JP4630267B2 - Diamine derivatives - Google Patents

Description

  The present invention relates to a novel compound that inhibits activated blood coagulation factor X (hereinafter abbreviated as FXa) and exhibits a strong anticoagulant action and can be administered orally, or a blood coagulation inhibitor containing the same as an active ingredient Alternatively, the present invention relates to a preventive and / or therapeutic agent for thrombus or embolism.

  Unstable angina pectoris, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Burger disease, deep vein thrombosis, generalized intravascular coagulation syndrome, thrombus formation after replacement of prosthetic valve, revascularization Increased blood coagulation ability is one of the important factors for subsequent reocclusion and thrombus formation during extracorporeal circulation, so it is highly dose-responsive, durable, has low risk of bleeding, and has few side effects Therefore, there is a demand for an excellent anticoagulant that can provide a sufficient effect even after oral administration (Non-patent Document 1).

  From studies of anticoagulants based on various mechanisms of action, it has been suggested that FXa inhibitors may be excellent anticoagulants. The blood coagulation system is a series of reactions in which a large amount of thrombin is produced through an amplification process by a multi-stage enzymatic reaction to produce insoluble fibrin. In the endogenous system, the activation factor IX activates factor X on the phospholipid membrane in the presence of activated factor VIII and calcium ions after a multi-step reaction following activation of the contact factor. In the extrinsic system, activated factor VII activates factor X in the presence of tissue factor. That is, activation of factor X to FXa in the coagulation system is an essential reaction in thrombin generation. Factor X (FXa) activated in both systems produces limited thrombin by limited degradation of prothrombin. The generated thrombin activates upstream clotting factors, further amplifying the production of thrombin. As described above, the coagulation system upstream of FXa is divided into an intrinsic system and an extrinsic system. Therefore, inhibition of the coagulation system enzyme upstream of FXa cannot sufficiently suppress the production of FXa, resulting in the production of thrombin. Will end up. Moreover, since the coagulation system is a self-amplification reaction, suppression of the coagulation system can be achieved efficiently by inhibiting FXa located upstream rather than inhibiting the generated thrombin (Non-patent Document 2). Another advantage of FXa inhibitors is that there is a large discrepancy between the effective dose in the thrombus model and the dose that prolongs the bleeding time in the experimental bleeding model. It is considered to be a low-risk anticoagulant.

Various compounds have been reported as FXa inhibitors, but in general, antithrombin III and antithrombin III-dependent pentasaccharides can inhibit the prothrombinase complex that plays a practical role in thrombus formation in vivo. Not known (Non-patent document 1, Non-patent document 3, Non-patent document 4), and further, oral administration does not show effectiveness. The tic anticoagulant peptide (TAP) (Non-patent document 5) and antistasin (AST) (Non-patent document 6) isolated from blood-sucking animals, mites and leeches, also inhibit FXa and Although antithrombotic effects are shown up to the thrombus model, these are high-molecular peptides and are ineffective in oral administration. In this way, development of an orally administrable small molecule FXa inhibitor that directly inhibits a coagulation factor independent of antithrombin III has been carried out.
Thrombosis Research, 68, 507-512, 1992 Thrombosis Research, 15, 617-629, 1979 Journal of Clinical Investigation, 71, 1383-1389, 1983 Mebio, Volume 14, August, pages 92-97 Science 248, 593-596, 1990 Journal of Biological Chemistry, 263, 10162-10167, 1988

  Accordingly, an object of the present invention is to provide a novel compound having a strong FXa inhibitory action and exhibiting a sufficient and sustained antithrombotic effect promptly by oral administration.

  As a result of studying the synthesis and pharmacological action of novel FXa inhibitors, the present inventors have found that diamine derivatives, their salts, their solvates or their N-oxides exhibit strong FXa inhibitory action and strong anticoagulant action. I found. Furthermore, since these compounds inhibit FXa quickly and persistently even after oral administration and exhibit strong anticoagulant and antithrombotic effects, they prevent and treat various diseases based on thrombosis / embolism. It was found useful as a medicine and the present invention was completed.

