H, d, J=7.5Hz), 9.12 (1H, d, J=7.5Hz), 11.77 (1H, s)
[embodiment 110] (3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidines -1- carboxylic acid tert-butyl esters
The compound that the compound and reference example 148 obtained by reference example 193 is obtained, title compound is obtained with the equally operation of embodiment 91.
1H-NMR(CDCl3)δ：1.12 (6H, d, J=6.6Hz), 1.47 (9H, s), 2.83-2.88 (4H, m), 2.94-2.99 (1H, m), 3.20-3.29 (1H, m), 3.31-3.42 (1H, m), 3.75-3.81 (2H, m), (3.98 1H, t, J=8.5Hz), 4.15-4.35 (2H, m), 4.50-4.65 (1H, m), 6.85,6.91 (whole 1H, each s), 7.15-7.90 (5H, m), 9.41,9.50 (whole 1H, each s)
[embodiment 111] N- ((3R, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } pyrrolidin-3-yl) -5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The compound obtained by embodiment 110, equally operates with embodiment 95, obtains title compound.
1H-NMR(CDCl3)δ：1.13 (6H, d, J=6.3Hz), 2.85 (4H, br.s), 2.96-3.05 (3H, m), 4.51-4.52 (1H, m), 4.76-4.80 (2H, m), 5.36-5.39 (2H, m), 5.53-5.58 (1H, m), 7.17-7.19 (1H, m), 7.27-7.31 (2H, m), 7.57 (1H, s), 7.64 (2H, br), 9.82 (1H, br)
[embodiment 112] 3- ((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) ethyl propionate
The compound and 3- ethyl bromides obtained by embodiment 111, equally operates with embodiment 102, obtains title compound.
1H-NMR(CDCl3)δ：1.14 (6H, d, J=6.5Hz), 1.26 (3H, t, J=7.0Hz), 2.51 (3H, t, J=7.0Hz), 2.63 (1H, dd, J=9.5, 6.5Hz), 2.73-2.91 (6H, m), 2.95-3.02 (1H, m), 3.22 (2H, q, J=7.0Hz), 3.81 (each 1H, AB types d, J=14.5Hz), 4.16 (2H, q, J=7.0Hz), 4.40-4.45 (1H, m), 4.52-4.59 (1H, m), 6.88 (1H, d, J=2.0Hz), 7.17-7.19 (1H, m), 7.30-7.32 (2H, m), 7.59 (1H, s), 7.62 (1H, s), 9.56 (1H, s)
MS(FAB)m/z：587(M+H+).
[embodiment 113] 3- ((3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidin-1-yl) propionic acid
Figure G2003801097466D04041
The compound obtained by embodiment 112, equally operates with embodiment 101, obtains title compound.
1H-NMR(DMSO-d6)δ：1.04 (6H, d, J=6.6Hz), 2.40 (2H, q, J=7.0Hz), 2.50 (4H, s), 2.60-2.74 (4H, m), 2.90-2.94 (2H, m), 3.02-3.06 (1H, m), 3.20-3.35 (2H, m), 4.50-4.53 (1H, m), 4.61-4.65 (1H, m), 7.15-7.18 (2H, m), 7.41 (1H, d, J=8.8Hz), 7.68 (1H, s), 8.78 (1H, d, J=7.5Hz), 8.90 (1H, d, J=8.0Hz), 11.73 (1H, s)
[embodiment 114] N- ((3R; 4R) -1- acetyl group -4- { [(5- chloro-indole -2- bases) carbonyl] amino } pyrrolidin-3-yl) -5- isopropyls -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04042
The compound and acetic anhydride obtained by embodiment 111, equally operates with embodiment 100, obtains title compound.
Fusing point：254~258 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.34-1.37 (6H, m), 1.96 (3H, s), 3.30-3.55 (5H, m), 3.66-3.82 (3H, m), 3.95 (1H, q, J=8.3Hz), 4.45-4.82 (4H, m), 7.15 (1H, s), (7.18 1H, d, J=9.0Hz), (7.41 1H, d, J=9.0Hz), 7.71 (1H, s), 8.75-8.81 (1H, m), 9.21 (1H, d, J=8.0Hz), 11.32 (1H, br), 11.83 (1H, d, J=7.3Hz)
MS(FAB)m/z：529(M+H+).
[embodiment 115] N- [(3R; 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (methyl sulphonyl) pyrrolidin-3-yl] -5- isopropyls -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and mesyl chloride obtained by embodiment 111, equally operates with embodiment 100, obtains title compound.
Fusing point：230~235 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.32-1.36 (6H, m), 3.32 (3H, s), 3.43-3.46 (5H, m), 3.68-3.75 (4H, m), 4.48 (1H, m), 4.62-4.72 (2H, m), 4.83 (1H, t, J=5.5Hz), 7.14 (1H, s), 7.18 (1H, d, J=8.6Hz), (7.40 1H, d, J=8.6Hz), 7.72 (1H, s), 8.82 (1H, br), 9.20 (1H, d, J=8.3Hz), 11.30 (1H, br), 11.86 (1H, d, J=7.5Hz)
MS(FAB)m/z：565(M+H+).
[embodiment 116] (3R, 4R) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } pyrrolidines -1- carboxylate hydrochlorides
Figure G2003801097466D04052
The compound and ethyl chloroformate obtained by embodiment 111, equally operates with embodiment 100, obtains title compound.
Fusing point：225~228 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.20 (3H, t, J=7.0Hz), 1.31-1.37 (6H, m), 3.33-3.45 (5H, m), 3.66-3.75 (4H, m), 4.05 (2H, q, J=7.0Hz), 4.45-4.77 (4H, m), 7.15 (1H, s), 7.17 (1H, dd, J=8.8,2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.71 (1H, d, J=2.0Hz), 8.77 (1H, d, J=7.0Hz), 9.20 (1H, d, J=8.0Hz), 11.30 (1H, br), 11.83 (1H, d, J=7.5Hz)
MS(FAB)m/z：559(M+H+).
[embodiment 117] (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -1- carboxylic acid tert-butyl esters
Figure G2003801097466D04061
The compound that the compound and reference example 10 obtained by reference example 207 is obtained, equally operates with embodiment 91, obtains title compound.
Fusing point：152~154 DEG C (decomposition)
1H-NMR(CDCl3)δ：1.53 (9H, s), 1.62-1.80 (1H, m), 2.23-2.30 (1H, m), 2.52 (3H, s), 2.75-3.05 (5H, m), 3.10-3.25 (1H, m), 3.68-3.82 (2H, m), 4.15-4.45 (4H, m), 6.89 (1H, s), 7.19 (1H, dd, J=8.8,1.8Hz), (7.32 1H, d, J=8.8Hz), (7.92 1H, d, J=1.8Hz), 7.75 (1H, br.s), 8.21 (1H, br.s), 9.39 (1H, s)
MS(ESI)m/z：573(M+H)+.
[embodiment 118] N- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4,5,6, the 7- tetrahydro-thiazoles simultaneously hydrochloride of [5,4-c] pyridine-2-carboxamide 2
The compound obtained by embodiment 117, it is same with embodiment 95, prepare title compound.
Fusing point：240~258 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.85-2.00 (1H, m), 2.05-2.20 (2H, m), 2.93 (3H, s), 3.05-3.60 (7H, m), 3.65-3.75 (1H, m), 4.10-4.52 (2H, m), 4.60-4.75 (2H, m), 7.10-7.21 (2H, m), (7.43 1H, d, J=8.6Hz), 7.70 (1H, s), 8.50 (1H, br.d, J=7.8Hz), 8.90-9.05 (2H, m), 9.27 (1H, br.s), 11.9 (1H, br.d, J=13.4Hz)
MS(ESI)m/z：473(M+H)+.
[embodiment 119] ((3R*, 4S*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -1- carboxylic acid tert-butyl esters
The compound and 5- chloro-indole -2- carboxylic acids obtained by reference example 208, equally operates with embodiment 91, obtains title compound.
Fusing point：187~189 DEG C (decomposition)
1H-NMR(CDCl3)δ：1.48 (9H, s), 1.72-1.90 (1H, m), 2.00 (1H, br.s), 2.00-2.10 (1H, m), 2.45 (3H, s), 2.60-2.70 (2H, m), 2.70-2.80 (2H, m), 3.23 (1H, t, J=10.8Hz), 3.35-3.50 (1H, m), 3.50-3.72 (2H, m), 3.90-4.20 (2H, m), 4.30-4.40 (1H, m), 4.45-4.55 (1H, m), 6.85 (1H, d, J=1.5Hz), 7.17 (1H, dd, J=8.8, 1.9Hz), 7.20-7.30 (1H, m), 7.33 (1H, d, J=8.8Hz), 7.58 (1H, d, J=1.9Hz), 10.17 (1H, s)
MS(ESI)m/z：573(M+H+).
[embodiment 120] N- ((3R*, 4S*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidin-4-yl) -5- methyl -4,5,6, the 7- tetrahydro-thiazoles simultaneously hydrochloride of [5,4-c] pyridine-2-carboxamide 2
Figure G2003801097466D04072
The compound obtained by embodiment 119, equally operates with embodiment 95, obtains title compound.
Fusing point：276~278 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.77-1.88 (1H, m), 2.40-2.50 (2H, m), 2.89 (3H, s), 2.90-3.20 (4H, m), 3.30-3.50 (2H, m), 3.63 (1H, br.s), 4.33-4.47 (2H, m), 4.62-4.75 (2H, m), 7.18 (1H, dd, J=8.8, 1.9Hz), 7.42 (1H, d, J=8.8Hz), 7.48 (1H, br.s), 7.71 (1H, d, J=1.9Hz), 8.66 (1H, br.s), 8.95 (1H, d, J=8.1Hz), 9.20-9.30 (1H, m), 9.45-9.70 (1H, m), 11.61 (1H, s), 11.90 (1H, s)
MS(ESI)m/z：473(M+H)+.
[embodiment 121] (3R*, 4S*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -1- carboxylic acid tert-butyl esters
Figure G2003801097466D04081
The compound that the compound and reference example 10 obtained by reference example 209 is obtained, equally operates with embodiment 91, obtains title compound.
1H-NMR(CDCl3)δ：1.53 (9H, s), 1.65-1.78 (1H, m), 2.23-2.32 (1H, br), 2.52 (3H, s), 2.78-3.03 (5H, m), 3.15-3.24 (1H, br), 3.68-3.82 (2H, br), 4.16-4.45 (4H, br), 6.91 (1H, s), 7.02 (1H, td, J=9.0, 2.7Hz), 7.30 (1H, dd, J=9.0, 2.7Hz), 7.34 (1H, dd, J=9.0, 4.4Hz), 7.65-7.90 (1H, br), 8.10-8.40 (1H, br), 9.31-9.41 (1H, br)
MS(ESI)m/z：557(M+H+).
[embodiment 122] N- ((3R*, 4S*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4,5,6, the 7- tetrahydro-thiazoles simultaneously hydrochloride of [5,4-c] pyridine-2-carboxamide 2
The compound obtained by embodiment 121, equally operates with embodiment 95, obtains title compound.
Fusing point：236~245 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.85-1.98 (1H, br), 2.06-2.18 (1H, br), 2.89 (3H, s), 3.05-3.75 (8H, s), 4.34-4.54 (2H, br), 4.60-4.75 (2H, br), 7.04 (1H, td, J=9.3,2.4Hz), 7.15 (1H, br.s), 7.37-7.44 (2H, m), 8.46 (1H, d, J=7.8Hz), 8.88-9.00 (1H, br), 9.09-9.27 (2H, br), 11.55-11.75 (1H, br), 11.76-11.84 (1H, br)
MS(FAB)m/z：457(M+H+).
[embodiment 123] N- ((3R*, 4S*) -1- acetyl group -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04091
The compound and acetic anhydride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：215~225 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.65-1.85 (1H, m), 1.88, 2.06 (whole 3H, each s), 1.90-2.10 (1H, m), 2.91 (3H, s), 3.00-3.30 (2H, m), 3.30-3.55 (2H, m), 3.60-3.90 (3H, m), 3.98-4.50 (4H, m), 4.65-4.75 (1H, m), 7.09 (1H, d, J=15.6Hz), 7.17 (1H, d, J=8.8Hz), 7.41 (1H, d, J=8.8Hz), 7.71 (1H, s), 8.23-8.53 (2H, m), 11.20-11.55 (1H, m), 11.85 (1H, br.d, J=5.4Hz)
MS(ESI)m/z：515(M+H+).
[embodiment 124] N- ((3R*, 4S*) -1- acetyl group -3- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidin-4-yl) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and acetic anhydride obtained by embodiment 120, equally operates with embodiment 100, obtains title compound.
Fusing point：225~250 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.65-1.80 (1H, m), 1.81, 2.05 (whole 3H, each s), 2.00-2.20 (1H, m), 2.70-2.85 (1H, m), 2.89 (3H, s), 3.00-3.20 (2H, m), 3.20-3.50 (2H, m), 3.64 (1H, br.s), 3.78-4.30 (2H, m), 4.30-4.50 (3H, m), 4.55-4.75 (1H, m), 7.05-7.23 (2H, m), 7.38-7.48 (1H, m), 7.70-7.80 (1H, m), 7.79, 8.12 (whole 1H, each d, J=6.8Hz), 8.73, 8.83 (whole 1H, each d, J=8.3Hz), 11.20-11.50 (1H, m), 11.89, 11.92 (whole 1H, each s)
MS(FAB)m/z：515(M+H+).
[embodiment 125] N- ((3R*, 4S*) -1- acetyl group -4- { [(5- fluoro indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04101
The compound and acetic anhydride obtained by embodiment 122, equally operates with embodiment 100, obtains title compound.
Fusing point：202 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.67-1.85 (1H, m), 1.87 (1.5H, s), 1.87-2.10 (1H, m), 2.06 (1.5H, s), 2.88-2.96 (3H, br.s), 3.05-3.30 (2H, m), 3.32-3.83 (5H, br), 3.97-4.33 (2H, m), 4.35-4.50 (2H, br), 4.67-4.78 (1H, br), 7.01-7.14 (2H, m), 7.38-7.44 (2H, m), 8.25-8.50 (2H, m), 10.85-11.15 (1H, br), 11.72-11.80 (1H, br)
MS(FAB)m/z：499(M+H+).
[embodiment 126] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (methyl sulphonyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and mesyl chloride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：225~23 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.80-1.90 (1H, m), 2.05-2.15 (1H, m), 2.30-2.80 (5H, m), 2.85-3.80 (9H, m), 4.20-4.90 (4H, m), 7.08 (1H, d, J=1.7Hz), 7.18 (1H, dd, J=8.7,1.7Hz), 7.42 (1H, d, J=8.7Hz), 7.77 (1H, s), 8.02-8.20 (1H, m), 8.40-8.50 (1H, m), 11.00-11.60 (1H, m), 11.87 (1H, s)
MS(ESI)m/z：551(M+H+).
[embodiment 127] N- [(3R*, 4S*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (methyl sulphonyl) piperidin-4-yl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and mesyl chloride obtained by embodiment 120, equally operates with embodiment 100, obtains title compound.
Fusing point：228~245 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.75-1.85 (1H, m), 2.25-2.40 (1H, m), 2.40-2.60 (2H, m), 2.76 (3H, br.s), 2.90 (3H, s), 2.93-3.05 (3H, m), 3.12 (1H, d, J=10.6Hz), 3.55-3.80 (2H, m), 4.25-4.40 (4H, m), 7.17 (1H, d, J=1.7Hz), 7.19 (1H, dd, J=8.7, 2.0Hz), 7.43 (1H, d, J=8.7Hz), 7.74 (1H, d, J=2.0Hz), 8.03 (1H, d, J=6.6Hz), 8.78 (1H, d, J=7.4Hz), 10.90-11.20 (1H, br.s), 11.89 (1H, s)
MS(ESI)m/z：551(M+H+).
[embodiment 128] N- [(3R*, 4S*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } -1- (methyl sulphonyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04121
The compound and mesyl chloride obtained by embodiment 122, equally operates with embodiment 100, prepares title compound.
Fusing point：216~250 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.80-1.90 (1H, m), 2.01-2.12 (1H, m), 2.92 (3H, s), 2.94 (3H, s), 3.00-3.80 (8H, m), 4.28-4.53 (3H, m), 4.60-4.80 (1H, br), 7.01-7.12 (2H, m), 7.37-7.44 (2H, m), 8.00-8.18 (1H, br), 8.39-8.50 (1H, br), 11.00-11.60 (1H, br), 11.72-11.80 (1H, br)
MS(FAB)m/z：535(M+H+).
[embodiment 129] (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -1- carboxylate methyl ester hydrochlorides
The compound and methylchloroformate obtained by embodiment 118, equally operates with embodiment 100, prepares title compound.
Fusing point：248~253 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.65-1.78 (1H, m), 1.88-2.03 (1H, m), 2.90 (3H, s), 3.00-3.80 (9H, m), 3.80-3.90 (1H, m), 3.95-4.08 (1H, m), 4.20-4.70 (4H, m), 7.10 (1H, s), 7.17 (1H, dd, J=8.8,1.8Hz), (7.42 1H, d, J=8.8Hz), (7.71 1H, d, J=1.8Hz), 8.29 (1H, br.s), 8.41 (1H, d, J=8.1Hz), 11.29 (1H, br.s), 11.85 (1H, s)
MS(ESI)m/z：531(M+H+).
[embodiment 130] (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -1- carboxylate hydrochlorides
Figure G2003801097466D04131
The compound and ethyl chloroformate obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：215~225 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：0.85-1.30 (3H, m), 1.65-1.78 (1H, m), 1.90-2.03 (1H, m), 2.90 (3H, s), 3.10-3.40 (4H, m), 3.48 (1H, br.s), 3.65 (1H, br.s), 3.75-4.15 (4H, m), 4.25 (1H, br.s), 4.32-4.50 (2H, m), 4.66 (1H, br.s), 7.09 (1H, s), 7.18 (1H, dd, J=8.8, 2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.71 (1H, d, J=2.0Hz), 8.23 (1H, br.s), 8.45 (1H, br.d, J=8.1Hz), 11.50 (1H, br.s), 11.86 (1H, s)
MS(ESI)m/z：545(M+H+).
[embodiment 131] (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -1- carboxylic acid 2- methoxy acrylate hydrochlorides
The compound and chloro-carbonic acid 2- methoxy acrylates obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：224~226 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.68-1.78 (1H, m), 1.90-2.03 (1H, m), 2.89 (3H, s), 3.00-3.75 (11H, m), 3.80-3.90 (1H, m), 3.95-4.18 (3H, m), 4.20-4.70 (4H, m), 7.10 (1H, s), 7.17 (1H, dd, J=8.8,2.0Hz), (7.41 1H, d, J=8.8Hz), (7.71 1H, d, J=2.0Hz), 8.26 (1H, br.s), 8.42 (1H, d, J=7.8Hz), 11.30 (1H, br.s), 11.86 (1H, s)
MS(ESI)m/z：575(M+H+).
[embodiment 132] (3R*, 4S*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-e] pyridine -2- bases) carbonyl] amino } piperidines -1- carbonyl acid ethyl ester hydrochloride salt
The compound and ethyl chloroformate obtained by embodiment 120, equally operates with embodiment 100, obtains title compound.
Fusing point：213~225 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：0.75-1.30 (3H, m), 1.60-1.72 (1H, m), 2.12-2.25 (1H, m), 2.89 (3H, s), 2.95-3.20 (4H, m), 3.40-3.88 (4H, m), 3.90-4.10 (2H, m), 4.10-4.30 (2H, m), 4.30-4.40 (1H, m), 4.40-4.80 (1H, m), 7.10 (1H, s), 7.18 (1H, dd, J=8.8, 2.0Hz), 7.43 (1H, d, J=8.8Hz), 7.74 (1H, s), 8.03 (1H, d, J=5.6Hz), 8.79 (1H, s), 11.37 (1H, s), 11.88 (1H, s)
MS(ESI)m/z：545(M+H+).
[embodiment 133] N- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- propionyl phenylpiperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04151
The compound and propionyl chloride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：214~228 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：0.88-1.10 (3H, m), 1.70-2.05 (2H, m), 2.06-2.60 (2H, m), 2.91 (3H, s), 3.14 (2H, br.s), 3.20-3.90 (5H, m), 3.95-4.80 (5H, m), (7.09 1H, d, J=11.0Hz), 7.17 (1H, dd, J=8.8,1.2Hz), 7.41 (1H, d, J=8.8Hz), 7.71 (1H, s), 8.20-8.50 (2H, m), 11.00-11.40 (1H, m), 11.86 (1H, s)
MS(ESI)m/z：529(M+H+).
[embodiment 134] N- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- isobutyryl piperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and isobutyryl chloride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：266~272 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：0.80-1.15 (6H, m), 1.70-2.05 (2H, m), 2.65-2.80 (1H, m), 2.90 (3H, s), 2.90-4.80 (12H, m), 7.09 (1H, d, J=11.0Hz), 7.17 (1H, dd, J=8.8,2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.71 (1H, s), 8.00-8.30 (1H, m), 8.30-8.50 (1H, m), 10.95-11.50 (1H, m), 11.86 (1H, s)
MS(ESI)m/z：543(M+H+).
[embodiment 135] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2,2- Dimethylpropanoyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and trimethyl-aceyl chloride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：250~255 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.20 (9H, s), 1.70-1.81 (1H, m), 1.90-2.00 (1H, m), 2.88 (3H, s), 3.10 (2H, br.s), 3.20-3.70 (4H, m), 3.95-4.08 (1H, m), 4.10-4.20 (1H, m), 4.25-4.35 (1H, m), 4.35-4.80 (3H, m), 7.10 (1H, s), 7.16 (1H, dd, J=8.8, 1.9Hz), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, d, J=1.9Hz), 8.06 (1H, br.s), 8.38 (1H, d, J=7.8Hz), 11.31 (1H, br.s), 11.84 (1H, s)
MS(ESI)m/z：557(M+H+).
[embodiment 136] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (3,3- dimethylbutanoyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and t-butylacetyl chloride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：260~265 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：0.91,1.04 (whole 9H, it is each s), 1.68-1.82 (1H, m), 1.93-2.40 (3H, m), 2.91 (3H, s), 3.00-3.20 (2H, m), 3.20-4.80 (10H, m), 7.08 (1H, s), 7.17 (1H, dd, J=8.7,1.2Hz), 7.41 (1H, d, J=8.7Hz), 7.69 (1H, d, J=7.6Hz), 7.93-8.18 (1H, m), 8.38-8.45 (1H, m), 10.95-11.30 (1H, m), 11.80-11.90 (1H, m)
MS(ESI)m/z：571(M+H+).
[embodiment 137] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2,2,2- trifluoroacetyl group) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04171
The compound and TFAA obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：262~267 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.82-1.98 (1H, m), 2.05-2.21 (1H, m), 2.89 (3H, s), 3.05-3.20 (2H, m), 3.40-3.75 (4H, m), 3.85-3.95 (1H, m), 4.00-4.07 (1H, m), 4.20-4.70 (4H, m), 7.10 (1H, s), 7.18 (1H, dd, J=8.6, 1.9Hz), 7.41 (1H, d, J=8.6Hz), 7.72 (1H, s), 8.47 (1H, dd, J=22.4, 7.9Hz), 8.60 (1H, br), 11.08 (1H, br.s), 11.87 (1H, s)
MS(ESI)m/z：569(M+H+).
[embodiment 138] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (cyclopropyl carbonyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and cyclopropane carbonyl chlorine obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：280~286 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：0.25-0.80 (4H, m), 1.65-2.15 (4H, m), 2.91 (3H, s), 2.90-3.20 (3H, m), 3.35-3.70 (2H, m), 4.00-4.80 (6H, m), 7.06 (1H, s), 7.18 (1H, d, J=8.8Hz), 7.42 (1H, d, J=8.7Hz), 7.71 (1H, s), (8.18 1H, br.s), 8.40,8.48 (whole 1H, each br.s), 11.11 (1H, br.s), 11.85 (1H, s)
MS(ESI)m/z：542(M+H+).
[embodiment 139] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (cyclobutyl carbonyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and cyclobutanecarbonyl chlorine obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：271~275 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.60-2.30 (8H, m), 2.89 (3H, s), 3.12 (2H, br.s), 3.20-3.75 (6H, m), 3.75-3.90 (1H, m), 4.05-4.80 (4H, m), 7.08 (1H, s), 7.15 (1H, dd, J=9.0,2.0Hz), 7.39 (1H, d, J=9.0Hz), 7.68 (1H, d, J=2.0Hz), 8.15 (1H, br.s), 8.39 (1H, br), 11.19 (1H, br.s), 11.84 (1H, s)
MS(ESI)m/z：555(M+H+).
[embodiment 140] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (cyclopentylcarbonyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04182
The compound and Cyclopentanecarbonyl chlorine obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：254~260 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.30-2.10 (10H, m), 2.90 (3H, s), 3.00-3.20 (2H, m), 3.20-3.75 (5H, m), 3.80-4.80 (6H, m), 7.09 (1H, s), 7.17 (1H, dd, J=8.7,2.0Hz), 7.42 (1H, d, J=8.7Hz), 7.71 (1H, s), 7.95-8.30 (1H, m), 8.35-8.50 (1H, m), 11.23 (1H, br.s), 11.85 (1H, s)
MS(ESI)m/z：569(M+H+).
[embodiment 141] acetic acid 2- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-1-yl) -2- oxoethyl esters
The compound and acetoxy acetyl chloride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
1H-NMR(CDCl3)δ：1.70-2.00 (1H, m), 2.05-2.48 (3H, m), 2.51 (3H, s), 2.70-3.05 (4H, m), 3.05-4.10 (5H, m), 4.20-4.48 (1H, m), 4.50-5.10 (4H, m), 6.87 (1H, br.s), 7.10-7.82 (4H, m), 7.32 (1H, d, J=8.8Hz), 8.35 (1H, br.s), 9.34,9.45 (whole 1H, each br.s)
MS(ESI)m/z：573(M+H+).
[embodiment 142] N- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- glycollyl piperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (301.8mg) that embodiment 141 is obtained is dissolved in tetrahydrofuran (10ml), adds 1N sodium hydrate aqueous solution (0.53ml), stirs 18 hours at room temperature.Add water, extracted with dichloromethane in reaction solution, organic layer uses water and saturated common salt water washing successively.With solvent is boiled off under decompression after anhydrous sodium sulfate drying, residue (dichloromethane: methanol=20: 1~10: 1) is refined with silica gel column chromatography, solvent is boiled off under decompression.The refined thing is dissolved in ethanol (3ml) and dichloromethane (2ml), the ethanol solution hydrochloride (0.40ml) for adding 1N is stirred 30 minutes.Solvent is boiled off under decompression, residue is solidified with ether, obtain title compound (195mg).
Fusing point：216~230 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.70-1.80 (1H, m), 1.88-2.10 (2H, m), 2.68 (3H, s), 3.18 (2H, s), 3.08-3.70 (5H, m), 3.80-3.95 (1H, m), 4.00-4.25 (3H, m), 4.25-4.50 (2H, m), 4.50-4.65 (1H, m), 7.09 (1H, d, J=11.0Hz), 7.17 (1H, dd, J=8.8, 2.0Hz), 7.42 (1H, d, J=8.8Hz), 7.71 (1H, s), 8.33 (1H, br.s), 8.35-8.50 (1H, m), 10.80-11.30 (1H, br.s), 11.84 (1H, br.s)
[embodiment 143] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：214~228 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.70-1.80 (1H, m), 1.85-2.05 (1H, m), 2.90 (3H, s), 3.00-3.20 (2H, m), 3.16 (3H, s), 3.22-3.82 (7H, m), 3.88-4.80 (5H, m), 7.09 (1H, d, J=9.0Hz), 7.17 (1H, dd, J=8.8,1.9Hz), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, d, J=1.9Hz), 8.29 (1H, br.s), 8.40-8.50 (1H, m), 11.34 (1H, br.s), 11.86 (1H, s)
MS(ESI)m/z：545(M+H)+.
[embodiment 144] N- [(3R*, 4S*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and methoxyacetyl chloride obtained by embodiment 122, equally operates with embodiment 100, obtains title compound.
Fusing point：190~208 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.70-1.83 (1H, br), 1.85-2.10 (1H, m), 2.91 (3H, s), 3.00-3.55 (10H, m), 3.62-3.85 (1H, m), 3.90-4.50 (6H, m), 4.63-4.78 (1H, br), 7.04 (1H, td, J=9.4,2.4Hz), 7.07-7.13 (1H, br), 7.37-7.44 (1H, m), 8.16-8.49 (2H, m), 11.30-11.70 (1H, br), 11.72-11.80 (1H, br)
MS(FAB)m/z：529(M+H+).
[embodiment 145] N- [(3R*, 4S*) -1- (3- { [tert-butyl group (diphenyl) silicyl] epoxide } -2; 2- Dimethylpropanoyls) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The dimethylformamide of thionyl chloride (3.0ml) and catalytic amount is added in chloroform (10ml) solution for the compound (261mg) that reference example 158 is obtained, in 60 DEG C of evenings of stirring one.The lower concentration of reaction solution of decompression, the compound (200mg) obtained by gained yellow oil and embodiment 118 equally operates with embodiment 100, obtains title compound (241mg).
Fusing point：153℃
1H-NMR(CDCl3)δ：1.07 (9H, s), 1.39 (6H, d, J=3.9Hz), 1.57 (1H, br.s), 2.26 (1H, d, J=10.7Hz), 2.57 (3H, s), 2.86 (4H, s), 2.97-3.01 (2H, m), 3.78 (4H, s), 4.20 (1H, br.s), 4.33 (1H, d, J=13Hz), 4.42 (1H, br.s), 4.67 (1H, d, J=13Hz), 6.88 (1H, s), 7.20-7.23 (1H, m), 7.32-7.46 (7H, m), 7.64-7.65 (6H, m), 7.86 (1H, d, J=6.8Hz), 8.23 (1H, s), 9.10 (1H, s)
[embodiment 146] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (3- hydroxyls -2,2- Dimethylpropanoyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Under ice cooling, tetrabutylammonium (1 mole of tetrahydrofuran solution, 0.594ml) is added in tetrahydrofuran (30ml) solution for the compound (241mg) that embodiment 145 is obtained, an evening is stirred at room temperature.After the lower concentration of reaction solution of decompression, dichloromethane is dissolved in by residue obtained, after water and saturated common salt water washing, with anhydrous sodium sulfate drying, solvent is boiled off under decompression.It is residue obtained (dichloromethane: methanol=9: 1) to be refined with preparation silica gel thin-layer chromatography, obtain title compound (116mg).
Fusing point：220 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.17 (6H, d, J=8.3Hz), 1.79 (1H, br.s), 1.91-1.97 (1H, m), 2.49 (3H, s), 2.87 (4H, s), 3.35-3.50 (4H, m), 3.81 (1H, br.s), 3.97 (1H, m), 4.10-4.15 (1H, m), 4.32 (1H, br.s), 4.42 (1H, br.s), 4.52 (1H, t, J=5.7Hz), 7.10 (1H, s), 7.16-7.19 (1H, m), 7.42 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.11 (1H, d, J=8.8Hz), 8.37 (1H, d, J=7.3Hz), 11.8 (1H, s)
MS(FAB)m/z：573(M+H+).
[embodiment 147] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (3- methoxyl groups -2,2- Dimethylpropanoyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D04222
The compound that the compound and reference example 160 obtained by embodiment 118 is obtained, it is same with embodiment 145, obtain title compound.
Fusing point：240 DEG C (decomposition)
1H-NMR(CDCl3)δ：1.34 (3H, s), 1.37 (3H, s), 1.65-1.77 (1H, m), 2.33-2.37 (1H, m), 2.53 (3H, s), 2.82-3.29 (6H, m), 3.34 (3H, s), 3.41 (1H, d, J=9.3Hz), 3.56 (1H, d, J=9.3Hz), 3.76 (2H, d, J=5.9Hz), 4.26 (1H, m), 4.44-4.53 (2H, m), 4.82 (1H, d, J=13.7Hz), 6.88 (1H, d, J=1.5Hz), 7.20-7.23 (1H, m), 7.33 (1H, d, J=8.8Hz), 7.64 (1H, d, J=1.5Hz), 7.90 (1H, d, J=7-1Hz), 8.22 (1H, d, J=5.1Hz), 9.18 (1H, s)
MS(FAB)m/z：587(M+H+).
[embodiment 148] acetic acid 2- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-1-yl) -1,1- dimethyl -2- oxoethyl esters
The compound and 2- acetoxyl group isobutyryl chlorides obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：190 DEG C (decomposition)
1H-NMR(CDCl3)δ：1.56-1.67 (8H, m), 2.08 (3H, s), 2.35 (1H, d, J=10.5Hz), 2.52 (3H, s), 2.82-2.84 (2H, m), 2.90-2.96 (2H, m), 3.14 (1H, br.s), 3.75 (2H, s), 4.25 (1H, br.s), 4.40-4.47 (1H, m), 4.54 (1H, br.s), 4.80 (1H, br.s), 6.86 (1H, s), 7.20-7.33 (3H, m), 7.64 (1H, d, J=1.7Hz), 7.76 (1H, d, J=7.3Hz), 9.11 (1H, s)
MS(FAB)m/z：601(M+H+).
[embodiment 149] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- hydroxy-2-methyls propiono) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D04241
Sodium methoxide (76.8mg) is added in methanol (50ml) solution for the compound (190mg) that embodiment 148 is obtained, an evening is stirred at room temperature.After the lower concentration of reaction solution of decompression, residue obtained use preparative thin layer chromatography (dichloromethane: methanol=9: 1) refines, obtains title compound (130mg).
Fusing point：190 DEG C (decomposition)
1H-NMR(CDCl3)δ：1.53 (3H, s), 1.56-1.78 (5H, m), 2.34 (1H, d, J=10.5Hz), 2.53 (3H, s), 2.83-2.86 (2H, m), 2.91-2.93 (2H, m), 3.30 (1H, d, J=12.5Hz), 3.75 (2H, s), 4.28 (1H, d, J=5.6Hz), 4.43 (1H, s), 4.65 (1H, d, J=13.5Hz), 4.95 (1H, d, J=13.5Hz), 6.92 (1H, d, J=1.5Hz), 7.20-7.23 (1H, m), 7.33 (1H, d, J=8.6Hz), 7.65 (1H, d, J=2.0Hz), 8.43 (1H, d, J=5.6Hz), 9.14 (1H, s)
MS(FAB)m/z：559(M+H+).
[embodiment 150] N- { (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- [(3- hydroxycyclobutyls) carbonyl] piperidines -3- bases -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04242
Tetrahydrofuran (20ml), dichloromethane (3.0ml), the N of the compound (117mg) obtained in reference example 152, the compound (306mg) of addition embodiment 118 acquisition, N-methylmorpholine (200 μ l), the hydrate of I-hydroxybenzotriazole 1 (87mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (197mg), are stirred 3 days at room temperature in the mixed solution of dinethylformamide (2.0ml).Reaction solution is divided into 2 layers with addition saturated sodium bicarbonate aqueous solution after dchloromethane.Organic layer is concentrated under reduced pressure with anhydrous sodium sulfate drying is used after saturated common salt water washing.Residue obtained use silica gel column chromatography (dichloromethane: methanol=10: 1) refines, obtains the free alkali (207mg) of title compound.The free alkali is handled with 1N ethanol solution hydrochloride, title compound is obtained.
Fusing point：200 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.78-2.10 (4H, m), 2.24-2.68 (3H, m), 2.75-5.20 (14H, m), 2.91 (3H, s), 7.08 (0.5H, s), 7.09 (0.5H, s), 7.18 (1H, dd, J=8.8,2.0Hz), (7.42 1H, d, J=8.8Hz), (7.70 1H, d, J=2.0Hz), 8.05-8.28 (1H, br), 8.38 (0.5H, br.d, J=7.3Hz), 8.43 (0.5H, br.d, J=8.3Hz), 10.80-11.25 (1H, br), 11.84 (1H, br.s)
MS(ESI)m/z：571(M+H+).
[embodiment 151] N- { (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- [(methoxy tetramethylcyclobutyl) carbonyl] piperidines -3- bases -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound that the compound and reference example 154 obtained by embodiment 118 is obtained, equally operates with embodiment 150, obtains title compound.
Fusing point：191 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.69-2.23 (4H, m), 2.25-2.40 (1H, m), 2.71-2.84 (0.5H, m), 2.89-3.93 (9.5H, m), 2.91 (3H, s), 3.01 (1H, s), 3.14 (2H, s), 4.05-4.80 (5H, m), 7.09 (1H, s), 7.18 (1H, d, J=8.4Hz), 7.42 (1H, d, J=8.4Hz), 7.70 (1H, s), 8.00-8.30 (1H, br), 8.36-8.53 (1H, m), 11.25-11.75 (1H, br), 11.85 (1H, br.s)
MS(ESI)m/z：585(M+H+).
[embodiment 152] N- { (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- [(3- methoxyl groups -2- (methoxy) propiono] piperidines -3- bases } -5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound that reference example 155 is obtained is hydrolyzed, the compound that gained carboxylic acid and embodiment 118 are obtained equally is condensed with embodiment 150, obtains title compound.
Fusing point：178~184 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.69-1.82 (1H, m), 1.84-2.04 (1H, m), 2.91 (3H, s), 3.00-3.75 (17H, m), 3.95-4.55 (5H, m), 4.60-4.80 (1H, m), 7.10 (1H, br.s), 7.18 (1H, dd, J=8.8,2.0Hz), 7.42 (1H, d, J=8.8Hz), 7.69 (0.5H, br.s), 7.71 (1H, br.s), 8.18-8.28 (1H, br), 8.35-8.50 (1H, br), 11.83 (1H, br.s)
MS(ESI)m/z：603(M+H+).
[embodiment 153] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (tetrahydrochysene -2H- pyrans -4- bases carbonyl) piperidines -3- bases] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04262
The compound that the compound and reference example 156 obtained by embodiment 118 is obtained, equally operates with embodiment 150, obtains title compound.
Fusing point：225~248 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.55-1.68 (4H, m), 1.70-1.85 (1H, m), 1.85-2.05 (1H, m), 2.60-2.95 (1H, m), 2.89 (3H, s), 2.95-3.20 (3H, m), 3.20-4.00 (9H, m), 4.00-4.80 (4H, m), 7.08 (1H, s), 7.17 (1H, dd, J=8.8,2.0Hz), 7.42 (1H, d, J=8.8Hz), 7.71 (1H, s), 8.00-8.30 (1H, m), 8.35-8.50 (1H, m), 11.16 (1H, br.s), 11.85 (1H, s)
MS(ESI)m/z：585(M+H+).
[embodiment 154] N- ((3R*, 4S*) -1- benzoyls -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and chlorobenzoyl chloride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：215~225 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.75-1.90 (1H, m), 1.90-2.20 (1H, m), 2.93 (3H, s), 3.10-4.00 (8H, m), 4.05-4.80 (4H, m), 7.00-7.60 (5H, m), 7.08 (1H, s), 7.16 (1H, dd, J=8.8,1.6Hz), 7.40 (1H, d, J=8.8Hz), 7.71 (1H, d, J=1.6Hz), 8.31 (1H, br.s), 8.46 (1H, br.s), 11.39 (1H, br.s), 11.86 (1H, s)
MS(FAB)m/z：577(M+H+).
[embodiment 155] (3R*, 4S*) -3- { [(5- (2- { [tert-butyl group (diphenyl) silicyl] epoxide } -1,1- dimethyl ethyls) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases] carbonyl } amino) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -1- carboxylic acid tert-butyl esters
The compound that the compound and reference example 42 obtained by reference example 207 is obtained, equally operates with embodiment 91, obtains title compound.
1H-NMR(DMSO-d6)δ：1.00 (9H, s), 1.12 (6H, s), 1.15-1.50 (9H, m), 1.63-1.75 (1H, m), 1.82-2.00 (1H, m), 2.60-2.80 (3H, m), 2.83-2.95 (2H, m), 3.12-3.30 (1H, m), 3.30 (2H, s), 3.58 (2H, s), 3.85-4.10 (2H, m), 4.19 (1H, br.s), 4.37 (1H, br.s), 7.04 (1H, s), 7.16 (1H, d, J=9.0Hz), 7.30-7.50 (7H, m), 7.50-7.65 (4H, m), 7.70 (1H, s), 7.99 (1H, d, J=6.8Hz), 8.45 (1H, br.s), 11.82 (1H, s)
MS(ESI)m/z：869(M+H+).
[embodiment 156] 5- (2- { [tert-butyl group (diphenyl) silicyl] epoxide } -1,1- dimethyl ethyls)-N- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- bases) -4,5,6, the 7- tetrahydro-thiazoles simultaneously hydrochloride of [5,4-c] pyridine-2-carboxamide 2
Figure G2003801097466D04281
It is same with embodiment 95, the compound that embodiment 155 is obtained is handled, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.04 (9H, s), 1.43, 1.48 (whole 6H, each s), 1.85-2.00 (1H, m), 2.05-2.20 (1H, m), 2.95-3.20 (2H, m), 3.25-3.60 (6H, m), 3.80-3.90 (1H, m), 3.95-4.05 (1H, m), 4.45-4.55 (1H, m), 4.60-4.85 (3H, m), 7.10-7.20 (2H, m), 7.35-7.55 (7H, m), 7.55-7.75 (5H, m), 8.52 (1H, dd, J=14.4, 7.8Hz), 8.93 (1H, br), 9.20-9.40 (2H, m), 11.30-11.50 (1H, m), 11.87, 11.92 (whole 1H, each s)
MS(ESI)m/z：769(M+H+).
[embodiment 157] 5- (2- { [tert-butyl group (diphenyl) silicyl] epoxide } -1,1- dimethyl ethyls)-N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls } piperidines -3- bases] -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D04282
The compound and methoxyacetyl chloride obtained by embodiment 156, equally operates with embodiment 100, obtains title compound.
1H-NMR(CDCl3)δ：1.07 (9H, s), 1.20 (6H, s), 1.60-1.85 (1H, m), 2.25-2.40 (1H, m), 2.36 (2H, s), 2.70-3.20 (4H, m), 3.20-3.55 (4H, m), 3.55-3.70 (2H, m), 3.95-4.10 (3H, m), 4.10-4.90 (4H, m), 6.90 (1H, d, J=1.5Hz), 7.15-7.30 (2H, m), 7.30-7.50 (6H, m), 7.60-7.70 (5H, m), 8.15-8.22 (1H, m), 8.46 (1H, d, J=5.1Hz), 9.28 (1H, s)
MS(ESI)m/z：842(M+H)+.
[embodiment 158] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- bases] -5- (2- hydroxyls -1; 1- dimethyl ethyls) -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound obtained by embodiment 157, equally operates with embodiment 146, obtains title compound.
Fusing point：221-232 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.32 (3H, s), 1.40 (3H, s), 1.70-1.85 (1H, m), 1.85-2.10 (1H, m), 2.60-3.35 (8H, m), 3.40-3.82 (3H, m), 3.85-4.05 (3H, m), 4.05-4.35 (2H, m), 4.50-4.60 (1H, m), 4.55-4.80 (2H, m), 5.75-5.85 (1H, m), 7.08 (1H, br.s), 7.17 (1H, d, J=8.8Hz), 7.41 (1H, d, J=8.8Hz), 7.71 (1H, s), 8.20-8.35 (1H, m), 8.40-8.55 (1H, m), 10.00-10.35 (1H, m), 11.87 (1H, s)
MS(ESI)m/z：603(M+H)+.
[embodiment 159] (3R*, 4S*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } -3- { [(5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -1- carboxylic acid tert-butyl esters
The compound that the compound and reference example 148 obtained by reference example 209 is obtained, equally operates with embodiment 91, obtains title compound.
1H-NMR(CDCl3)δ：1.16 (6H, d, J=6.6Hz), 1.53 (9H, s), 1.65-1.80 (1H, m), 2.23-2.32 (1H, m), 2.80-3.10 (6H, m), 3.10-3.25 (1H, m), 3.80-3.90 (2H, m), 4.00-4.50 (4H, m), 6.91 (1H, s), 6.95-7.05 (1H, m), 7.25-7.40 (2H, m), 7.74 (1H, br.s), 8.21 (1H, br.s), 9.30 (1H, s)
MS(ESI)m/z：585(M+H)+.
[embodiment 160] N- ((3R*, 4S*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- isopropyls -4,5,6, the 7- tetrahydro-thiazoles simultaneously hydrochloride of [5,4-c] pyridine-2-carboxamide 2
It is same with embodiment 95, the compound that embodiment 159 is obtained is handled, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.28-1.40 (6H, m), 1.85-2.00 (1H, m), 2.05-2.20 (1H, m), 2.40-2.60 (1H, m), 2.95-3.90 (8H, m), 4.40-4.55 (2H, m), 4.60-4.75 (2H, m), 7.00-7.20 (2H, m), 7.30-7.50 (2H, m), 8.45-8.60 (1H, m), 8.85-9.05 (1H, m), 9.05-9.50 (2H, m), 11.60-11.90 (2H, m)
MS(ESI)m/z：485(M+H)+.
[embodiment 161] N- [(3R*, 4S*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- bases] -5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and methoxyacetyl chloride obtained by embodiment 160, equally operates with embodiment 100, obtains title compound.
Fusing point：214~228 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.25-1.40 (6H, m), 1.68-1.82 (1H, m), 1.85-2.10 (1H, m), 2.90-3.60 (8H, m), 3.60-3.85 (2H, m), 3.85-4.40 (5H, m), 4.40-4.55 (2H, m), 4.60-4.75 (1H, m), 7.00-7.15 (2H, m), 7.35-7.50 (2H, m), 8.15-8.50 (2H, m), 10.80-11.30 (1H, m), 11.73 (1H, d, J=6.6Hz)
MS(ESI)m/z：557(M+H)+.
[embodiment 162] N- { (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- [(dimethylamino) carbonyl] piperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04312
The compound and N, N- dimethylcarbamyl chloride obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：267~270 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.65-1.78 (1H, m), 1.97-2.10 (1H, m), 2.70 (6H, s), 2.90 (3H, s), 2.95-3.80 (8H, m), 4.25-4.80 (4H, m), 7.08 (1H, s), 7.16 (1H, dd, J=8.8,1.8Hz), 7.41 (1H, d, J=8.8Hz), 7.70 (1H, s), 8.31 (1H, br.s), 8.40 (1H, d, J=7.3Hz), 11.15-11.60 (1H, m), 11.82 (1H, s)
MS(ESI)m/z：544(M+H)+.
[embodiment 163] N- { (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- [(dimethylamino) carbonyl] piperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and ethyl isocyanate obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：221~235 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：0.98 (3H, t, J=7.1Hz), 1.60-1.70 (1H, m), 1.80-1.95 (1H, m), 2.90 (3H, s), 2.95-3.40 (6H, m), 3.40-4.00 (4H, m), 4.25-4.80 (4H, m), 6.60-6.80 (1H, m), 7.09 (1H, s), 7.16 (1H, dd, J=8.8, 1.9Hz), 7.41 (1H, d, J=8.8Hz), 7.68 (1H, d, J=1.9Hz), 8.02 (1H, br.s), 8.35 (1H, d, J=7.1Hz), 11.20-11.70 (1H, m), 11.82 (1H, s)
MS(FAB)m/z：544(M+H)+.
[embodiment 164] N- ((3R*, 4S*) -1- [(tert-butylamino) carbonyl] -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04322
The compound and tert-butyl isocyanate obtained by embodiment 118, equally operates with embodiment 100, obtains title compound.
Fusing point：236~238 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.21 (9H, s), 1.60-1.70 (1H, m), 1.80-1.90 (1H, m), 2.87 (3H, s), 3.00-3.40 (6H, m), 3.49 (1H, br.s), 3.80-3.90 (1H, m), 3.90-4.00 (1H, m), 4.20-4.35 (2H, m), 4.47 (1H, br.s), 5.90 (1H, s), 7.06 (1H, s), 7.16 (1H, dd, J=8.8, 1.9Hz), 7.41 (1H, d, J=8.8Hz), 7.67 (1H, d, J=1.9Hz), 8.04 (1H, d, J=6.8Hz), 8.34 (1H, d, J=7.3Hz), 11.22 (1H, br.s), 11.79 (1H, s)
MS(FAB)m/z：572(M+H)+.
[embodiment 165] 2- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(- 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -3- bases) 2 hydrochloride of ethyl acetate
The mixing obtained by embodiment 118 and methyl bromoacetate, equally operate with embodiment 102, obtain title compound.
Fusing point：253~255 DEG C (decomposition)
1H-NMR(DMSO-d6,δ：1.95-2.10 (1H, m), 2.10-2.25 (1H, m), 2.88 (3H, s), 3.00-3.73 (8H, m), 3.75 (3H, s), 3.97-4.15 (2H, m), 4.30-4.80 (4H, m), 7.08-7.20 (2H, m), 7.44 (1H, d, J=8.6Hz), 7.63 (1H, d, J=2.0Hz), 8.42 (1H, d, J=7.3Hz), 8.62 (1H, br.s), 11.82 (1H, br.s)
MS(ESI)m/z：545(M+H)+.
[embodiment 166] 2- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -3- { [(- 5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidines -3- bases) acetic acid hydrochloride
Figure G2003801097466D04333
The compound that embodiment 165 is obtained is carried out and the same processing of embodiment 101, acquisition title compound.
Fusing point：234~240 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.75-1.95 (1H, m), 2.05-2.20 (1H, m), 2.88 (3H, s), 2.95-3.90 (10H, m), 4.20-4.70 (4H, m), 7.11 (1H, s), 7.16 (1H, dd, J=8.8,2.0Hz), (7.41 1H, d, J=8.8Hz), (7.66 1H, d, J=2.0Hz), (8.46 1H, br.d, J=7.8Hz), 8.65 (1H, br.s), 11.60-12.70 (2H, br.s), 11.91 (1H, br.s)
[embodiment 167] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- methoxy ethyls) piperidines -3- bases] -5- methyl -4,5,6, the 7- tetrahydro-thiazoles simultaneously hydrochloride of [5,4-c] pyridine-2-carboxamide 2
Figure G2003801097466D04341
The compound and 2- bromo-ethyl-methyl ethers obtained by embodiment 118, title compound is equally obtained with embodiment 102 (NMR is determined with free alkali).
Fusing point：238~242 DEG C (decomposition)
1H-NMR(CDCl3)δ：1.75-1.83 (2H, m), 2.27-2.39 (2H, m), 2.52 (3H, s), 2.60-2.66 (1H, m), 2.69-2.75 (1H, m), 2.81-2.90 (2H, m), 2.96-3.07 (2H, m), 3.41 (3H, s), 3.53-3.60 (2H, m), 3.75 (each 1H, AB types d, J=15.5Hz), 4.02-4.05 (1H, m), 4.40 (1H, br), 6.88 (1H, d, J=1.5Hz), 7.18-7.21 (1H, m), 7.31-7.33 (1H, m), 7.63 (1H, d, J=1.5Hz), 8.17 (1H, d, J=5.0Hz), 8.26 (1H, d, J=7.0Hz), 9.30 (1H, br.s)
MS(FAB)m/z：531(M+H)+.
[embodiment 168] N- [(3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- fluoro ethyls) piperidines -3- bases] -5- methyl -4,5,6, the 7- tetrahydro-thiazoles simultaneously hydrochloride of [5,4-c] pyridine-2-carboxamide 2
Figure G2003801097466D04342
The compound and 2- fluoro ethyl bromines obtained by embodiment 118, equally handles with embodiment 102, obtains title compound (NMR is determined with free alkali).
Fusing point：228~233 DEG C (decomposition)
1H-NMR(CDCl3)δ：1.77 (2H, dq, J=12.5, 4.0Hz), 2.28-2.32 (1H, m), 2.41 (1H, t, J=12.5Hz), 2.52 (3H, s), 2.65 (1H, d, J=10.5Hz), 2.76-2.81 (1H, m), 2.83-2.86 (3H, m), 2.98-3.05 (3H, m), 3.75 (each 1H, AB types d, J=15.5Hz), 4.02-4.08 (1H, m), 4.45 (1H, br), 4.54-4.59 (1H, m), 4.64-4.70 (1H, m), 6.87 (1H, d, J=1.5Hz), 7.19-7.22 (1H, m), 7.32 (1H, d, J=8.5Hz), 7.64 (1H, d, J=2.0Hz), 8.11 (1H, d, J=5.5Hz), 8.20 (1H, d, J=7.3Hz), 9.30 (1H, br)
MS(FAB)m/z：519(M+H)+.
[embodiment 169] N- ((3R; 4S) -1- acetyl group -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04351
In the compound that reference example 214 is obtained (4N Yan Suan dioxane solutions (7.0ml) are added in 630mg) dioxane solutions (15ml), are stirred 1 hour at room temperature.Be concentrated under reduced pressure reaction solution, the compound (379mg) obtained with gained yellow solid (590mg) and reference example 10, is equally operated with embodiment 91, obtains the free alkali (330mg) of title compound.The free alkali is handled with ethanol solution hydrochloride, title compound is obtained (NMR is determined with free alkali).
Fusing point：202~222 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.65-1.85 (1H, m), 1.87, 2.06 (whole 3H, each s), 1.88-2.10 (1H, m), 2.37 (3H, s), 2.65-2.77 (2H, m), 2.79-2.89 (2H, m), 2.99-3.09 (0.5H, m), 3.30-3.52 (2H, m), 3.64 (2H, s), 3.70-3.80 (0.5H, m), 3.96-4.21 (2H, m), 4.27 (1H, br.s), 4.35-4.48 (1H, m), 7.07, 7.11 (whole 1H, each s), 7.18 (1H, d, J=8.8Hz), 7.42 (1H, d, J=8.8Hz), 7.71 (1H, s), 8.16-8.22 (1H, m), 8.37, 8.46 (whole 1H, each d, J=7.8Hz), 11.81, 11.83 (whole 1H, each s)
MS(ESI)m/z：515(M+H)+.
[α]D 25=-56.0 ° (c=0.50, methanol)
[embodiment 170] N- ((3R; 4R) -1- acetyl group -4- { [(5- chloro-indole -2- bases) carbonyl] amino } piperidines -3- bases) -5- methyl -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04361
Equally handled with embodiment 169, the compound that the compound and reference example 10 obtained by reference example 219 is obtained prepares title compound.
Fusing point：221~238 DEG C
1H-NMR(DMSO-d6)δ：1.45-1.56 (0.5H, m), 1.60-1.70 (0.5H, m), 1.89-2.01 (1H, m), 2.05 (3H, s), 2.51-2.67 (1H, m), 2.88 (3H, s), 3.00-3.22 (3H, m), 3.31-3.40 (3H, m), 3.56-3.67 (0.5H, m), 3.78-4.02 (1.5H, m), 4.22-4.44 (2H, m), 4.56-4.72 (1H, m), 7.02 (1H, s), 7.15 (1H, dd, J=8.8, 2.0Hz), 7.37 (1H, d, J=8.8Hz), 7.67 (1H, d, J=2.0Hz), 8.42 (1H, d, J=9.8Hz), 8.67-8.78 (1H, m), 11.02-11.14 (1H, m), 11.72 (0.5H, s), 11.74 (0.5H, s)
MS(FAB)m/z：515(M+H)+.
[α]D 25=-105.4 ° (c=0.58, methanol)
[embodiment 171] N- [(3R; 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Equally handled with embodiment 169, the compound obtained by reference example 221 prepares title compound.
Fusing point：207~220 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：1.70-1.80 (1H, m), 1.85-2.05 (1H, m), 2.90 (3H, s), 3.00-3.20 (2H, m), 3.16 (3H, s), 3.22-3.82 (7H, m), 3.88-4.80 (5H, m), 7.09 (1H, d, J=9.0Hz), 7.17 (1H, dd, J=8.8,1.9Hz), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, d, J=1.9Hz), 8.29 (1H, br.s), 8.40-8.50 (1H, m), 11.20-11.50 (1H, m), 11.85 (1H, s)
MS(ESI)m/z：545(M+H)+.
[α]D 25=-53.4 ° (c=0.52, methanol)
[embodiment 172] N- [(3R; 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Equally handled with embodiment 169, the compound obtained by reference example 223 prepares title compound.
Fusing point：213~230 DEG C
1H-NMR(DMSO-d6)δ：1.45-1.56 (0.5H, m), 1.61-1.70 (0.5H, m), 1.89-2.00 (1H, m), 2.05 (3H, s), 2.45-2.67 (1H, m), 2.88 (3H, s), 3.00-3.21 (4H, m), 3.32-3.56 (7H, m), 3.78-3.89 (2H, m), 4.00-4.24 (2H, m), 4.26-4.43 (2H, m), 7.02 (1H, s), 7.13 (1H, dd, J=8.8, 2.0Hz), 7.37 (1H, d, J=8.8Hz), 7.67 (1H, d, J=2.0Hz), 8.41 (1H, d, J=9.8Hz), 8.74 (1H, d, J=9.8Hz), 10.80-10.90 (1H, m), 11.72 (1H, s)
MS(FAB)m/z：545(M+H)+.
[α]D 25=-100.3 ° (c=0.51, methanol)
[embodiment 173] N- ((3R, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -6- oxo tetrahydrochysene -2H- pyrans -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04372
The compound that the low polar compound and reference example 10 obtained by reference example 176 is obtained, equally handles with embodiment 169, obtains title compound.
1H-NMR(DMSO-d6)δ：2.41-2.56 (2H, m), 2.91 (3H, s), 3.01-3.23 (1H, m), 3.24-3.56 (5H, m), 3.62-3.67 (1H, m), 4.21-4.44 (1H, m), 4.56-4.78 (2H, m), 7.11 (1H, s), 7.16 (1H, dd, J=8.8,2.0Hz), (7.22 1H, d, J=8.5Hz), (7.41 1H, d, J=8.8Hz), (7.69 1H, d, J=2.0Hz), 8.40-8.50 (1H, m), 11.34-11.56 (1H, m), 11.82 (1H, s)
MS(FAB)m/z：488(M+H)+.
[embodiment 174] N- ((3R, 4S) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -6- oxo tetrahydrochysene -2H- pyrans -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04381
The compound that the highly polar compound and reference example 10 obtained by reference example 176 is obtained, equally handles with embodiment 169, obtains title compound.
1H-NMR(DMSO-d6)δ：2.41-2.56 (2H, m), 2.91 (3H, s), 3.23-3.41 (2H, m), 3.43-3.50 (2H, m), 3.56-3.67 (2H, m), 4.37 (1H, dd, J=13.9, 7.1Hz), 4.40-4.50 (1H, m), 4.56-4.78 (2H, m), 7.12 (1H, s), 7.17 (1H, dd, J=8.8, 2.0Hz), 7.41 (1H, d, J=8.8Hz), 7.71 (1H, d, J=2.0Hz), 8.44 (1H, d, J=8.5Hz), 8.15 (1H, d, J=8.5Hz), 11.42-11.53 (1H, m), 11.79 (1H, s)
MS(FAB)m/z：488(M+H+).
[embodiment 175] (3R, 4S) -5- { [tert-butyl group (diphenyl) silicyl] epoxide } -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } ethyl valerate
Figure G2003801097466D04382
The compound obtained by reference example 225, equally handles with embodiment 169, obtains title compound.
1H-NMR(CDCl3)δ：1.09 (9H, s), 1.21 (3H, t, J=7.4Hz), 2.49 (3H, s), 2.65 (1H, dd, J=15.9, 5.4Hz), 2.67-2.90 (5H, m), 3.60 (1H, d, J=14.9Hz), 3.72 (1H, d, J=14.9Hz), 3.78-3.91 (2H, m), 4.00-4.21 (2H, m), 4.43-4.50 (1H, m), 4.78-4.89 (1H, m), 6.81 (1H, s), 7.20 (1H, dd, J=8.8, 2.0Hz), 7.32-7.52 (m, 7H), 7.63-7.74 (6H, m), 7.89-8.01 (1H, m), 9.18 (1H, s)
[embodiment 176] (3R, 4S) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- hydroxyls -4- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } ethyl valerate
Under ice cooling, after instilling hydrogen fluoride pyridine (0.4ml) in the mixed solution of the compound (0.54g) that reference example 175 is obtained, pyridine (4.0ml) and tetrahydrofuran (10ml) formation, stirred 18 hours while reaction solution is slowly warmed to room temperature.Concentration of reaction solution, residue obtained use silica gel column chromatography (chloroform: methanol=9: 1) refines, obtains title compound (0.31g).
1H-NMR(CDCl3)δ：1.20 (3H, t, J=7.4Hz), 2.49 (3H, s), 2.67-2.90 (6H, m), 3.62-3.74 (3H, m), 3.78-3.94 (1H, m), 4.00-4.20 (2H, m), 4.30-4.40 (1H, m), 4.80-4.89 (1H, m), 6.93 (1H, s), 7.23 (1H, dd, J=8.8,2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.56 (1H, d, J=8.5Hz), 7.61 (1H, d, J=2.0Hz), 7.88 (1H, d, J=8.5Hz), 9.29 (1H, s)
[embodiment 177] N- ((3S, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -6- oxo tetrahydrochysene -2H- pyrans -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04392
4N Yan Suan dioxane solutions (20ml) are added in the compound (0.31g) that embodiment 176 is obtained, are heated to reflux 4 hours.Concentration of reaction solution, residue obtained use Diethyl ether recrystallization obtains title compound (0.23g).
Fusing point：221~238 DEG C (decomposition)
1H-NMR and MS：It is consistent with as the embodiment 174 of enantiomer
[embodiment 178] N- ((3R*, 4R*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04401
The compound and 5- chloro-indole -2- carboxylic acids obtained by reference example 227, equally handles with embodiment 91, obtains the free alkali of title compound.The free alkali is handled with ethanol solution hydrochloride, title compound is obtained.
Fusing point：241~244 DEG C
1H-NMR(DMSO-d6)δ：2.14 (1H, br), 2.30-2.34 (1H, m), 2.92 (3H, s), 3.10-3.18 (2H, m), 3.41 (4H, br), 3.68 (2H, br), 4.44 (1H, br), 4.63-4.78 (3H, m), 7.16-7.18 (1H, m), 7.21 (1H, s), (7.43 1H, d, J=8.5Hz), (7.67 1H, d, J=4.6Hz), 8.39 (1H, br), 8.94 (1H, br), 11.82 (1H, br)
MS(ESI)m/z：522(M+H)+.
[embodiment 179] N- ((3R*, 4R*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and 5- fluoro indole -2- carboxylic acids obtained by reference example 227, equally handles with embodiment 91, obtains the free alkali of title compound.The free alkali is handled with ethanol solution hydrochloride, title compound is obtained.
Fusing point：243~245 DEG C
1H-NMR(DMSO-d6)δ：2.14 (1H, br), 2.30-2.33 (1H, m), 2.92 (3H, s), 3.13 (2H, br), 3.51 (4H, br), 3.63 (2H, br), 4.63 (3H, br), 4.78 (1H, br), 7.01-7.05 (1H, m), 7.21 (1H, s), 7.37-7.44 (2H, m), 8.36 (1H, br), 8.93 (1H, d, J=6.8Hz), 11.72 (1H, br)
MS(ESI)m/z：506(M+H+).
[embodiment 180] N- ((3R*, 4R*) -3- { [(5- chloro-indole -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -4- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04411
The compound that the compound and reference example 10 obtained by reference example 229 is obtained, equally handles with embodiment 91, obtains the free alkali of title compound.The free alkali is handled with ethanol solution hydrochloride, title compound is obtained.
Fusing point：242~247 DEG C
1H-NMR(DMSO-d6)δ：2.16 (1H, br), 2.45 (1H, br), 2.93 (3H, s), 3.13 (2H, br), 3.26 (4H, br), 3.69 (2H, br), 4.45 (1H, br), 4.65-4.77 (3H, m), 7.01 (1H, s), 7.17 (1H, dd, J=8.7,1.4Hz), 7.43 (1H, d, J=8.5Hz), 7.69 (1H, s), 8.35-8.40 (1H, m), 9.04 (1H, br), 11.86 (1H, s)
MS(ESI)m/z：522(M+H+).
[embodiment 181] N- ((3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound and 5- chloro-indole -2- carboxylic acids obtained by reference example 231, equally handles with embodiment 91, obtains the free alkali of title compound.The free alkali is handled with ethanol solution hydrochloride, title compound is obtained.
Fusing point：244~249 DEG C
1H-NMR(DMSO-d6)δ：2.17-2.27 (2H, m), 2.90 (3H, s), 3.09 (1H, br), 3.18-3.21 (2H, m), 3.31-3.34 (2H, m), 3.60-3.67 (3H, m), 4.41-4.49 (2H, m), 4.54-4.59 (2H, m), 7.04 (1H, s), 7.09-7.13 (1H, m), 7.39 (1H, d, J=8.5Hz), 7.61 (1H, d, J=9.9Hz), 8.52-8.56 (1H, m), 8.83-8.85 (1H, m), 11.65 (1H, d, J=11.9Hz)
MS(ESI)m/z：522(M+H+).
[embodiment 182] N- ((3R*, 4S*) -4- { [(5- fluoro indole -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04421
The compound and 5- fluoro indole -2- carboxylic acids obtained by reference example 231, equally handles with embodiment 91, obtains the free alkali of title compound.The free alkali is handled with ethanol solution hydrochloride, title compound is obtained.
Fusing point：236~241 DEG C
1H-NMR(DMSO-d6)δ：2.20-2.24 (2H, m), 2.89 (3H, s), 3.07 (1H, br), 3.19-3.22 (2H, m), 3.60-3.66 (4H, m), 4.43-4.58 (5H, m), 6.95-7.00 (1H, m), 7.04 (1H, s), 7.32-7.38 (2H, m), 8.50 (1H, d, J=8.5Hz), 8.83 (1H, d, J=8.5Hz), 11.59 (1H, s)
MS(ESI)m/z：506(M+H+).
[embodiment 183] N- ((3R*, 4R*) -3- { [(5- fluoro indole -2- bases) carbonyl] amino } -1,1- dioxo hexahydro -1- thiapyran -4- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound that the compound and reference example 10 obtained by reference example 233 is obtained, equally handles with embodiment 91, obtains the free alkali of title compound.The free alkali is handled with ethanol solution hydrochloride, title compound is obtained.
Fusing point：244~249 DEG C
1H-NMR(DMSO-d6)δ：2.12-2.18 (1H, m), 2.50 (1H, br), 2.92 (3H, s), 3.17 (3H, br), 3.50-3.61 (5H, m), 4.45 (1H, br), 4.62-4.78 (3H, m), 6.98-7.03 (2H, m), 7.36-7.42 (2H, m), 8.30 (1H, br), 9.00 (1H, d, J=8.0Hz), 11.74 (1H, s)
MS(ESI)m/z：506(M+H+).
[embodiment 184] N- ((3S, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- methyl -6- oxo-piperidine -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (low polar compound) and N- ((3R, 4R) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- methyl -6- oxo-piperidine -3- bases) -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide (highly polar compound)
The low highly polar compound of polar compound
The compound that the compound and reference example 10 obtained by reference example 236 is obtained, equally handles with embodiment 169, obtains title compound.
Low polar compound：
Fusing point：189~203 DEG C (decomposition)
1H-NMR(CDCl3)δ：2.52 (3H, s), 2.59 (1H, q, J=8.8Hz), 2.71-2.78 (2H, m), 2.89-3.00 (2H, m), 3.03 (3H, s), 3.12 (1H, dd, J=17.6, 5.4Hz), 3.43 (1H, dd, J=12.7, 5.1Hz), 3.70 (1H, d, J=15.2Hz), 3.77 (1H, d, J=15.2Hz), 3.83 (1H, dd, J=12.7, 3.9Hz), 4.55-4.67 (2H, m), 6.99 (1H, s), 7.23 (1H, dd, J=8.8, 2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.65 (1H, d, J=2.0Hz), 8.07 (1H, d, J=5.1Hz), 8.16 (1H, d, J=5.4Hz), 9.43 (1H, s)
MS(FAB)m/z：501(M+H+).
Highly polar compound：
Fusing point：183~195 DEG C (decomposition)
1H-NMR(DMSO-d6)δ：2.33 (3H, s), 2.41-2.50 (1H, m), 2.62-2.73 (3H, m), 2.75-2.81 (1H, m), 2.82 (3H, s), 3.21-3.32 (2H, m), 3.34-3.50 (2H, m), 3.55 (1H, d, J=15.4Hz), 3.63 (1H, d, J=15.4Hz), 4.30-4.40 (0.5H, m), 4.50-4.60 (0.5H, m), 7.04 (1H, s), 7.15 (1H, dd, J=8.8, 2.0Hz), 7.38 (1H, d, J=8.8Hz), 7.67 (1H, d, J=2.0Hz), 8.49 (1H, d, J=8.5Hz), 8.71 (1H, d, J=8.5Hz), 11.74 (1H, s)
MS(FAB)m/z：501(M+H+).
Chloro- the N- ((1R of [embodiment 185] 5-*, 2S*) -2- { [4- (pyridin-4-yl) benzoyl] amino } cyclohexyl) indole 2-carboxamides hydrochloride
By method similarly to Example 2, the compound that the compound obtained by reference example 71 and reference example 237 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.40-1.52 (2H, m), 1.60-1.80 (4H, m), 1.96-2.10 (2H, m), 4.24-4.39 (2H, m), 7.15 (1H, dd, J=8.8,2.0Hz), 7.21 (1H, s), 7.40 (1H, d, J=8.8Hz), 7.64 (1H, d, J=2.0Hz), 8.06 (4H, s), 8.18 (1H, J=7.3Hz), 8.34-8.42 (3H, m), 8.94 (2H, d, J=6.9Hz), 11.91 (1H, s)
MS(FAB)m/z：473(M+H)+
[embodiment 186] 4- (4- { [((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl phenyl) pyridine N-oxides
Figure G2003801097466D04442
Using method similarly to Example 2, the compound that the compound obtained by reference example 71 and reference example 240 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.40-1.52 (2H, m), 1.60-1.80 (4H, m), 1.88-2.00 (2H, m), 4.21-4.36 (2H, m), 7.12-7.18 (2H, m), (7.41 1H, d, J=8.6Hz), 7.66 (1H, s), 7.80-7.87 (4H, m), 7.91 (2H, d, J=8.3Hz), 8.01 (1H, d, J=7.6Hz), 8.09 (1H, d, J=7.3Hz), 8.27 (2H, d, J=6.6Hz), 11.79 (1H, s)
MS(FAB)m/z：489(M+H)+.
Chloro- the N- ((1R of [embodiment 187] 5-*, 2S*) -2- { [4- (pyridine -2- bases) benzoyl] amino } cyclohexyl) indole 2-carboxamides hydrochloride
Figure G2003801097466D04451
Using method similarly to Example 2, the compound obtained by reference example 71 and 4- (2- pyridine radicals) benzoic acid (Japanese Patent Laid-Open 2000-119253) obtain title compound.
1H-NMR(DMSO-d6)δ：1.39-1.51 (2H, m), 1.60-1.80 (4H, m), 1.89-2.00 (2H, m), 4.24-4.38 (2H, m), 7.12-7.16 (2H, m), 7.36-7.39 (1H, m), (7.42 1H, d, J=8.8Hz), (7.66 1H, d, J=2.0Hz), 7.87-7.90 (1H, m), 7.92 (2H, d, J=8.3Hz), 7.98-8.11 (3H, m), 8.15 (2H, d, J=8.3Hz), 8.69 (1H, d, J=4.6Hz), 11.80 (1H, s)
MS(FAB)m/z：473(M+H)+.
[embodiment 188] 2- (4- { [((1R*, 2S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl phenyl) pyridine N-oxides
Using method similarly to Example 2, the compound that the compound obtained by reference example 71 and reference example 241 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.39-1.51 (2H, m), 1.60-1.79 (4H, m), 1.89-2.00 (2H, m), 4.23-4.37 (2H, m), 7.12-7.17 (2H, m), 7.39-7.43 (3H, m), 7.61-7.64 (1H, m), 7.67 (1H, d, J=2.0Hz), 7.89 (4H, s), 8.00-8.06 (1H.m), 8.08-8.02 (1H, m), 8.32-8.35 (1H, m), 11.79 (1H, s)
MS(FAB)m/z：489(M+H)+.
Chloro- the N- [(1R of [embodiment 189] 5-*, 2R*) -2- ({ [5- (4- pyridine -2- bases) thiazol-2-yl] carbonyl } amino } cyclohexyl] indole 2-carboxamides hydrochloride
Using method similarly to Example 2, the compound obtained by reference example 69 and 5- (4- pyridine radicals) thiazole -2- carboxylic acid lithium salts (Japanese Patent Laid-Open 2000-143623) prepare title compound.
1H-NMR(DMSO-d6)δ：1.44 (2H, br.s), 1.65 (4H, br.s), 1.85-2.06 (2H, m), 4.23 (1H, br.s), 4.30 (1H, br.s), 7.14-7.23 (2H, m), 7.41 (1H, d, J=8.8Hz), 7.69 (1H, s), 8.04-8.13 (2H, m), 8.13 (1H, d, J=8.8Hz), 8.59 (1H, d, J=8.0Hz), 8.75-8.87 (3H, m), 11.83 (1H, s)
MS(ESI)m/z：480(M+H)+.
Chloro- the N- [(1R of [embodiment 190] 5-*, 2S*) -2- ({ [1- (pyridin-4-yl) piperidin-4-yl] carbonyl } amino } cyclohexyl] indole 2-carboxamides hydrochloride
Figure G2003801097466D04461
By 1- (4- pyridine radicals) piperidines -4- carboxylic acids (Tetrahedron, 1998, volume 44, page 7095) (206mg) be suspended in dichloromethane (50ml), and thionyl chloride (144 μ l) is added under ice-cooling to be stirred 30 minutes.Added in reaction solution after triethylamine (969 μ l), the compound (328mg) for adding the acquisition of reference example 71 is stirred 30 minutes at room temperature.The lower concentration of reaction solution of decompression, concentrate solution under being depressurized after being added water in residue, the sediment that leaching is separated out obtains title compound (310mg).
1H-NMR(DMSO-d6)δ：1.30-2.00 (10H, m), 2.74 (1H, br.s), 3.18 (2H, q, J=12.3Hz), 4.03 (1H, br.s), 4.10-4.25 (3H, m), 7.15-7.55 (4H, m), 7.42 (1H, d, J=8.8Hz), 7.65 (1H, s), (7.91 1H, d, J=8.8Hz), 8.20-8.35 (3H, m), 11.91 (1H, s), (13.47 1H, br.s)
MS(FAB)m/z：480(M+H)+.
[embodiment 191] N1- (4- chlorphenyls)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (288mg) that reference example 242 is obtained is dissolved in tetrahydrofuran (8.0ml), sequentially adds lithium hydroxide (46mg) and water (1.0ml), stirs 2 hours at room temperature.The lower concentration of reaction solution of decompression obtains the thick product (292mg) of 2- (4- chloroanilinos) -2- Oxoacetic Acid lithium salts in colorless solid to solid.The compound that the thick product and reference example 253 are obtained is dissolved in N, dinethylformamide (15ml), the hydrate of I-hydroxybenzotriazole 1 (164mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (251mg) are added, are stirred 64.5 hours at room temperature.Solvent is boiled off under decompression, saturated sodium bicarbonate aqueous solution is added in residue and dichloromethane is carried out after point liquid, organic layer anhydrous sodium sulfate drying.Boiled off under decompression after solvent, residue (dichloromethane: methanol=47: 3) is refined with silica gel column chromatography.Gained faint yellow solid is dissolved in dichloromethane, 1N ethanol solution hydrochloride (0.52ml) is added, solvent is boiled off under decompression.Methanol and ether are added in residue, the precipitation of leaching generation obtains title compound (245mg).
1H-NMR(DMSO-d6)δ：1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 1.95-2.10 (2H, m), 2.79 (3H, s), 2.80-3.00 (1H, m), 2.92 (3H, s), 2.94 (3H, s), 3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.40-4.80 (3H, m), 7.40 (2H, d, J=8.8Hz), 7.83 (2H, d, J=8.8Hz), 8.75 (1H, d, J=7.1Hz), 9.00-9.10 (1H, br), 10.81 (1H, s), 11.45-11.75 (1H, m)
MS(FAB)m/z：547(M+H)+.
[embodiment 192] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (240mg) that reference example 243 is obtained is dissolved in tetrahydrofuran (8.0ml), sequentially adds lithium hydroxide (41mg) and water (1.0ml), stirs 2.5 hours at room temperature.The lower concentration of reaction solution of decompression obtains 2- [(5- chloropyridine -2- bases) amino] -2- Oxoacetic Acids lithium salts (249mg) as solid.
On the other hand, add and be stirred at room temperature in 10% palladium carbon (200mg), nitrogen atmosphere 18 hours in methanol (10ml) solution for the compound (293mg) that reference example 252 is obtained.Filter off and lower concentration filtrate is depressurized after palladium carbon, obtain N- { (1R, 2S, 5S) -2- amino -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6, the thick product (259mg) of 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide.
In N, the thick product (259mg) and above-mentioned lithium salts (249mg) are added in dinethylformamide (15ml), the hydrate of I-hydroxybenzotriazole 1 (166mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (235mg) are added, is stirred 63.5 hours at room temperature.Solvent is boiled off under decompression, is added in residue after saturated sodium bicarbonate aqueous solution and dichloromethane point liquid, gained organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=93: 7) is refined with silica gel column chromatography.Gained faint yellow solid is dissolved in dichloromethane, 1N ethanol solution hydrochloride (0.855ml) is added, solvent is boiled off under decompression.Methanol and ether are added in residue, the precipitation of leaching generation obtains title compound (209mg).
1H-NMR(DMSO-d6)δ：1.40-1.57 (1H, m), 1.60-1.80 (3H, m), 1.95-2.13 (2H, m), 2.79 (3H, s), 2.80-3.00 (1H, m), 2.92 (3H, s), 2.94 (3H, s), 3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.37-4.80 (3H, m), 7.90-8.10 (2H, m), 8.45 (1H, d, J=2.2Hz), 8.71 (1H, d, J=7.6Hz), 9.10-9.30 (1H, br), 10.26 (1H, s), 11.30-11.60 (1H, br)
MS(FAB)m/z：548(M+H)+.
[embodiment 193] N1- (3- chlorphenyls)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (222mg) and 3- chloroanilines (63 μ l) that reference example 270 is obtained are dissolved in N, dinethylformamide (10ml), the hydrate of I-hydroxybenzotriazole 1 (68mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (144mg) are added, are stirred 40 hours at room temperature.Solvent is boiled off under decompression, is added in residue after saturated sodium bicarbonate aqueous solution and dichloromethane point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=30: 1) is refined with silica gel column chromatography.Gained faint yellow solid is dissolved in dichloromethane, 1N ethanol solution hydrochloride (0.50ml) is added, solvent is boiled off under decompression.Ether is added in residue, the precipitation of leaching generation obtains title compound (174mg).
1H-NMR(DMSO-d6)δ：1.45-1.62 (1H, m), 1.65-1.90 (3H, m), 1.98-2.20 (2H, m), 2.79 (3H, s), 2.88-3.10 (1H, m), 2.93 (3H, s), 2.94 (3H, s), 3.15-3.40 (2H, m), 3.40-3.90 (2H, m), 3.95-4.10 (1H, m), 4.40-4.80 (3H, m), 7.19 (1H, dd, J=9.3, 2.0Hz), 7.37 (1H, d, J=8.2Hz), 7.77 (1H, d, J=8.3Hz), 7.92-8.05 (1H, m), 8.75 (1H, d, J=7.3Hz), 8.95-9.20 (1H, br), 10.87 (1H, s), 11.25-11.45 (1H, br)
[embodiment 194] N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (4- fluorophenyls) oxalamide hydrochloride
It is same with the method that embodiment 191 is recorded, the compound that reference example 254 is obtained is hydrolyzed, after the compound condensation obtained with reference example 253, handled using hydrochloric acid, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.40-2.13 (6H, m), 2.77 (3H, s), 2.93 (3H, s), 2.97 (3H, s), 3.12-3.82 (7H, m), 3.93-4.04 (1H, m), 4.38-4.46 (1H, m), 4.35-4.75 (1H, m), 7.11-7.21 (2H, m), 7.72-7.84 (2H, m), 8.73 (1H, d, J=7.6Hz), 8.93-9.02 (1H, m), 10.70 (1H, s)
MS(FAB)m/z：531(M+H)+.
[embodiment 195] N1- (4- bromophenyls)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (152mg) that reference example 255 is obtained is dissolved in tetrahydrofuran (5.0ml), sequentially adds 1N sodium hydrate aqueous solution (1.20ml) and methanol (5.0ml), stirs 2.5 hours at room temperature.The lower concentration of reaction solution of decompression, the hydrochloric acid (2.0ml) that dichloromethane (10ml) and 1N are added in residue carries out a point liquid.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, the thick product of 2- (4- bromobenzenes amido) -2- Oxoacetic Acids in colorless solid is obtained.The compound (280mg) that the thick product and reference example 253 are obtained is dissolved in N, dinethylformamide (30ml), the hydrate of I-hydroxybenzotriazole 1 (90mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (226mg) are added, an evening is stirred at room temperature.Solvent is boiled off under decompression, is added in residue after saturated sodium bicarbonate aqueous solution and dichloromethane point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=97: 3) is refined with silica gel column chromatography.Gained faint yellow solid is dissolved in dichloromethane, 1N ethanol solution hydrochloride (191 μ l) is added, solvent is boiled off under decompression.Methanol and ether are added in residue, the precipitation of leaching generation obtains title compound (103mg).
1H-NMR(DMSO-d6)δ：1.43-1.57 (1H, m), 1.59-1.80 (3H, m), 1.97-2.10 (2H, m), 2.79 (3H, s), 2.84-2.98 (7H, m), 3.18 (2H, br.s), 3.39-3.72 (2H, m), 3.95-4.05 (1H, m), 4.20-4.80 (3H, m), (7.53 2H, d, J=8.8Hz), (7.77 2H, d, J=8.8Hz), (8.75 1H, d, J=7.3Hz), 8.97-9.09 (1H, m), 10.82 (1H, s), 11.11 (1H, br.s)
MS(FAB)m/z：591(M+H)+.
[embodiment 196] N1- (4- chloro-2-methyls phenyl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using the method same with embodiment 191, the compound that reference example 256 is obtained is hydrolyzed, then the compound condensation for making it be obtained with reference example 253, processing is then carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 2.00-2.10 (2H, m), 2.19 (3H, s), 2.79 (3H, s), 2.80-3.00 (7H, m), 3.31 (2H, br.s), 3.40-3.70 (2H, br), 3.95-4.05 (1H, m), 4.35-4.70 (3H, m), 7.20-7.30 (1H, m), 7.35 (1H, d, J=2.5Hz), 7.43 (1H, d, J=8.6Hz), 8.76 (1H, d, J=6.6Hz), 9.00-9.15 (1H, br), 10.19 (1H, s)
MS(FAB)m/z：561(M+H)+.
[embodiment 197] N1- (the chloro- 3- aminomethyl phenyls of 4-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04502
Using the method same with embodiment 191, the compound that reference example 257 is obtained is hydrolyzed, then the compound condensation for making it be obtained with reference example 253, processing is then carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.47-1.53 (1H, m), 1.68-1.80 (3H, m), 1.98-2.09 (2H, m), 2.29 (3H, s), 2.79 (3H, s), 2.80-3.00 (1H, m), 2.95 (6H, s), 3.17-3.19 (3H, m), 3.40-3.80 (1H, m), 3.93-4.02 (1H, m), 4.44-4.56 (3H, m), 7.38 (1H, d, J=8.8Hz), 7.65 (1H, d, J=8.8Hz), 7.74 (1H, s), 8.75 (1H, d, J=7.8Hz), 8.96 (1H, d, J=8.0Hz), 10.69 (1H, s)
MS(FAB)m/z：561(M+H)+.
[embodiment 198] N1- (the chloro- 2- fluorophenyls of 4-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04511
Using the method same with embodiment 191, the compound that reference example 258 is obtained is hydrolyzed, then the compound condensation for making it be obtained with reference example 253, processing is then carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.40-1.55 (1H, m), 1.58-1.80 (3H, m), 1.95-2.12 (2H, m), 2.77 (3H, s), 2.80-3.00 (1H, m), 2.91 (3H, s), 2.92 (3H, s), 3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.30-4.80 (3H, m), 7.29 (1H, d, J=8.5Hz), 7.52 (1H, dd, J=10.3, 2.0Hz), 7.61 (1H, t, J=8.4Hz), 8.72 (1H, d, J=6.8Hz), 9.00-9.20 (1H, br), 10.38 (1H, s), 11.20-11.45 (1H, br)
MS(FAB)m/z：565(M+H)+.
[embodiment 199] N1- (2,4- dichlorophenyl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (300mg) that reference example 270 is obtained is dissolved in N, dinethylformamide (5ml), add 2,4- dichloroanilines (165mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (260mg) and the hydrate of I-hydroxybenzotriazole 1 (91mg), are stirred 2 days at room temperature.Solvent is boiled off under decompression, added in residue after saturated sodium bicarbonate aqueous solution and dichloromethane point liquid, after organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression, residue (dichloromethane: methanol=47: 3) is refined with silica gel column chromatography, obtains the free alkali of title compound.Dichloromethane is dissolved in, 1N ethanol solution hydrochloride (108 μ l) is added, solvent is boiled off under decompression.A small amount of methanol is added in residue, ether is instilled while ultrasonic irradiation is carried out, the precipitation of leaching generation is washed to it with ether, obtains title compound (60mg).
1H-NMR(DMSO-d6)δ：1.45-1.77 (4H, m), 2.03-2.12 (2H, m), 2.79 (3H, s), 2.92-2.96 (7H, m), 3.25 (2H, br.s), 3.49 (1H, br.s), 3.69 (1H, br.s), 3.98-4.04 (1H, m), 4.40-4.43 (1H, m), 4.45 (1H, br.s), 4.69 (1H, br.s), 7.48 (1H, dd, J=8.5, 2.4Hz), 7.75 (1H, d, J=2.4Hz), 7.89 (1H, d, J=8.5Hz), 8.75 (1H, d, J=6.8Hz), 9.21 (1H, br.s), 10.25 (1H, s), 11.55 (1H, br.s)
MS(FAB)m/z：581(M+H)+.
[embodiment 200] N1- (3,4- dichlorophenyl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
Figure G2003801097466D04521
3,4-DCA (1.62g) is dissolved in dichloromethane (20ml), triethylamine (1.67ml), chlorine oxoacetic acid methyl ester (1.01ml) are sequentially added under ice-cooling, is stirred 21 hours at room temperature.Added in reaction solution after water and dichloromethane point liquid, water layer is extracted with dichloromethane.Merge organic layer, dried with anhydrous magnesium sulfate, solvent is boiled off under decompression.Ethanol (50ml) is dissolved in by residue obtained, water (25ml), the hydrate of lithium hydroxide 1 (629mg) is sequentially added, stirred 12.5 hours at room temperature.Then, the hydrate of lithium hydroxide 1 (629mg) is added, is stirred 5.5 hours at room temperature.The lower concentration of reaction solution of decompression is to solid.Added in residue after water and ether point liquid, hydrochloric acid is added in water layer makes it in acidity.The solid generated by leaching, obtains the thick product (1.62g) of 2- (3,4-DCA base) -2- Oxoacetic Acids in colorless solid.The compound (250mg) that the thick product (191mg) and reference example 253 are obtained is dissolved in N, dinethylformamide (10ml), the hydrate of I-hydroxybenzotriazole 1 (110mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (157mg) are added, are stirred 67 hours at room temperature.Solvent is boiled off under decompression, is added in residue after saturated sodium bicarbonate aqueous solution and ethyl acetate point liquid, water layer is extracted 3 times with dichloromethane.Merge organic layer, use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=95: 5) is refined with silica gel column chromatography, obtains title compound (154mg).
1H-NMR(CDCl3)δ：1.77-1.88 (1H, m), 1.91-1.95 (1H, m), 2.05-2.10 (3H, m), 2.51 (3H, s), 2.77-2.99 (6H, m), 2.95 (3H, s), 3.05 (3H, s), 3.68 (1H, d, J=15.5Hz), 3.74 (1H, d, J=15.5Hz), 4.08-4.13 (1H, m), 4.69-4.72 (1H, m), 7.40 (2H, s), 7.41 (1H, d, J=7.7Hz), 7.90 (1H, s), 8.01 (1H, d, J=7.7Hz), 9.27 (1H, s)
MS(ESI)m/z：581(M+H)+.
[embodiment 201] N1- (2,4- difluorophenyl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
Figure G2003801097466D04531
Using the method same with embodiment 191, after the compound hydrolysis obtained to reference example 259, the compound condensation obtained with reference example 253 obtains title compound.
1H-NMR(CDCl3)δ：1.55-1.62 (1H, m), 1.67-1.98 (2H, m), 2.01-2.18 (4H, m), 2.52 (3H, s), 2.77-3.00 (4H, m), 2.95 (3H, s), 2.99 (3H, s), 3.65-3.78 (2H, m), 4.06-4.15 (1H, m), 4.66-4.73 (1H, m), 6.85-6.94 (2H, m), 7.38 (1H, d, J=8.5Hz), 7.96 (1H, d, J=7.3Hz), 8.22-8.29 (1H, m), 9.36 (1H, br)
[embodiment 202] N1- (3,4- difluorophenyl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
Figure G2003801097466D04532
Using the method same with embodiment 191, after the compound hydrolysis obtained to reference example 260, the compound condensation obtained with reference example 253 obtains title compound.
1H-NMR(CDCl3)δ：1.56-1.73 (1H, m), 1.77-1.99 (2H, m), 2.00-2.18 (4H, m), 2.52 (3H, s), 2.75-3.00 (4H, m), 2.95 (3H, s), 3.06 (3H, s), 3.64-3.79 (2H, m), 4.05-4.14 (1H, m), 4.68-4.75 (1H, m), 7.09-7.21 (2H, m), 7.38 (1H, d, J=8.8Hz), 7.72 (1H, ddd, J=12.0,7.1,2.6Hz), 7.95 (1H, d, J=7.8Hz), 9.22 (1H, br)
[embodiment 203] N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (pyridin-4-yl) oxalamide hydrochloride
Figure G2003801097466D04541
Using the method same with embodiment 191, after the compound hydrolysis obtained to reference example 261, then the compound condensation obtained with reference example 253 is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.40-2.10 (6H, m), 2.77 (3H, s), 2.927 (3H, s), 2.933 (3H, s), 3.05-4.20 (8H, m), 4.40-4.55 (1H, m), 8.27 (2H, d, J=6.8Hz), 8.67 (1H, d, J=8.0Hz), 8.71 (2H, d, J=6.8Hz), 9.10-9.30 (1H, br), 11.81 (1H, s)
MS(FAB)m/z：514(M+H)+.
[embodiment 204] N1- (5- bromopyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04542
Using the method same with embodiment 195, after the compound hydrolysis obtained to reference example 262, then the compound condensation obtained with reference example 253 carries out processing with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.43-1.57 (1H, m), 1.61-1.81 (3H, m), 1.98-2.15 (2H, m), 2.79 (3H, s), 2.86 (3H, s), 2.89-3.01 (4H, m), 3.18 (2H, br.s), 3.50 (2H, br.s), 3.95-4.05 (1H, m), 4.35-4.62 (3H, m), 7.97 (1H, d, J=9.0Hz), 8.12 (1H, dd, J=9.0, 2.4Hz), 8.52 (1H, d, J=2.4Hz), 8.70 (1H, d, J=7.5Hz), 9.18 (1H, d, J=7.5Hz), 10.25 (1H, br.s)
MS(FAB)m/z：592(M+H)+.
[embodiment 205] N1- (6- chloropyridine -3- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (200mg) that reference example 263 as thick product is obtained is dissolved in methanol (10ml), and in 50 DEG C of heating, the sodium hydrate aqueous solution (3ml) for adding 1N is stirred 5 minutes.1N aqueous hydrochloric acid solution is added wherein, and pH is adjusted under faintly acid, decompression to boil off solvent, the residue containing 2- [(2- chloropyridine -5- bases) amino] -2- Oxoacetic Acids is obtained.N is added in the compound (250mg) that the residue and reference example 253 are obtained, dinethylformamide (5ml), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (328mg) and the hydrate of I-hydroxybenzotriazole 1 (46mg) are added, is stirred 3 days at room temperature.Solvent is boiled off under decompression, saturated sodium bicarbonate aqueous solution is added in residue and dichloromethane carries out a point liquid.Organic layer (dichloromethane: methanol=47: 3) is refined with silica gel column chromatography with solvent, residue is boiled off under decompression after anhydrous sodium sulfate drying, obtains the free alkali of the title compound in faint yellow solid.Dichloromethane is dissolved in, 1N ethanol solution hydrochloride (862 μ l) is added, solvent is boiled off under decompression.A small amount of methanol is added in residue, ethyl acetate and ether are instilled while ultrasonic wave is irradiated, the precipitation of leaching generation is washed with ethyl acetate, obtains title compound (229mg).
1H-NMR(DMSO-d6)δ：1.46-1.75 (4H, m), 1.99-2.09 (2H, m), 2.79 (3H, s), 2.92-2.95 (7H, m), 3.12-3.53 (3H, m), 3.70 (1H, br.s), 3.99-4.06 (1H, m), 4.44 (2H, br.s), 4.69, 4.73 (1H, each s), 7.53 (1H, d, J=8.5Hz), 8.23-8.25 (1H, m), 8.72-8.77 (1H, m), 8.85 (1H, s), 9.07, 9.16 (1H, each d, J=8.1Hz), 11.09 (1H, d, J=8.1Hz), 11.78 (1H, br.s)
MS(FAB)m/z：548(M+H)+.
[embodiment 206] N1- (6- chlorine pyridazine -3- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using the method same with embodiment 191, after the compound hydrolysis that reference example 264 is obtained, then the compound condensation obtained with reference example 253 carries out processing with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.44-1.57 (1H, m), 1.62-1.80 (3H, m), 2.00-2.10 (2H, m), 2.79 (3H, s), 2.86 (3H, br.s), 2.94 (3H, s), 2.95-3.01 (1H, m), 3.14-3.23 (2H, m), 3.45-3.63 (2H, m), 3.96-4.08 (1H, m), 4.40-4.60 (3H, m), 7.97 (1H, d, J=9.3Hz), 8.26 (1H, d, J=9.3Hz), 8.69 (1H, d, J=7.6Hz), 9.20 (1H, d, J=7.6Hz), 11.06 (1H, s)
MS(FAB)m/z：549(M+H)+.
[embodiment 207] N1- (5- chlorine thiazol-2-yl)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04561
Using the method same with embodiment 191, after the compound hydrolysis that reference example 265 is obtained, then the compound condensation obtained with reference example 253 carries out processing with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.35-2.10 (6H, m), 2.77 (3H, s), 2.92 (3H, s), 2.93 (3H, s), 3.05-4.23 (8H, m), 4.32-4.80 (2H, m), 7.59 (1H, s), (8.63 1H, d, J=7.6Hz), 9.14 (1H, d, J=7.6Hz)
MS(FAB)m/z：554(M+H)+.
[embodiment 208] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (350mg) that the compound (210mg) and reference example 272 that reference example 266 is obtained are obtained is dissolved in N, dinethylformamide (15ml), the hydrate of I-hydroxybenzotriazole 1 (205mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (290mg) are added, are stirred 20 hours at room temperature.Solvent is boiled off under decompression, saturated sodium bicarbonate aqueous solution is added in residue and dichloromethane carries out a point liquid.Organic layer with after anhydrous sodium sulfate drying depressurize under boil off solvent, residue (dichloromethane: methanol=20: 1) is refined with silica gel column chromatography, gained faint yellow solid is dissolved in dichloromethane, 1N ethanol solution hydrochloride (0.46ml) is added, solvent is boiled off under decompression.Methanol and ether are added in residue, the precipitation of leaching generation obtains title compound (248mg).
1H-NMR(DMSO-d6)δ：1.47-1.50 (1H, m), 1.69-1.76 (3H, m), 1.98-2.06 (2H, m), 2.79 (3H, s), 2.95 (3H, s), 2.98-3.05 (1H, m), 3.10 (3H, s), 3.49-4.62 (6H, m), 7.98-8.03 (2H, m), 8.45 (1H, s), 8.73 (1H, d, J=7.6Hz), 9.10 (1H, d, J=8.0Hz), 10.30 (1H, s)
MS(FAB)m/z：534(M+H)+.
[embodiment 209] N- { (1R; 2S; 5S) -2- { [2- (4- chloroanilinos) acetyl group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04571
The compound (2.3g) that reference example 267 is obtained is dissolved in ethanol (10ml), adds 1N sodium hydrate aqueous solution (20ml), stirs 2 hours at room temperature.Add after 1N aqueous hydrochloric acid solution (20ml), be diluted with water in reaction solution, stir 30 minutes.The insoluble matter that leaching is separated out.Obtain 2- (4- chloroanilinos) acetic acid (1.05g) in colorless solid.The compound (0.25g) that the solid and reference example 253 are obtained is dissolved in N, dinethylformamide (10ml), the hydrate of I-hydroxybenzotriazole 1 (0.11g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (0.23g) are added, are stirred 4 days at room temperature.Chloroform dilute reaction solution is used, after saturated sodium bicarbonate aqueous solution and saturated common salt water washing, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (chloroform: methanol=97: 3) is refined with silica gel column chromatography, gained faint yellow solid is dissolved in into ethanol, added 1N ethanol solution hydrochloride, solvent is boiled off under decompression.Methanol and ether are added in residue, the precipitation of leaching generation obtains title compound (0.15g).
1H-NMR(DMSO-d6)δ：1.35-1.41 (1H, m), 1.59-1.80 (3H, m), 1.82-1.95 (2H, m), 2.76 (3H, s), 2.93 (3H, s), 2.94 (3H, s), 2.99-3.10 (1H, m), 3.10-3.22 (2H, m), 3.42-3.60 (2H, m), 3.60-3.77 (2H, m), 3.80-3.90 (1H, m), 4.35-4.48 (2H, m), 4.68-4.80 (1H, m), 6.40 (1H, d, J=6.7Hz), 6.44 (1H, d, J=6.7Hz), 6.90 (1H, d, J=6.7Hz), 7.00 (1H, d, J=6.7Hz), 7.70-7.89 (1H, m), 8.35-8.42 (1H, m), 11.05-11.38 (1H, m)
[embodiment 210] N- { (1R; 2S; 5S) -2- { [2- (the chloro- 2- fluoroanilinos of 4-) acetyl group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04581
Using the method same with embodiment 209, after the compound hydrolysis obtained to reference example 268, then the compound condensation obtained with reference example 253 carries out processing with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.35-1.42 (1H, m), 1.55-1.78 (3H, m), 1.80-2.00 (2H, m), 2.76 (3H, s), 2.92 (3H, s), 2.94 (3H, s), 2.99-3.10 (1H, m), 3.10-3.22 (2H, m), 3.42-3.60 (2H, m), 3.60-3.77 (2H, m), 3.85-4.00 (1H, m), 4.33-4.48 (2H, m), 4.65-4.80 (1H, m), 6.41 (1H, t, J=8.8Hz), 6.73 (1H, dt, J=8.8, 1.2Hz), 7.08 (1H, dd, J=11.7, 1.2Hz), 7.78-7.92 (1H, m), 8.35-8.42 (1H, m), 11.18-11.50 (1H, m)
[embodiment 211] N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04582
Using method similarly to Example 2, make the compound that reference example 432 is obtained and handled after the compound condensation that reference example 34 is obtained with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.70-2.15 (6H, m), 2.80 (3H, s), 2.97 (3H, s), 2.95-3.15 (2H, m), 3.35-3.55 (2H, m), 4.05-4.20 (1H, m), 4.46 (2H, s), 4.50-4.65 (1H, m), 7.05 (1H, s), 7.16 (1H, dd, J=8.8,2.2Hz), 7.41 (1H, d, J=8.8Hz), 7.68 (1H, s), 8.30-8.45 (1H, br), 9.30-9.50 (1H, br), 11.78 (1H, s)
MS(ESI)m/z：529(M+H)+.
[embodiment 212] N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- (4, oxazole -2- the bases of 5- dihydros -) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The compound (250mg) that embodiment 211 is obtained is suspended in dichloromethane, adds saturated sodium bicarbonate aqueous solution and is sufficiently stirred for.Organic layer is separated, after being dried with anhydrous magnesium sulfate, triethylamine (0.5ml) and bromo ethyl isocyanate (43 μ l) is added, stirs 20 hours at room temperature.Saturated sodium bicarbonate aqueous solution is added in reaction solution, organic layer is separated, is dried with anhydrous magnesium sulfate.Solvent is boiled off under decompression, residue (dichloromethane: methanol=22: 3) is refined with silica gel column chromatography, obtains title compound (227mg)
1H-NMR(CDCl3)δ：1.50-2.15 (4H, m), 2.15-2.40 (2H, m), 2.80-3.00 (1H, m), 2.97 (3H, s), 3.11 (3H, s), 3.70-3.95 (4H, m), 4.10-4.30 (1H, m), 4.30-4.50 (2H, m), 4.60-4.70 (1H, m), 4.74 (2H, s), 6.85 (1H, s), 7.21 (1H, dd, J=8.8, 2.2Hz), 7.34 (1H, d, J=8.8Hz), 7.50 (1H, br.s), 7.62 (1H, s), 7.87 (1H, br.s), 9.48 (1H, br.s)
MS(ESI)m/z：598(M+H)+.
[embodiment 213] N- { (1R, 2S, 5S) -2- { [(the chloro- 4- fluoro indoles -2- bases of 5-) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04592
The compound (140mg) that reference example 144 is obtained is dissolved in N, dinethylformamide (10ml), compound (100mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (140mg) and the hydrate of I-hydroxybenzotriazole 1 (110mg) that reference example 274 is obtained are added, is stirred 18 hours at room temperature.Solvent is boiled off under decompression, residue is dispensed into water-ethyl acetate, aqueous layer with ethyl acetate extraction.After organic layer with the merging of saturated common salt water washing, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 19) is refined with silica gel column chromatography, obtain (1R, 2S, 5S) -2- { [(the chloro- 4- fluoro indoles -2- bases of 5-) carbonyl] amino } -5- [(dimethylamino) carbonyl] Cyclohexylamino t-butyl formate (260mg).
Above-mentioned powder is dissolved in dichloromethane (5ml), 4N Yan Suan dioxane solutions (1.2ml) are added.After being stirred 3.5 hours to reaction solution at room temperature, solvent is boiled off under decompression.Dichloromethane (10ml) is added in residue to be concentrated, after the operation is repeated 3 times, decompression is lower to dry residue, obtain rough N- { (1S, 2R, 4S) -2- amino -4- [(dimethylamino) carbonyl] cyclohexyl } the chloro- 4- fluoro indoles -2- formamides of -5-.It is dissolved in N, dinethylformamide (50ml), compound (150mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (140mg) and the hydrate of I-hydroxybenzotriazole 1 (110mg) that reference example 10 is obtained are added, is stirred 18 hours at room temperature.Solvent is boiled off under decompression, residue is dispensed into water-ethyl acetate-tetrahydrofuran mixed liquor, aqueous layer with ethyl acetate extraction.After organic layer with the merging of saturated common salt water washing, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 19) is refined with silica gel column chromatography, obtains the free alkali (270mg) of title compound.By the alkali soluble in dichloromethane (10ml), 1N ethanol solution hydrochloride (0.72ml) is added, is stirred 30 minutes at room temperature, the crystallization that leaching is separated out obtains title compound (200mg).
1H-NMR(DMSO-d6)δ：1.24-1.98 (6H, m), 2.33-3.33 (6H, m), 2.81 (3H, s), 2.90 (3H, s), 2.99 (3H, s), 4.12 (1H, br.s), 4.30-4.70 (1H, m), 4.60 (1H, br.s), 7.21 (1H, s), 7.27 (2H, br.s), 8.37 (1H, d, J=8.1Hz), 8.43 (1H, d, J=7.6Hz), 12.11 (1H, s)
MS(FAB)m/z：561(M+H)+.
[embodiment 214] N- { (1R, 2S, 5S) -2- { [(the chloro- 3- fluoro indoles -2- bases of 5-) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (250mg) that reference example 279 is obtained is dissolved in dichloromethane (60ml), adds 4N Yan Suan dioxane solutions (1.3ml).After being stirred 5.5 hours to reaction solution at room temperature, 4N Yan Suan dioxane solutions (0.65ml) are added, are stirred 1 hour at room temperature.Solvent is boiled off under decompression, dichloromethane (10ml) is added in residue and is concentrated, the operation is repeated 3 times.Decompression is lower to dry residue, the thick product of gained is dissolved in N, dinethylformamide (50ml), compound (160mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (150mg) and the hydrate of I-hydroxybenzotriazole 1 (120mg) that reference example 10 is obtained are added, is stirred 18 hours at room temperature.Solvent is boiled off under decompression, residue is dispensed into water-ethyl acetate mixtures, aqueous layer with ethyl acetate extraction.After organic layer with the merging of saturated common salt water washing, anhydrous sodium sulfate drying is used.Solvent is boiled off under decompression, residue (methanol: dichloromethane=2: 23 → 1: 9) is carried out 2 times and refined, obtain the free alkali (260mg) of title compound with silica gel column chromatography.By the alkali soluble in dichloromethane, 1N ethanol solution hydrochloride (0.69ml) is added, solvent is boiled off after stirring 30 minutes at room temperature.Residue is dissolved in methanol, adding ether and hexane crystallizes it, leaching crystallization obtains title compound (230mg).
1H-NMR(DMSO-d6)δ：1.50-1.56 (1H, m), 1.73-1.78 (3H, m), 1.94-2.02 (2H, m), 2.33-3.55 (6H, m), 2.80 (3H, s), 2.92 (3H, s), 2.98 (3H, s), 4.17 (1H, br.s), 4.30-4.80 (1H, br), 4.62 (1H, br.s), 7.25 (1H, d, J=8.8, 1.7Hz), 7.40 (1H, d, J=8.8, 1.7Hz), 7.65 (1H, d, J=1.7Hz), 7.72 (1H, d, J=5.9Hz), 8.74 (1H, d, J=8.0Hz), 10.85-11.35 (1H, br), 11.71 (1H, s)
MS(FAB)m/z：561(M+H)+.
[embodiment 215] N- { (1R, 2S, 5S) -2- { [(the bromo- 5- chloro-indoles -2- bases of 3-) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 214, after the compound obtained with 4N Yan Suan dioxane solutions to reference example 282 is handled, title compound is made in the compound condensation for making it be obtained with reference example 10.
1H-NMR(DMSO-d6)δ：1.51-2.01 (6H, m), 2.33-3.29 (7H, m), 2.81 (3H, s), 2.88 (3H, s), 3.01 (3H, s), 4.20 (1H, br.s), 4.48 (1H, br), 4.70-4.73 (1H, m), 7.29 (1H, dd, J=8.9,1.8Hz), 7.45-7.49 (2H, m), 7.80 (1H, d, J=7.6Hz), 8.76 (1H, d, J=8.8Hz), 12.31 (1H, s)
MS(FAB)m/z：622(M+H)+.
[embodiment 216] N- { (1R, 2S, 5S) -2- { [(the chloro- 5- fluoro indoles -2- bases of 3-) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04612
Using method similarly to Example 5, the compound that the compound obtained by reference example 253 and reference example 284 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.40-1.51 (1H, m), 1.75-2.00 (5H, m), 2.79 (3H, s), 2.92 (3H, s), 2.99 (3H, s), 3.10-3.21 (3H, m), 3.29-3.41 (4H, m), 4.11-4.21 (1H, m), 4.62-4.75 (1H, m), 7.14 (1H, dt, J=8.8, 2.4Hz), 7.24 (1H, dd, J=8.8, 2.4Hz), 7.45 (1H, dd, J=8.8, 4.4Hz), 7.69 (1H, d, J=2.5Hz), 8.79 (1H, d, J=2.5Hz), 12.10 (1H, s)
MS(FAB)m/z：561(M+H)+.
[embodiment 217] N- { (1R; 2S; 5S) -2- { [(the chloro- 3- formyl indoles -2- bases of 5-) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04621
Using method similarly to Example 5, the compound that the compound obtained by reference example 253 and reference example 286 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.40-1.51 (1H, m), 1.75-1.89 (4H, m), 1.90-2.01 (1H, m), 2.80 (3H, s), 2.91 (3H, s), 3.03 (3H, s), 3.05-3.33 (3H, m), 3.60-3.71 (1H, m), 4.11-4.21 (1H, m), 4.32-4.44 (1H, m), 4.62-4.75 (2H, m), 7.35 (1H, dd, J=8.0, 1.4Hz), 7.56 (1H, d, J=8.0Hz), 8.21 (1H, d, J=1.4Hz), 8.65 (1H, t, J=7.4Hz), 9.92 (1H, d, J=6.8Hz), 10.15 (1H, t, J=9.1Hz), 13.00 (1H, d, J=6.4)
MS(FAB)m/z：571(M+H)+.
The chloro- N of [embodiment 218] 5-2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N3, N3- dimethyl indole -2,3- diformamide hydrochloride
Using method similarly to Example 5, the compound that the compound obtained by reference example 253 and reference example 289 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.40-1.51 (1H, m), 1.75-2.01 (5H, m), 2.78 (9H, s), 2.93 (3H, s), 3.01 (3H, s), 3.10-3.33 (3H, m), 3.40-3.50 (1H, m), 3.65-3.75 (1H, m), 4.01-4.09 (1H, m), 4.32-4.44 (1H, m), 4.62-4.75 (2H, m), 7.25 (1H, d, J=8.0Hz), 7.40-7.50 (2H, m), 8.62 (1H, br), 9.08 (1H, br), 12.28 (1H, br)
MS(FAB)m/z：614(M+H)+.
[embodiment 219] N- { (1R, 2S, 5S) -2- [(the chloro- 2- naphthoyls of 6-) amino] -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (270mg) that reference example 294 is obtained is dissolved in dichloromethane (10ml), adds 1N acidic alcohol (10ml), stirs 90 minutes.Solvent is boiled off under decompression, N is dissolved in by residue obtained, dinethylformamide (7ml), compound (110mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (100mg) and the hydrate of I-hydroxybenzotriazole 1 (70mg) that reference example 10 is obtained are added, is stirred 23 hours at room temperature.The reaction solution that is concentrated under reduced pressure adds water, and is extracted with ethyl acetate, and uses anhydrous sodium sulfate drying.Decompression boils off solvent, and residue (dichloromethane: methanol=20: 1 → 10: 1) is carried out 2 times and refined, gained free alkali is dissolved in into methanol, add 1N ethanol solution hydrochloride (0.30ml) with silica gel column chromatography.Decompression boils off solvent, and residue with ethyl acetate washing obtains title compound (130mg).
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.10 (2H, m), 2.81 (3H, s), 2.91 (3H, s), 3.00 (3H, s), 3.00-3.22 (3H, m), 3.53 (2H, br), 4.10-4.20 (1H, m), 4.30-4.70 (3H, m), 7.59 (1H, dd, J=8.8, 2.2Hz), 7.87 (1H, d, J=8.5Hz), 7.96 (1H, d, J=8.5Hz), 8.02 (1H, d, J=8.8Hz), 8.10 (1H, d, J=2.2Hz), 8.33 (1H, s), 8.43 (1H, d, J=8.1Hz), 8.52 (1H, d, J=7.3Hz)
MS(FAB)m/z：554(M+H)+.
Chloro- the N- ((1S of [embodiment 220] 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) cinnolines -3- carboxamide hydrochlorides
Figure G2003801097466D04632
Using the method same with embodiment 219, after the compound obtained with ethanol solution hydrochloride to reference example 299 is handled, title compound is made in the compound condensation for making it be obtained with reference example 10.
1H-NMR(CDCl3)δ：1.50-1.65 (1H, m), 1.70-1.90 (3H, m), 2.05-2.15 (1H, m), 2.15-2.30 (1H, m), 2.81 (3H, s), 2.85-3.05 (8H, m), 3.15-3.25 (2H, m), 3.40-3.80 (1H, m), 4.25-4.80 (4H, m), 8.02 (1H, dd, J=8.8,2.0Hz), (8.38 1H, d, J=8.8Hz), 8.66 (1H, s), 8.91 (1H, s), 8.96 (1H, d, J=7.3Hz), 9.53 (1H, br)
MS(FAB)m/z：556(M+H)+.
[embodiment 221] N- { (1R, 2S, 5S) -2- { [(5- chloro benzimidazole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04641
Using the method same with embodiment 219, after the compound obtained with ethanol solution hydrochloride to reference example 300 is handled, the compound condensation for making it be obtained with reference example 10 obtains title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.60-1.83 (3H, m), 2.00-2.20 (2H, m), 2.78 (3H, s), 2.92 (6H, s), 3.00-3.30 (3H, m), 3.47 (2H, br.s), 4.10-4.75 (4H, m), 7.30 (1H, d, J=8.8Hz), 7.62 (1H, d, J=12.5Hz), 7.63 (1H, s), 8.75-8.87 (1H, m), 9.09 (1H, dd, J=12.5,8.8Hz), 11.20-11.40 (1H, m)
MS(FAB)m/z：546(M+H)+.
[embodiment 222] N- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -7- fluorine isoquinolin -3- carboxamide hydrochlorides
Using method similarly to Example 5, the compound that the compound obtained by reference example 253 and reference example 304 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.50-1.60 (1H, m), 1.70-1.85 (3H, m), 1.95-2.05 (1H, m), 2.10-2.20 (1H, m), 2.80 (3H, s), 2.90-3.90 (5H, m), 2.93 (3H, s), 2.96 (3H, s), 4.10-4.75 (4H, m), 7.75-7.85 (1H, m), 8.00-8.05 (1H, m), 8.30-8.35 (1H, m), 8.61 (1H, s), 8.93 (2H, d, J=7.3Hz), 9.31 (1H, s)
MS(FAB)m/z：539(M+H)+.
[embodiment 223] N- { (1R, 2S, 5S) -2- { [(the chloro- 2H- chromenes -3- bases of 7-) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The compound (220mg) that reference example 252 is obtained is dissolved in methanol (10ml), adds 10% palladium carbon (180mg), is stirred at room temperature in nitrogen atmosphere 4 hours.After filtering reacting liquid, the lower concentration filtrate of decompression.Residue is dissolved in N, dinethylformamide (30ml), compound (108mg), the hydrate of I-hydroxybenzotriazole 1 (78mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (196mg) that reference example 306 is obtained are added, an evening is stirred at room temperature.The lower concentration of reaction solution of decompression, dichloromethane is added in residue and saturated sodium bicarbonate aqueous solution is carried out after point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=100: 3) is refined with silica gel column chromatography, obtains faint yellow blister material.The blister material is dissolved in dichloromethane (2ml), 1N ethanol solution hydrochloride (363 μ l) is added.After the lower concentrate solution of decompression, ether is added in residue, the sediment that leaching is separated out obtains title compound (175mg).
1H-NMR(DMSO-d6)δ：1.40-1.52 (1H, m), 1.55-1.96 (5H, m), 2.78 (3H, s), 2.90 (3H, s), 2.98 (3H, s), 3.01-3.12 (1H, m), 3.13-3.28 (2H, m), 3.40-3.85 (2H, m), 3.92-4.00 (1H, m), 4.35-4.80 (3H, m), 4.84 (1H, d, J=14.5Hz), 4.89 (1H, d, J=14.5Hz), 6.92 (1H, s), 6.98 (1H, dd, J=8.1, 1.7Hz), 7.08 (1H, s), 7.17 (1H, d, J=8.3Hz), 8.12 (1H, d, J=8.1Hz), 8.34 (1H, d, J=8.1Hz)
MS(FAB)m/z：558(M+H)+.
[embodiment 224] N- { (1R; 2S; 5S) -2- { [(E) -3- (4- chlorphenyls) -2- acryloyl groups] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04652
Using the method same with embodiment 219, after the compound obtained with ethanol solution hydrochloride to reference example 307 is handled, the compound condensation for making it be obtained with reference example 10 obtains title compound.
1H-NMR(DMSO-d6)δ：1.35-1.55 (1H, m), 1.55-1.90 (4H, m), 2.79 (3H, s), 2.92 (3H, s), 2.99 (3H, s), 3.05-3.30 (3H, m), 3.40-3.55 (1H, m), 3.60-3.75 (1H, m), 3.93-4.03 (2H, m), 4.35-4.50 (1H, m), 4.50-4.60 (1H, m), 4.60-4.75 (1H, m), 6.65 (1H, d, J=15.7Hz), 7.35 (1H, d, J=15.7Hz), 7.44 (1H, d, J=8.6Hz), 7.55 (1H, d, J=8.6Hz), 8.03 (1H, d, J=8.1Hz), 8.34 (1H, br.s), 11.25-11.70 (1H, br)
MS(ESI)m/z：530(M+H)+.
Chloro- the N- ((1S of [embodiment 225] 6-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -4- oxo-Isosorbide-5-Nitrae-EEDQ -2- carboxamide hydrochlorides
Figure G2003801097466D04661
Using method similarly to Example 5, the compound that the compound obtained by reference example 253 and reference example 309 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.43-1.60 (1H, m), 1.65-2.10 (3H, m), 2.79 (3H, s), 2.92 (3H, s), 2.99 (3H, s), 3.05-3.20 (2H, m), 3.20-3.80 (5H, m), 4.08-4.20 (1H, m), 4.35-4.50 (1H, m), 4.60-4.70 (1H, m), 4.70 (1H, d, J=15.6Hz), 6.77 (1H, br.s), 7.73 (1H, d, J=8.9Hz), 7.94 (1H, d, J=8.9Hz), 7.97 (1H, d, J=2.2Hz), 8.54 (1H, br.s), 8.80-9.00 (1H, m), 11.18-11.42 (1H, br), 11.70-12.50 (1H, br)
MS(ESI)m/z：571(M+H)+.
[embodiment 226] 2- [({ (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } amino) carbonyl] -4,6- dihydro -5H- pyrrolo-es [3,4-d] thiazole-5-carboxylic acid tert-butyl ester
1) compound (1.46g) obtained reference example 310 is dissolved in dichloromethane (10ml), and ethanol solution hydrochloride (10ml) is added at room temperature and is stirred 1 hour.After reaction terminates, solvent is boiled off, ethanol concentration is added, isopropyl ether is added in residue, is solidified, leaching, obtain N- { (1S, 2R, 4S) -2- amino -4- [(dimethylamino) carbonyl] cyclohexyl } -5- chloro-indole -2- carboxamide hydrochlorides.
2) at room temperature, the hydrochloride is dissolved in N, dinethylformamide (5ml), compound (1.31mg), the hydrate of I-hydroxybenzotriazole 1 (640mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (1.36g) that reference example 406 is obtained are added, is stirred 3 days at room temperature.Concentration of reaction solution, adds dichloromethane and saturated sodium bicarbonate aqueous solution is carried out after point liquid, organic layer anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (methanol: dichloromethane=1: 19) is refined with silica gel column chromatography, obtains title compound (1.22g).
1H-NMR(CDCl3)δ：1.53 (9H, s), 1.70-2.40 (6H, m), 2.80-3.20 (7H, m), 4.15-4.25 (1H, m), 4.55-4.80 (5H, m), 6.83 (1H, d, J=1.5Hz), 7.20 (1H, dd, J=8.8,2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.40-7.50 (1H, m), 7.61 (1H, br.s), 7.72-7.80 (1H, m), 9.41 (1H, br.s)
MS(ESI)m/z：615(M+H)+.
Chloro- the N- { (1S of [embodiment 227] 5-, 2R, 4S) -2- [[(5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino] -4- [(dimethylamino) carbonyl] cyclohexyl } indole 2-carboxamides hydrochloride
Figure G2003801097466D04671
The compound (1.22g) that embodiment 226 is obtained is dissolved in dichloromethane (5ml), and ethanol solution hydrochloride (10ml) is added at room temperature and is stirred 1 hour.Saturated sodium bicarbonate aqueous solution and dichloromethane point liquid, organic layer anhydrous sodium sulfate drying are added after concentration of reaction solution.Solvent is boiled off, residue (methanol: dichloromethane=1: 9) is refined with silica gel column chromatography, obtains the free alkali (636mg) of the title compound in colorless glassy solid.The free alkali (200mg) is dissolved in 1N ethanol solution hydrochloride (1ml), ethyl acetate solidification is added after concentration, the colourless powder obtained by leaching obtains title compound (195mg) after drying.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.05 (2H, m), 2.80 (3H, s), 2.98 (3H, s), 2.98-3.15 (1H, m), 4.05-4.20 (1H, m), 4.44 (2H, br.s), 4.58 (3H, br.s), 7.05 (1H, d, J=1.5Hz), 7.16 (1H, dd, J=8.7, 1.8Hz), 7.42 (1H, d, J=8.7Hz), 7.68 (1H, d, J=1.8Hz), 8.38 (1H, d, J=7.8Hz), 8.42 (1H, d, J=7.8Hz), 10.45-10.65 (2H, br), 11.78 (1H, br.s)
MS(FAB)m/z：515(M+H)+.
Chloro- the N- ((1S of [embodiment 228] 5-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl } indole 2-carboxamides hydrochloride
Using method similarly to Example 18, the compound and formalin obtained by embodiment 227 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.65-1.90 (3H, m), 1.90-2.05 (2H, m), 2.80 (3H, s), 2.98 (3H, s), 2.98-3.06 (1H, m), 3.06 (3H, s), 4.05-4.20 (1H, m), 4.30-5.00 (5H, br.s), 7.04 (1H, d, J=1.7Hz), 7.17 (1H, dd, J=8.8, 2.1Hz), 7.41 (1H, d, J=8.8Hz), 7.68 (1H, d, J=2.1Hz), 8.36 (1H, d, J=7.8Hz), 8.42 (1H, d, J=8.1Hz), 11.78 (1H, br.s), 12.14 (1H, br.s)
MS(FAB)m/z：529(M+H)+.
[embodiment 229] 2- { [((1R, 2S, 5S) -5- [(dimethylamino) carbonyl] -2- { [(5- fluoro indole -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl } -4,6- dihydro -5H- pyrrolo-es [3,4-d] thiazole-5-carboxylic acid tert-butyl ester
Using the method same with embodiment 226, the compound that the compound obtained by reference example 311 and reference example 406 are obtained prepares title compound.
1H-NMR(CDCl3)δ：1.53 (9H, s), 1.60-2.40 (6H, m), 2.80-3.20 (7H, m), 4.15-4.25 (1H, m), 4.55-4.80 (5H, m), 6.84-6.87 (1H, m), 7.01 (1H, dt, J=2.4,9.1Hz), 7.25-7.30 (1H, m), 7.34 (1H, dd, J=9.1,4.3Hz), 7.42-7.49 (1H, m), 7.70-7.80 (1H, m), 9.37-9.45 (1H, m)
MS(ESI)m/z：599(M+H)+.
[embodiment 230] N- { (1S, 2R, 4S) -2- [[(5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino] -4- [(dimethylamino) carbonyl] cyclohexyl } -5- fluoro indole -2- carboxamide hydrochlorides
Using the method same with embodiment 227, the compound obtained by embodiment 229 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.65-1.90 (3H, m), 1.90-2.10 (2H, m), 2.80 (3H, s), 2.97 (3H, s), 2.98-3.15 (1H, m), 4.05-4.20 (1H, m), 4.35-4.50 (2H, m), 4.58 (3H, br.s), 6.97-7.10 (2H, m), 7.35-7.47 (2H, m), 8.34 (1H, d, J=7.8Hz), 8.41 (1H, d, J=8.1Hz), 10.53 (2H, br.s), 11.68 (1H, br.s)
MS(FAB)m/z：499(M+H)+.
[embodiment 231] N- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) -5- fluoro indole -2- carboxamide hydrochlorides
Using method similarly to Example 18, the compound and formalin obtained by embodiment 230 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.65-1.90 (3H, m), 1.90-2.10 (2H, m), 2.80 (3H, s), 2.90-3.20 (7H, m), 4.05-4.20 (1H, m), 4.30-5.00 (5H, br.s), 6.95-7.10 (2H, m), 7.35-7.50 (2H, m), (8.33 1H, d, J=7.6Hz), (8.41 1H, d, J=8.1Hz), 11.67 (1H, br.s), 12.37 (1H, br.s)
MS(FAB)m/z：513(M+H)+.
[embodiment 232] N- { (1R; 2S; 5S) -2- [(the chloro- 2- naphthoyls of 6-) amino] -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- carboxamide hydrochlorides
Using the method same with embodiment 226, the compound that the compound obtained by reference example 294 and reference example 293 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.48-1.56 (1H, m), 1.71-1.84 (3H, m), 1.95-2.04 (2H, m), 2.81 (3H, s), 3.00 (3H, s), 3.02 (3H, s), 3.06-3.15 (2H, m), 4.13-4.14 (1H, m), 4.52-4.63 (4H, m), 7.60 (1H, d, J=8.5Hz), 7.87 (1H, d, J=8.8Hz), 7.96 (1H, d, J=8.5Hz), 8.01 (1H, d, J=8.8Hz), 8.10 (1H, s), 8.32 (1H, s), 8.45 (1H, d, J=8.1Hz), 8.51 (1H, d, J=7.3Hz)
MS(FAB)m/z：540(M+H)+.
Chloro- the N- ((1S of [embodiment 233] 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) cinnolines -3- carboxamide hydrochlorides and chloro- the N- ((1S of 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) cinnolines -3- formamides
The compound obtained in reference example 299 (adds 4N Yan Suan dioxane solutions (3.0ml), stirred 30 minutes at room temperature in 330mg) dioxanes (3.0ml)-dichloromethane (3.0ml) mixing suspension.Solvent is boiled off under decompression, gained white powder is dissolved in N, dinethylformamide (5.0ml), the compound (172mg) of the addition acquisition of reference example 293, the hydrate of I-hydroxybenzotriazole 1 (130mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (192mg), are stirred 15 hours at room temperature.Solvent is boiled off under decompression, dichloromethane and saturated sodium bicarbonate aqueous solution are added in residue.Organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Solvent is boiled off under decompression, residue (dichloromethane: methanol=20: 1) is refined with silica gel column chromatography.1N ethanol solution hydrochloride (0.35ml) is added in ethanol (4.0ml) solution of the highly polar main product of gained, solvent is boiled off under decompression.Ethanol and ether are added in residue, the precipitation of leaching generation, obtain chloro- the N- ((1S of 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) cinnolines -3- carboxamide hydrochlorides (184mg).
1H-NMR(DMSO-d6)δ：1.50-1.65 (1H, m), 1.70-1.90 (3H, m), 2.03-2.12 (1H, m), 2.15-2.30 (1H, m), 2.81 (3H, s), 2.90-3.05 (1H, m), 2.96 (3H, s), 3.07 (3H, s), 4.28-4.37 (1H, m), 4.40-4.95 (5H, br), 8.02 (1H, d, J=8.8Hz), 8.38 (1H, d, J=8.8Hz), 8.66 (1H, s), 8.91 (1H, s), 8.97 (1H, d, J=7.1Hz), 9.43-9.57 (1H, br), 11.75-11.95 (0.5H, br), 12.35-12.55 (0.5H, br)
MS(FAB)m/z：542(M+H)+.
In addition, pass through the refined of silica gel column chromatography, obtain chloro- the N- ((1S of 7- as the secondary product of low polarity, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) cinnolines -3- formamides (98mg)
1H-NMR(CDCl3)δ：1.90-2.25 (6H, m), 2.85-3.00 (1H, m), 2.95 (3H, s), 3.05 (3H, s), 3.91 (3H, s), 4.43-4.54 (1H, m), 4.86-4.95 (1H, m), 6.70 (1H, d, J=1.5Hz), 7.19 (1H, d, J=1.5Hz), 7.59 (1H, d, J=8.8Hz), 7.76 (1H, d, J=8.8Hz), 7.95 (1H, d, J=8.8Hz), 8.53 (1H, s), 8.64 (1H, d, J=8.0Hz), 8.73 (1H, s)
MS(FAB)m/z：540(M+H)+.
Chloro- the N- ((1S of [embodiment 234] 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) isoquinolin -3- carboxamide hydrochlorides
The compound (500mg) that reference example 146 is obtained is dissolved in ethanol solution hydrochloride (5ml), stirs 30 minutes at room temperature.Solvent is boiled off under decompression, N is dissolved in by residue obtained, dinethylformamide (7ml), the compound (299mg) of the addition acquisition of reference example 293, the hydrate of I-hydroxybenzotriazole 1 (71mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (403mg), stir an evening at room temperature.Solvent is boiled off under decompression, the aqueous solution and dichloromethane that saturated sodium bicarbonate is added in residue are carried out after point liquid, and water layer is extracted with dichloromethane.Merge organic layer, use anhydrous sodium sulfate drying.Solvent is boiled off under decompression, residue (dichloromethane: methanol=93: 7) is refined with silica gel column chromatography, obtains the free alkali (260mg) of the title compound in faint yellow solid.The solid is dissolved in dichloromethane, 1N ethanol solution hydrochloride (961 μ l) is added, solvent is boiled off under decompression.A small amount of methanol is added in residue, and instills ether, the precipitation of leaching generation is washed with ether, obtains title compound (260mg).
1H-NMR(DMSO-d6)δ：1.47-1.56 (1H, m), 1.71-1.75 (3H, m), 1.95-1.99 (1H, m), 2.12-2.15 (1H, m), 2.78 (3H, s), 2.95 (3H, s), 2.98 (1H, br.s), 3.05 (3H, s), 4.19-4.22 (1H, m), 4.44-4.52 (3H, m), 4.74-4.88 (2H, m), 7.87 (1H, dd, J=8.8, 1.7Hz), 8.24 (1H, d, J=8.8Hz), 8.36 (1H, d, J=1.7Hz), 8.58 (1H, s), 8.90-8.92 (2H, m), 9.30 (1H, s), 12.65-12.75 (1H, m)
MS(FAB)m/z：541(M+H)+.
[embodiment 235] 2- [({ (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } amino) carbonyl] -6,6- dimethyl -6,7- thiazolines simultaneously [4,5-c] pyridine -5 (4H)-carboxylic acid tert-butyl ester
Under an argon, the compound (95.4mg) reference example 316 obtained is dissolved in ether (1ml), and tert-butyl lithium (1.60N pentane solution, 244 μ l) is instilled in -78 DEG C.After -78 DEG C are stirred 1 hour, with 10 minutes introducing carbon dioxide gas.It is warming up to after room temperature and depressurizes lower concentration of reaction solution, residue is dissolved in N, dinethylformamide (5ml), compound (178mg), the hydrate of I-hydroxybenzotriazole 1 (48.0mg) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (136mg) of the acquisition of reference example 432 are sequentially added, is stirred all night at room temperature.Concentration of reaction solution, adds dichloromethane and saturated sodium bicarbonate aqueous solution carries out a point liquid.After organic layer anhydrous sodium sulfate drying, solvent is boiled off under decompression.Residue (methanol: dichloromethane=1: 19) is refined with silica gel column chromatography, obtains title compound (140mg).
1H-NMR(CDCl3)δ：1.50 (9H, s), 1.52 (3H, s), 1.54 (3H, s), 1.70-2.10 (4H, m), 2.15-2.45 (2H, m), 2.80-3.20 (9H, m), 4.10-4.25 (1H, br), 4.60-4.75 (3H, m), 6.85 (1H, br.s), 7.21 (1H, dd, J=8.8,1.8Hz), (7.34 1H, d, J=8.8Hz), (7.48 1H, d, J=7.3Hz), 7.61-7.63 (1H, m), 7.89 (1H, br.s), 9.27 (1H, br.s)
MS(ESI)m/z：657(M+H)+.
[embodiment 236] N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -6,6- dimethyl -4,5,6,7- tetrahydro-thiazoles simultaneously [4,5-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 227, the compound obtained by embodiment 235 prepares title compound.
1H-NMR(DMSO-d6)δ：1.40 (6H, s), 1.45-1.60 (1H, m), 1.70-2.05 (5H, m), 2.81 (3H, s), 2.95-3.15 (6H, m), 4.05-4.20 (1H, br), 4.25-4.45 (2H, m), 4.55-4.65 (1H, m), 7.06 (1H, d, J=1.7Hz), 7.17 (1H, dd, J=8.8, 2.0Hz), 7.42 (1H, d, J=8.8Hz), 7.68 (1H, d, J=2.0Hz), 8.34-8.39 (2H, m), 9.77 (1H, br.s), 9.84 (1H, br.s), 11.79 (1H, br.s)
MS(ESI)m/z：557(M+H)+.
[embodiment 237] 2- [({ (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } amino) carbonyl] -5,7- dihydro -6H- pyrrolo-es [3,4-d] pyrimidine -6- carboxylic acid tert-butyl esters
The compound (1.27g) that reference example 50 is obtained is dissolved in tetrahydrofuran (48ml), adds lithium hydroxide (117mg) and water (6.0ml), stirs 4.5 hours at room temperature.The lower evaporation reaction solution of decompression is obtained after rough carboxylic acid lithium salt (1.24g), using 2) the same method with embodiment 226, the compound condensation obtained with reference example 432 prepares title compound to solid.
1H-NMR(CDCl3)δ：1.50-1.70 (1H, m), 1.54 (9H, s), 1.80-2.10 (3H, m), 2.25-2.50 (2H, m), 2.85-2.95 (1H, m), 2.99 (3H, s), 3.14 (3H, s), 4.15-4.25 (1H, m), 4.65-4.75 (1H, m), 4.80-4.90 (4H, m), 6.97 (1H, s), 7.15-7.25 (1H, m), 7.30-7.40 (1H, m), 7.60-7.65 (1H, m), 8.15-8.25 (1H, m), 8.40-8.45 (1H, m), 8.75-8.85 (1H, m), 9.40-9.45 (1H, m)
MS(ESI)m/z：611(M+H)+.
[embodiment 238] N- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -6- methyl -6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine -2- carboxamide hydrochlorides
The compound (367mg) that embodiment 237 is obtained is dissolved in dichloromethane (10ml), adds trifluoroacetic acid (10ml), stirs 2 hours at room temperature.The lower evaporation reaction solution of decompression, by the thick product of gained and formalin, title compound is obtained using method similarly to Example 18 to solid.
1H-NMR(DMSO-d6)δ：1.50-1.60 (1H, m), 1.65-2.10 (5H, m), 2.81 (3H, s), 2.90-3.00 (1H, m), 2.96 (3H, s), 3.05 (3H, s), 4.10-4.20 (1H, m), 4.55-4.65 (1H, m), 4.65-4.90 (4H, br), 7.06 (1H, s), 7.15 (1H, dd, J=8.7, 2.1Hz), 7.41 (1H, d, J=8.8Hz), 7.66 (1H, d, J=1.7Hz), 8.35-8.45 (1H, m), 8.57 (1H, d, J=8.1Hz), 9.00 (1H, s), 11.80 (1H, s), 11.90-12.20 (1H, m)
MS(FAB)m/z：524(M+H)+.
Chloro- the N- ((1S of [embodiment 239] 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(6- methyl -6,7- thiazolines simultaneously [4,5-d] pyrimidine -2-base) carbonyl] amino } cyclohexyl) isoquinolin -3- carboxamide hydrochlorides
Figure G2003801097466D04741
Using the method same with embodiment 49, after the compound obtained with ethanol solution hydrochloride to reference example 146 is handled, the compound condensation for making it be obtained with reference example 322 obtains title compound.
1H-NMR(DMSO-d6)δ：1.50-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.15 (2H, m), 2.81 (3H, s), 2.95 (3H, s), 2.90-3.05 (1H, m), 3.26 (3H, s), 4.20-4.55 (2H, m), 5.00 (2H, s), 7.91 (1H, d, J=8.8Hz), 8.27 (1H, d, J=8.8Hz), 8.37 (1H, s), 8.54 (1H, s), 8.62 (1H, s), 8.79 (1H, d, J=8.3Hz), 8.94 (1H, d, J=8.1Hz), 9.32 (1H, s)
MS(ESI)m/z：554(M+H)+
Chloro- the N- ((1S of [embodiment 240] 7-, 2R, 4S) -4- { [ethyl (methyl) amino] carbonyl } -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) isoquinolin -3- carboxamide hydrochlorides
Figure G2003801097466D04742
Using method similarly to Example 2, the compound that the compound obtained by reference example 325 and reference example 10 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：0.98, 1.04 (3H, each t, J=7.1Hz), 1.52-1.60 (1H, m), 1.74-1.77 (3H, m), 1.96-2.05 (1H, m), 2.15-2.18 (1H, m), 2.77-2.93 (8H, m), 3.17-3.32 (3H, m), 3.49 (1H, br.s), 4.22 (1H, br.s), 4.41-4.45 (1H, m), 4.51 (1H, br.s), 4.69-4.72 (1H, m), 7.89 (1H, d, J=8.7Hz), 8.26 (1H, d, J=8.7Hz), 8.37 (1H, s), 8.60 (1H, s), 8.91-8.98 (2H, m), 9.32 (1H, d, J=6.6Hz), 11.39, 11.53 (1H, each m)
MS(FAB)m/z：569(M+H)+.
[embodiment 241] N- { (1R*, 2S*, 5S*) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [2- (dimethylamino) -2- oxoethyls] cyclohexyl -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04751
Using method similarly to Example 2, the compound that the compound obtained by reference example 336 and reference example 10 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.13-1.22 (1H, m), 1.40-1.46 (1H, m), 1.68-1.99 (5H, m), 2.18-2.29 (2H, m), 2.80 (3H, s), 2.92 (3H, s), 2.96 (3H, s), 3.22 (2H, br.s), 3.49 (1H, br.s), 3.70 (1H, br.s), 4.09-4.16 (1H, m), 4.42-4.46 (2H, m), 4.67 (1H, br.s), 7.03 (1H, s), 7.16 (1H, dd, J=8.5, 1.5Hz), 7.42 (1H, d, J=8.5Hz), 7.67 (1H, s), 8.01 (1H, d, J=8.5Hz), 8.40 (1H, d, J=7.8Hz), 11.35-11.58 (1H, m), 11.76 (1H, br.s)
MS(FAB)m/z：557(M+H)+.
[embodiment 242] N- { (1R; 2S; 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(methyl sulphonyl) methyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 219, the compound obtained with ethanol solution hydrochloride to reference example 340 is handled, then the compound condensation obtained with reference example 10, obtains title compound.
1H-NMR(DMSO-d6)δ：1.35-1.40 (1H, m), 1.55-1.62 (1H, m), 1.70-1.76 (1H, m), 1.88-1.94 (1H, m), 2.03-2.07 (1H, m), 2.13-2.17 (1H, m), 2.30-2.33 (1H, m), 2.43-3.48 (10H, m), 3.60-3.73 (2H, m), 4.11-4.16 (1H, m), 4.40-4.42 (2H, m), 4.68-4.73 (1H, m), 7.05 (1H, s), 7.16 (1H, dd, J=2.0, 8.8Hz), 7.41 (1H, d, J=8.8Hz), 7.68 (1H, s), 8.26 (1H, d, J=7.8Hz), 8.39 (1H, d, J=7.8Hz), 11.78 (1H, br.s)
MS(ESI)m/z：564(M+H)+.
[embodiment 243] N- { (1R, 2S, 5S) -2- { [(the chloro- 6H- thienos [2 of 2-, 3-b] pyrroles -5- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D04761
Using the method same with embodiment 223, after the compound for catalysis reduction that reference example 252 is obtained, the compound condensation for making it be obtained with reference example 345 obtains title compound.
1H-NMR(CDCl3)δ：1.56-1.66 (1H, m), 1.76-1.93 (2H, m), 2.02-2.06 (1H, m), 2.19-2.26 (1H, m), 2.30-2.34 (1H, m), 2.52 (3H, s), 2.79-2.88 (3H, m), 2.91-2.94 (2H, m), 2.96 (3H, s), 3.09 (3H, s), 3.69-3.77 (2H, m), 4.13-4.19 (1H, m), 4.58-4.61 (1H, m), 6.72 (1H, s), 6.84 (1H, s), 7.50 (1H, d, J=7.3Hz), 7.60 (1H, d, J=5.8Hz), 10.54 (1H, br)
MS(ESI)m/z：549(M+H)+.
[embodiment 244] N- { (1R; 2S; 5S) -2- { [3- (4- chlorphenyls) -2- propine acyl group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04762
Using the method same with embodiment 223, after the compound for catalysis reduction that reference example 252 is obtained, the compound condensation for making it be obtained with reference example 347 obtains title compound.
1H-NMR(DMSO-d6)δ：1.38-1.50 (1H, m), 1.58-1.92 (4H, m), 2.78 (3H, s), 2.90 (3H, s), 2.97 (3H, s), 3.01-3.24 (3H, m), 3.26-3.80 (2H, m), 3.90-3.98 (1H, m), 4.30-4.78 (3H, m), (7.51 1H, d, J=8.8Hz), (7.57 1H, d, J=8.8Hz), (8.34 1H, d, J=8.8Hz), 8.83 (1H, d, J=7.8Hz)
MS(FAB)m/z：528(M+H)+.
Chloro- the N- ((1S of [embodiment 245] 6-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -4- oxo-Isosorbide-5-Nitrae-dihydroquinazoline -2- carboxamide hydrochlorides
Figure G2003801097466D04771
Using the method same with embodiment 223, after the compound for catalysis reduction that reference example 252 is obtained, the compound condensation obtained with reference example 349 obtains title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.20 (3H, m), 2.80 (3H, s), 2.93 (3H, s), 2.97 (3H, s), 2.98-3.80 (4H, m), 4.05-4.20 (2H, m), 4.35-4.80 (3H, m), (7.63 1H, d, J=8.3Hz), (7.90 1H, d, J=7.3Hz), 8.75-9.00 (2H, m), 11.00-11.50 (1H, br), 12.53 (1H, br.s)
MS(ESI)m/z：573(M+H)+.
[embodiment 246] N- { (1R; 2S; 5S) -2- { [2- (4- chloroanilinos) -2- oxos ethanethioyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D04772
The compound (150mg) that the compound (184mg) and reference example 351 that reference example 253 is obtained are obtained is dissolved in methanol (1ml)-dichloromethane (4ml), in 150 DEG C of heating stirrings, boil off and continue to heat 5 minutes after solvent.Product (dichloromethane: methanol=24: 1) is refined with silica gel column chromatography, obtains title compound (59mg) after natural cooling.
1H-NMR(CDCl3)δ：1.65-1.90 (2H, m), 1.90-2.00 (1H, m), 2.00-2.15 (2H, m), 2.20-2.30 (1H, m), 2.52 (3H, s), 2.75-2.95 (5H, m), 2.96 (3H, s), 3.07 (3H, s), 3.68 (1H, d, J=15.2Hz), 3.75 (1H, d, J=15.7Hz), 4.45-4, 60 (1H, m), 4.80-4.85 (1H, m), 7.31 (2H, d, J=8.8Hz), 7.44 (1H, d, J=8.6Hz), 7.60 (2H, d, J=8.8Hz), 9.99 (1H, d, J=7.6Hz), 10.15 (1H, s)
MS(ESI)m/z：563(M+H)+.
[embodiment 247] N- { (1R; 2S; 5S) -2- { [2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D04781
The compound (150mg) that the compound (184mg) and reference example 353 that reference example 253 is obtained are obtained is dissolved in methanol (0.3ml)-dichloromethane (0.3ml), in 150 DEG C of heating stirrings, boil off and continue to heat 5 minutes after solvent.Product (dichloromethane: methanol=24: 1) is refined with silica gel column chromatography, obtains title compound (52mg) after natural cooling.
1H-NMR(CDCl3)δ：1.60-2.00 (3H, m), 2.00-2.20 (2H, m), 2.25-2.40 (1H, m), 2.53 (3H, s), 2.80-2.95 (5H, m), 2.96 (3H, s), 3.08 (3H, s), 3.70 (1H, d, J=15.4Hz), 3.75 (1H, d, J=15.4Hz), 4.45-4, 60 (1H, m), 4.75-4.85 (1H, m), 7.45 (1H, d, J=8.3Hz), 7.67 (1H, dd, J=8.8, 2.5Hz), 8.18 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.0Hz), 10.06 (1H, d, J=6.3Hz), 10.56 (1H, s)
MS(ESI)m/z：564(M+H)+.
[embodiment 248] N- { (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- ethanethioyls } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D04782
The compound (72mg) and 2- amino -5- chloropyridines (100mg) that reference example 355 is obtained are dissolved in methanol (0.2ml)-dichloromethane (0.2ml), in 150 DEG C of heating stirrings, are boiled off and are heated 8 minutes after solvent.Product (dichloromethane: methanol=23: 2) is refined with silica gel thin-layer chromatography is prepared, obtains title compound (4mg) after natural cooling.
1H-NMR(CDCl3)δ：1.60-2.00 (3H, m), 2.00-2.20 (3H, m), 2.53 (3H, s), 2.75-3.00 (5H, m), 2.95 (3H, s), 3.05 (3H, s), 3.65-3.80 (2H, m), 4.05-4.15 (1H, m), 4.70-4.80 (1H, m), 7.28 (1H, d), (7.43 1H, d, J=9.3Hz), 7.75 (1H, dd, J=8.8,2.7Hz), 8.41 (1H, d, J=2.7Hz), 9.05 (1H, d, J=8.8Hz), 11.56 (1H, s)
MS(ESI)m/z：564(M+H)+.
[embodiment 249] N1- (the chloro- 2- thienyls of 5-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04791
Using the method same with embodiment 191, the compound that reference example 356 is obtained is hydrolyzed, after the compound condensation obtained with reference example 253, handled with hydrochloric acid, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.40-1.55 (1H, m), 1.60-1.85 (3H, m), 1.90-2.15 (2H, m), 2.79 (3H, s), 2.90-3.15 (1H, m), 2.92 (3H, s), 2.94 (3H, s), 3.15-3.30 (2H, m), 3.50-3.80 (2H, m), 3.95-4.05 (1H, m), 4.35-4.90 (3H, m), 6.90 (1H, d, J=4.2Hz), 6.94 (1H, d, J=4.2Hz), 8.72 (1H, d, J=7.3Hz), 9.13 (1H, br.s), 11.21 (1H, br.s), 12.32 (1H, br.s)
MS(ESI)m/z：553(M+H)+.
[embodiment 250] N- { (1R, 2S, 5S) -2- { [(4- chloroanilinos) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04801
Isocyanic acid 4- chlorobenzenes ester (76.8mg) is added in dichloromethane (2ml) solution for the compound (183mg) that reference example 253 is obtained, is stirred 24 hours at room temperature.Solvent is boiled off under decompression, residue (dichloromethane: methanol=20: 1 → 10: 1) is refined with silica gel column chromatography, boils off solvent.Residue is dissolved in ethanol (2ml) and dichloromethane (2ml), 1N ethanol solution hydrochloride (0.4ml) is added, stirred 30 minutes at room temperature.The lower concentration of reaction solution of decompression, residue is solidified, obtain title compound (160mg) with ether.
1H-NMR(DMSO-d6)δ：1.35-1.50 (1H, m), 1.60-1.90 (5H, m), 2.79 (3H, s), 2.92 (3H, s), 3.00 (3H, s), 3.10-3.60 (4H, m), 3.60-3.90 (2H, m), 4.35-4.80 (3H, m), 6.26 (1H, br.s), 7.23 (2H, d, J=9.0Hz), 7.37 (2H, d, J=9.0Hz), 8.53 (1H, br.s), 8.72 (1H, br.s), 11.35,11.67 (whole 1H, each s)
MS(ESI)m/z：519(M+H)+.
[embodiment 251] N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (5- fluorine pyridine -2- bases) oxalamide hydrochloride
Using the method same with embodiment 191, the compound that reference example 357 is obtained is hydrolyzed, after the compound condensation obtained with reference example 253, processing is carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.47-1.53 (1H, m), 1.68-1.75 (3H, m), 1.99-2.10 (2H, m), 2.80 (3H, s), 2.80-3.00 (1H, m), 2.95 (6H, s), 3.18-3.21 (2H, m), 3.40-3.80 (2H, m), 3.87-4.82 (4H, m), 7.82-7.85 (1H, m), 8.01-8.05 (1H, m), 8.40 (1H, d, J=2.9Hz), 8.71 (1H, d, J=7.7Hz), 9.13 (1H, d, J=7.3Hz), 10.27 (1H, s)
MS(FAB)m/z：532(M+H)+.
[embodiment 252] N1- (4- chlorphenyls)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04811
Using the method same with embodiment 191, the compound that the compound obtained by reference example 242 and reference example 272 are obtained prepares title compound.
1H-NMR(DMSO-d6)δ：1.47-1.51 (1H, m), 1.69-1.75 (3H, m), 1.98-2.05 (2H, m), 2.80 (3H, s), 2.95 (3H, s), 2.98-3.04 (1H, m), 3.10 (3H, s), 3.40-4.61 (6H, m), 7.41 (2H, d, J=8.8Hz), 7.81 (2H, d, J=8.8Hz), 8.76 (1H, d, J=7.6Hz), 8.95 (1H, d, J=8.3Hz), 10.79 (1H, s)
MS(FAB)m/z：533(M+H)+.
[embodiment 253] N1- [4- chloro- 2- (trifluoromethyl) phenyl]-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Thionyl chloride (1ml) is added in the chloroformic solution (10ml) for the compound (269mg) that reference example 359 is obtained, is stirred 30 minutes in 75 DEG C, solvent and drying is boiled off under decompression.Under ice cooling, dichloromethane solution (7ml), the pyridine (3ml) for the compound (286mg) that reference example 253 is obtained are added wherein, are stirred 2 hours while being warming up to room temperature.Add saturated sodium bicarbonate aqueous solution (10ml) in reaction solution to carry out after point liquid operation, gained organic layer anhydrous sodium sulfate drying.Boiled off under decompression after solvent, gained residue silica gel column chromatography (dichloromethane: methanol=20: 1) and LH-20 column chromatography (molecular sieves, methanol) it is refined, obtain the free alkali (90mg) of the title compound in faint yellow non-crystalline solids.Dichloromethane (5ml), ethanol (5ml) and 1N ethanol solution hydrochloride (1ml) are added wherein, and the lower distillation drying of decompression obtains title compound.
1H-NMR(DMSO-d6)δ：1.41-1.55 (1H, m), 1.59-1.80 (3H, m), 1.98-2.13 (2H, m), 2.77 (3H, s), 2.91 (6H, s), 3.12-3.26 (2H, m), 3.30-3.58 (2H, m), 3.60-3.78 (1H, m), 3.94-4.04 (1H, m), 4.35-4.63 (2H, m), 4.64-4.80 (1H, m), 7.73-7.82 (2H, m), 7.85 (1H, s), 8.68-8.73 (1H, m), 9.18 (1H, br.s), 10.31 (1H, s)
MS(ESI)m/z：615(M+H)+.
[embodiment 254] N1- { the chloro- 2- of 4- [(dimethylamino) carbonyl] phenyl }-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04821
Using the method same with embodiment 191, the compound that reference example 362 is obtained is hydrolyzed, after the compound condensation obtained with reference example 253, processing is carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.42-1.56 (1H, m), 1.59-1.82 (3H, m), 1.98-2.14 (2H, m), 2.79 (3H, s), 2.91 (3H, s), 2.93 (3H, s), 2.95 (3H, s), 2.98 (3H, s), 3.10-3.30 (4H, m), 3.62-3.79 (1H, m), 3.92-4.01 (1H, m), 4.34-4.50 (2H, m), 4.66-4.79 (1H, m), 7.52 (1H, d, J=2.4Hz), 7.55 (1H, dd, J=2.4, 8.5Hz), 8.05 (1H, d, J=8.5Hz), 8.75 (1H, br), 9.10-9.24 (1H, m), 10.52 (1H, s)
MS(ESI)m/z：618(M+H)+.
[embodiment 255] N1- [4- chloro- 2- (hydroxymethyl) phenyl]-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using the method same with embodiment 199, make after compound that reference example 270 is obtained and 4- chlorine-2-hydroxyl methylanilines be condensed, to be handled with hydrochloric acid, acquisition title compound.
1H-NMR(DMSO-d6)δ：1.42-1.57 (1H, m), 1.58-1.81 (3H, m), 1.98-2.14 (2H, m), 2.79 (3H, s), 2.93 (6H, s), 3.12-3.58 (4H, m), 3.67-3.80 (1H, m), 3.94-4.04 (1H, m), 4.37-4.50 (1.5H, m), 4.55 (2H, s), 4.67-4.80 (1H, m), 5.77-5.92 (0.5H, m), 7.37 (1H, dd, J=2.4, 8.6Hz), 7.42 (1H, d, J=2.4Hz), 7.91 (1H, d, J=8.6Hz), 8.74-8.81 (1H, m), 9.03-9.19 (1H, m), 10.79 (1H, s)
MS(ESI)m/z：577(M+H)+.
[embodiment 256] N1- (the chloro- 2- methoxyphenyls of 4-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using the method same with embodiment 191, the compound that reference example 364 is obtained is hydrolyzed, then the compound condensation obtained with reference example 253, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.40-1.55 (1H, m), 1.58-1.79 (3H, m), 1.94-2.11 (2H, m), 2.77 (3H, s), 2.92 (6H, s), 3.05-3.55 (4H, m), 3.65-3.75 (1H, br), 3.90 (3H, s), 3.91-4.00 (1H, m), 4.36-4.47 (2H, br), 4.65-4.77 (1H, br), 7.04 (1H, dd, J=8.5, 2.0Hz), 7.20 (1H, d, J=2.0Hz), 8.06 (1H, d, J=8.5Hz), 8.65-8.80 (1H, br), 9.10-9.25 (1H, br), 9.74 (1H, s), 11.10-11.35 (1H, br)
MS(ESI)m/z：577(M+H)+.
[embodiment 257] N- { (1R; 2S; 5S) -2- { [2- (4- chloroanilinos) -2- (oxyimino) acetyl group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D04832
Using the method same with embodiment 214, after the compound deprotection for obtaining reference example 366 by HCl treatment, the compound condensation obtained with reference example 10, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.41-1.53 (1H, m), 1.57-1.77 (3H, m), 1.88-2.04 (2H, m), 2.77 (3H, s), 2.91 (6H, s), 3.00-3.60 (4H, m), 3.65-3.74 (1H, br), 3.87-3.96 (1H, m), 4.37-4.48 (2H, m), 4.66-4.76 (1H, m), 6.70 (2H, d, J=8.8Hz), 7.04 (1H, d, J=8.8Hz), 7.10 (1H, d, J=8.8Hz), 8.40-8.53 (2H, m), 8.57-8.66 (1H, m), 10.30-10.47 (1H, br), 10.66-10.76 (1H, br)
MS(ESI)m/z：562(M+H)+.
[embodiment 258] N1- (4- chlorphenyls)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide hydrochloride
Using the method same with embodiment 214, after the compound deprotection for obtaining reference example 367 by HCl treatment, the compound condensation obtained with reference example 10, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.60-1.72 (1H, m), 1.99-2.22 (1H, m), 2.90 (3H, s), 3.03-4.80 (17H, m), 7.40 (2H, d, J=8.8Hz), 7.83 (2H, d, J=8.8Hz), 8.56-8.73 (1H, br), 9.14-9.33 (1H, br), 10.83 (1H, s), 11.20-11.55 (1H, br)
MS(ESI)m/z：549(M+H)+.
[embodiment 259] N1- (5- chloropyridine -2- bases)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide hydrochloride
Using the method same with embodiment 214, after the compound deprotection for obtaining reference example 368 by HCl treatment, the compound condensation obtained with reference example 10, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.60-1.72 (1H, m), 1.98-2.20 (1H, m), 2.90 (3H, s), 3.00-4.77 (17H, m), 7.20-7.35 (0.8H, br), 7.48-7.56 (0.2H, br), 7.94-8.07 (1H, br), 8.40-8.70 (1H, br), 8.48-8.70 (1H, br), 9.23-9.45 (1H, br), 10.21-10.35 (1H, br), 11.30-11.70 (1H, br)
MS(ESI)m/z：550(M+H)+.
[embodiment 260] N1- (5- bromopyridine -2- bases)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide hydrochloride
Using the method same with embodiment 214, after the compound deprotection for obtaining reference example 369 by HCl treatment, the compound condensation obtained with reference example 10, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.60-1.73 (1H, m), 1.97-2.20 (1H, m), 2.90 (3H, s), 3.03-3.52 (7H, m), 3.64-4.07 (5H, m), 4.10-4.50 (4H, m), 4.65-4.78 (1H, m), 7.28-7.35 (0.2H, m), 7.97 (1H, d, J=8.8Hz), 8.11 (1H, dd, J=8.8, 2.2Hz), 8.51 (1H, d, J=2.2Hz), 8.55-8.67 (1H, m), 9.22-9.41 (1H, m), 10.20-10.31 (0.8H, m), 11.25-11.70 (1H, br)
MS(ESI)m/z：594(M+H)+.
[embodiment 261] N1- (4- chlorphenyls)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) malonamide hydrochloride
Using method similarly to Example 5, make after the compound condensation that the compound that reference example 371 is obtained is obtained with reference example 253, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.32-1.50 (1H, m), 1.55-1.87 (5H, m), 2.78 (3H, m), 2.92 (3H, s), 2.98 (3H, s), 2.99-3.00 (1H, m), 3.05-3.50 (5H, m), 3.65-3.75 (1H, m), 3.80-3.92 (1H, m), 4.35-4.45 (1H, m), 4.45-4.55 (1H, m), 4.65-4.80 (1H, m), 7.34 (2H, d, J=8.8Hz), 7.58 (2H, d, J=8.8Hz), 8.00-8.10 (1H, m), 8.30-8.40 (1H, m), 10.29 (1H, d, J=12.5Hz), 12.40 (1H, br.s)
MS(FAB)m/z：561(M+H)+.
[embodiment 262] N1- (3- chlorphenyls)-N3- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) malonamide hydrochloride
Figure G2003801097466D04861
Using method similarly to Example 5, make after the compound that reference example 373 is obtained and the compound condensation that reference example 253 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.32-1.50 (1H, m), 1.55-1.90 (5H, m), 2.77 (3H, s), 2.91 (3H, s), 2.98 (3H, s), 2.99-3.00 (1H, m), 3.05-3.50 (5H, m), 3.65-3.80 (1H, m), 3.80-3.90 (1H, m), 4.35-4.50 (1H, m), 4.50-4.60 (1H, m), 4.65-4.80 (1H, m), 7.09 (1H, d, J=8.8Hz), 7.31 (1H, d, J=8.8Hz), 7.38 (1H, t, J=8.8Hz), 7.79 (1H, s), 8.00-8.10 (1H, m), 8.30-8.40 (1H, m), 10.28 (1H, d, J=12.5Hz), 11.67 (1H, br.s)
MS(FAB)m/z：561(M+H)+.
[embodiment 263] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- { [ethyl (methyl) amino] carbonyl } -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Add under 10% palladium carbon (0.3g), nitrogen atmosphere and stir 24 hours in ethanol (20ml) solution for the compound (0.33g) that reference example 404 is obtained.Insoluble matter, the lower concentration filtrate of decompression are filtered off by diatomite.Residue obtained (0.37g) is dissolved in N, dinethylformamide (20ml), compound (0.3g), the hydrate of I-hydroxybenzotriazole 1 (0.2g) and 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (0.37g) of the acquisition of reference example 266 are sequentially added at room temperature, are stirred 18 hours at room temperature.The lower concentration of reaction solution of decompression, the mixed solvent dilution of residue obtained use chloroform-methanol (9: 1), then with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Boiled off under organic layer anhydrous sodium sulfate drying, decompression after solvent, and residue obtained use silica gel column chromatography (chloroform: methanol=95: 5) separation and purification, concentrate the part as purpose thing.In residue obtained middle addition 1N ethanol solution hydrochloride, be formed as after hydrochloride, recrystallized with the mixed solvent of methanol and ether, obtain title compound (0.28g).
1H-NMR(DMSO-d6)δ：0.95 (1.5H, t, J=6.9Hz), 1.42 (1.5H, t, J=6.9Hz), 1.40-1.52 (1H, m), 1.60-1.78 (3H, m), 1.92-2.11 (2H, m), 2.74 (3H, s), 2.90 (3H, s), 3.10-3.38 (5H, m), 3.40-3.52 (1H, m), 3.68-3.70 (1H, m), 3.96-4.05 (1H, m), 4.41 (2H, s), 4.70 (1H, d, J=15.9Hz), 8.00-8.01 (2H, m), 8.44 (1H, s), 8.71 (1H, dd, J=10.1, 2.2Hz), 9.14 (0.5H, d, J=7.8Hz), 9.22 (0.5H, d, J=8.3Hz), 10.24 (0.5H, s), 10.28 (0.5H, s), 11.48 (1H, br.s), 11.61 (1H, br.s)
MS(FAB)m/z：562(M+H)+.
[embodiment 264] N1- (4- chlorphenyls)-N2- ((1S, 2R, 4S) -4- { [ethyl (methyl) amino] carbonyl } -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04871
Using the method same with embodiment 263, the compound that reference example 404 is obtained is changed into after amine, the compound condensation obtained with reference example 374, and processing is carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：0.97 (1.5H, t, J=6.9Hz), 1.04 (1.5H, t, J=6.9Hz), 1.40-1.60 (1H, m), 1.60-1.80 (3H, m), 1.92-2.11 (2H, m), 2.74 (3H, s), 2.89 (3H, s), 3.10-3.32 (5H, m), 3.40-3.52 (1H, m), 3.65-3.80 (1H, m), 3.90-4.05 (1H, m), 4.40 (2H, s), 4.70 (1H, d, J=15.9Hz), 7.39 (2H, d, J=8.8Hz), 7.82 (2H, d, J=8.8Hz), 8.75 (1H, dd, J=10.1, 2.2Hz), 9.00 (0.5H, d, J=7.8Hz), 9.08 (0.5H, d, J=8.3Hz), 10.81 (1H, d, J=4.9Hz), 11.45 (1H, br.s)
MS(FAB)m/z：561(M+H)+.
[embodiment 265] N1- (5- bromopyridine -2- bases)-N2- ((1S, 2R, 4S) -4- { [ethyl (methyl) amino] carbonyl } -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using the method same with embodiment 263, the compound that reference example 404 is obtained is changed into after amine, the compound condensation obtained with reference example 375, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.02 (1.5H, t, J=6.9Hz), 1.08 (1.5H, t, J=6.9Hz), 1.49-1.60 (1H, m), 1.60-1.86 (3H, m), 2.00-2.20 (2H, m), 2.81 (3H, s), 2.97 (3H, s), 3.15-3.42 (6H, m), 3.50-3.60 (1H, m), 3.70-3.82 (1H, m), 4.48 (2H, s), 4.77 (1H, d, J=15.9Hz), 8.04 (1H, d, J=8.8Hz), 8.17 (1H, d, J=8.8Hz), 8.58 (1H, s), 8.78 (1H, dd, J=10.1, 2.2Hz), 9.21 (0.5H, d, J=7.8Hz), 9.29 (0.5H, d, J=8.3Hz), 10.29 (0.5H, s), 10.33 (0.5H, s), 11.53 (0.5H, br.s), 11.65 (0.5H, br.s)
MS(FAB)m/z：607(M+H)+.
[embodiment 266] N1- (the chloro- 3- fluorophenyls of 4-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using the method same with embodiment 263, the compound that reference example 252 is obtained is changed into after amine, the compound condensation obtained with reference example 378, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.44-1.52 (1H, m), 1.65-1.76 (3H, m), 2.01-2.07 (2H, m), 2.77 (3H, s), 2.93 (6H, s), 2.94-3.00 (1H, m), 3.10-3.38 (3H, m), 3.68-3.70 (1H, m), 3.96-4.05 (1H, m), 4.42 (2H, s), 4.70 (1H, d, J=15.9Hz), 7.56 (1H, t, J=8.8Hz), 7.68 (1H, d, J=8.8Hz), 7.90 (1H, dd, J=11.7, 1.5Hz), 8.73 (1H, dd, J=12.5, 7.3Hz), 9.06 (1H, dd, J=12.5, 8.1Hz), 11.01 (1H, d, J=5.8Hz), 11.30-11.42 (1H, m)
MS(FAB)m/z：565(M+H)+.
[embodiment 267] N- { (1R; 2S; 5S) -2- { [3- (4- chlorphenyls) -3- oxos propiono] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Figure G2003801097466D04891
Using the method same with embodiment 214, after the compound deprotection for obtaining reference example 383 by HCl treatment, the compound condensation obtained with reference example 10, then handled with hydrochloric acid, obtain title compound.
1H-NMR(CDCl3) (free alkali) δ：1.22-1.32 (1H, m), 1.49-1.92 (3H, m), 1.95-2.10 (2H, m), 2.53 (3H, s), 2.70-2.79 (1H, m), 2.80-2.90 (2H, m), 2.93 (6H, s), 2.95-3.09 (2H, m), 3.72 (2H, s), 3.87 (2H, s), 4.05-4.19 (1H, m), 4.60-4.70 (1H, m), 7.20-7.40 (2H, m), (7.42 2H, d, J=8.3Hz), 7.87 (2H, d, J=8.3Hz)
MS(FAB)m/z：546(M+H)+.
[embodiment 268] N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide
Using the method same with embodiment 214, after the compound deprotection for obtaining reference example 386 by HCl treatment, the compound condensation obtained with reference example 293 obtains title compound.
1H-NMR(DMSO-d6)δ：1.00-2.35 (7H, m), 2.96 (3H, s), 3.04 (3H, s), 3.85-3.95 (1H, m), 3.88 (3H, s), 4.60-4.75 (1H, m), 6.68 (1H, d, J=2.0Hz), 7.17 (1H, d, J=2.0Hz), and 7.20-7.32 (1H, m), 7.67 (1H, dd, J=8.8,2.8Hz), 7.99 (1H, d, J=8.4Hz), 8.21 (1H, d, J=8.8Hz), 8.25 (1H, d, J=2.8Hz), 9.64 (1H, s)
HRMS(FAB)m/z：532.1520(M+H)+.
(calculated value；C23H27ClN7O4S：532.1534)
[embodiment 269] N1- [(5- chloropyridine -2- bases) amino]-N2- ((1R, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04901
Using the method same with reference example 253, the compound that reduction reference example 387 is obtained, the compound condensation that with reference example 266 obtains same with the method that embodiment 208 is recorded is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.50-1.98 (6H, m), 2.82 (3H, s), 2.91 (3H, s), 2.95 (3H, s), 2.86-3.92 (7H, m), 4.30-4.81 (2H, m), 7.92-8.09 (2H, m), 8.39-8.47 (1H, m), 8.56-8.72 (2H, m), 10.17 (1H, s)
MS(ESI)m/z：548(M+H)+.
[embodiment 270] N1- (4- chlorphenyls)-N2- ((1R, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
Figure G2003801097466D04902
Same with the method that reference example 253 is recorded, the compound that reduction reference example 387 is obtained is same with the method that embodiment 191 is recorded, and lithium salts formed by the compound obtained with hydrolysis reference example 242 is condensed, and is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.50-1.97 (6H, m), 2.82 (3H, s), 2.91 (3H, s), 2.98 (3H, s), 2.83-3.88 (7H, m), 4.30-4.79 (2H, m), 7.37 (2H, d, J=8.8Hz), 7.89 (2H, d, J=8.8Hz), 8.34 (1H, d, J=8.4Hz), 8.63 (1H, d, J=8.8Hz), 10.72 (1H, s)
MS(ESI)m/z：547(M+H)+.
[embodiment 271] N1- { (1R, 2R, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl }-N2- (pyridin-4-yl) oxalamide hydrochloride
The compound for obtaining reference example 310 by HCl treatment is deprotected; it is same with the method that embodiment 191 is recorded; after 2- [(pyridin-4-yl) amino] -2- Oxoacetic Acids lithium salts condensation obtained by the compound hydrolysis obtained with reference example 261, processing is carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.40-2.01 (6H, m), 2.79 (3H, s), 3.01 (3H, s), 3.00-3.18 (1H, m), 4.02-4.19 (1H, m), 4.45-4.55 (1H, m), 7.09 (1H, s), 7.13-7.22 (1H, m), 7.41 (1H, d, J=8.4Hz), 7.64 (1H, br.s), 8.28 (2H, d, J=6.8Hz), 8.36 (1H, d, J=8.0Hz), 8.62 (1H, d, J=8.8Hz), 8.72 (2H, d, J=6.8Hz), 11.74 (1H, s), 11.83 (1H, s)
MS(FAB)m/z：511(M+H)+.
[embodiment 272] N1- { (1R, 2R, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl }-N2- (pyridin-3-yl) oxalamide hydrochloride
Figure G2003801097466D04912
It is same with the method that reference example 242 is recorded, it is condensed 3- aminopyridines and 2- chloro-2-oxos methyl acetate, using gained 2- [(pyridin-3-yl) amino] -2- oxoacetic acid methyl esters and the compound of the acquisition of reference example 310 as raw material, using the method same with embodiment 271, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.40-2.05 (6H, m), 2.80 (3H, s), 3.02 (3H, s), 2.92-3.15 (1H, m), 4.02-4.17 (1H, m), 4.42-4.58 (1H, m), 7.10 (1H, s), 7.12-7.19 (1H, m), 7.40 (1H, d, J=8.4Hz), 7.62-7.87 (2H, m), 8.36-8.64 (4H, m), 9.18 (1H, s), 11.39 (1H, s), 11.79 (1H, s)
MS(FAB)m/z：511(M+H)+.
[embodiment 273] N1- { (1R, 2S, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl }-N2- (piperidin-4-yl) oxalamide hydrochloride
At room temperature, add and stirred 5 hours at the 4N sour dioxane solution (8.0ml) of salt, identical temperature in ethanol (5.0ml) solution for the compound (400mg) that reference example 389 is obtained.Solvent is boiled off under decompression, after being washed with dichloromethane, filtration washing insoluble matter obtains title compound (320mg).
1H-NMR(DMSO-d6)δ：1.38-1.92 (10H, m), 2.77 (3H, s), 2.96 (3H, s), 2.82-3.35 (6H, m), 3.88-4.10 (2H, m), 4.34-4.43 (1H, m), 7.05 (1H, s), 7.11-7.17 (1H, m), 7.38 (1H, d, J=8.8Hz), 7.65 (1H, s), 8.25 (1H, d, J=8.0Hz), 8.34 (1H, d, J=7.6Hz), 8.89 (1H, d, J=8.4Hz), 11.75 (1H, s)
MS(ESI)m/z：517(M+H)+.
[embodiment 274] N1- { (1R, 2R, 5S) -2- { [(5- chloro-indole -2- bases) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl }-N2- (1- methyl piperidine -4- bases) oxalamide hydrochloride
Figure G2003801097466D04922
It is same with the method that reference example 9 is recorded, after the compounds methyl that embodiment 273 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.40-2.01 (11H, m), 2.67 (3H, s), 2.79 (3H, s), 2.98 (3H, s), 2.85-4.48 (7H, m), 7.07 (1H, s), 7.16 (1H, dd, J=8.8,2.0Hz), 7.40 (1H, d, J=8.8Hz), 7.68 (1H, d, J=2.0Hz), 8.25-8.35 (1H, m), (8.37 1H, d, J=7.6Hz), 8.90-9.02 (1H, m), 9.82 (1H, br.s), 11.78 (1H, s)
MS(ESI)m/z：531(M+H)+.
[embodiment 275] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N1- methyl oxalamide hydrochloride
Figure G2003801097466D04931
Using the method same with embodiment 191, the compound that reference example 390 is obtained is hydrolyzed, after the compound condensation obtained with reference example 253, handled with hydrochloric acid, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.32-1.97 (6H, m), 2.42-2.51 (1H, m), 2.76 (3H, s), 2.91 (3H, s), 2.93 (3H, s), 3.27 (3H, s), 3.00-4.80 (8H, m), 7.45 (1H, br.s), 7.88-7.97 (1H, m), 8.25-8.41 (2H, m), 8.78-8.91 (1H, m)
MS(FAB)m/z：562(M+H)+.
[embodiment 276] N1- (5- chlorine pyrimidine -2-base)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
It is same with the method that embodiment 191 is recorded, the compound that reference example 391 is obtained is hydrolyzed, after the compound condensation obtained with reference example 253, handled with hydrochloric acid, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.38-2.10 (7H, m), 2.77 (3H, s), 2.90 (3H, s), 2.93 (3H, s), 3.04-4.80 (8H, m), 8.60-8.70 (2H, m), 8.82 (2H, s), 9.08 (1H, br.s), 10.64 (1H, s), 11.57 (1H, br.s)
MS(FAB)m/z：549(M+H)+.
[embodiment 277] N1- (4- chlorphenyls)-N2- ((1S, 2R, 4S) -4- { [ethyl (methyl) amino] carbonyl } -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04941
Method with the record of reference example 253 is same, the compound that reduction reference example 392 is obtained, same with the method that embodiment 195 is recorded, the carboxylic acid condensation with hydrolyzing the gained compound of reference example 242 and obtaining, and is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：0.96, 1.02 (3H, each t, J=7.0Hz), 1.47-1.58 (1H, m), 1.65-1.77 (3H, m), 1.98-2.08 (2H, m), 2.76-2.91 (4H, m), 3.07 (3H, s), 3.19-3.41 (2H, m), 3.98-4.04 (1H, m), 4.42 (1H, br.s), 4.46-4.94 (4H, m), 7.41 (2H, d, J=8.8Hz), 7.83 (2H, d, J=8.8Hz), 8.74-8.80 (1H, m), 9.02 (1H, d, J=7.3Hz), 10.82 (1H, s), 12.41 (1H, br.s)
MS(FAB)m/z：547(M+H)+.
[embodiment 278] N1- (5- bromopyridine -2- bases)-N2- ((1S, 2R, 4S) -4- { [ethyl (methyl) amino] carbonyl } -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Same with the method that embodiment 277 is recorded, the compound that the compound and reference example 262 obtained by reference example 392 is obtained prepares title compound.
1H-NMR(DMSO-d6)δ：0.90-1.08 (3H, m), 1.40-2.13 (6H, m), 2.70-3.53 (13H, m), 3.92-4.08 (1H, m), 4.35-4.47 (1H, m), 7.95 (1H, d, J=8.8Hz), 8.10 (1H, dd, J=8.8,2.4Hz), 8.50-8.55 (1H, m), 8.68-8.78 (1H, m), 9.12-9.18 (1H, m), 10.26 (1H, s)
MS(FAB)m/z：592(M+H)+.
[embodiment 279] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- { [ethyl (methyl) amino] carbonyl } -2- { [(5- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04951
Same with the method that embodiment 277 is recorded, the compound that the compound and reference example 243 obtained by reference example 392 is obtained prepares title compound.
1H-NMR(DMSO-d6)δ：[0.95 (t, J=7.0Hz), 1.01 (t, J=6.8Hz), 3H], and 1.45-1.72 (4H, m), 1.96-2.07 (2H, m), 2.74-2.90 (4H, m), 3.06 (3H, s), 3.18-3.40 (2H, m), 3.95-4.02 (1H, m), 4.41 (1H, br.s), 4.54-4.90 (4H, m), 8.00 (2H, br.s), 8.45 (1H, s), 8.70-8.75 (1H, m), 9.15 (1H, br.s), 10.27 (1H, br.s), 12.29 (1H, br.s)
MS(ESI)m/z：548(M+H)+.
[embodiment 280] N1- (the chloro- 3- methoxyphenyls of 4-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04952
It is same with the method that embodiment 2 is recorded, make the compound that reference example 395 is obtained and the compound condensation that reference example 10 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.46-1.54 (1H, m), 1.67-1.77 (3H, m), 2.01-2.10 (2H, m), 2.79 (3H, s), 2.92-2.98 (7H, m), 3.21 (2H, br.s), 3.49 (1H, br.s), 3.69 (1H, br.s), 3.80 (3H, s), 3.98-4.03 (1H, m), 4.42-4.50 (2H, m), 4.69 (1H, br.s), 7.37 (1H, d, J=8.7Hz), 7.48 (1H, dd, J=8.7, 2.2Hz), 7.72 (1H, d, J=2.2Hz), 8.75 (1H, d, J=7.3Hz), 9.06 (1H, br.s), 10.77 (1H, s), 11.44 (1H, br.s)
MS(FAB)m/z：577(M+H)+.
[embodiment 281] N1- (4- chlorphenyls)-N2-((1R*, 2R*) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclopenta) oxalamide hydrochloride
Same with the method that embodiment 195 is recorded, after the compound that hydrolysis reference example 242 is obtained, the compound condensation obtained with reference example 62 is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.65-1.73 (4H, m), 1.91-1.96 (2H, m), 2.91 (3H, s), 3.15 (2H, br.s), 3.49 (1H, br.s), 3.66 (1H, br.s), 4.32-4.42 (3H, m), 4.66 (1H, br.s), 7.40 (2H, d, J=8.9Hz), 7.84 (2H, d, J=8.9Hz), 8.92 (1H, d, J=8.5Hz), 9.03 (1H, d, J=8.3Hz), 10.76 (1H, s), 11.32 (1H, br.s)
MS(FAB)m/z：462(M+H)+.
[embodiment 282] N1- (5- chloropyridine -2- bases)-N2-((1R*, 2R*) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclopenta) oxalamide hydrochloride
It is same with the method that embodiment 208 is recorded, reference example 62 is obtained after the compound condensation that compound and reference example 266 are obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.71 (4H, br.s), 1.96 (2H, br.s), 2.90 (3H, s), 3.14 (1H, br.s), 3.21 (1H, br.s), 3.47 (1H, br.s), 3.68 (1H, br.s), 4.34-4.45 (3H, m), 4.66 (1H, br.s), 7.99-8.06 (2H, m), 8.43-8.44 (1H, m), 8.94 (1H, d, J=8.3Hz), 9.20 (1H, d, J=8.5Hz), 10.20 (1H, br.s), 11.78 (1.1H, br.s)
MS(FAB)m/z：463(M+H)+.
[embodiment 283] N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (4- ethynyl phenyls) oxalamide
Using the method same with embodiment 263, make the compound that reference example 252 is obtained and the compound condensation that reference example 397 is obtained, prepare title compound.
1H-NMR(CDCl3)δ：1.67-2.16 (6H, m), 2.51 (3H, s), 2.76-2.91 (5H, m), 2.94 (3H, s), 3.04 (3H, s), 3.07 (1H, s), [3.65 (1H, d, J=15.5Hz), 3.73 (1H, d, J=15.5Hz) AB types], and 4.09-4.16 (1H, m), 4.72-4.75 (1H, m), 7.42-7.46 (3H, m), 7.58 (2H, d, J=8.5Hz), 8.02 (1H, d, J=8.1Hz), 9.36 (1H, s)
MS(FAB)m/z：537(M+H)+.
[embodiment 284] N1- (5- chloropyrazine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04972
It is same with the method that reference example 97 is recorded, make after the compound that reference example 253 is obtained and the compound condensation that reference example 399 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.44-1.52 (1H, m), 1.65-1.77 (3H, m), 2.00-2.10 (2H, m), 2.77 (3H, s), 2.91-2.97 (7H, m), 3.20 (2H, br.s), 3.48 (1H, br.s), 3.68 (1H, br.s), 3.97-4.02 (1H, m), 4.40-4.46 (2H, m), 4.68 (1H, br.s), 8.64 (1H, d, J=1.2Hz), 8.70 (1H, d, J=7.3Hz), 9.02 (1H, s), 9.21 (1H, br.s), 10.91 (1H, br.s), 11.50 (1H, br.s)
MS(FAB)m/z：549(M+H)+.
[embodiment 285] N1- (the chloro- 3- nitrobenzophenones of 4-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04981
It is same with the method that reference example 97 is recorded, make after the compound that reference example 253 is obtained and the compound condensation that reference example 400 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.44-1.53 (1H, m), 1.66-1.73 (3H, m), 1.97-2.07 (2H, m), 2.77 (3H, s), 2.89-3.05 (7H, m), 3.20 (2H, br.s), 3.55 (2H, br.s), 4.00 (1H, br.s), 4.44 (1H, br.s), 4.52 (2H, br.s), 7.75 (1H, d, J=8.8Hz), 8.08 (1H, d, J=8.8Hz), 8.59 (1H, s), 8.71 (1H, d, J=7.3Hz), 9.07 (1H, d, J=8.0Hz), 11.24 (1H, s), 11.58 (1H, br.s)
MS(FAB)m/z：592(M+H)+.
[embodiment 286] N1- (the chloro- 2- nitrobenzophenones of 4-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D04982
It is same with the method that embodiment 208 is recorded, make after the compound that reference example 253 is obtained and the compound condensation that reference example 401 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.46-1.54 (1H, m), 1.66-1.77 (3H, m), 2.03-2.10 (2H, m), 2.79 (3H, s), 2.90-2.93 (7H, m), 3.17-3.28 (2H, m), 3.49 (1H, br.s), 3.68 (1H, br.s), 3.99-4.04 (1H, m), 4.41 (1H, br.s), 4.46 (1H, br.s), 4.68 (1H, br.s), 7.89 (1H, d, J=9.0Hz), 8.20-8.21 (2H, m), 8.73 (1H, d, J=6.4Hz), 9.28 (1H, br.s), 11.49 (1H, br.s), 11.56 (1H, s)
MS(FAB)m/z：592(M+H)+.
[embodiment 287] N1- (3- amino -4- chlorphenyls)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (236mg) that embodiment 285 is obtained is dissolved in ethanol (25ml), adds the Raney nickel of catalytic amount, is stirred at room temperature in nitrogen atmosphere 17 hours.Then, the Raney nickel of additional catalytic amount is stirred for 7 hours.Catalyst is filtered off, solvent is boiled off under decompression.Residue (dichloromethane: methanol=23: 2) is refined with silica gel column chromatography, obtains faint yellow solid (101mg).Dichloromethane is dissolved in, 1N ethanol solution hydrochloride (360 μ l) is added.Solvent is boiled off under decompression, a small amount of methanol is added in residue, ether is instilled while ultrasonic wave is irradiated.The precipitation of leaching generation, is washed with ether, obtains title compound (95mg).
1H-NMR(DMSO-d6)δ：1.45-1.53 (1H, m), 1.66-1.73 (3H, m), 1.97-2.10 (2H, m), 2.78 (3H, s), 2.91-2.94 (7H, br.s), 3.11-3.19 (1H, m), 3.29 (1H, br.s), 3.48 (1H, br.s), 3.69 (1H, br.s), 3.95-4.02 (1H, m), 4.44 (2H, br.s), 4.68, 4.72 (1H, each br.s), 4.86 (2.5H, br.s), 6.98 (1H, dd, J=8.5, 1.9Hz), 7.14 (1H, d, J=8.5Hz), 7.35, 7.38 (1H, each br.s), 8.72-8.77 (1H, m), [8.91 (d, J=7.8Hz), 8.99 (d, J=8.5Hz), 1H], 10.45, 10.47 (1H, each br.s), 11.74 (1H, br.s)
MS(FAB)m/z：562(M+H)+.
[embodiment 288] N1- (2- amino -4- chlorphenyls)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Same with the method that embodiment 287 is recorded, the compound obtained by embodiment 286 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.77 (4H, m), 2.06-2.09 (2H, m), 2.78 (3H, s), 2.92 (7H, br.s), 3.12-3.19 (1H, m), 3.26-3.28 (1H, m), 3.48 (1H, br.s), 3.70 (1H, br.s), 4.00-4.44 (5.7H, m), 4.70, 4.74 (1H, each br.s), 6.63-6.66 (1H, m), 6.85 (1H, br.s), 7.18-7.21 (1H, m), 8.77-8.81 (1H, m), [8.97 (d, J=7.8Hz), 9.06 (d, J=8.1Hz), 1H], 9.98 (1H, s), 11.60 (1H, br.s)
MS(FAB)m/z：562(M+H)+.
[embodiment 289] N1- (the chloro- 4- picolines -3- bases of 6-)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using the method same with embodiment 199, make after the compound that reference example 270 is obtained and the compound condensation that reference example 402 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.45-1.54 (1H, m), 1.65-1.77 (3H, m), 2.02-2.08 (2H, m), 2.22 (3H, s), 2.79 (3H, s), 2.89-2.93 (7H, m), 3.19 (2H, br.s), 3.54 (2H, br.s), 3.99-4.04 (1H, m), 4.40-4.42 (1H, m), 4.50 (2H, br.s), 7.49 (1H, s), 8.32 (1H, s), 8.75 (1H, d, J=7.1Hz), 9.09 (1H, d, J=7.3Hz), 10.48 (1H, s), 11.40 (0.9H, br.s)
MS(FAB)m/z：562(M+H)+.
[embodiment 290] N- { (1R, 2S, 5S) -2- ({ [(E) -2- (4- chlorphenyls) diazenyl] carbonyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
10% palladium carbon (200mg) is added in tetrahydrofuran (10ml) solution for the compound (700mg) that reference example 252 is obtained, it is stirred at room temperature after 2 days and filters in the nitrogen atmosphere of 1 air pressure, concentrate filtrate, in the N of gained amine, the compound (470mg) that reference example 405 is obtained is added in dinethylformamide (5.0ml) solution, is stirred 18 hours in 95 DEG C.Concentration of reaction solution, adds saturated sodium bicarbonate aqueous solution (50ml), water (50ml) and dichloromethane (30ml), and water layer is extracted with dichloromethane (2 × 20ml) after point liquid.Merge organic layer, concentrated with after anhydrous sodium sulfate drying, (dichloromethane: methanol=12: 1) refined with silica gel column chromatography, then handled with 1N hydrochloric acid, obtain title compound (100mg).
1H-NMR(DMSO-d6)δ：1.40-1.60 (1H, m), 1.65-2.05 (5H, m), 2.80 (3H, s), 2.91 (3H, s), 2.99 (3H, s), 3.00-3.20 (2H, m), 3.20-3.32 (1H, m), 3.43 (1H, br.s), 3.69 (1H, br.s), 3.95 (1H, br.s), 4.45 (1H, br.s), 4.60-4.80 (2H, m), 7.68 (2H, d, J=8.7Hz), 7.83 (2H, d, J=8.7Hz), 8.41 (1H, br.s), 8.68 (1H, d, J=7.6Hz), 11.40-11.80 (1H, br)
MS(ESI)m/z：532(M+H)+.
[embodiment 291] N- { (1R, 2S, 5S) -2- ({ [2- (4- chlorphenyls) diazanyl] carbonyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
The reaction condition for the reaction that embodiment 290 is recorded is changed to 40 DEG C and stirred 3 days, obtains title compound.
1H-NMR(DMSO-d6)δ：1.30-1.50 (1H, m), 1.50-1.80 (3H, m), 1.80-1.97 (2H, m), 2.76 (3H, s), 2.80-3.05 (2H, m), 2.91 (6H, s), 3.05-3.30 (2H, m), 3.47 (2H, br.s), 4.30-4.50 (2H, m), 4.72 (1H, t, J=12.8Hz), 6.40-6.60 (2H, m), 6.55-6.70 (2H, m), 6.95-7.20 (2H, m), 7.88 (1H, d, J=11.3Hz), 8.48-8.65 (1H, m), 11.48-11.80 (1H, br)
MS(ESI)m/z：534(M+H)+.
[embodiment 292] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D05021
It is same with the method that embodiment 17 is recorded, make after the compound that reference example 34 is obtained and the compound condensation that reference example 420 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 1.95-2.10 (2H, m), 2.78 (3H, s), 2.85-3.00 (4H, m), 3.11 (2H, br s), 3.40-3.55 (2H, m), 3.95-4.07 (1H, m), 4.37-4.45 (1H, m), 4.48 (2H, br s), and 8.00-8.01 (2H, m), (8.10 1H, d, J=7.1Hz), 8.43-8.47 (1H, m), 9.16 (1H, d, J=7.8Hz), 9.43 (2H, br s), 10.27 (1H, s)
MS(FAB)m/z：534(M+H)+.
[embodiment 293] N- { (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- [(1- hydroxycyclopropyls) carbonyl] piperidines -3- bases -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05022
Using the method same with embodiment 150, make after compound and the condensation of 1- hydroxyl -1- cyclopropane-carboxylic acids of the acquisition of embodiment 118, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：0.60-0.90 (3H, br), 0.92-1.03 (1H, m), 1.71-1.84 (1H, m), 1.85-2.03 (1H, m), 2.91 (3H, s), 3.00-3.80 (7H, m), 4.05-4.80 (5H, m), 6.28-6.42 (1H, br), 7.09 (1H, s), 7.18 (1H, dd, J=8.8,1.5Hz), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, d, J=1.5Hz), 8.14-8.29 (1H, br), 8.41 (1H, brd, J=7.6Hz), 11.83 (1H, s)
MS(ESI)m/z：557(M+H)+.
[embodiment 294] N- { (3R*, 4S*) -4- { [(5- chloro-indole -2- bases) carbonyl] amino } -1- [(1- mcthoxycyclopropyls) carbonyl] piperidines -3- bases -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05031
Using the method same with embodiment 150, make after the compound that embodiment 118 is obtained and the compound condensation that reference example 409 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：0.65-1.05 (4H, m), 1.74-1.88 (1H, m), 1.92-2.10 (1H, m), 2.91 (3H, s), 3.00-3.80 (10H, m), 4.05-4.83 (6H, m), 7.08 (1H, s), 7.18 (1H, dd, J=8.6, 2.0Hz), 7.42 (1H, d, J=8.6Hz), 7.71 (1H, d, J=2.0Hz), 8.08-8.30 (1H, br), 8.41 (1H, br d, J=7.8Hz), 10.60-10.80 (0.5H, br), 10.85-11.05 (0.5H, br), 11.84 (1H, s)
Chloro- the N- ((3R of [embodiment 295] 7-; 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) -3- isoquinolinecarboxamide hydrochlorides
Same with the method that embodiment 219 is recorded, the compound obtained with 4N Yan Suan dioxane solutions to reference example 410 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.60-1.80 (1H, m), 2.13-2.38 (1H, m), 2.90 (3H, s), 3.00-3.87 (10H, m), 3.89-4.10 (2H, m), 4.15-4.58 (4H, m), 4.60-4.78 (1H, m), 7.89 (1H, d, J=8.8Hz), 8.25 (1H, d, J=8.8Hz), 8.37 (1H, s), 8.61 (1H, s), 8.70-8.95 (1H, m), 9.05-9.29 (1H, m), 9.36 (1H, s), 11.20-11.40 (0.5H, br), 11.45-11.65 (0.5H, br)
MS(ESI)m/z：557(M+H)+.
[embodiment 296] N1- (the chloro- 3- fluorophenyls of 4-)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide hydrochloride
Same with the method that embodiment 219 is recorded, the compound obtained with 4N Yan Suan dioxane solutions to reference example 411 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.60-1.72 (1H, m), 1.98-2.21 (1H, m), 2.91 (3H, s), 3.00-3.52 (9H, m), 3.56-4.05 (3H, m), 4.08-4.50 (4H, m), 4.60-4.78 (1H, br), 7.56 (1H, t, J=8.8Hz), 7.70 (1H, d, J=9.0Hz), 7.91 (1H, dd, J=8.8, 2.3Hz), 8.50-8.72 (1H, m), 9.15-9.35 (1H, m), 11.02 (1H, s), 11.15-11.33 (0.5H, br), 11.35-11.50 (0.5H, br)
MS(FAB)m/z：567(M+H)+.
[embodiment 297] N1- (the chloro- 2- acetenyls of 5-)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide hydrochloride
Figure G2003801097466D05042
Same with the method that embodiment 219 is recorded, the compound obtained with 4N Yan Suan dioxane solutions to reference example 412 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.60-1.73 (1H, m), 1.96-2.19 (1H, m), 2.91 (3H, s), 3.04-3.54 (9H, m), 3.60-4.05 (3H, m), 4.07-4.34 (3H, m), 4.35-4.54 (1H, br), 4.60-4.80 (1H, br), 6.89 (1H, d, J=4.2Hz), 6.93 (1H, d, J=4.2Hz), 8.48-8.70 (1H, m), 9.18-9.40 (1H, m), 12.31 (1H, s)
MS(ESI)m/z：555(M+H)+.
[embodiment 298] N- { (1R; 2S; 5S) -2- { [2- (4- chlorophenoxies) acetyl group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05051
It is same with the method that embodiment 223 is recorded, handled after the compound that reduction reference example 252 is obtained, with parachlorophen-oxyacetic acid condensation with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.35-1.47 (1H, m), 1.55-1.90 (5H, m), 2.77 (3H, s), 2.92 (3H, s), 2.96 (3H, s), 2.98-3.10 (1H, m), 3.10-3.80 (3H, m), 3.85-3.95 (1H, m), 4.35-4.50 (4H, m), 4.50-4.80 (1H, br), (6.85 2H, d, J=8.5Hz), 7.15-7.35 (1H, br), 7.88-8.03 (1H, br), 8.46 (1H, d, J=8.8Hz), 11.30-11.65 (1H, br)
MS(FAB)m/z：534(M+H)+.
Chloro- the N- ((1S of [embodiment 299] 7-, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) -3- isoquinolinecarboxamide hydrochlorides
Figure G2003801097466D05052
The compound that reference example 413 is obtained is hydrolyzed, makes the lithium salts of gained carboxylic acid and the compound that reference example 146 is obtained is carried out after compound condensation of the acid treatment after deprotection, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.00-1.11 (2H, m), 1.45-1.60 (1H, m), 1.65-1.85 (1H, m), 1.95-2.06 (1H, m), 2.10-2.24 (1H, m), 2.78 (3H, s), 2.87-3.02 (1H, m), 2.94 (3H, s), 3.88 (3H, s), 4.16-4.27 (1H, m), 4.45-4.56 (1H, m), 7.03 (1H, s), 7.55 (1H, s), 7.87 (1H, br d, J=8.3Hz), 8.24 (1H, br d, J=8.8Hz), 8.33 (1H, s), 8.59 (1H, s), 8.85 (1H, br d, J=7.6Hz), 9.01 (1H, br d, J=7.8Hz), 9.28 (1H, s)
MS(ESI)m/z：539(M+H)+.
[embodiment 300] N- { (1R, 2S, 5S) -2- { [(the chloro- 4- oxos -4H- chromenes -2- bases of 6-) carbonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Same with the method that embodiment 219 is recorded, the compound obtained with 4N Yan Suan dioxane solutions to reference example 417 is handled, and is handled after the compound condensation for making gained compound and the acquisition of reference example 10 with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.40-1.53 (1H, m), 1.67-2.04 (5H, m), 2.40-2.53 (1H, m), 2.80 (3H, s), 2.92 (3H, s), 3.01 (3H, s), 3.09-3.22 (3H, m), 3.66-3.77 (1H, m), 4.01-4.10 (1H, m), 4.34-4.49 (1H, m), 4.58-4.76 (2H, m), 6.80 (1H, d, J=4.9Hz), 7.59-7.70 (1H, m), 7.90-8.00 (1H, m), 7.96 (1H, s), 8.52-8.60 (1H, m), 8.80-8.90 (1H, m), 11.10-11.25 (0.5H, br), 11.40-11.55 (0.5H, br)
MS(ESI)m/z：572(M+H)+.
Chloro- the N- ((3R of [embodiment 301] 7-; 4S) -1- (2- Methoxyacetyls) -3- { [(5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) -3- cinnolinecarboxamide hydrochlorides
Figure G2003801097466D05062
Same with the method that embodiment 219 is recorded, the compound obtained with 4N Yan Suan dioxane solutions to reference example 418 is handled, and is handled after the compound condensation for making gained compound and the acquisition of reference example 10 with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.70-1.80 (1H, m), 1.85-2.05 (1H, m), 2.90 (3H, s), 3.00-3.20 (2H, m), 3.16 (3H, s), 3.22-3.82 (7H, m), 3.88-4.80 (5H, m), 7.09 (1H, d, J=9.0Hz), 7.17 (1H, dd, J=8.8,1.9Hz), 7.42 (1H, d, J=8.8Hz), 7.70 (1H, d, J=1.9Hz), 8.29 (1H, br s), 8.40-8.50 (1H, m), 11.20-11.50 (1H, br m), 11.85 (1H, s)
MS(ESI)m/z：558(M+H)+.
[embodiment 302] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D05071
With hydrochloric acid make reference example 421 obtain compound be deprotected, with embodiment 18 record method it is same methylate after, is carried out with hydrochloric acid processing acquisition title compound.
1H-NMR(DMSO-d6)δ：1.42-1.58 (1H, m), 1.59-1.80 (3H, m), 1.83-1.95 (1H, m), 1.97-2.10 (1H, m), 2.78 (3H, s), 2.89 (3H, s), 2.96 (3H, s), 3.00-3.10 (1H, m), 3.10-3.20 (2H, m), 3.45-3.80 (1H, m), 3.90-4.00 (2H, m), 4.00-4.50 (3H, m), 7.77 (1H, s), 7.95-8.05 (3H, m), 8.44 (1H, t, J=1.6Hz), 8.90 (1H, d,=8.6Hz), 10.25 (1H, s), 11.12 (1H, br s)
MS(ESI)m/z：547(M+H)+.
[embodiment 303] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- isopropyls -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D05072
It is same with the method that embodiment 2 is recorded, make after the compound that reference example 148 is obtained and the compound condensation that reference example 420 is obtained, processing is carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.30-1.40 (6H, m), 1.38-1.58 (1H, m), 1.59-1.82 (3H, m), 1.95-2.13 (2H, m), 2.40-2.65 (1H, m), 2.49 (3H, s), 2.87-3.55 (4H, m), 2.49 (3H, s), 3.60-3.82 (2H, m), 3.93-4.04 (1H, m), 4.37-4.55 (2H, m), 4.55-4.72 (1H, m), 7.94-8.10 (2H, m), 8.43 (1H, s), 8.64-8.77 (1H, m), 9.12 (1/2H, d, J=7.8Hz), 9.24 (1/2H, d, J=7.8Hz), 10.22 (1/2H, s), 10.26 (1/2H, s), 11.25 (1/2H, brs), 11.44 (1/2H, br s)
MS(FAB)m/z：578(M+H)+.
[embodiment 304] N- ((1R; 2S; 5S) -5- [(dimethylamino) carbonyl] -2- { [2- (4- fluoroanilinos) -2- oxos ethanethioyl] amino } cyclohexyl) -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 424 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.60-1.80 (3H, m), 2.00-2.10 (1H, m), 2.20-2.35 (1H, m), 2.79 (3H, s), 2.93 (3H, s), 2.95 (3H, s), 2.95-3.10 (1H, m), 3.10-3.30 (2H, m), 3.40-3.60 (1H, m), 3.60-3.80 (1H, m), 4.35-4.50 (1H, m), 4.50-4.60 (1H, m), 4.60-4.80 (2H, m), 7.20 (2H, t, J=8.8Hz), 7.77 (2H, dd, J=9.0, 5.1Hz), 8.80 (1H, br), 10.42 (1H, s), 10.93 (1H, br), 11.28 (1H, br)
MS(ESI)m/z：547(M+H)+.
[embodiment 305] N- [(1R; 2S; 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(5- fluorine pyridine -2- bases) amino] -2- oxos ethanethioyl } amino) cyclohexyl] -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 427 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.43-1.57 (1H, m), 1.64-1.87 (3H, m), 2.00 (1H, br s), 2.17-2.34 (1H, m), 2.78 (3H, s), 2.90 (3H, s), 2.95 (3H, s), 2.95-3.10 (1H, m), 3.10-3.30 (2H, m), 3.40-3.60 (1H, m), 3.68 (1H, br s), 4.44 (1H, br s), 4.45-4.56 (1H, m), 4.60-4.73 (2H, m), 7.80-7.90 (1H, m), 8.08 (1H, dd, J=9.1, 3.9Hz), 8.41 (1H, d, J=2.9Hz), 8.79 (1H, d, J=6.6Hz), 10.49 (1H, s), 11.07 (1H, brs), 11.69 (1H, br)
MS(ESI)m/z：548(M+H)+.
[embodiment 306] N- { (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -5H- pyrrolo-es [3,4-d] thiazole -2- formamides
It is same with the method that embodiment 219 is recorded, compound is obtained to reference example 428 with hydrochloric acid and carried out after processing deprotection, the compound condensation obtained with reference example 293 obtains title compound.
1H-NMR(DMSO-d6)δ：1.45-1.58 (1H, m), 1.63-1.73 (2H, m), 1.73-1.87 (2H, m), 2.00-2.10 (1H, m), 2.20-2.35 (1H, m), 2.79 (3H, s), 2.95 (3H, s), 2.96-3.10 (1H, m), 3.89 (3H, s), 4.48-4.58 (1H, m), 4.60-4.70 (1H, m), 7.05 (1H, d, J=1.7Hz), 7.55 (1H, d, J=1.7Hz), 8.00 (1H, dd, J=8.9, 2.4Hz), 8.05 (1H, d, J=8.9Hz), 8.44 (1H, d, J=2.4Hz), 8.71 (1H, d, J=7.3Hz), 10.57 (1H, s), 11.13 (1H, d, J=7.8Hz)
MS(FAB)m/z：548(M+H)+.
[embodiment 307] N- { (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -5; 6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- carboxamide hydrochlorides
Figure G2003801097466D05092
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 428 is carried out after processing deprotection, the compound condensation obtained in argon atmospher with reference example 293, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.42-1.58 (1H, m), 1.65-1.87 (3H, m), 1.97-2.10 (1H, m), 2.17-2.30 (1H, m), 2.80 (3H, s), 2.96 (3H, s), 2.98-3.10 (1H, m), 3.07 (3H, s), 4.30-5.00 (6H, m), 8.00-8.10 (1H, m), 8.46 (1H, d, J=2.4Hz), 8.79 (1H, t, J=7.3Hz), 10.54 (1H, s), 11.04 (1H, d, J=7.8Hz), 12.24 (1H, br s)
MS(ESI)m/z：550(M+H)+.
[embodiment 308] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- ({ [6- (dimethylamino) -4,5,6,7- tetrahydro benzothiazol -2- bases] carbonyl } amino) cyclohexyl] oxalamide
Figure G2003801097466D05101
The compound obtained with hydrochloric acid to reference example 431 is carried out after processing deprotection, same with the method that embodiment 18 is recorded to methylate, and processing is carried out with hydrochloric acid and obtains title compound.
1H-NMR(DMSO-d6)δ：1.42-1.58 (1H, m), 1.59-1.80 (3H, m), 1.90-2.12 (3H, m), 2.30-2.45 (1H, m), 2.70-3.00 (11H, m), 2.92 (3H, s), 3.00-3.20 (2H, m), 3.25-3.45 (1H, m), 3.63-3.80 (1H, m), 3.88-4.02 (1H, m), 4.35-4.47 (1H, m), 8.02 (1H, s), 8.42-8.55 (1H, m), 8.60-8.68 (1H, m), 8.93 (1H, dd, J=14.5, 8.2Hz), 9.19 (1H, dd, J=17.7, 8.2Hz), 10.28 (1H, s), 10.91 (1H, br s)
MS(ESI)m/z：576(M+H)+.
[embodiment 309] N- { (1R; 2S; 5S) -2- [({ [(4- chlorphenyls) sulfonyl] amino } carbonyl) amino] -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Isocyanic acid 4- Chlorophenylsulfonyls ester (148 μ l) is added in dichloromethane (10ml) solution for the compound (328.0mg) that reference example 253 is obtained, is stirred 24 hours at room temperature.Solvent is boiled off under decompression, residue (dichloromethane: methanol=9: 1) is refined with silica gel thin-layer column chromatography is prepared.Gained product is dissolved in ethanol (2ml) and dichloromethane (2ml), 1N ethanol solution hydrochloride (0.25ml) is added, stirred 30 minutes at room temperature.The lower concentration of reaction solution of decompression, residue ether solidifies, and obtains title compound (104.3mg).
1H-NMR(DMSO-d6)δ：1.25-1.45 (1H, m), 1.45-1.80 (5H, m), 2.76 (3H, s), 2.94 (3H, s), 2.97 (3H, s), 3.00-3.80 (6H, m), 4.35-4.85 (3H, m), 6.53 (1H, brs), 7.66 (2H, d, J=8.5Hz), 7.86 (2H, d, J=8.5Hz), 8.50-8.82 (1H, m), 10.64 (1H, br s), 11.10-11.80 (1H, br)
MS(ESI)m/z：583(M+H)+.
[embodiment 310] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
Method with embodiment 2 is same, and the compound that the compound and reference example 10 obtained by reference example 435 is obtained prepares title compound.
1H-NMR(CDCl3)δ：1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J=15.4Hz), 3.75 (1H, d, J=15.4Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, d, J=8.8, 0.6Hz), 7.68 (1H, dd, J=8.8, 2.4Hz), 8.03 (1H, d, J=7.8Hz), 8.16 (1H, dd, J=8.8, 0.6Hz), 8.30 (1H, dd, J=2.4, 0.6Hz), 9.72 (1H, s)
MS(ESI)m/z：548(M+H)+.
[embodiment 311] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) 1 hydrate of oxalamide tosilate
Figure G2003801097466D05112
The compound 6.2g that embodiment 310 is obtained is dissolved in dichloromethane (120ml), adds 1mol/L p-methyl benzenesulfonic acid-ethanol solution (11.28ml), boils off solvent.15% hydrous ethanol (95ml) is added in residue, dissolving is stirred in 60 DEG C.It is then cooled to which room temperature, is stirred 1 day.The crystallization that leaching is separated out, is dried under reduced pressure 2 hours at room temperature after being washed with ethanol, obtains title compound (7.4g)
1H-NMR(DMSO-d6)δ：1.45-1.54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H, m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m), 7.11 (2H, d, J=7.8Hz), 7.46 (2H, d, J=8.2Hz), 8.01 (2H, d, J=1.8Hz), 8.46 (1H, t, J=1.8Hz), 8.75 (1H, d, J=6.9Hz), 9.10-9.28 (1H, br), 10.18 (1H, br), 10.29 (1H, s)
MS(ESI)m/z：548(M+H)+
Elementary analysis：C24H30ClN7O4S·C7H8O3S·H2O
Theoretical value：C；50.43, H；5.46, N；13.28, Cl；4.80, S；8.69
Measured value：C；50.25, H；5.36, N；13.32, Cl；4.93, S；8.79
Mp (decomposition)：245~248 DEG C
[embodiment 312] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 437 is carried out after processing deprotection, the compound condensation with the acquisition of reference example 10, then is carried out with hydrochloric acid handling acquisition title compound.1H-NMR(DMSO-d6)δ：1.48-1.61 (1H, m), 1.61-1.74 (2H, m), 1.74-1.82 (1H, m), 1.98-2.12 (2H, m), 2.29-2.38 (1H, m), 2.53 (3H, d, J=4.2Hz), 2.92 (3H, s), 3.10-3.40 (4H, br), 3.40-3.80 (1H, br), 3.97-4.05 (1H, m), 4.28-4.34 (1H, m), 4.34-4.80 (1H, br), 7.70-7.78 (1H, m), 7.97-8.07 (2H, m), 8.43-8.50 (1H, m), 8.49 (1H, br.s), 9.27 (1H, d, J=7.8Hz), 10.26 (1H, br.s), 11.48 (1H, br.s) .MS (ESI) m/z：534[(M+H)+, Cl35], 535 [(M+H)+, Cl37].
[embodiment 313] N1- (5- chloropyridine -2- bases)-N2- ((3R, 4S) -1- (2- Methoxyacetyls) -3- { [4- (pyridin-4-yl) benzoyl] amino } piperidin-4-yl) oxalamide hydrochloride
Same with the method that embodiment 219 is recorded, the compound obtained with 4N Yan Suan dioxane solutions to reference example 368 is carried out after processing deprotection, the compound condensation obtained with reference example 237, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.62-1.75 (1H, m), 2.00-2.20 (1H, m), 2.80-4.40 (11H, m), 7.90-8.00 (4H, m), 8.05-8.13 (2H, m), 8.14-8.43 (3H, m), 8.40-8.45 (1H, m), 8.87-9.04 (3H, m), 10.20-10.50 (2H, br)
MS(FAB)m/z  551[(M+H)+, Cl35], 553 [(M+H)+, Cl37].
[embodiment 314] N- { (1R; 2S; 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(5- picoline -2- bases) amino] -2- oxos ethanethioyl } amino) cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05131
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 440 is carried out after processing deprotection, the compound condensation with the acquisition of reference example 10, then is carried out with hydrochloric acid handling acquisition title compound.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.65-1.90 (3H, m), 2.00-2.10 (1H, m), 2.20-2.40 (1H, m), 2.28 (3H, s), 2.80 (3H, s), 2.91 (3H, s), 2.95-3.10 (1H, m), 2.96 (3H, s), 3.15-3.30 (1H, m), 3.32 (2H, s), 3.50-3.80 (1H, m), 4.45-4.60 (2H, m), 4
.60-4.80 (2H, m), 7.72 (1H, d, J=8.5Hz), 7.97 (1H, d, J=8.5Hz), 8.23 (1H, s), 8.83 (1H, d, J=7.3Hz), 10.38 (1H, s), 11.06 (1H, d, J=7.6Hz), 11.49 (1H, br.s)
MS(ESI)m/z：544(M+H)+.
[embodiment 315] N- [(3R; 4S) -4- { [2- (4- chloroanilinos) -2- oxos ethanethioyl] amino } -1- (2- Methoxyacetyls) piperidines -3- bases] -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05132
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 441 is carried out after processing deprotection, the compound condensation with the acquisition of reference example 10, then is carried out with hydrochloric acid handling acquisition title compound.
1H-NMR(DMSO-d6)δ：1.71-1.82 (1H, m), 2.18-2.44 (1H, m), 2.89 (3H, s), 3.00-4.85 (17H, m), 7.41 (2H, d, J=8.8Hz), 7.77 (2H, d, J=8.8Hz), and 8.48-8.73 (1H, m), 10.48 (1H, br.s), 10.90-11.06 (1H, m), 11.45-11.90 (1H, br)
MS(ESI)m/z：565[(M+H)+, Cl35], 567 [(M+H)+, Cl37].
[embodiment 316] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) thioformyl] -2- { [(5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
It is same with the method that embodiment 3 is recorded, make the compound that reference example 445 is obtained and the compound condensation that reference example 10 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.66-2.15 (6H, m), 2.93 (3H, s), 3.15-3.40 (9H, m), 3.49 (1H, br.s), 3.71 (1H, br.s), 3.97-4.01 (1H, m), 4.42 (2H, br.s), 4.70 (1H, br.s), 8.01 (2H, br.s), 8.46 (1H, br.s), 8.78 (1H, d, J=6.8Hz), 9.24 (1H, br.s), 10.28 (1H, s), (11.29 1H, br.s)
MS(FAB)m/z：564[(M+H)+, Cl35], 566 [(M+H)+, Cl37].
[embodiment 317] N1- (5- chloropyridine -2- bases)-N2- ((3R; 4S) -1- (2- methoxyl groups ethanethioyl) -3- { [(5- methyl -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } piperidin-4-yl) oxalamide hydrochloride
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 448 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.74-1.85 (1H, m), 2.13-2.35 (1H, m), 2.89 (3H, s), 2.95-3.98 (9H, m), 4.05-5.33 (8H, m), 7.95-8.06 (2H, m), 8.43 (1H, s), 8.48-8.73 (1H, br), 9.29-9.45 (1H, br), 10.21-10.34 (1H, br), 11.45-11.90 (1H, br)
MS(ESI)m/z：566[(M+H)+, Cl35], 568 [(M+H)+, Cl37].
[embodiment 318] (1S; 3R; 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -3- { [(5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid 2; 2,2- trichloro ethyl esters
Figure G2003801097466D05151
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 453 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(CDCl3)δ：1.60-1.87 (2H, m), 2.04-2.15 (2H, m), 2.21-2.32 (2H, m), 2.52 (3H, s), 2.73-2.89 (3H, m), 2.92-2.98 (2H, m), 3.71 (1H, d, J=15.4Hz), 3.73 (1H, d, J=15.4Hz), 4.08-4.16 (1H, m), 4.66-4.71 (1H, m), 4.72 (1H, d, J=12.0Hz), 4.82 (1H, d, J=12.0Hz), 7.37 (1H, d, J=8.8Hz), 7.69 (1H, dd, J=8.8, 2.4Hz), 8.05 (1H, d, J=8.1Hz), 8.16 (1H, d, J=8.8Hz), 8.30 (1H, d, J=2.4Hz), 9.69 (1H, s)
MS(ESI)m/z：651[(M+H)+, 3 × Cl35], 653 [(M+H)+, 2 × Cl35, Cl37], 655 [(M+H)+, Cl35, 2 × Cl37].
[embodiment 319] (1S; 3R; 4S) -4- ({ 2- (5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -3- { [(5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid
The compound (475mg) that embodiment 318 is obtained is dissolved in tetrahydrofuran (50ml), and zinc (2.85g) and acetic acid (5.7ml) are sequentially added in the solution, stirs 3 hours at room temperature.Diatomite 545 (2.85g) is added in reaction solution to filter off after insoluble matter, the lower concentration filtrate of decompression, in residue obtained middle addition dichloromethane, stirs while add 1N sodium hydrate aqueous solution, fluidity is adjusted to pH7.Separate after organic layer, saturated aqueous common salt (50ml) is added in water layer, extracted with dichloromethane (10 × 50ml).Merge gained organic layer, dried with anhydrous magnesium sulfate.Solvent is boiled off, residue obtained use silica gel column chromatography (dichloromethane: methanol=95: 5 → 9: 1 → 4: 1) refines, obtains title compound (140mg).
1H-NMR(DMSO-d6)δ：1.50-1.80 (3H, m), 1.84-1.95 (1H, m), 1.95-2.10 (1H, m), 2.15-2.30 (1H, m), 2.38 (3H, s), 2.40-2.50 (1H, m), 2.67-2.80 (2H, m), 2.80-2.95 (2H, m), 3.66 (2H, m), 4.03 (1H, br.s), 4.33 (1H, br.s), 7.97-8.10 (2H, m), 8.45 (1H, s), 8.53 (1H, d, J=6.8Hz), 9.19 (1H, d, J=8.3Hz), 10.27 (1H, br.s)
MS(FAB)m/z：521[(M+H)+,35Cl], 523 [(M+H)+,37Cl].
[embodiment 320] N- { (1R, 2S, 5S) -2- { [2- (4- chloroanilinos) -1- methoxyimino -2- oxoethyls] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05161
It is same with the method that reference example 142 is recorded, it is same with the method that reference example 143 is recorded after the ester for the compound that hydrolysis reference example 454 is obtained, it is condensed with 4- chloroanilines, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.30-1.17 (1H, m), 1.50-1.62 (1H, m), 1.62-1.75 (2H, m), 1.85-2.00 (2H, m), 2.76 (3H, s), 2.93 (6H, br.s), 3.00-3.10 (1H, m), 3.18 (1H, br.s), 3.27 (1H, br.s), 3.49 (1H, br.s), 3.71 (1H, br.s), 3.76 (3H, s), 3.93 (1H, br.s), 4.35-4.50 (2H, m), 4.66-4.77 (1H, m), 6.09 (0.5H, d, J=7.8Hz), 6.19 (0.5H, d, J=7.8Hz), 7.38 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.8Hz), 8.70-8.79 (1H, m), 10.28 (1H, d, J=11.0Hz), 11.53 (0.5H, br.s), 11.45 (0.5H, br.s)
MS(FAB)m/z：576[(M+H)+,35Cl], 578 [(M+H)+,37Cl].
[embodiment 321] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- ({ [1- (pyridin-4-yl) piperidin-4-yl] carbonyl } amino) cyclohexyl] oxalamide hydrochloride
It is same with the method that embodiment 2 is recorded, make compound and 1- (pyridin-4-yl) piperidines -4- carboxylic acids (WO 96/10022) condensation that reference example 420 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.35-1.49 (1H, m), 1.49-1.78 (6H, m), 1.78-1.98 (3H, m), 2.75-2.90 (1H, m), 2.78 (3H, s), 3.02 (3H, s), 3.03-3.14 (1H, m), 3.14-3.28 (2H, m), 3.74-3.85 (1H, m), 4.13-4.30 (3H, m), 7.18 (2H, d, J=7.3Hz), 7.99 (2H, s), 8.10-8.23 (3H, m), 8.41 (1H, s), 8.50 (1H, d, J=8.1Hz), 10.19 (1H, s), 13.73 (1H, br.s)
MS(FAB)m/z：556[(M+H)+,35Cl], 558 [(M+H)+,37Cl].
[embodiment 322] N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (5- ethynyl pyridine -2- bases) oxalamide
The compound (348mg) that reference example 455 is obtained is dissolved in tetrahydrofuran (14ml), adds tetrabutylammonium (1N tetrahydrofuran solution, 628 μ l), stirs 30 minutes at room temperature.Activated carbon (about 1g) is added in reaction solution to decolourize, and uses anhydrous sodium sulfate drying.Solvent is boiled off under being depressurized after filtering, residue (dichloromethane: methanol=93: 7) is refined with silica gel column chromatography.Residue is dissolved in dichloromethane (about 1ml), hexane (about 10ml) is added, the precipitation of leaching generation obtains title compound (116mg).
1H-NMR(CDCl3)δ：1.62-2.14 (8H, m), 2.52 (3H, s), 2.79-2.95 (6H, m), 3.05 (3H, s), 3.19 (1H, s), [(the 1H of AB types 3.71, d, J=15.5Hz), 3.74 (1H, d, J=15.5Hz)], 4.08-4.14 (1H, m), 4.66-4.69 (1H, m), 7.41 (1H, d, J=8.6Hz), 7.80 (1H, dd, J=8.6, 2.2Hz), 8.03 (1H, d, J=7.6Hz), 8.15 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.2Hz), 9.75 (1H, s)
MS(ESI)m/z538(M+H)+.
[embodiment 323] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6- dihydro -4H- thienos [2,3-c] pyrroles -2- bases) carbonyl] amino } cyclohexyl) oxalamide
It is same with the method that embodiment 191 is recorded, the compound that reference example 456 is obtained is hydrolyzed, then the compound condensation obtained with reference example 420, prepare title compound.
1H-NMR(CDCl3)δ：1.80-2.15 (6H, m), 2.64 (3H, s), 2.76-2.79 (1H, m), 2.94 (3H, s), 3.03 (3H, s), 3.84-3.86 (2H, m), 3.94-3.99 (3H, m), 4.58-4.59 (1H, m), 6.70 (1H, d, J=6.3Hz), 7.31 (1H, s), 7.70 (1H, dd, J=8.8,2.3Hz), 8.15-8.18 (2H, m), 8.30 (1H, d, J=2.3Hz), 9.72 (1H, br.s)
MS(FAB)m/z：533[(M+H)+, Cl35], 535 [(M+H)+, Cl37].
[embodiment 324] N- { (1R; 2S; 5S) -2- ({ 2- [(6- chlorine pyridazine -3- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
It is same with the method that embodiment 3 is recorded, make the compound that reference example 460 is obtained and the compound condensation that reference example 10 is obtained, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.48-1.51 (1H, m), 1.71-1.79 (3H, m), 2.00 (1H, br.s), 2.20-2.23 (1H, m), 2.78 (3H, s), 2.90 (3H, s), 2.96 (3H, s), 3.05 (1H, br.s), 3.16-3.47 (3H, m), 3.69 (1H, br.s), 4.43 (1H, br.s), 4.53 (1H, br.s), 4.69 (2H, br.s), 7.97 (1H, d, J=9.6Hz), 8.32 (1H, d, J=9.6Hz), 8.73 (1H, d, J=7.3Hz), 11.08 (2H, br.s), 11.61-11.75 (1H, m)
MS(FAB)m/z：565[(M+H)+, Cl35], 567 [(M+H)+, Cl37].
[embodiment 325] N- { (1R; 2S; 5S) -2- ({ 2- [(6- chloropyridine -3- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
It is same with the method that embodiment 3 is recorded, make the compound that reference example 464 is obtained and handled after the compound condensation that reference example 10 is obtained with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.47-1.55 (1H, m), 1.66-1.78 (3H, m), 2.02-2.05 (1H, m), 2.21-2.33 (1H, m), 2.79 (3H, s), 2.91 (3H, s), 2.95 (3H, s), 2.99-3.04 (1H, m), 3.21 (2H, br.s), 3.45-3.75 (2H, br), 4.40-4.75 (4H, m), 7.53 (1H, d, J=8.6Hz), 8.20 (1H, dd, J=8.6, 2.6Hz), 8.77 (1H, d, J=7.3Hz), 8.80 (1H, d, J=2.6Hz), 10.73 (1H, s), 10.94 (1H, br.d, J=7.6Hz), 11.37 (1H, br.s)
MS(FAB)m/z：564[(M+H)+, Cl35], 566 [(M+H)+, Cl37].
[embodiment 326] N1- [(3R, 4S) -3- ({ [2 '-(amino-sulfonyl) [1,1 '-biphenyl] -4- bases] carbonyl } amino) -1- (2- Methoxyacetyls) piperidin-4-yl]-N2- (5- chloropyridine -2- bases) oxalamide
Using the method same with embodiment 219, the compound obtained with hydrochloric acid to reference example 368 is carried out after processing deprotection, the compound condensation obtained with reference example 465, prepares title compound.
1H-NMR(CDCl3)δ：1.59-1.85 (1H, m), 2.09-2.23 (1H, m), 2.88-3.13 (1H, m), 3.29-3.51 (4H, m), 4.06-4.20 (4H, m), 4.51-4.78 (4H, m), 7.09 (0.25H, br.s), 7.30 (1H, d, J=7.1Hz), 7.51-7.54 (3.75H, m), 7.60 (1H, t, J=7.0Hz), 7.69 (1H, dd, J=8.9, 2.2Hz), 7.94-7.96 (2H, m), 8.13-8.22 (2H, m), 8.30 (1H, d, J=2.2Hz), 8.91 (0.75H, br.d, J=5.9Hz), 9.18 (0.25H, br.s), 9.70 (1H, s)
MS(FAB)m/z：629[(M+H)+, Cl35], 631 [(M+H)+, Cl37]
[embodiment 327] N1- (5- chloropyridine -2- bases)-N2- { (1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- [(thieno [3,2-b] pyridine -2- bases carbonyl) amino] cyclohexyl } oxalamide hydrochloride
Figure G2003801097466D05192
Using method similarly to Example 2, make compound and thieno [3,2-b] pyridine-2-carboxylic acids lithium salts (Japanese Patent Laid-Open 2001-294572) condensation that reference example 420 is obtained, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.44-1.57 (1H, m), 1.62-1.84 (3H, m), 1.86-1.98 (1H, m), 2.04-2.19 (1H, m), 2.78 (3H, s), 2.99 (3H, s), 3.11-3.25 (1H, m), 3.85-4.10 (1H, br), 4.44-4.55 (1H, br), 7.51-7.62 (1H, m), 7.98 (2H, br.s), 8.43 (2H, br.s), 8.60 (1H, s), 8.66 (1H, br.d, J=8.1Hz), 8.81 (1H, br.d, J=4.2Hz), 9.05 (1H, br.d, J=7.8Hz), 10.24 (1H, s)
MS(ESI)m/z：529[(M+H)+, Cl35], 531 [(M+H)+, Cl37].
[embodiment 328] N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (5- picoline -2- bases) oxalamide hydrochloride
Figure G2003801097466D05201
It is same with the method that embodiment 208 is recorded, make the compound that reference example 467 is obtained and the compound condensation that reference example 253 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.42-1.57 (1H, m), 1.60-1.80 (3H, m), 1.95-2.15 (2H, m), 2.28 (3H, s), 2.78 (3H, s), 2.90-3.10 (1H, m), 2.92 (3H, s), 2.94 (3H, s), 3.07-3.38 (2H, m), 3.40-3.58 (1H, br), 3.60-3.80 (1H, m), 3.95-4.05 (1H, m), 4.36-4.50 (2H, m), 4.66-4.80 (1H, m), 7.73 (1H, d, J=8.0Hz), 7.90-7.94 (1H, m), 8.24 (1H, s), 8.70-8.80 (1H, m), 9.13 (0.5H, d, J=7.3Hz), 9.21 (0.5H, d, J=8.0Hz), 10.06 (1H, s), 11.46 (0.5H, br.s), 11.57 (0.5H, br.s)
MS(FAB)m/z：528(M+H)+.
[embodiment 329] N1- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- (4- aminomethyl phenyls) oxalamide hydrochloride
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 469 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.42-1.55 (1H, m), 1.60-1.80 (3H, m), 1.95-2.15 (2H, m), 2.26 (3H, s), 2.79 (3H, s), 2.93 (7H, br.s), 3.07-3.35 (2H, m), 3.40-3.55 (1H, m), 3.65-3.77 (1H, m), 3.95-4.06 (1H, m), 4.38-4.52 (2H, br), 4.67-4.80 (1H, m), 7.13 (2H, d, J=8.3Hz), 7.66 (2H, d, J=8.3Hz), 8.72-8.80 (1H, m), 8.96 (0.5H, d, J=7.8Hz), 9.04 (0.5H, d, J=8.1Hz), 10.56 (1H, d, J=6.6Hz), 11.30 (1H, br.s)
MS(FAB)m/z：527(M+H)+.
[embodiment 330] { chloro- 5- [({ (1R of 4-; 2S, 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } amino) carbonyl] -3- thienyls } methyl (methyl) t-butyl carbamate
Figure G2003801097466D05211
Using method similarly to Example 2, make the compound that reference example 471 is obtained and the compound condensation that reference example 420 is obtained, obtain title compound.
1H-NMR(CDCl3)δ：1.48 (9H, s), 1.50-1.70 (1H, m), 1.80-2.00 (2H, m), 2.00-2.12 (2H, m), 2.14-2.22 (1H, m), 2.72-2.83 (1H, m), 2.88, 2.89 (whole 3H, each s), 2.96 (3H, s), 3.04 (3H, s), 4.05-4.15 (1H, m), 4.32-4.50 (1H, m), 4.73-4.80 (1H, m), 7.22 (1H, d, J=8.8Hz), 7.38 (1H, br.s), 7.69 (1H, dd, J=8.8, 2.6Hz), 7.99 (1H, d, J=7.6Hz), 8.17 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.6Hz), 9.70 (1H, br.s)
MS(ESI)m/z：655(M+H)+.
[embodiment 331] N1- { (1S, 2R, 4S) -2- [({ the chloro- 4- of 3- [(methylamino) methyl] -2- thienyls } carbonyl) amino] -4- [(dimethylamino) carbonyl] cyclohexyl }-N2- (5- chloropyridine -2- bases) oxalamide
Using the method same with embodiment 227, the compound obtained by embodiment 330 prepares title compound.
1H-NMR(CDCl3)δ：1.55-1.70 (1H, m), 1.75-1.98 (2H, m), 2.00-2.22 (2H, m), 2.22-2.32 (1H, m), 2.52 (3H, s), 2.72-2.86 (1H, m), 2.96 (3H, s), 3.05 (3H, s), 3.53-3.82 (1H, m), 3.78 (2H, s), 4.05-4.16 (1H, m), 4.72-4.80 (1H, m), 7.27 (1H, d, J=7.8Hz), 7.52 (1H, s), 7.67 (1H, dd, J=8.8, 2.6Hz), 8.09 (1H, d, J=7.6Hz), 8.09 (1H, d, J=7.6Hz), 8.13 (1H, d, J=8.8Hz), 8.29 (1H, d, J=2.6Hz), 9.90-11.00 (1H, br)
MS(ESI)m/z：555(M+H)+.
[embodiment 332] N1- { (1S, 2R, 4S) -2- { [(the chloro- 4- of 3- { [4,5- dihydro -1,3- oxazole -2- bases (methyl) amino] methyl } -2- thienyls) carbonyl] amino } -4- [(dimethylamino) carbonyl] cyclohexyl }-N2- (5- chloropyridine -2- bases) oxalamide hydrochloride
Figure G2003801097466D05221
Triethylamine (0.735ml), 2- bromoethyls isocyanates (0.106ml) are added in dichloromethane (20ml) suspension for the compound (590mg) that embodiment 331 is obtained, is stirred 18 hours at room temperature.Dchloromethane reaction solution is used, successively with water, 0.5N hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing.Lower concentrate is depressurized after organic layer anhydrous sodium sulfate drying.Residue (dichloromethane: methanol=20: 1) refines for the flash column chromatography of carrier to silica gel, solvent is boiled off under decompression.The thick product of gained is dissolved in dichloromethane (2ml) and ethanol (3ml), 1N ethanol solution hydrochloride (0.5ml) is added, lower concentrate is depressurized after stirring 30 minutes at room temperature.Ether is added in residue, the solid that leaching is separated out obtains the title compound (197mg) in colourless powder after washing.
1H-NMR(DMSO-d6)δ：1.45-1.60 (1H, m), 1.60-1.83 (3H, m), 1.85-2.02 (3H, m), 2.80 (3H, s), 2.84 (3H, s), 2.90-3.01 (1H, m), 2.97 (3H, s), 3.25-3.40 (2H, m), 3.60 (2H, t, J=6.6Hz), 3.95-4.05 (1H, m), 4.30-4.45 (3H, m), 6.80 (1H, t, J=5.5Hz), 7.51 (1H, s), 7.94-8.06 (2H, m), 8.10 (1H, d, J=6.8Hz), 8.42-8.50 (1H, m), 8.97 (1H, d, J=8.6Hz), 10.27 (1H, s)
MS(ESI)m/z：624(M+H)+.
[embodiment 333] [the chloro- 5- of 4- ({ [(1R, 2S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) cyclohexyl] amino } carbonyl) -3- thienyls] methyl (methyl) t-butyl carbamate
Figure G2003801097466D05222
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 472 is carried out after processing deprotection, the compound condensation obtained with reference example 471, obtains title compound.
1H-NMR(CDCl3)δ：1.15-2.00 (6H, m), 1.46 (9H, s), 2.87 (3H, s), 4.15-4.25 (1H, m), 4.30-4.45 (2H, m), 4.48-4.56 (1H, m), 7.20 (1H, d, J=8.1Hz), 7.27-7.32 (1H, m), 7.70 (1H, dd, J=8.8,2.2Hz), 8.01 (1H, d, J=8.3Hz), 8.18 (1H, d, J=8.8Hz), 8.30 (1H, d, J=2.6Hz), 9.73 (1H, br.s)
MS(ESI)m/z：584(M+H)+.
[embodiment 334] N1- { (1S, 2R) -2- [({ the chloro- 4- of 3- [(methylamino) methyl] -2- thienyls } carbonyl) amino] cyclohexyl }-N2- (5- chloropyridine -2- bases) oxalamide
Using the method same with embodiment 227, the compound obtained by embodiment 333 prepares title compound.
1H-NMR(CDCl3)δ：1.48-2.02 (8H, m), 2.46 (3H, s), 3.72 (2H, s), 4.15-4.25 (1H, m), 4.45-4.55 (1H, m), 7.22 (1H, d, J=8.1Hz), 7.42 (1H, s), 7.71 (1H, dd, J=8.8,2.6Hz), 8.03 (1H, d, J=9.3Hz), 8.19 (1H, dd, J=8.8,0.73Hz), 8.31 (1H, dd, J=2.6,0.73Hz)
MS(ESI)m/z：484(M+H)+.
[embodiment 335] N1- ((1S, 2R) -2- [(the chloro- 4- of 3- { [4,5- dihydro -1,3- oxazole -2- bases (methyl) amino] methyl } -2- thienyls } carbonyl] amino } cyclohexyl)-N2- (5- chloropyridine -2- bases) oxalamide
Figure G2003801097466D05232
Using the method same with embodiment 332, title compound is made in the compound obtained by embodiment 334.
1H-NMR(CDCl3)δ：1.50-2.00 (8H, m), 2.94 (3H, s), 3.80 (2H, t, J=8.5Hz), 4.17-4.25 (1H, m), 4.32 (2H, t, J=8.5Hz), 4.39 (1H, d, J=16.5Hz), 4.41 (1H, d, J=16.5Hz), 4.58-4.67 (1H, m), 7.18 (1H, d, J=8.3Hz), 7.40 (1H, s), 7.69 (1H, dd, J=8.8, 2.4Hz), 8.00 (1H, d, J=8.1Hz), 8.17 (1H, d, J=8.8Hz), 8.29 (1H, d, J=2.4Hz), 9.73 (1H, br.s)
MS(ESI)m/z：553(M+H)+.
[embodiment 336] N1- (5- chloropyridine -2- bases)-N2- ((1R, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -5,6,7,8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D05233
- 2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using method similarly to Example 2, make the compound that reference example 477 is obtained and the compound condensation that reference example 420 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.42-1.58 (1H, m), 1.60-1.84 (3H, m), 1.85-2.15 (4H, m), 2.79 (6H, br.s), 2.93 (4H, br.s), 3.05-3.25 (2H, m), 3.49 (1H, br.s), 3.63 (1H, br.s), 3.95-4.05 (1H, m), 4.42 (1H, br.s), 4.64 (1H, br.s), 4.78 (1H, br.s), 8.01 (2H, br.s), 8.46 (1H, br.s), 8.65 (1H, d, J=7.3Hz), 9.19 (1H, d, J=8.1Hz), 10.29 (1H, s), 10.64 (1H, br.s)
MS(FAB)m/z：562(M+H)+.
[embodiment 337] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(4,4,5- trimethyls -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazol-2-yl) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D05242
Using the method same with reference example 10, the compound obtained by reference example 479 prepares 4,4,5- trimethyl -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- carboxylic acid lithium salts.Then, compound condensation same with the method that embodiment 2 is recorded, making the lithium salts be obtained with reference example 420, is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.45-1.55 (4H, m), 1.60-1.85 (6H, m), 1.85-2.10 (2H, m), 2.78 (3H, s), 2.85-3.08 (7H, m), 3.93-4.05 (1H, br), 4.41-4.53 (1H, br), 4.52-4.68 (1H, br), 4.70-4.83 (1H, br), 8.01 (2H, br.s), 8.45 (1H, br.s), 8.63 (0.5H, d, J=7.6Hz), 8.68 (0.5H, d, J=7.6Hz), 9.07-9.20 (1H, m), 10.29 (0.5H, s), 10.26 (0.5H, s), 11.83 (0.5H, br.s), 11.76 (0.5H, br.s)
MS(FAB)m/z：562(M+H)+.
[embodiment 338] 6- [({ (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } amino) carbonyl] -1; 3- dihydro-2 h-pyrroles simultaneously [3,4-c] the pyridine-2-carboxylic acids tert-butyl ester
Figure G2003801097466D05251
It is same with the method that embodiment 2 is recorded, the compound that reference example 481 is obtained and the compound that reference example 420 is obtained are condensed, title compound is prepared.
1H-NMR(CDCl3)δ：1.53 (4.5H, s), 1.61 (4.5H, s), 1.54-2.20 (6H, m), 2.76-2.90, (1H, m), 2.96 (3H, s), 3.07 (3H, s), 4.05-4.15 (1H, m), 4.46-4.85 (5H, m), 7.67 (1H, dd, J=8.8,2.3Hz), 8.10-8.23 (3H, m), 8.30 (1H, d, J=2.3Hz), 8.30-8.40 (1H, m), 8.45 (0.5H, br.s), 8.49 (0.5H, br.s), 9.72 (1H, br.s)
MS(ESI)m/z：614(M+H)+.
[embodiment 339] N1- (5- chloro-2-pyridyls)-N2- { (1S, 2R, 4S) -2- [(2,3- dihydro -1H- pyrrolo-es [3,4-c] pyridine -6- bases carbonyl) amino] -4- [(dimethylamino) carbonyl] cyclohexyl } oxalamide hydrochloride
Figure G2003801097466D05252
Using the method same with embodiment 227, the compound obtained by embodiment 338 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.61 (1H, m), 1.62-1.84 (3H, m), 1.95-2.10 (2H, m), 2.78 (3H, s), 2.79-2.90 (1H, m), 2.90 (3H, s), 3.90-4.15 (1H, m), 4.45-4.53 (1H, br), 4.55-4.68 (4H, m), 8.00 (2H, br.s), 8.10 (1H, s), 8.45 (1H, d, J=1.5Hz), 8.67 (1H, d, J=7.6Hz), 8.75 (1H, s), 9.19 (1H, d, J=8.3Hz), 10.11 (2H, br.s), 10.26 (1H, br.s)
MS(FAB)m/z：514(M+H)+.
[embodiment 340] N1- (5- chloro-2-pyridyls)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(2- methyl -2,3- dihydro -1H- pyrrolo-es [3,4-c] pyridine -6- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D05253
Using method similarly to Example 18, the compound and formalin obtained by embodiment 339 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.59 (1H, m), 1.60-1.85 (3H, m), 1.91-2.10 (2H, m), 2.78 (3H, br.s), 2.80-2.90 (1H, m), 2.90 (1.5H, s), 2.92 (1.5H, s), 3.01 (1.5H, s), 3.02 (1.5H, s), 3.90-4.05 (1H, m), 4.42-4.60 (3H, m), 4.80-5.00 (2H, m), 8.00 (2H, br.s), 8.11 (1H, s), 8.44 (1H, d, J=1.5Hz), 8.60-8.70 (1H, m), 8.75 (1H, s), 9.18 (1H, d, J=7.8Hz), 10.25 (0.5H, s), 10.28 (0.5H, s), 11.95 (0.5H, s), 12.02 (0.5H, s)
MS(FAB)m/z：528(M+H)+.
[embodiment 341] N1- (5- chloropyridine -2- bases)-N2- { (1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- [(5,6,7,8- tetrahydrochysenes [1,6] naphthyridines -2- bases carbonyl) amino] cyclohexyl } oxalamide hydrochloride
Figure G2003801097466D05261
Similarly to Example 2, to 6- (tert-butoxycarbonyl) -5,6,7,8- tetrahydrochysenes [1,6] naphthyridines -2- carboxylate methyl esters (Japanese Patent Laid-Open 2000-119253) are hydrolyzed, the compound condensation for obtaining the lithium salts and reference example 420 of gained carboxylic acid, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.45-1.62 (1H, m), 1.62-1.87 (3H, m), 1.89-2.05 (2H, m), 2.80 (3H, s), 2.81-2.94 (1H, m), 2.95 (3H, s), 3.15-3.35 (2H, m), 3.51 (2H, br.s), 3.90-4.05 (1H, m), 4.38 (2H, br.s), 4.43-4.55 (1H, m), 7.88 (2H, br.s), 8.01 (2H, br.s), 8.45 (1H, d, J=1.5Hz), 8.51 (1H, d, J=8.3Hz), 9.16 (1H, d, J=7.8Hz), 9.85 (1H, br.s), 10.02 (1H, br.s), 10.27 (1H, br.s)
MS(FAB)m/z：528(M+H)+.
[embodiment 342] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(6- methyl -5,6,7,8- tetrahydrochysenes [1,6] naphthyridines -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using method similarly to Example 18, the compound and formalin obtained by embodiment 341 prepares title compound.
1H-NMR(DMSO-d6)δ：1.45-1.62 (1H, m), 1.63-1.80 (3H, m), 1.86-2.06 (2H, m), 2.80 (3H, br.s), 2.81-2.96 (7H, m), 3.14-3.27 (1H, m), 3.11-3.63 (2H, m), 3.76 (1H, br.s), 3.99 (1H, br.s), 4.35-4.52 (2H, m), 4.53-4.65 (1H, m), 7.84 (1H, J=8.0Hz), 7.89 (1H, J=8.0Hz), 8.00 (2H, br.s), 8.40-8.55 (2H, m), 9.07 (0.4H, d, J=7.6Hz), 9.19 (0.6H, d, J=8.1Hz), 10.24 (0.6H, s), 10.28 (0.4H, s), 11.42-11.80 (1H, br)
MS(FAB)m/z：542(M+H)+.
[embodiment 343] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- ({ [5- (pyridin-4-yl) pyrimidine -2-base] carbonyl } amino) cyclohexyl] oxalamide hydrochloride
Figure G2003801097466D05271
Similarly to Example 2, make compound and the acquisition compound condensation of reference example 483 that reference example 420 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.50-1.63 (1H, m), 1.67-1.85 (3H, m), 1.95-2.12 (2H, m), 2.80 (3H, s), 2.86-2.95 (1H, m), 2.95 (3H, s), 4.00-4.10 (1H, m), 4.45-4.55 (1H, m), 8.01 (2H, br.s), 8.34 (2H, d, J=5.6Hz), 8.44-8.47 (1H, m), 8.79 (1H, d, J=7.6Hz), 8.99 (2H, d, J=5.6Hz), 9.08 (1H, d, J=8.3Hz), 9.54 (2H, s), 10.31 (1H, s)
MS(FAB)m/z：551(M+H)+.
[embodiment 344] N1- (5- chloropyridine -2- bases)-N2- { (1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- [({ 2 '-[(dimethylamino) methyl] [1,1 '-biphenyl] -4- bases } carbonyl) amino] cyclohexyl } oxalamide hydrochloride
Similarly to Example 2, make the compound that reference example 420 is obtained and the compound condensation that reference example 488 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.45-1.56 (1H, m), 1.60-1.85 (3H, m), 1.85-2.15 (2H, m), 2.40-2.55 (6H, m), 2.80 (3H, s), 2.99 (3H, s), 3.05-3.20 (1H, m), 3.93-4.06 (1H, m), 4.25-4.33 (2H, m), 4.45-4.55 (1H, m), 7.30-7.37 (1H, m), 7.48 (2H, d, J=8.3Hz), 7.50-7.58 (2H, m), 7.84-7.90 (1H, m), 7.95-8.05 (4H, m), 8.15 (1H, d, J=7.3Hz), 8.46 (1H, br.s), 9.20 (1H, d, J=8.3Hz), 10.15-10.29 (1H, br), 10.30 (1H, br.s)
MS(FAB)m/z：605(M+H)+.
[embodiment 345] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- ({ 4- [2- (hydroxymethyl) pyridin-4-yl] benzoyl } amino) cyclohexyl] oxalamide hydrochloride
Figure G2003801097466D05281
Similarly to Example 2, by the compound hydrolysis of reference example 490, then the compound condensation for obtaining the lithium salts and reference example 420 of gained carboxylic acid is handled with hydrochloric acid, prepares title compound.
1H-NMR(DMSO-d6)δ：1.44-1.58 (1H, m), 1.63-1.81 (3H, m), 1.89-1.99 (1H, m), 1.99-2.13 (1H, m), 2.79 (3H, s), 2.97 (3H, s), 3.06-3.17 (1H, m), 3.93-4.02 (1H, m), 4.44-4.51 (1H, m), 4.89 (2H, s), 7.99 (2H, s), 8.08 (4H, m), 8.19 (1H, d, J=6.3Hz), 8.24 (1H, d, J=7.3Hz), 7.29 (1H, s), 8.44-8.46 (1H, m), 8.80 (1H, d, J=5.9Hz), 9.01 (1H, d, J=8.3Hz), 10.27 (1H, s)
MS(ESI)m/z：579(M+H)+.
[embodiment 346] N1{ (1S, 2R, 4S) -2- ({ 4- [2- (amino methyl) pyridin-4-yl] benzoyl } amino) -4- [(dimethylamino) carbonyl] cyclohexyl }-N2- (5- chloropyridine -2- bases) oxalamide hydrochloride
Figure G2003801097466D05282
Similarly to Example 2, to the compound hydrolysis of reference example 491, the compound condensation for obtaining the lithium salts and reference example 420 of gained carboxylic acid, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.40-1.58 (1H, m), 1.58-1.83 (3H, m), 1.87-1.98 (1H, m), 1.98-2.13 (1H, m), 2.78 (3H, s), 2.97 (3H, s), 3.05-3.17 (1H, m), 3.93-4.03 (1H, m), 4.17-4.30 (2H, m), 4.40-4-50 (1H, m), 7.80 (1H, dd, J=5.2, 1.6Hz), 7.90-8.06 (7H, m), 8.18 (1H, d, J=7.6Hz), 8.43-8.46 (1H, m), 8.50 (3H, br.s), 8.70 (1H, d, J=5.2Hz), 9.01 (1H, d, J=8.5Hz), 10.27 (1H, s)
MS(ESI)m/z：578(M+H)+.
[embodiment 347] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- ({ [1- (phenyl sulfonyl) piperidin-4-yl] carbonyl } amino) cyclohexyl] oxalamide
Figure G2003801097466D05291
Using method similarly to Example 2, make the compound that reference example 420 is obtained and the compound condensation that reference example 493 is obtained, prepare title compound.
1H-NMR(CDCl3)δ：1.60-2.10 (10H, m), 2.12-2.21 (1H, m), 2.40 (2H, br.t, J=11.2Hz), 2.65-2.77 (1H, m), 2.92 (3H, s), 2.99 (3H, s), 3.77 (2H, br.d, J=11.7Hz), 3.92-4.05 (1H, m), 4.42-4.53 (1H, m), 6.31 (1H, br.d, J=7.3Hz), 7.53 (2H, t, J=7.3Hz), 7.62 (1H, t, J=7.3Hz), 7.67-7.78 (3H, m), 8.01 (1H, brd, J=7.3Hz), 8.16 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.2Hz), 9.72 (1H, s)
MS(ESI)m/z：619(M+H)+.
[embodiment 348] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- ({ [1- (4- fluorobenzoyls) piperidin-4-yl] carbonyl } amino) cyclohexyl] oxalamide D22-5792
Using method similarly to Example 2, make the compound that reference example 420 is obtained and the compound condensation that reference example 495 is obtained, prepare title compound.
1H-NMR(CDCl3)δ：1.60-2.16 (10H, m), 2.37-2.48 (1H, m), 2.64-2.78 (1H, m), 2.80-3.13 (2H, m), 2.94 (3H, s), 3.02 (3H, s), 3.65-4.18 (1H, br), 3.93-4.01 (1H, m), 4.43-4.80 (2H, br), 6.32 (1H, br.d, J=7.1Hz), 7.09 (2H, t, J=8.5Hz), 7.40 (2H, dd, J=8.5, 5.4Hz), 7.71 (1H, dd, J=8.8, 2.4Hz), 8.04 (1H, br.d, J=7.6Hz), 8.15 (1H, d, J=8.8Hz), 8.30 (1H, d, J=2.4Hz), 9.71 (1H, s)
MS(ESI)m/z：601(M+H)+.
[embodiment 349] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [4- (pyrrolidin-1-yl carbonyl) benzoyl] amino } cyclohexyl) oxalamide
Figure G2003801097466D05301
Using method similarly to Example 2, make the compound that reference example 420 is obtained and the compound condensation that reference example 497 is obtained, prepare title compound.
1H-NMR(CDCl3)δ：1.68-2.23 (9H, m), 2.33 (1H, br.d, J=7.4Hz), 2.85-3.02 (1H, m), 2.92 (3H, s), 2.98 (3H, s), 3.31 (2H, t, J=6.8Hz), 3.61 (2H, t, J=6.8Hz), 4, 13-4.22 (1H, m), 4.54-4.63 (1H, m), 7.28 (2H, d, J=8.1Hz), 7.63-7.69 (1H, m), 7.66 (2H, d, J=8.1Hz) 7.95 (1H, br.d, J=5.6Hz), 8.05 (1H, d, J=8.8Hz), 8.30 (1H, d, J=2.4Hz), 8.54 (1H, brd, J=8.3Hz), 9.76 (1H, s)
MS(ESI)m/z：569(M+H)+.
[embodiment 350] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [4- (pyrrolidin-1-yl methyl) benzoyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D05302
Similarly to Example 2, the compound that reference example 498 is recorded is hydrolyzed, the compound condensation for obtaining the lithium salts and reference example 420 of gained carboxylic acid, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.43-1.57 (1H, m), 1.62-2.10 (9H, m), 2.78 (3H, s), 2.95 (3H, s), 2.96-3.12 (3H, m), 3.28-3.50 (2H, m), 3.92-4.01 (1H, m), 4.35-4.48 (3H, m), 7.69 (2H, d, J=8.1Hz), 7.92 (2H, d, J=8.1Hz), 7.99 (2H, s), 8.09 (1H, br.d, J=7.6Hz), 8.44 (1H, s), 8.99 (1H, br.d, J=8.3Hz), 10.27 (1H, s), 10.65-10.80 (1H, br)
MS(ESI)m/z：555(M+H)+.
[embodiment 351] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) thioformyl] -2- { [(5- methyl -4; 5; 6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Same with the method that embodiment 214 is recorded, the compound obtained with 4N Yan Suan dioxane solutions to reference example 501 is carried out after processing deprotection, the compound condensation with the acquisition of reference example 10, then is carried out with hydrochloric acid handling acquisition title compound.
1H-NMR(DMSO-d6)δ：1.60-2.18 (6H, m), 2.70-2.95 (4H, m), 2.90 (3H, s), 3.06-3.40 (2H, m), 3.42-3.54 (1H, br), 3.62-3.78 (1H, br), 3.96-4.05 (1H, m), 4.24-4.34 (1H, br), 4.35-4.52 (1H, br), 4.60-4.76 (1H, m), 7.96-8.04 (2H, m), 8.43 (1H, s), 8.48-8.60 (1H, br), 9.39 (1H, br.d, J=7.8Hz), 9.91-10.03 (1H, br), 10.18-10.30 (1H, m), 11.72-11.95 (1H, br)
MS(ESI)m/z：550(M+H)+.
[embodiment 352] N- { (1R; 2S; 5S) -2- { [(4- chloroanilinos) sulfonyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05312
Chlorosulfonic acid (146 μ l) is added in 0 DEG C of dichloromethane (15ml) solution in 4- chloroanilines (255mg).After being stirred 1 hour at identical temperature, stir 2 hours at room temperature.Phosphorus pentachloride (458mg) is added in reaction solution to be heated to reflux 2 hours.Temperature is returned back into room temperature, the compound (731mg) that reference example 253 is obtained is added, triethylamine is added, pH is adjusted to neutral.After stirring 17 hours at room temperature, add water a point liquid in reaction solution.Water layer is extracted with dichloromethane, the organic layer of merging is carried out after 2 washings with water, uses anhydrous sodium sulfate drying.Solvent is boiled off under decompression, first to flash column chromatography (dichloromethane: methanol=93: 7) of the silica gel for carrier, (dichloromethane: methanol=9: 1) refined 2 times with preparative thin layer chromatography again, obtain faint yellow solid (46mg).The solid is dissolved in dichloromethane, 1N ethanol solution hydrochloride (83 μ l) is added.Solvent is boiled off under decompression, a small amount of methanol and ether is added in residue, the precipitation of leaching generation obtains the title compound (34mg) in faint yellow solid.
1H-NMR(DMSO-d6)δ：1.34-1.69 (5H, m), 1.98 (1H, br.s), 2.75 (3H, s), 2.85-2.94 (8H, m), 3.17 (2H, br.s), 3.50 (1H, br.s), 3.69 (1H, br.s), 4.39-4.50 (2H, m), 4.69 (1H, br.s), 7.08-7.15 (4H, m), 7.74 (1H, br.s), 7.98 (1H, br.s), 9.90 (1H, s), 11.35 (1H, br.s)
MS(FAB)m/z：555(M+H)+.
[embodiment 353] N- { (1R; 2S; 5S) -2- ({ 2- [(5- chlorine pyrimidine -2-base) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 219, the compound obtained with hydrochloric acid to reference example 503 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO)δ：1.49-1.54 (1H, m), 1.68-1.79 (3H, m), 1.99-2.02 (1H, m), 2.16-2.22 (1H, m), 2.80 (3H, s), 2.91 (3H, s), 2.97 (3H, s), 3.06 (1H, br.s), 3.20 (2H, br.s), 3.49 (1H, br.s), 3.64 (1H, br.s), 4.40-4.55 (2H, m), 4.70 (2H, br.s), 8.68 (1H, d, J=7.1Hz), 8.81 (2H, s), 10.87 (1H, br.s), 10.99 (1H, br.s), 11.47 (1H, br.s)
MS(FAB)m/z：565(M+H)+.
[embodiment 354] N- { (1R; 2S; 5S) -2- { [2- (the chloro- 3- nitrobenzene amidos of 4-) -2- oxos ethanethioyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05322
Using the method same with embodiment 219, the compound obtained with hydrochloric acid to reference example 505 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO)δ：1.48-1.54 (1H, m), 1.67-1.78 (3H, m), 1.99-2.03 (1H, m), 2.22-2.33 (1H, m), 2.79 (3H, s), 2.91 (3H, s), 2.96 (3H, s), 3.01-3.67 (5H, m), 4.40-4.80 (4H, m), 7.78 (1H, d, J=8.8Hz), 8.05 (1H, dd, J=8.8,1.4Hz), 8.59 (1H, d, J=1.4Hz), 8.75 (1H, d, J=7.6Hz), 10.89-10.92 (2H, m), 11.43 (1H, br.s)
MS(ESI)m/z：608(M+H)+.
[embodiment 355] N- { (1R; 2S; 5S) -2- { [2- (3- amino -4- chloroanilinos) -2- oxos ethanethioyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05331
10% palladium carbon (1.00g) is added in ethanol (30ml) solution for the compound (458mg) that embodiment 354 is obtained, is stirred 3 days at room temperature.Catalyst is filtered off, solvent is boiled off under decompression.(dichloromethane: methanol=94: 6) residue is refined for the flash column chromatography of carrier to silica gel, gained yellow solid (137mg) is dissolved in dichloromethane (5ml), 1N acidic alcohol (474 μ l) is added.Ether (20ml) is added, leaching solid is washed with ether, obtain the title compound (144mg) in yellow solid.
1H-NMR(DMSO-d6)δ：1.46-1.54 (1H, m), 1.70-1.78 (3H, m), 1.98-2.07 (1H, m), 2.21-2.23 (1H, m), 2.79 (3H, s), 2.91 (3H, s), 2.96 (3H, s), 3.03 (1H, br.s), 3.11-3.19 (1H, m), 3.30 (1H, br.s), 3.47 (1H, br.s), 3.69 (1H, br.s), 4.10-4.51 (4H, m), 4.68 (2H, s), 6.95 (1H, dd, J=8.6, 2.3Hz), 7.18 (1H, d, J=8.6Hz), 7.31 (0.5H, s), 7.33 (0.5H, s) 8.74-8.80 (1H, m), 10.18 (1H, d, J=9.8Hz), 10.83 (0.5H, d, J=7.6Hz), 10.89 (0.5H, d, J=8.0Hz), 11.79 (0.5H, br.s), 11.87 (0.5H, br.s)
MS(ESI)m/z：578(M+H)+.
[embodiment 356] 6- [({ (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls] amino) -5- [(dimethylamino) carbonyl] cyclohexyl } amino) carbonyl] -1; 3- dihydro-2 h-pyrroles simultaneously [3,4-c] the pyridine-2-carboxylic acids tert-butyl ester
Figure G2003801097466D05332
Using the method same with embodiment 219, the compound obtained with hydrochloric acid to reference example 428 is carried out after processing deprotection, and title compound is obtained with the compound condensation that reference example 481 is obtained.
1H-NMR(CDCl3)δ：1.53 (9H, s), 1.56-2.42 (6H, m), 2.85-2.94, (1H, m), 2.98 (3H, s), 3.10 (3H, s), 4.45-4.52 (1H, m), 4.70-4.85 (5H, m), 7.67 (1], dd, J=8.8,2.4Hz), 8.18 (0.5H, br.s), 8.18 (1H, d, J=8.8Hz), 8.23 (0.5H, b.s), (8.31 1H, d, J=2.4Hz), 8.40-8.52 (2H, m), 10.29 (1H, br.s), 10.60 (1H, r.s)
MS(ESI)m/z：630(M+H)+
[embodiment 357] N- { (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl] amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -2- methyl -2; 3- dihydro -1H- pyrrolo-es [3,4-c] pyridine -6- carboxamide hydrochlorides
The compound obtained with hydrochloric acid to embodiment 356 is carried out after processing deprotection, same with the method that embodiment 18 is recorded to methylate, then carries out with hydrochloric acid processing acquisition title compound.
1H-NMR(DMSO-d6)δ：1.46-1.61 (1H, m), 1.62-1.95 (3H, m), 1.95-2.10 (1H, m), 2.10-2.30 (1H, m), 2.79 (3H, br.s), 2.84-2.94 (4H, m), 2.95 (3H, s), 4.45-4.60 (3H, m), 4.75 (1H, br.s), 4.80-5.00 (2H, m), 7.97-8.13 (2H, m), 8.16 (1H, br.s), 8.46 (1H, br.s), 8.76 (2H, br.s), 10.51 (0.5H, s), 10.55 (0.5H, s), 11.09 (1H, br.s), 11.92 (0.5H, br.s), 11.99 (0.5H, br.s)
MS(FAB)m/z：544(M+H)+.
[embodiment 358] N- { (1R; 2S, 5S) -2- (2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl] and amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -1- (pyridin-4-yl) -4- piperidine formyl amine hydrochlorates
Figure G2003801097466D05342
It is same with the method that embodiment 219 is recorded; the compound obtained with hydrochloric acid to reference example 428 is carried out after processing deprotection; with 1- (pyridin-4-yl) -4- piperidine carboxylic acids (Tetrahedron; 1998; volume 44; page 7095) condensation, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.38-1.52 (1H, m), 1.52-1.73 (4H, m), 1.73-1.88 (3H, m), 1.88-2.02 (2H, m), 2.80 (3H, s), 3.04 (3H, s), 3.10-3.40 (4H, m), 4.14-4.36 (3H, m), 4.48-4.57 (1H, m), 7.18 (2H, d, J=6.8Hz), 7.90-8.11 (2H, m), 8.11-8.30 (3H, m), 8.30-8.45 (1H, m), 10.33 (1H, s), 10.56 (1H, d, J=7.3Hz), 13.48 (1H, br.s)
MS(ESI)m/z：572(M+H)+.
[embodiment 359] N- { (1R; 2S; 5S) -2- { [(7- chlorine cinnolines -3- bases) thioformyl] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
It is same with the method that embodiment 2 is recorded, make the compound that reference example 509 is obtained and the compound condensation that reference example 10 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.55-1.63 (1H, m), 1.72-1.78 (1H, m), 1.86-1.89 (2H, m), 2.10 (1H, br.s), 2.40-2.46 (1H, m), 2.81 (3H, s), 2.91 (3H, s), 2.97 (3H, s), 3.04 (1H, br.s), 3.15-3.20 (1H, m), 3.27 (1H, br.s), 3.49 (1H, br.s), 3.69 (1H, br.s), 4.43 (1H, br.s), 4.67 (1H, br.s), 4.81 (1H, br.s), 4.95 (1H, br.s), 8.00 (1H, d, J=8.8Hz), 8.41 (1H, d, J=8.8Hz), 8.65 (1H, s), 9.06 (1H, br.s), 9.20 (1H, s), 11.44 (1H, br.s), 11.66 (1H, br.s)
MS(ESI)m/z：572(M+H)+.
[embodiment 360] N- { (1R; 2S; 5S) -2- ({ [(4- chlorobenzene formacyls) amino] carbonyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
It is same with the method that embodiment 2 is recorded, make the compound that reference example 511 is obtained and the compound condensation that reference example 10 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.45-1.50 (1H, m), 1.74-1.84 (4H, m), 1.87-1.95 (1H, m), 2.80 (3H, s), 2.92 (3H, s), 3.02 (3H, s), 3.13-3.35 (3H, m), 3.47 (1H, br.s), 3.69 (1H, br.s), 3.97 (1H, br.s), 4.41-4.44 (1H, m), 4.62-4.72 (2H, m), (7.56 2H, d, J=8.6Hz), 7.86-7.88 (2H, m), 8.68 (1H, br.s), 8.83 (1H, br.s)
MS(FAB)m/z：547(M+H)+.
[embodiment 361] N- { (1R; 2S; 5S) -2- { [(E) -3- (5- chloropyridine -2- bases) acryloyl group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05361
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 513 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.37-1.52 (1H, m), 1.57-1.92 (5H, m), 2.77 (3H, s), 2.89 (3H, s), 2.99 (3H, s), 3.04-3.20 (2H, m), 3.20-3.38 (1H, m), 3.47 (1H, br.s), 3.60-3.90 (1H, m), 3.90-4.03 (1H, m), 4.36-4.48 (1H, m), 4.52-4.62 (1H, m), 4.67 (1H, br.d, J=16.2Hz), 7.08 (1H, d, J=15.4Hz), 7.38 (1H, dd, J=15.4, 3.9Hz), 7.60 (1H, d, J=8.4Hz), 7.94 (1H, d, J=8.4Hz), 8.28 (1H, d, J=7.1Hz), 8.35 (1H, d, J=9.8Hz), 8.59 (1H, s), 11.72 (0.5, br.s), 11.88 (0.5H, br.s)
MS(ESI)m/z：531(M+H)+.
[embodiment 362] N- { (1R; 2S; 5S) -2- { [(Z) -3- (4- chlorphenyls) -2- fluoropropenes acyl group] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05362
Using the method same with embodiment 49, the compound obtained with hydrochloric acid to reference example 519 is carried out after processing deprotection, the compound condensation obtained with reference example 516, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.47-1.75 (4H, m), 1.97-2.20 (2H, m), 2.79 (3H, s), 2.92-2.96 (7H, m), 3.20 (2H, br.s), 3.50 (1H, br.s), 3.67 (1H, br.s), 4.03 (1H, br.s), 4.47 (2H, br.s), 4.66 (1H, br.s), 6.88 (1H, d, J=38.6Hz), 7.50 (2H, d, J=8.4Hz), 7.66 (2H, d, J=8.4Hz), 8.52-8.56 (2H, m), 11.36 (1H, br.s)
MS(EI)m/z：547(M+).
[embodiment 363] N- { (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(methylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 214, the compound obtained with 4N Yan Suan dioxane solutions to reference example 521 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.48-1.61 (1H, m), 1.61-1.72 (1H, m), 1.72-1.87 (2H, m), 2.02-2.12 (1H, m), 2.15-2.30 (1H, m), 2.33-3.43 (1H, m), 2.52 (3H, d, J=4.4Hz), 2.86 (3H, s), 3.17 (2H, br.s), 3.50 (2H, br.s), 4.35-4.60 (4H, m), 7.73-7.80 (1H, m), 8.00 (1H, dd, J=9.0, 2.4Hz), 8.05 (1H, d, J=9.0Hz), 8.43 (1H, d, J=2.4Hz), 8.51-8.58 (1H, m), 10.55 (1H, s), 11.13 (1H, d, J=7.8Hz)
MS(ESI)m/z：550(M+H)+.
[embodiment 364] N- [(1R; 2S; 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(5- fluorine pyridine -2- bases) amino] -2- oxos ethanethioyl } amino) cyclohexyl] -5- methyl -5; 6; 7; 8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-c] azepine
Figure G2003801097466D05372
- 2- carboxamide hydrochlorides
Figure G2003801097466D05373
Using method similarly to Example 2, make the compound that reference example 522 is obtained and the compound condensation that reference example 477 is obtained, handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.43-1.60 (1H, m), 1.61-1.90 (3H, m), 1.92-2.18 (3H, m), 2.18-2.35 (1H, m), 2.70-2.88 (6H, m), 2.96 (3H, br.s), 2.96-3.00 (1H, m), 3.05-3.27 (2H, m), 3.40-3.52 (1H, br), 3.60-3.80 (1H, br), 4.45-4.60 (1H, m), 4.60-4.75 (2H, m), 4.75-4.90 (1H, m), 7.87 (1H, dt, J=2.9, 9.0Hz), 8.05-8.27 (1H, m), 8.43 (1H, d, J=2.9Hz), 8.70-8.82 (1H, m), 10.54 (1H, s), 11.05-11.30 (2H, m)
MS(FAB)m/z：562(M+H)+.
[embodiment 365] (3- { [(1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl } phenyl) (imino group) methyl carbamic acid tert-butyl ester
Figure G2003801097466D05381
At room temperature, water (1.0ml) and lithium hydroxide (20.5mg) are added in tetrahydrofuran (3.0ml) solution for the compound (250mg) that reference example 524 is obtained.Lower concentrate is depressurized in stirring after 15 hours.At room temperature, I-hydroxybenzotriazole (140mg) and 1- [3- (dimethylamino) propyl group] -3- ethyl-carbodiimide hydrochlorides (330mg) are added in DMF (5.0ml) solution for the compound (464mg) that gained solid and reference example 253 are obtained.After being stirred 21 hours at identical temperature, solvent is boiled off under decompression, is added after dichloromethane, water and saturated sodium bicarbonate aqueous solution point liquid, water layer is extracted with dichloromethane.Merge organic layer, after anhydrous sodium sulfate drying, solvent is boiled off under decompression, it is residue obtained (dichloromethane: methanol=10: 1) to refine for the middle compression leg chromatography of carrier to silica gel, obtain the title compound (213mg) in Sandy blister solid.
1H-NMR(CDCl3)δ：1.40-2.32 (6H, m), 1.56 (9H, s), 2.52 (3H, s), 2.77-2.90 (3H, m), 2.90-3.05 (2H, m), 2.96 (3H, s), 3.11 (3H, s), 3.70 (1H, d, J=15.5Hz), 3.73 (1H, d, J=15.5Hz), 4.15-4.23 (1H, m), 4.58-4.64 (1H, m), 7.43-7.57 (2H, m), 7.91 (1H, d, J=6.1Hz), 7.98 (1H, d, J=6.6Hz), 8.12 (1H, d, J=7.8Hz), 8.23 (1H, s), 9.30-10.00 (2H, br)
MS(ESI)m/z：612(M+H)+.
[embodiment 366] N- { (1R, 2S, 5S) -2- ({ 3- [amino (imino group) methyl] benzoyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
At room temperature, 4N Yan Suan dioxane solutions (4.0ml) are added in dichloromethane (4.0ml) solution for the compound (210mg) that embodiment 365 is obtained.After stirring 1 hour, saturation ethanol solution hydrochloride (20ml) is added.Solvent is boiled off under being depressurized stir all night after.In residue obtained middle addition water (4.0ml), boil off and dried after solvent under decompression, obtain the title compound (210mg) in Sandy solid.
1H-NMR(DMSO-d6)δ：1.20-2.10 (6H, m), 2.78 (3H, s), 2.90-3.20 (1H, m), 2.91 (3H, s), 2.99 (3H, s), 3.20-3.35 (1H, m), 3.35-3.80 (3H, m), 4.00-4.13 (1H, m), 4.35-4.80 (3H, m), 7.60-7.75 (1H, m), 7.85-8.10 (2H, m), 8.10-8.25 (1H, m), 8.40-8.53 (1H, m), 8.53-8.70 (1H, m), 9.25-9.80 (4H, m), 11.91 (1H, br.s)
MS(ESI)m/z：512(M+H)+.
[embodiment 367] N- { (1R, 2S, 5S) -2- [(3- Cyanophenacyls) amino] -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
Same with the method that embodiment 214 is recorded, the compound obtained with 4N Yan Suan dioxane solutions to reference example 525 is carried out after processing deprotection, the compound condensation obtained with reference example 10, obtains title compound.
1H-NMR(CDCl3)δ：1.50-1.66 (1H, m), 1.74-1.88 (1H, m), 1.90-2.07 (2H, m), 2.22-2.37 (2H, m), 2.53 (3H, s), 2.79-2.91 (3H, m), 2.91-3.03 (2H, m), 2.97 (3H, s), 3.13 (3H, s), 3.73 (1H, d, J=15.4Hz), 3.74 (1H, d, J=15.4Hz), 4.13-4.21 (1H, m), 4.58-4.64 (1H, m), 7.47 (1H, d, J=7.1Hz), 7.55 (1H, t, J=7.8Hz), 7.74 (1H, d, J=7.8Hz), 8.03 (1H, d, J=5.6Hz), 8.06 (1H, d, J=7.8Hz), 8.12 (1H, s)
MS(ESI)m/z：494(M+).
[embodiment 368] N- { (1R, 2S, 5S) -2- ({ 3- [amino (oxyimino) methyl] benzoyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Ethanol (5.0ml) and tetrahydrofuran (2.0ml) are added in the compound (270mg) that embodiment 367 is obtained dissolves it, and hydroxylamine hydrochloride (114mg) and triethylamine (230 μ l) are added at room temperature.It is heated to reflux after 3 hours, adds saturated sodium bicarbonate aqueous solution and dichloromethane, dichloromethane aqueous layer extracted is used after point liquid.Merge organic layer, with after anhydrous sodium sulfate drying depressurize under boil off solvent.It is residue obtained to silica gel for carrier column chromatography (dichloromethane: methanol=7: 1), cross-linked dextran gel column (methanol) and prepares anti-phase high-speed liquid chromatography (acetonitrile-water-formic acid system) carry out refine after, be formed as hydrochloride with 1N hydrochloric acid, refined successively with cross-link dextran post (methanol) again, obtain the title compound (175mg) of white solid.
1H-NMR(CD3OD)δ：1.53-1.67 (1H, m), 1.78-1.97 (5H, m), 2.84 (3H, s), 2.96-3.15 (2H, m), 3.00 (3H, s), 3.03 (3H, s), 3.15-3.26 (2H, m), 3.64 (2H, br.s), 4.09-4.18 (1H, m), 4.55 (2H, br.s), 7.55 (1H, t, J=7.8Hz), 7.72 (1H, d, J=7.8Hz), 7.94 (1H, d, J=7.8Hz), 8.01 (1H, s), 8.08 (1H, d, J=9.1Hz), 8.45 (1H, d, J=7.6Hz)
MS(ESI)m/z：528(M+H)+.
[embodiment 369] (3- { [((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) amino] carbonyl } phenyl) (imino group) methyl carbamic acid ethyl ester
Figure G2003801097466D05401
Same with embodiment 365, the compound that hydrolysis reference example 526 is recorded, the compound condensation for obtaining the lithium salts and reference example 253 of gained carboxylic acid obtains title compound.
1H-NMR(CDCl3)δ：1.36 (3H, t, J=7.1Hz), 1.55-1.71 (1H, m), 1.73-2.05 (3H, m), 2.05-2.35 (2H, m), 2.52 (3H, s), 2.75-3.05 (5H, m), 2.97 (3H, s), 3.11 (3H, s), 3.67-3.80 (2H, m), 4.10-4.35 (3H, m), 4.55-4.67 (1H, m), 7.09 (1H, br.s), 7.40-7.60 (2H, m), 7.94 (1H, d, J=6.1Hz), 8.03 (1H, d, J=7.8Hz), 8.16 (1H, d, J=7.8Hz), 8.27 (1H, s), 9.68 (1H, br.s)
MS(ESI)m/z：584(M+H)+.
[embodiment 370] N- [(1R, 2S, 5S) -5- [(dimethylamino) carbonyl] -2- ({ 3- [imino group (methylamino) methyl] benzoyl } amino) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide formates D22-9226
At room temperature, saturation ethanol solution hydrochloride (30ml) is added in the compound (400mg) that embodiment 367 is obtained.Lower concentration is depressurized in stirring after 2 days, obtain white solid.The solid is dissolved in after methanol (10ml), methylamine (2.0M tetrahydrofuran solutions) (30ml) is added at room temperature.Stirring depressurized after 2 hours it is lower concentrate, residue is successively with preparing anti-phase high-speed liquid chromatography (acetonitrile-water-formic acid system) and cross-link dextran post (methanol) is refined, the title compound (152mg) of the white solid of acquisition.
1H-NMR(DMSO-d6)δ：1.40-1.54 (1H, m), 1.57-1.71 (2H, m), 1.71-1.80 (1H, m), 1.90-2.06 (2H, m), 2.32 (3H, s), 2.45 (3H, s), 2.68 (2H, d, J=5.6Hz), 2.75 (3H, s), 2.75-2.85 (2H, m), 2.91 (3H, s), 2.91-3.00 (1H, m), 3.42 (3H, br.s), 3.59 (2H, s), 4.00-4.12 (1H, m), 4.43-4.52 (1H, m), 7.59 (1H, t, J=7.8Hz), 7.81 (1H, d, J=7.8Hz), 7.96 (1H, d, J=7.8Hz), 8.15 (1H, s), 8.34-8.47 (2H, m), 8.89 (1H, d, J=7.6Hz)
MS(ESI)m/z：526(M+H)+.
[embodiment 371] N- { (1R, 2S, 5S) -2- ({ 3- [amino (methoxyimino) methyl] benzoyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Figure G2003801097466D05411
Saturation ethanol solution hydrochloride (30ml) is added in the compound (300mg) that embodiment 367 is obtained at room temperature.Lower concentration is depressurized in stirring after 2 days, obtain faint yellow solid.The solid is dissolved in after methanol (10ml), O- methyl hydroxylamine hydrochlorides (1.01g) and triethylamine (1.69ml) are added at room temperature.Stirring adds dichloromethane and saturated sodium bicarbonate aqueous solution point liquid after 2 hours, water layer is extracted with dichloromethane.Merge organic layer, concentrated with decompression after anhydrous sodium sulfate drying is lower, it is residue obtained successively to medium pressure chromatography (dichloromethane: methanol=20: 1 → 7: 1) and prepares anti-phase high-speed liquid chromatography (acetonitrile-water-formic acid system) refined of the silica gel for carrier, handled again with 1N hydrochloric acid, obtain the title compound (51.8mg) of white solid.
1H-NMR(DMSO-d6)δ：1.44-1.57 (1H, m), 1.63-1.88 (3H, m), 1.88-2.05 (2H, m), 2.79 (3H, s), 2.85-3.85 (5H, m), 2.90 (3H, s), 2.96 (3H, s), 3.73 (3H, s), 4.04-4.13 (1H, m), 4.42 (1H, br.s), 4.50-4.60 (1H, m), 4.67 (1H, br.s), 6.22 (2H, br.s), 7.44 (1H, t, J=7.8Hz), 7.75 (2H, d, J=7.8Hz), 7.99 (1H, s), 8.33-8.50 (2H, m), 11.20-11.60 (1H, br)
MS(ESI)m/z：542(M+H)+.
[embodiment 372] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [4- (3- oxomorpholin -4- bases) benzoyl] amino } cyclohexyl) oxalamide
Figure G2003801097466D05421
It is same with the method that embodiment 2 is recorded, make the compound that reference example 531 is obtained and the compound condensation that reference example 420 is obtained, obtain title compound.
1H-NMR(CDCl3)δ：1.72-2.16 (6H, m), 2.78-2.88 (1H, m), 2.95 (3H, s), 3.02 (3H, s), 3.76-3.80 (2H, m), 4.01-4.08 (3H, m), 4.32 (2H, s), 4.59-4.65 (1H, m), 7.07 (1H, d, J=6.9Hz), 7.38 (2H, dt, J=8.6, 2.2Hz), 7.70 (1H, dd, J=8.8, 2.5Hz), 7.78 (2H, dt, J=8.6, 2.2Hz), 8.16 (1H, d, J=8.8Hz), 8.28-8.31 (2H, m), 9.73 (1H, s)
MS(FAB)m/z：571(M+H)+.
[embodiment 373] N- { (1R; 2S; 5S) -2- { [(Z) -3- (5- chlorothiophene -2- bases) the fluoro- 2- acryloyl groups of -2-] amino } -5- [(dimethylamino) carbonyl] cyclohexyl } -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide hydrochloride
Using the method same with embodiment 49, compound is obtained to reference example 519 with hydrochloric acid and carried out after processing deprotection, the compound condensation obtained with reference example 534, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.42-2.01 (6H, m), 2.79 (3H, s), 2.91-3.02 (7H, m), 3.19 (1H, br.s), 3.25 (1H, br.s), 3.49 (1H, br.s), 3.70 (1H, br.s), 3.98-4.05 (1H, m), 4.39-4.50 (2H, m), 4.70 (1H, br.s), 7.19 (1H, dd, J=3.9, 1.7Hz), 7.22 (1H, d, J=37.6Hz), 7.37 (1H, d, J=3.9Hz), 8.50 (1H, d, J=7.3Hz), 8.57 (1H, br.s), 11.38-11.53 (1H, m)
MS(FAB)m/z：554(M+H)+.
[embodiment 374] N- { (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -6- methyl -5; 6; 7; 8- tetrahydrochysene -4H- thiazoles simultaneously [5,4-d] azepine
Figure G2003801097466D05423
2- carboxamide hydrochlorides
Figure G2003801097466D05431
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 428 is carried out after processing deprotection, the compound condensation obtained with reference example 537, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.44-1.58 (1H, m), 1.62-1.74 (1H, m), 1.74-1.88 (2H, m), 1.95-2.07 (1H, m), 2.15-2.30 (1H, m), 2.45-2.65 (1H, m), 2.79 (3H, s), 2.84-3.08 (7H, m), 3.16-3.72 (7H, m), 4.45-4.55 (1H, m), 4.61-4.70 (1H, m), 8.02 (1H, dd, J=8.8, 2.4Hz), 8.07 (1H, d, J=8.8Hz), 8.46 (1H, d, J=2.4Hz), 8.59-8.68 (1H, m), 10.56 (1H, d, J=4.0Hz), 10.85 (1H, br.s), 11.00-11.09 (1H, m)
MSm/z：578(M+H)+.
[embodiment 375] N1- (5- chloropyridine -2- bases)-N2- { (1S, 2R, 4S) -2- [(6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazol-2-yl carbonyl) amino] -4- [(dimethylamino) carbonyl] cyclohexyl } oxalamide
It is same with the method that embodiment 2 is recorded, make the compound that reference example 26 is obtained and the compound condensation that reference example 420 is obtained, obtain title compound.
1H-NMR(DMSO-d6)δ：1.39-1.56 (1H, m), 1.58-1.80 (3H, m), 1.97-2.13 (2H, m), 2.77 (3H, s), 2.92 (6H, br.s), 3.90-4.06 (3H, m), 4.35-4.45 (1H, m), 4.83 (2H, s), 7.96-8.06 (2H, m), 8.44 (1H, br.s), 8.61 (1H, d, J=7.3Hz), 9.22 (1H, d, J=8.1Hz), 10.25 (1H, br.s)
MS(FAB)m/z：535(M+H)+.
[embodiment 376] N- { (1R; 2S; 5S) -2- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -5- [(dimethylamino) carbonyl] cyclohexyl } -6- methyl -5; 6; 7; 8- tetrahydrochysenes [1,6] naphthyridines -2- formamides
Same with the method that embodiment 219 is recorded, the compound obtained with hydrochloric acid to reference example 428 is carried out after processing deprotection, the compound condensation obtained with reference example 540, obtains title compound.
1H-NMR(CDCl3)δ：1.50-1.75 (2H, m), 1.80-2.10 (3H, m), 2.10-2.20 (1H, m), 2.30-2.45 (1H, m), 2.52 (3H, s), 2.75-2.85 (2H, m), 2.98 (3H, s), 2.95-3.10 (2H, m), 3.11 (3H, s), 3.66 (2H, s), 4.45-4.55 (1H, m), 4.65-4.80 (1H, m), 7.52 (1H, d, J=7.8Hz), 7.67 (1H, dd, J=8.8, 2.4Hz), 8.05 (1H, d, J=7.8Hz), 8.21 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.7Hz), 8.50 (1H, d, J=7.5Hz), 10.49 (1H, d, J=7.3Hz), 10.60 (1H, s)
MS(ESI)m/z：558(M+H)+.
[embodiment 377] (1S; 3R; 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -3- { [(5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } the cyclohexane-carboxylic acid tert-butyl ester
Figure G2003801097466D05442
It is same with the method that embodiment 2 is recorded, make the compound that reference example 543 is obtained and the compound condensation that reference example 10 is obtained, obtain title compound.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.58-1.78 (2H, m), 1.95-2.33 (4H, m), 2.49-2.61 (1H, m), 2.52 (3H, s), 2.80-2.88 (2H, m), 2.93-3.00 (2H, m), 3.66-3.79 (2H, m), 4.40-4.54 (1H, m), 4.71-4.84 (1H, m), 7.43 (1H, d, J=8.3Hz), 7.68 (1H, dd, J=8.8, 2.4Hz), 8.19 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.4Hz), 10.13 (1H, d, J=7.6Hz), 10.55 (1H, s)
MS(ESI)m/z：593(M+H)+.
[embodiment 378] (1S; 3R; 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxos ethanethioyl } amino) -3- { [(5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexane-carboxylic acid hydrochloride
The compound obtained in embodiment 377 (adds the 4N dioxane solution of hydrochloric acid-(10ml), stirred 16 hours at room temperature in 293mg) dioxanes (8.0ml) solution.After the lower concentration of reaction solution of decompression, residue is suspended in diisopropyl ether after leaching, gained powder is dissolved in water, is neutralized with saturated sodium bicarbonate aqueous solution.The aqueous solution is extracted with dichloromethane, organic layer is with anhydrous sodium sulfate drying is used after saturated common salt water washing, decompression is lower to be concentrated.1N hydrochloric acid-ethanol solution (0.50ml) is added in residue, decompression is lower to be concentrated, and residue is dissolved in after water and is freeze-dried, title compound (242mg) is obtained.
1H-NMR(DMSO-d6)δ：1.50-1.64 (1H, m), 1.66-1.86 (2H, m), 1.89-2.04 (1H, m), 2.16-2.32 (2H, m), 2.51-2.64 (1H, m), 2.93 (3H, s), 3.12-3.58 (3H, m), 3.64-3.80 (1H, m), 4.36-4.80 (4H, m), 8.03 (1H, dd, J=8.8,2.7Hz), (8.08 1H, d, J=8.8Hz), (8.46 1H, d, J=2.7Hz), 8.73 (1H, br.s), 10.57 (1H, s), 10.94-11.45 (2H, m)
MS(ESI)m/z：537(M+H)+.
[embodiment 379] (1S; 3R; 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -3- [(6; 7- dihydro -4H- pyrans simultaneously [4,3-d] thiazol-2-yl carbonyl) amino] the cyclohexane-carboxylic acid tert-butyl ester
Figure G2003801097466D05452
1N hydrochloric acid-ethyl acetate solution (3.09ml) is added in the compound (307mg) that reference example 544 is obtained, gained suspension is stirred 7 hours at room temperature.Then, 2N hydrochloric acid-ethyl acetate solution (40ml) is added in the suspension, is stirred 2 hours at room temperature.Boiled off under decompression after solvent, in residue obtained middle addition ether, the solid of leaching precipitation, the lower drying of decompression.The solid is dissolved in N, in dinethylformamide (10ml), compound (191mg), 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (288mg) and I-hydroxybenzotriazole (135mg) that reference example 26 is obtained are added in the solution, is stirred 4 days at room temperature.Solvent is boiled off under decompression, is added in residue after dichloromethane and saturated sodium bicarbonate aqueous solution point liquid, organic layer saturated common salt water washing.Lower concentration is depressurized after organic layer anhydrous sodium sulfate drying, residue (methanol: dichloromethane=1: 49) refines for the flash column chromatography of carrier to silica gel, obtains title compound (124mg).
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.58-1.76 (2H, m), 1.90-2.21 (4H, m), 2.45-2.55 (1H, m), 2.97 (2H, t, J=5.6Hz), 3.99-4.14 (3H, m), 4.62-4.71 (1H, m), 4.88 (2H, br.s), 7.35 (1H, d, J=8.8Hz), 7.69 (1H, dd, J=8.8,2.7Hz), 7.99 (1H, d, J=8.1Hz), 8.17 (1H, d, J=8.8Hz), 8.30 (1H, d, J=2.7Hz), 9.70 (1H, br.s)
MS(ESI)m/z：564(M+H)+.
[embodiment 380] (1S; 3R; 4S) -4- ({ 2- [(5- chloropyridine -2- bases) amino] -2- oxoacetyls } amino) -3- [(6; 7- dihydro -4H- pyrans simultaneously [4,3-d] thiazol-2-yl carbonyl) amino] cyclohexane-carboxylic acid
Figure G2003801097466D05461
Same with the method that embodiment 378 is recorded, the compound obtained by embodiment 379 prepares title compound.
1H-NMR(DMSO-d6)δ：1.44-1.80 (3H, m), 1.83-2.11 (2H, m), 2.17-2.27 (1H, m), 2.45-2.54 (1H, m), 2.92 (2H, br.s), 3.90-4.10 (3H, m), 4.33 (1H, br.s), 4.84 (2H, br.s), 7.98-8.07 (2H, m), 8.45 (1H, d, J=2.2Hz), 8.59 (1H, d, J=7.4Hz), 9.19 (1H, d, J=8.1Hz), 10.27 (1H, s), 12.23 (1H, s)
MS(FAB)m/z：508(M+H)+.
[embodiment 381] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- [(dimethylamino) carbonyl] -2- { [(2- methyl isophthalic acids, 2,3,4- tetrahydroisoquinoline -6- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Similarly to Example 2, the compound that reference example 545 is obtained is hydrolyzed, the compound condensation for obtaining the lithium salts and reference example 420 of gained carboxylic acid is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.31-1.46 (1H, m), 1.49-1.72 (3H, m), 1.75-2.01 (2H, m), 2.68 (3H, s), 2.80 (3H, s), 2.86 (3H, s), 2.90-3.06 (1H, m), 3.05-3.42 (3H, m), 3.49-3.61 (1H, m), 3.80-3.92 (1H, m), 4.13-4.48 (3H, m), 7.20 (1H, d, J=8.0Hz), 7.62 (1H, d, J=8.0Hz), 7.64 (1H, s), 7.85-7.95 (2H, m), 7.95-8.05 (1H, m), 8.34 (1H, s), 8.84-8.96 (1H, m), 10.16 (1H, s), 11.10 (1H, br.s)
MS m/z：541(M+H)+.
[embodiment 382] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4R) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (thiazol-2-yl) cyclohexyl] oxalamide hydrochloride and N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (thiazol-2-yl) cyclohexyl] oxalamide hydrochloride
Figure G2003801097466D05471
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 549 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then 2 kinds of stereoisomers of gained are handled with hydrochloric acid, obtains title compound.
Low polar compound：1H-NMR(DMSO-d6)δ：1.60-1.84 (2H, m), 1.86-1.97 (1H, m), 2.00-2.14 (2H, m), 2.21-2.34 (1H, m), 2.89 (3H, br.s), 3.01-3.52 (4H, m), 3.61-3.74 (1H, m), 4.06-4.49 (3H, m), 4.63-4.75 (1H, m), 7.63 (1H, d, J=3.2Hz), 7.75 (1H, d, J=3.2Hz), 7.98-8.10 (2H, m), 8.44 (1H, br.s), 8.78-8.87 (1H, m), 9.13-9.29 (1H, m), 10.34-10.42 (1H, m), 11.66 (1H, br.s)
MS(FAB)m/z：560(M+H)+
Highly polar compound：1H-NMR(DMSO-d6)δ：1.67-1.80 (2H, m), 1.89-1.99 (1H, m), 2.10-2.25 (2H, m), 2.30-2.46 (1H, m), 2.90 (3H, br.s), 3.08-3.53 (4H, m), 3.65-3.76 (1H, m), 4.05-4.53 (3H, m), 4.64-4.75 (1H, m), 7.62 (1H, br.s), 7.73 (1H, br.s), 7.97-8.10 (2H, m), 8.44 (1H, br.s), 8.69-8.81 (1H, m), 9.18-9.34 (1H, m), 10.20-10.35 (1H, m), 11.48-11.92 (1H, m)
MS(FAB)m/z：560(M+H)+.
[embodiment 383] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,2,4- oxadiazole -3- bases) cyclohexyl] oxalamide hydrochloride
Figure G2003801097466D05472
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 550 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.64-1.79 (2H, m), 1.84-1.95 (1H, m), 2.01-2.22 (2H, m), 2.30-2.43 (1H, m), 2.91 (4H, br.s), (3.19 2H, br.s), 3.34-3.79 (2H, m), 4.06-4.17 (1H, m), 4.35-4.75 (3H, m), 7.97-8.06 (2H, m), 8.42 (1H, s), (8.81 1H, d, J=7.1Hz), (9.21 1H, br.s), 9.51 (1H, s), 10.28 (1H, s)
MS(FAB)m/z：545(M+H)+.
[embodiment 384] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) cyclohexyl] oxalamide hydrochloride
Figure G2003801097466D05481
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 552 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.66-1.80 (2H, m), 1.87-1.96 (1H, m), 2.04-2.20 (2H, m), 2.35-2.43 (1H, m), 2.45 (3H, s), 2.93 (3H, s), 3.16-3.31 (2H, m), 3.43-3.57 (2H, m), 3.63-3.80 (1H, m), 4.08-4.19 (1H, m), 4.37-4.52 (2H, m), 4.65-4.82 (1H, m), 7.99-8.08 (2H, m), 8.44-8.48 (1H, m), 8.84 (1H, d, J=6.8Hz), 9.22 (1H, br.s), 10.30 (1H, s), 10.96-11.25 (1H, m)
MS(EI)m/z：558(M+).
[embodiment 385] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,3,4- oxadiazole -2- bases) cyclohexyl] oxalamide
Figure G2003801097466D05482
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 554 is carried out after processing deprotection, the compound condensation obtained with reference example 10, obtains title compound.
1H-NMR(CDCl3)δ：1.72-2.00 (2H, m), 2.13-2.23 (2H, m), 2.28-2.36 (1H, m), 2.39-2.46 (1H, m), 2.53 (3H, s), 2.80-2.91 (2H, m), 2.93-3.00 (2H, m), 3.28-3.38 (1H, m), 3.69-3.79 (2H, m), 4.14-4.24 (1H, m), 4.68-4.77 (1H, m), 7.51 (1H, d, J=8.3Hz), 7.70 (1H, dd, J=8.8, 2.5Hz), 8.14 (1H, d, J=7.8Hz), 8.18 (1H, d, J=8.8Hz), 8.31 (1H, d, J=2.5Hz), 8.38 (1H, s), 9.72 (1H, s)
MS(FAB)m/z：545(M+H)+.
[embodiment 386] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,3- oxazole -2- bases) cyclohexyl] oxalamide hydrochloride
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 556 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.65-1.82 (2H, m), 1.85-2.00 (1H, m), 2.01-2.22 (2H, m), 2.31-2.48 (1H, m), 2.94 (3H, s), 3.08-3.74 (4H, m), 3.65-3.83 (1H, m), 4.06-4.20 (1H, m), 4.36-4.55 (2H, m), 4.65-4.82 (1H, m), 7.14 (1H, s), 8.00-8.17 (3H, m), 8.48 (1H, s), 8.77-8.90 (1H, m), 9.14-9.34 (1H, m), 10.25-10.40 (1H, m), 11.35-11.68 (1H, m)
MS m/z：544(M+H)+.
[embodiment 387] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
The compound (110mg) that reference example 560 is obtained is dissolved in dichloromethane (5ml), and the 4N dioxane solution of hydrochloric acid-(5ml) is added in the solution, stirs 3 hours at room temperature.Solvent is boiled off under decompression, gained yellow solid is dissolved in N, dinethylformamide (5ml), compound (71.1mg), I-hydroxybenzotriazole (42.7mg) and 1- (the dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (80.9mg) of the acquisition of reference example 266 are sequentially added in the solution, is stirred all night at room temperature.After the lower concentration of reaction solution of decompression, dichloromethane and sodium bicarbonate aqueous solution point liquid, organic layer anhydrous sodium sulfate drying are added in residue.Solvent is boiled off under decompression, (methanol: dichloromethane=1: 19) is refined with silica gel column chromatography.The ethanol solution hydrochloride that 1N is added in gained episome is concentrated, and adds ether, and the colourless powder of leaching precipitation obtains title compound (69.8mg).
1H-NMR(DMSO-d6)δ：1.65-1.85 (2H, m), 1.89-1.92 (1H, m), 2.05-2.22 (2H, m), 2.32 (3H, s), 2.35-2.46 (1H, m), 2.93 (3H, br.s), 3.05-3.56 (4H, m), 3.65-3.78 (1H, m), 4.05-4.18 (1H, m), 4.35-4.53 (2H, m), 4.65-4.83 (1H, m), 7.97-8.10 (2H, m), 8.46 (1H, br.s), 8.78-8.90 (1H, m), 9.15-9.32 (1H, m), 10.30 (1H, br.s), 10.90-11.30 (1H, m)
MS(FAB)m/z：559(M+H)+.
[embodiment 388] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,3,4- thiadiazoles -2- bases) cyclohexyl] oxalamide hydrochloride
Same with the method that embodiment 387 is recorded, the compound obtained with hydrochloric acid to reference example 562 is carried out after processing deprotection, the compound condensation obtained with reference example 266, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.68-1.86 (2H, m), 1.96-2.08 (1H, m), 2.11-2.28 (2H, m), 2.38-2.47 (1H, m), 2.94 (3H, s), 3.10-3.30 (1H, m), 3.37-3.62 (2H, m), 3.63-3.80 (1H, m), 4.11-4.23 (1H, m), 4.38-4.51 (2H, m), 4.65-4.81 (1H, m), 7.99-8.08 (2H, m), 8.44-8.48 (1H, m), 8.76-8.84 (1H, m), 9.20-9.34 (1H, m), 9.52 (1H, s), 10.29 (1H, br.s), 10.99-11.33 (1H, m)
MS(ESI)m/z：561(M+H)+.
[embodiment 389] N- [(1R; 2S; 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(5- fluorine pyridine -2- bases) amino] -2- oxos ethanethioyl } amino) cyclohexyl] -5- methyl -4; 5; 6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide
The N of the compound (76.3g) obtained in reference example 563, compound (38.4g), the hydrate of I-hydroxybenzotriazole 1 (28.8g), 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride (37.6g) and diisopropylethylamine (35ml) that reference example 10 is obtained are added in dinethylformamide (1.0L) solution, is stirred 63 hours at room temperature.After the lower concentration of reaction solution of decompression, dichloromethane (1.2L) and sodium bicarbonate aqueous solution (500ml) are added in residue.Water layer is extracted with dichloromethane, after organic layer is washed with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, and with anhydrous sodium sulfate drying, decompression is lower to be concentrated.Residue (dichloromethane: methanol=50: 1 → 10: 1) is refined with silica gel column chromatography.Gained powder (77.2g) is dissolved in dichloromethane (500ml), insoluble matter, the lower concentration filtrate of decompression is filtered off.Dichloromethane (250ml) is added again, ether (1L) is instilled, and leaching after being stirred 30 minutes in 0 DEG C obtains title compound (71.5g).
1H-NMR(CDCl3)δ：1.61-1.75 (1H, m), 1.78-2.21 (5H, m), 2.19 (3H, s), 2.27-2.37 (1H, m), 2.52 (3H, s), 2.77-2.95 (4H, m), 2.96 (3H, s), 3.70 (1H, d, J=15.4Hz), 3.75 (1H, d, J=15.6Hz), 4.48-4.57 (1H, m), 4.76-4.85 (1H, m), 7.40-7.49 (2H, m), 8.21 (2H, dd, J=8.2,4.8Hz), 10.06 (1H, br.d, J=7.6Hz), 10.55 (1H, br.s)
MS(ESI)m/z：548(M+H)+.
[embodiment 390] N- [(1R; 2S; 5S) -5- [(dimethylamino) carbonyl] -2- ({ 2- [(5- fluorine pyridine -2- bases) amino] -2- oxos ethanethioyl } amino) cyclohexyl] -5- methyl -4; 5; 6; the 7- tetrahydro-thiazoles simultaneously hydrate of [5,4-c] pyridine-2-carboxamide citrate 1
The compound (6.26g) for obtaining embodiment 389 is suspended in 20% hydrous ethanol 100ml, adds 1M aqueous citric acid solution 11.4ml.20% hydrous ethanol is slowly added into while 60 DEG C of heating stirrings to be dissolved.After filtering while hot, stir while naturally cool to room temperature, placement 1 day.The crystallization that leaching is separated out, is dried under reduced pressure 2 hours at room temperature, places 1 day, obtains title compound (6.95g).
1H-NMR(DMSO-d6)δ：1.44-1.56 (1H, m), 1.64-1.72 (1H, m), 1.74-1.84 (2H, m), 2.05 (1H, d, J=14.2Hz), 2.21-2.32 (1H, m), 2.47-2.53 (1H, m), 2.50 (3H, s), 2.71 (2H, d, J=15.1Hz), 2.62 (2H, d, J=15.6Hz), 2.79 (3H, s), 2.94-3.01 (2H, m), 2.94 (3H, s), 4.48-4.56 (1H, m), 4.62-4.68 (1H, m), 7.86-7.90 (1H, dt, J=8.2Hz), 8.10 (1H, dd, J=9.2, 3.7Hz), 8.42 (1H, d, J=2.7Hz), 8.72 (1H, d, J=6.9Hz), 10.53 (1H, s), 11.11 (1H, d, J=7.8Hz)
Elementary analysis：C24H30FN7O3S2C6H8O7H2O
Theoretical value：C；47.55, H；5.32, N；12.94, F；2.51, S；8.46
Measured value：C；47.48, H；5.10, N；13.05, F；2.55, S；8.61mp (decomposition)：176~179
[embodiment 391] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases) cyclohexyl] oxalamide hydrochloride
Same with the method that embodiment 387 is recorded, the compound obtained with hydrochloric acid to reference example 566 is carried out after processing deprotection, the compound condensation obtained with reference example 266, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.67-1.82 (2H, m), 1.92-2.03 (1H, m), 2.06-2.26 (2H, m), 2.35-2.44 (1H, m), 2.68 (3H, s), 2.94 (3H, s), 3.13-3.27 (2H, m), 3.40-3.56 (2H, m), 3.66-3.80 (1H, m), 4.09-4.22 (1H, m), 4.37-4.51 (2H, m), 4.64-4.82 (1H, m), 7.98-8.07 (2H, m), 8.44-8.48 (1H, m), 8.79 (1H, br.s), 9.16-9.34 (1H, m), 10.29 (1H, s)
MS(ESI)m/z：575(M+H)+.
[embodiment 392] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,3- oxazole -5- bases) cyclohexyl] oxalamide hydrochloride
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 568 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.1H-NMR(DMSO-d6)δ：1.50-1.87 (3H, m), 1.97-2.40 (3H, m), 2.93 (3H, s), 2.96-3.83 (5H, m), 4.04-4.16 (1H, m), 4.30-4.53 (2H, m), 4.62-4.80 (1H, m), 6.93 (1H, s), 7.96-8.10 (2H, m), 8.22 (1H, s), 8.45 (1H, s), 8.66-8.80 (1H, m), 9.17-9.37 (1H, m), 10.24-10.37 (1H, m), 11.20-11.54 (1H, m)
MS(ESI)m/z：544(M+H)+.
[embodiment 393] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Same with the method that embodiment 387 is recorded, the compound obtained with hydrochloric acid to reference example 572 is carried out after processing deprotection, the compound condensation obtained with reference example 266, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.63-1.79 (2H, m), 1.80-1.94 (1H, m), 1.98-2.24 (2H, m), 2.27-2.41 (1H, m), 2.56 (3H, s), 2.83 (3H, s), 3.04-3.88 (6H, m), 4.06-4.18 (1H, m), 4.29-4.53 (2H, m), 7.98-8.10 (2H, m), 8.46 (1H, d, J=2.4Hz), 8.79 (1H, d, J=6.8Hz), 9.23 (1H, d, J=8.0Hz), 10.31 (1H, s)
MS(ESI)m/z：559(M+H)+.
[embodiment 394] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (4H-1,2,4- triazole-4-yls) cyclohexyl) oxalamide hydrochloride
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 576 is carried out after processing deprotection, the compound condensation obtained with reference example 564, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.69-1.79 (1H, m), 1.87-2.00 (1H, m), 2.04-2.14 (1H, m), 2.17-2.40 (3H, m), 2.92 (3H, s), 3.02-3.84 (4H, m), 4.13-4.22 (1H, m), 4.35-4.83 (4H, m), 7.99-8.05 (2H, m), 8.45-8.47 (1H, m), 8.65 (2H, s), 8.69-8.76 (1H, m), 9.39 (1H, d, J=8.1Hz), 10.29 (1H, s), 11.49 (1H, br.s)
MS(ESI)m/z：544(M+H)+.
[embodiment 395] N1- (5- chloropyridine -2- thienyls)-N2- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide citrate
In 0 DEG C, the N for the compound (317mg) that the lithium salts (249mg) and reference example 577 of the carboxylic acid obtained in the compound hydrolysis of reference example 356 are obtained, 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (308mg) and I-hydroxybenzotriazole (159mg) are added in dinethylformamide (8ml) solution, is stirred 11 hours at room temperature.After reaction solution ethyl acetate dilutes, successively with 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, then anhydrous sodium sulfate drying is used.Decompression is lower to be concentrated, and gained solid is dissolved in into dichloromethane (10ml), the 4N dioxane solution of hydrochloric acid-(10ml) is added, stirred 1 hour at room temperature.Be concentrated under reduced pressure reaction mixture, residue is dissolved in N, dinethylformamide (8ml), adds compound (262mg), I-hydroxybenzotriazole (174mg), 1- (dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (308mg) and triethylamine (149 μ l) that reference example 10 is obtained at room temperature.Dchloromethane is used after being stirred 19 hours to reaction solution, then is washed with saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying is used.It is concentrated under reduced pressure, it is residue obtained (dichloromethane: methanol=10: 1) to be refined with preparation silica gel thin-layer chromatography.Gained compound is dissolved in ethanol, hexane, the solid that leaching is separated out is added.Ethanol (15ml) and the hydrate of citric acid 1 (138mg) are added in the gained solid (371mg), it is dissolved, is added water after being concentrated under reduced pressure, is dried after azeotropic 3 times, acquisition title compound (503mg).
1H-NMR(DMSO-d6)δ：1.69-1.84 (2H, m), 1.87-1.99 (1H, m), 2.05-2.22 (2H, m), 2.35-2.52 (1H, m) 2.48 (3H, s), 2.65 (2H, d, J=15.4Hz), 2.75 (2H, d, J=15.4Hz), 2.98 (3H, s), 3.03-3.84 (5H, m), 3.84-3.95 (2H, m), 4.10-4.21 (1H, m), 4.38-4.48 (1H, m), 6.93 (1H, d, J=4.4Hz), 6.98 (1H, d, J=4.4Hz), 8.77 (1H, d, J=7.6Hz), 9.22 (1H, d, J=8.4Hz), 12.34 (1H, s)
MS(ESI)m/z：564(M+H)+.
[embodiment 396] N1- (5- bromo-2-pyridyls base)-N2- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 579 is carried out after processing deprotection, the compound condensation obtained with reference example 564, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.70-2.15 (5H, m), 2.32-2.43 (1H, m), 2.45 (3H, s), 2.92 (3H, s), 3.10-3.30 (3H, m), 3.49 (1H, br.s), 3.70 (1H, br.s), 4.09-4.17 (1H, m), 4.38-4.52 (2H, m), 4.69 (1H, br.s), 7.99 (1H, d, J=8.8Hz), 8.13 (1H, dd, J=8.8, 2.5Hz), 8.53 (1H, d, J=2.5Hz), 8.83 (1H, br.s), 9.22 (1H, br.s), 10.28 (1H, s), 11.43 (1H, br.s)
MS(FAB)m/z：603(M+H)+.
[embodiment 397] N1- (4- chlorphenyls)-N2- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide citrate
Figure G2003801097466D05552
It is same with the method that embodiment 395 is recorded; make after the compound that reference example 577 is obtained and the compound condensation that reference example 374 is obtained, processing deprotection, then the compound condensation obtained with reference example 10 are carried out with hydrochloric acid; then handled with citric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.66-1.82 (2H, m), 1.85-1.97 (1H, m), 2.02-2.23 (2H, m), 2.34-2.48 (1H, m), 2.46 (3H, s), 2.63 (2H, d, J=15.4Hz), 2.72 (2H, d, J=15.4Hz), 2.95 (3H, s), 3.03-3.82 (5H, m), 3.84-3.92 (2H, m), 4.07-4.20 (1H, m), 4.37-4.46 (1H, m), 7.42 (2H, d, J=8.8Hz), 7.84 (2H, d, J=8.8Hz), 8.78 (1H, d, J=7.3Hz), 9.13 (1H, d, J=8.1Hz), 10.83 (1H, s)
MS(ESI)m/z：558(M+H)+.
[embodiment 398] N1- (5- chloropyridine -2- bases)-N2- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(6- methyl -5,6,7,8- tetrahydrochysenes [1,6] naphthyridines -2- bases) carbonyl] amino } cyclohexyl) oxalamide citrate
Figure G2003801097466D05561
It is same with the method that embodiment 395 is recorded; make after the compound that reference example 577 is obtained and the compound condensation that reference example 266 is obtained, processing deprotection, then the compound condensation obtained with reference example 540 are carried out with hydrochloric acid; then handled with citric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.70-1.87 (2H, m), 1.90-2.21 (3H, m), 2.29-2.40 (1H, m), 2.47 (3H, s), 2.59 (3H, s), 2.62 (2H, d, J=15.4Hz), 2.71 (2H, d, J=15.4Hz), 2.90-3.80 (5H, m), 3.87-3.95 (2H, m), 4.08-4.19 (1H, m), 4.48-4.58 (1H, m), 7.74 (1H, d, J=8.1Hz), 7.84 (1H, d, J=8.1Hz), 7.98-8.07 (2H, m), 8.44-8.48 (1H, m), 8.59 (1H, d, J=8.1Hz), 9.21 (1H, d, J=7.8Hz), 10.31 (1H, s) .MS (ESI) m/z：553(M+H)+.
[embodiment 399] N- [(1R, 2S, 5S) -2- { [(the chloro- 1H- indoles -2- bases of 5-) carbonyl] amino } -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) cyclohexyl] -5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide citrate
Figure G2003801097466D05562
It is same with the method that embodiment 395 is recorded, make after compound and the condensation of 5- chloro-indole -2- carboxylic acids of the acquisition of reference example 577, processing deprotection, then the compound condensation obtained with reference example 10 are carried out with hydrochloric acid, is then handled with citric acid, title compound is obtained.
1H-NMR(DMSO-d6)δ：1.71-1.85 (2H, m), 1.90-2.21 (3H, m), 2.31-2.43 (1H, m), 2.47 (3H, s), 2.63 (2H, d, J=15.2Hz), 2.72 (2H, d, J=15.2Hz), 2.94 (3H, s), 3.05-3.95 (7H, m), 4.20-4.31 (1H, m), 4.49-4.58 (1H, m), 7.10 (1H, d, J=1.6Hz), 7.19 (1H, dd, J=8.8, 2.0Hz), 7.44 (1H, d, J=8.8Hz), 7.70 (1H, d, J=2.0Hz), 8.40 (1H, d, J=7.6Hz), 8.44 (1H, d, J=7.6Hz), 11.79 (1H, s) .MS (ESI) m/z：554(M+H)+.
[embodiment 400] N1- (the chloro- 2- thienyls of 5-)-N2- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(6- methyl -5,6,7,8- tetrahydrochysenes [1,6] naphthyridines -2- bases) carbonyl] amino } cyclohexyl) oxalamide citrate
It is same with the method that embodiment 395 is recorded; after the compound condensation that the lithium salts and reference example 577 for the carboxylic acid for making the compound hydrolysis of reference example 356 and obtaining are obtained; processing deprotection is carried out with hydrochloric acid; the compound condensation obtained again with reference example 540; then handled with citric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.70-1.86 (2H, m), 1.90-2.21 (3H, m), 2.27-2.39 (1H, m), 2.46 (3H, s), 2.58 (3H, s), 2.61 (2H, d, J=15.4Hz), 2.71 (2H, d, J=15.4Hz), 2.98-3.95 (7H, m), 4.09-4.19 (1H, m), 4.47-4.56 (1H, m), 6.90 (1H, d, J=4.2Hz), 6.95 (1H, d, J=4.2Hz), 7.74 (1H, d, J=7.8Hz), 7.83 (1H, d, J=7.8Hz), 8.58 (1H, d, J=8.0Hz), 9.15 (1H, d, J=8.0Hz), 12.32 (1H, s)
MS(ESI)m/z：558(M+H)+.
[embodiment 401] N1- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl)-N2- { 5- [2- (trimethyl silyl) acetenyl] pyridine -2- bases } oxalamide
Same with the method that reference example 455 is recorded, the compound obtained by embodiment 396 prepares title compound.1H-NMR(CDCl3)δ：0.26 (9H, s), 1.77-1.92 (2H, m), 2.08-2.43 (4H, m), 2.52 (6H, s), 2.81-2.89 (2H, m), 2.93-2.98 (2H, m), 3.19-3.28 (1H, m), 3.68-3.77 (2H, m), 4.13-4.22 (1H, m), 4.68-4.74 (1H, m), 7.48 (1H, d, J=8.4Hz), 7.78 (1H, dd, J=8.4,2.3Hz), 8.11-8.17 (2H, m), 8.44 (1H, d, J=2.3Hz), 9.73 (1H, s) .MS (FAB) m/z：621(M+H)+.
[embodiment 402] N1- (5- ethynyl pyridine -2- bases)-N2- ((1S, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide
Figure G2003801097466D05581
Potassium fluoride (116mg) is added in methanol (30ml) solution for the compound (617mg) that embodiment 401 is obtained, is stirred 7 hours at room temperature.Solvent is boiled off under decompression, dichloromethane and moisture liquid are added in residue.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression.Residue (dichloromethane: methanol=93: 7) is refined to silica gel for the flash column chromatography of carrier.Gained solid is dissolved in methanol, solvent is boiled off under the decompression that adds water, obtains title compound (287mg).
1H-NMR(CDCl3)δ：1.81-1.96 (2H, m), 2.07-2.19 (2H, m), 2.27 (1H, br.s), 2.41 (1H, d, J=13.2Hz), 2.52 (3H, s), 2.58 (3H, s), 2.88-3.07 (4H, m), 3.22 (1H, s), 3.27 (1H, br.s), 3.76-3.92 (2H, m), 4.20 (1H, s), 4.71-4.76 (1H, m), 7.60 (1H, d, J=8.3Hz), 7.79 (1H, d, J=8.3Hz), 8.14 (1H, d, J=8.3Hz), 8.23 (1H, d, J=7.4Hz), 8.45 (1H, s), 9.81 (1H, s)
MS(FAB)m/z：549(M+H)+.
Chloro- the N- ((1S of [embodiment 403] 7-, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -3- cinnolinecarboxamide citrates
Using the method same with embodiment 214, the compound obtained with hydrochloric acid to reference example 580 is carried out after processing deprotection, the compound condensation obtained with reference example 10, is handled with citric acid, obtains title compound.1H-NMR(DMSO-d6)δ：1.75-1.90 (2H, m), 1.91-2.03 (1H, m), 2.10-2.22 (1H, m), 2.25-2.52 (2H, m), 2.47 (3H, s), 2.63 (2H, d, J=15.4Hz), 2.73 (2H, d, J=15.4Hz), 2.96 (3H, s), 3.00-3.95 (7H, m), 4.41-4.58 (2H, m), 8.02 (1H, ddd, J=8.8, 2.0, 2.0Hz), 8.39 (1H, dd, J=8.8, 1.6Hz), 8.65-8.70 (1H, m), 8.90-8.94 (1H, m), 9.00 (1H, d, J=6.8Hz), 9.66 (1H, d, J=8.4Hz)
MS(ESI)m/z：567(M+H)+.
[embodiment 404] N- [(1R; 2S; 5S) -2- { [(Z) -3- (4- chlorphenyls) -2- fluoropropenes acyl group] amino } -5- (5- methyl isophthalic acids; 3; 4- oxadiazole -2- bases) cyclohexyl] -5- methyl -4,5,6; 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2-carboxamide citrate
Using the method same with embodiment 395; make after the compound that reference example 577 is obtained and the compound condensation that reference example 516 is obtained, processing deprotection, then the compound condensation obtained with reference example 10 are carried out with hydrochloric acid; then handled with citric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.66-1.80 (2H, m), 1.85-1.96 (1H, m), 2.00-2.16 (2H, m), 2.30-2.41 (1H, m), 2.46 (3H, s), 2.63 (2H, d, J=15.6Hz), 2.72 (2H, d, J=15.6Hz), 2.96 (3H, s), 3.10-3.95 (7H, m), 4.11-4.22 (1H, m), 4.40-4.50 (1H, m), 6.90 (1H, d, J=38.8Hz), 7.51 (2H, d, J=8.4Hz), 7.68 (2H, d, J=8.4Hz), 8.54 (1H, d, J=7.2Hz), 8.62 (1H, d, J=7.6Hz)
MS(ESI)m/z：559(M+H)+.
Chloro- the N- ((1S of [embodiment 405] 7-, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -3- isoquinolinecarboxamide citrates
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 581 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with citric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.69-1.86 (2H, m), 1.89-2.03 (1H, m), 2.05-2.19 (1H, m), 2.20-2.34 (1H, m), 2.34-2.49 (1H, m), 2.47 (3H, s), 2.63 (2H, d, J=15.4Hz), 2.72 (2H, d, J=15.4Hz), 2.96 (3H, s), 3.00-3.80 (5H, m), 3.84-3.91 (2H, m), 4.30-4.42 (1H, m), 4.47-4.56 (1H, m), 7.91 (1H, dd, J=8.8, 2.2Hz), 8.27 (1H, d, J=8.8Hz), 8.37-8.41 (1H, m), 8.61 (1H, s), 8.95 (1H, d, J=7.3Hz), 9.08 (1H, d, J=8.3Hz), 9.36 (1H, s)
MS(ESI)m/z：566(M+H)+.
Chloro- the N- ((1S of [embodiment 406] 6-, 2R, 4S) -4- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -4- oxo-Isosorbide-5-Nitrae-dihydro -2- quinazoline carboxamide citrate salts
Figure G2003801097466D05601
Using the method same with embodiment 395; make after the compound that reference example 577 is obtained and the compound condensation that reference example 349 is obtained, processing deprotection, then the compound condensation obtained with reference example 10 are carried out with hydrochloric acid; then handled with citric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.71-1.88 (2H, m), 1.90-2.02 (1H, m), 2.07-2.26 (2H, m), 2.34-2.44 (1H, m), 2.47 (3H, s), 2.63 (2H, d, J=15.4Hz), 2.73 (2H, d, J=15.4Hz), 2.95 (3H, s), 3.17-3.94 (7H, m), 4.18-4.30 (1H, m), 4.46-4.56 (1H, m), 7.76 (1H, d, J=8.8Hz), 7.89-7.94 (1H, m), 8.08-8.13 (1H, m), 8.76-8.85 (1H, m), 8.96-9.06 (1H, m)
MS(ESI)m/z：583(M+H)+.
[embodiment 407] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,2,4- oxadiazole -5- bases) cyclohexyl] oxalamide hydrochloride
Figure G2003801097466D05602
Using the method same with embodiment 387, the compound obtained with hydrochloric acid to reference example 583 is carried out after processing deprotection, the compound condensation obtained with reference example 266, is then handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.65-1.85 (2H, m), 1.92-2.05 (1H, m), 2.09-2.23 (2H, m), 2.37-2.50 (1H, m), 2.92 (3H, s), 3.11-3.57 (4H, m), 3.71 (1H, br.s), 4.14 (1H, br.s), 4.44 (2H, br.s), 4.64-4.79 (1H, m), 7.98-8.09 (2H, m), 8.46 (1H, br.s), 8.84 (1H, br.s), 8.91 (1H, br.s), 9.15-9.33 (1H, m), 10.29 (1H, br.s), 11.36-11.67 (1H, m)
MS(FAB)m/z：545(M+H)+.
[embodiment 408] N1- (5- chloropyridine -2- bases)-N2- { (1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- [5- (trifluoromethyl) -1,3,4- oxadiazole -2- bases) cyclohexyl } oxalamide hydrochloride
Using the method same with embodiment 214, the compound obtained with hydrochloric acid to reference example 586 is carried out after processing deprotection, the compound condensation obtained with reference example 10, is then handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.70-1.88 (2H, m), 1.95-2.06 (1H, m), 2.10-2.23 (2H, m), 2.42-2.49 (1H, m), 2.92 (3H, s), 3.09-3.81 (5H, m), 4.15 (1H, br.s), 4.33-4.56 (2H, m), 4.57-4.79 (1H, m), 7.99-8.08 (2H, m), 8.46 (1H, br.s), (8.86 1H, d, J=7.1Hz), 9.24 (1H, br.s), 10.30 (1H, s), 11.48 (1H, br.s)
MS(ESI)m/z：613(M+H)+.
[embodiment 409] N1- (the chloro- 2- thienyls of 5-)-N2- ((1S, 2R, 4S) -4- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Using the method same with embodiment 387, the compound obtained with hydrochloric acid to reference example 560 is carried out after processing deprotection, with the compound hydrolysis of reference example 356 and the lithium salts of carboxylic acid that obtains is condensed, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.65-1.82 (2H, m), 1.90-1.99 (1H, m), 2.06-2.18 (2H, m), 2.31 (3H, s), 2.36-2.46 (1H, m), 2.92 (3H, s), 3.21 (2H, br.s), 3.32-3.38 (1H, m), 3.50 (1H, br.s), 3.68 (1H, br.s), 4.08-4.16 (1H, m), 4.37-4.74 (3H, m), 6.91 (1H, d, J=4.2Hz), 6.94 (1H, d, J=4.2Hz), 8.83 (1H, d, J=6.9Hz), 9.15 (1H, br.s), 11.43 (1H, br.s), 12.31 (1H, s)
MS(FAB)m/z：564(M+H)+.
[embodiment 410] N1- (6- chlorine pyridazine -3- bases)-N2- ((1S, 2R, 4S) -4- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) oxalamide hydrochloride
Figure G2003801097466D05621
Using the method same with embodiment 387, the compound obtained with hydrochloric acid to reference example 560 is carried out after processing deprotection, with the compound hydrolysis of reference example 264 and the lithium salts of carboxylic acid that obtains is condensed, then handled with hydrochloric acid, obtain title compound.
1H-NMR(DMSO-d6)δ：1.69-1.82 (2H, m), 1.97-2.03 (1H, m), 2.08-2.20 (2H, m), 2.32 (3H, s), 2.39-2.45 (1H, m), 2.81-2.83 (4H, m), 3.10-3.53 (3H, m), 4.10-4.18 (1H, m), 4.36-4.46 (4H, m), 7.98 (1H, d, J=9.2Hz), 8.29 (1H, d, J=9.2Hz), 8.79 (1H, d, J=7.1Hz), 9.27 (1H, d, J=7.8Hz), 11.06 (1H, s)
MS(FAB)m/z：560(M+H)+.
[embodiment 411] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (2- oxo -1,3- oxane -3- bases) cyclohexyl] oxalamide
The hydrate of p-methyl benzenesulfonic acid 1 (301mg) is added in methanol (70ml) solution for the compound (696mg) that reference example 589 is obtained, an evening is heated to reflux.The additional hydrate of p-methyl benzenesulfonic acid 1 (82mg), reheats backflow 2 hours, solvent is boiled off under decompression in reaction solution.Residue is dissolved in N, dinethylformamide (50ml), compound (338mg), 3- (3- dimethylaminopropyls) -1- ethyl-carbodiimide hydrochlorides (552mg) and I-hydroxybenzotriazole (97mg) that reference example 564 is obtained are added, an evening is stirred at room temperature.Triethylamine (599 μ l) is added in the reactive mixture, in 45 DEG C of evenings of stirring one.Water and ethyl acetate point liquid, organic layer water and saturated common salt water washing are added in reaction solution.Solvent is boiled off under organic layer anhydrous sodium sulfate drying, decompression, it is residue obtained (dichloromethane: methanol=93: 7) to be refined for the flash column chromatography of carrier to silica gel, concentrating part purpose product, ether is added, the solid of generation is filtered, title compound (83mg) is obtained.
1H-NMR(CDCl3)δ：1.46 (9H, s), 1.58-1.65 (2H, m), 1.79-2.05 (4H, m), 3.47-3.55 (2H, m), 3.84-3.93 (2H, m), 4.29 (1H, br.s), 4.33-4.39 (2H, m), 5.08 (1H, br.s), 7.70 (1H, dd, J=8.8,2.5Hz), 8.10 (1H, br.s), 8.19 (1H, dd, J=8.8,0.7Hz), 8.31 (1H, dd, J=2.5,0.7Hz), 9.71 (1H, s)
MS(ESI)m/z：562(M+H)+.
[embodiment 412] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (tetrazolium -1- bases) cyclohexyl] oxalamide
Figure G2003801097466D05631
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 592 is carried out after processing deprotection, the compound condensation obtained with reference example 10, obtains title compound.
1H-NMR(CDCl3)δ：1.90-2.02 (1H, m), 2.16-2.29 (2H, m), 2.40-2.52 (2H, m), 2.52 (3H, s), 2.59-2.66 (1H, m), 2.80-2.91 (2H, m), 2.94-2.98 (2H, m), 3.68-3.78 (2H, m), 4.23-4.32 (1H, m), 4.78-4.92 (2H, m), 7.55 (1H, d, J=8.1Hz), 7.70 (1H, dd, J=8.9, 2.6Hz), 8.05 (1H, d, J=7.6Hz), 8.16 (1H, dd, J=8.9, 0.6Hz), 8.32 (1H, dd, J=2.6, 0.6Hz), 8.72 (1H, s), 9.72 (1H, s)
MS(ESI)m/z：545(M+H)+.
[embodiment 413] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1H- pyrroles -1- bases) cyclohexyl] oxalamide hydrochloride
Figure G2003801097466D05632
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 594 is carried out after processing deprotection, the compound condensation obtained with reference example 564, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.67-1.78 (1H, m), 1.82-1.95 (1H, m), 1.97-2.06 (1H, m), 2.13-2.31 (3H, m), 2.94 (3H, s), 3.29-3.39 (2H, m), 3.51 (1H, br.s), 3.73 (1H, br.s), 4.12-4.30 (2H, m), 4.43 (2H, br.s), 4.66-4.80 (1H, m), 5.96 (2H, br.s), 6.85 (2H, br.s), 7.98-8.06 (2H, m), 8.46 (1H, br.s), 8.72 (1H, br.s), 9.36 (1H, br.s), 10.28 (1H, br.s), 11.20-11.48 (1H, m)
MS(FAB)m/z：542(M+H)+.
[embodiment 414] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1,2,4- triazole -5- bases) cyclohexyl] oxalamide hydrochloride
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 597 is carried out after processing deprotection, the compound condensation obtained with reference example 564, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.64-1.79 (2H, m), 1.83-1.95 (1H, m), 1.97-2.08 (1H, m), 2.09-2.21 (1H, m), 2.28-2.38 (1H, m), 2.89 (3H, s), 2.97-3.63 (5H, m), 4.04-4.16 (1H, m), 4.34-4.62 (3H, m), 7.81 (1H, br.s), 8.01 (1H, dd, J=8.9, 2.3Hz), 8.05 (1H, d, J=8.9Hz), 8.46 (1H, d, J=2.3Hz), 8.74 (1H, d, J=6.Hz), 9.24 (1H, br.s), 10.28 (1H, s), 13.67 (1H, br.s)
MS(FAB)m/z：544(M+H)+.
[embodiment 415] N1- (5- chloropyridine -2- bases)-N2- [(1S, 2R, 4S) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -4- (1- methyl isophthalic acids H-1,2,4- triazole -5- bases) cyclohexyl] oxalamide hydrochloride
Figure G2003801097466D05642
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 599 is carried out after processing deprotection, the compound condensation obtained with reference example 564, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.60-1.76 (2H, m), 1.77-1.88 (1H, m), 1.94-2.04 (1H, m), 2.05-2.18 (1H, m), 2.25-2.36 (1H, m), 2.85-2.98 (4H, m), 3.15-3.67 (4H, m), 3.78 (3H, s), 4.08 (1H, br.s), 4.31-4.70 (3H, m), 7.97-8.08 (2H, m), 8.30 (1H, s), 8.44 (1H, br.s), 8.71 (1H, d, J=6.8Hz), 9.14-9.26 (1H, m), 10.27 (1H, s) .MS (FAB) m/z：558(M+H)+.
MS(FAB)m/z：544(M+H)+.
Chloro- the N- ((1S of [embodiment 416] 7-, 2R, 4S) -4- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) -2- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } cyclohexyl) -3- cinnolinecarboxamide hydrochlorides
Figure G2003801097466D05651
Same with the method that embodiment 387 is recorded, the compound obtained with hydrochloric acid to reference example 560 is carried out after processing deprotection, the compound condensation obtained with reference example 298, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.76-1.90 (2H, m), 1.97-2.06 (1H, m), 2.16-2.23 (1H, m), 2.28-2.38 (4H, m), 2.44-2.52 (1H, m), 2.88 (3H, s), 3.21 (2H, br.s), 3.27-3.42 (1H, m), 3.55 (2H, br.s), 4.41-4.56 (4H, m), 8.01 (1H, dd, J=8.8, 1.7Hz), 8.38 (1H, d, J=9.1Hz), 8.67 (1H, s), 8.91 (1H, s), 9.06 (1H, d, J=6.9Hz), 9.64 (1H, d, J=7.8Hz)
MS(ESI)m/z：567(M+H)+.
[embodiment 417] N1- (5- chloropyridine -2- bases)-N2- ((3R, 4S) -3- { [(5- methyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- bases) carbonyl] amino } -1- (thiazol-2-yl) piperidin-4-yl) oxalamide hydrochloride
Same with the method that embodiment 214 is recorded, the compound obtained with hydrochloric acid to reference example 603 is carried out after processing deprotection, the compound condensation obtained with reference example 10, then is handled with hydrochloric acid, obtains title compound.
1H-NMR(DMSO-d6)δ：1.73-1.87 (1H, m), 2.21-2.37 (1H, m), 2.91 (3H, s), 3.03-3.29 (2H, m), 3.31-3.52 (2H, (2H, m), 3.84-4.53 (5H, m), 4.64-4.76 (1H, m), 6.91 (1H, br.s), 7.23 (1H, br.s), 8.02 (2H, s), 8.46 (1H, s), 8.70-8.93 (1H, m), 9.28, 9.36 (whole 1H, each d, J=7.8Hz), 10.28, 10.33 (whole 1H, each br.s), 11.30-11.64 (1H, br)
MS(ESI)m/z：561(M+H)+.
[test example 1] people's FXa inhibitory action (IC50Value) measure
Added in each hole of the microwell plate in 96 holes with test sample 5%DMSO solution 10 μ l, Tris buffer solution (100mM Tris, 200mM potassium chloride, 0.2%BSA, pH 7.4) 40 μ l, 0.0625U/ml of appropriate interval setting concentration people FXa (Enzyme Research Labolatories, Inc., with Tris buffer solutions and dilution) after 10 μ l, the μ l of the S-2222 aqueous solution (Chromogenix companies) 40 of 750 μM of addition, 405nm absorbance is determined at room temperature 10 minutes, obtain the increase (Δ OD/ minutes) of absorbance.In control group test sample is substituted with Tris buffer solutions.
Using the inhibiting rate (%) under each ultimate density for the test sample obtained by the use of following formula as the longitudinal axis of logarithmic probability paper, using the ultimate density of test sample as transverse axis, curve is drawn respectively, obtains 50% inhibition concentration (IC50Value).
Inhibiting rate (%)=(Δ of the OD/ minutes ÷ control groups of Δ of 1- test samples OD/ minutes) × 100
(result) table 1 shows that the compound of the present invention has the FXa inhibitory action of strength.
Table 1
The measure of anti-FXa activity in rat plasma after [test example 2] is oral
(A) administration and blood sampling
Dissolved to Oral Administration in Rats (10ml/kg) test sample 10mg or be suspended in drug solution (1mg/ml) formed by 0.5% methylcellulose (MC).Administration 0.5,1,2, after 4 hours, with the injection needle tube of 3.13% (w/v) the citrate trisodium dihydrate aqueous solution for being filled with 50 μ l, 0.5ml blood (collection blood flow volume is gathered from jugular vein：0.45ml).Rat to control group is taken after 0.5%MC solution, is taken a blood sample as described above.Each blood sample is centrifuged 10 minutes in 4 DEG C, with 1500 × g, isolated after blood plasma, is stored at a temperature of -40 DEG C until for following blood plasma moderate resistance FXa determinations of activity.
(B) in blood plasma FXa inhibitory activity measure
In the measure of blood plasma moderate resistance FXa activity, it is measured using S-2222 as matrix.Mix Tris buffer solutions (100mM Tris, 200mM potassium chloride, 0.2%BSA, pH 7.4) 5456 μ l, the μ l of people FXa (2.5U/ml) 44 and the μ l of water 550.Income earner FXa solution is used for following experiment.The μ l of rat plasma 5 obtained by aforesaid operations (A) are added in each hole of the microwell plate in 96 holes, then the above-mentioned μ l of people FXa solution 55,750 μM of the μ l of the S-2222 aqueous solution 40 are sequentially added, then extinction photometer SPECTRA max340 or 190 (Molecular Devices Co. are used at once, U.S.A.), 405nm absorbance is determined at room temperature, obtains reaction speed (Δ OD/ minutes).
Anti- FXa activity, i.e., inhibiting rate (%) is calculated by following formula.
Inhibiting rate (%)=[1- (the Δ average value of OD/ minutes of the OD/ minutes ÷ control groups of Δ of sample)] × 100
The compound that (result) embodiment 63,191,192,194 and 204 is recorded shows FXa inhibitory activity in 62%~96% stronger blood plasma with 10mg/kg when oral.

Claims (12)

1. following compound or its salts,
Figure F2003801097466C00021
2. the pharmaceuticals with activated form factor X inhibitory action, it is characterised in that contain the compound or its salt described in claim 1.
3. activated form factor X inhibitor, it is characterised in that contain the compound or its salt described in claim 1.
4. Coagulative inhibitors agent, it is characterised in that contain the compound or its salt described in claim 1.
5. prevention and/or the therapeutic agent of thrombus or embolism, it is characterised in that contain the compound or its salt described in claim 1.
6. the thrombosis, blood flow after cerebral infarction, cerebral embolism, miocardial infarction, angina pectoris, lung infraction, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, artificial valve/joint replacement build again after thrombosis and again occlusion, systemic inflammatory reaction syndrome, MODS, extracorporal circulatory system when thrombosis or blood clotting during blood sampling prevention and/or therapeutic agent, characterized in that, containing the compound or its salt described in claim 1.
7. the medical composition with activated form factor X inhibitory action, it is characterised in that contain the carrier allowed in the compound or its salt and medicine described in claim 1.
8. application of the compound or its salt in the preparation of the pharmaceuticals with activated form factor X inhibitory action described in claim 1.
9. application of the compound or its salt in the preparation of activated form factor X inhibitor described in claim 1.
10. application of the compound or its salt in the preparation of Coagulative inhibitors agent described in claim 1.
11. application of the compound or its salt in the prevention of thrombus or embolism and/or the preparation of therapeutic agent described in claim 1.
12. the compound or its salt described in claim 1 is in cerebral infarction, cerebral embolism, miocardial infarction, angina pectoris, lung blocks, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve/joint replacement, blood flow build again after thrombosis and inaccessible again, systemic inflammatory reacts syndrome, MODS, the application in the prevention of blood clotting and/or the preparation of therapeutic agent when thrombosis during extracorporal circulatory system or blood sampling.
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