  That is, the present invention relates to the general formula (1)

[Wherein, R ¹ and R ² each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
Q ¹ is a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, a substituent A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent Show;
Q ² is a single bond, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, a linear or branched carbon atom. An alkynylene group of 2 to 6; a divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group that may have a substituent; 7-membered heterocyclic group, divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or divalent saturated or unsaturated which may have a substituent Represents a saturated bicyclic or tricyclic fused heterocyclic group;
Q ³ is the following group

[In the group, Q ⁵ represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group — (CH ₂ ) _m —CH ₂ —A—CH ₂ — (CH ₂ ) _n — (in the group , M and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, — NH—NH—, —S—NH—, —SO—NH— or —SO ₂ —NH— are indicated);
R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom or a halogenoalkyl group. Group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, Alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group , Alkoxy carbon An amino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, having a substituent 3 to 6 members A ring carbonyl group, a carbamoylalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, a carbamoyloxy An alkyl group, an N-alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an optionally substituted 3- to 6-membered heterocyclic carbonylalkyl group, and an optionally substituted 3- 6-membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, 3-6 membered heterocyclic group optionally having substituent, 3-6 membered heterocyclic alkyl group optionally having substituent , Alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl Group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, alkoxycarbonylalkyloxy group, Acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group Acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfuric group An aryl group, an alkoxyalkylsulfonyl group, an optionally substituted 3-6 membered heterocyclic sulfonyl group, an optionally substituted 3-6 membered heterocyclic oxy group, an N-alkylaminoacyl group, N, N-dialkylaminoacyl group, N, N-dialkylcarbamoyl acyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group Alkylsulfonylacyl group, N-arylcarbamoyl group, N-3 to 6-membered heterocyclic carbamoyl group, N-alkyl-N-arylcarbamoyl group, N-alkyl-N-3 to 6-membered heterocyclic carbamoyl group, N-arylcarbamoylalkyl group, N-3 to 6-membered heterocyclic carbamoylalkyl group, N-alkyl-N-arylcarbamoylal Group, N-alkyl-N-3 to 6-membered heterocyclic carbamoylalkyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group, alkoxyalkyl (thio Carbonyl) group, alkylthioalkyl group or N-acyl-N-alkylaminoalkyl group, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms Group, a C1-C5 alkylenedioxy group or a carbonyldioxy group. );

Q ⁴ represents an aryl group that may have a substituent, an arylalkenyl group that may have a substituent, an arylalkynyl group that may have a substituent, a heteroaryl group that may have a substituent, or a substituent. A heteroarylalkenyl group which may have, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, a saturated or unsaturated bicyclic which may have a substituent or Represents a tricyclic fused heterocyclic group;
T ⁰ represents a carbonyl group or a thiocarbonyl group;
T ¹ is a carbonyl group, a sulfonyl group, a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′). -, Group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(in which R 'is A hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —A ¹ —N (R ″) — (wherein A ¹ may have a substituent having 1 to 1 carbon atoms; 5 represents an alkylene group, and R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —NH—, a group —C (═S) —NH—, a group —C (═O) —NH—NH—, group —C (═O) —A ² —C (═O) — (wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms). -C (= O) in ^{-A 3 -C (= O) -NH-} ( group, A ³ is the number of carbon atoms Shows the 5 alkylene group), group -C (= O) -C (= NOR a) -N (R b) -., Group -C (= S) -C (= NOR a) -N (R ^b )-(wherein R ^a represents a hydrogen atom, an alkyl group or an alkanoyl group, R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group —C (═O) —N═N -, group -C (= S) -N = N- , group ^{-C (= NOR C) -C (} = O) -N (R d) - ( the radical, R ^C is a hydrogen atom, an alkyl group, an alkanoyl A group, an aryl group or an aralkyl group, R ^d represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group —C (═N—N (R ^e ) (R ^f )) — C (═O ) -N (R ^g) - (in groups, each independently R ^e and R ^f, a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl (thiocarbonyl) shows the group , R ^g represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), group -C (= O) -NH-C (= O) -., Group -C (= S) -NH-C (= O ) -, group -C (= O) -NH-C (= S) -, group -C (= S) -NHC (= S) -, group -C (= O) -NH-SO 2 -, group —SO ₂ —NH—, a group —C (═NCN) —NH—C (═O) —, a group —C (═S) —C (═O) — or a thiocarbonyl group is shown. Or a salt thereof, a solvate thereof, or an N-oxide thereof.

The present invention also relates to a pharmaceutical comprising the compound represented by the above general formula (1), a salt thereof, a solvate thereof or an N-oxide thereof, particularly an activated blood coagulation factor X inhibitor, blood coagulation Inhibitor, preventive and / or therapeutic agent for thrombosis or embolism, as well as cerebral infarction, cerebral embolism, myocardial infarction, angina, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, generalized intravascular coagulation syndrome Thrombosis after prosthetic valve / joint replacement, thrombus formation and reocclusion after revascularization, systemic inflammatory response syndrome (SIRS), multiple organ failure (MODS), thrombus formation during extracorporeal circulation or blood clotting during blood collection It is intended to provide a preventive and / or therapeutic agent.
Moreover, this invention provides the intermediate body for manufacturing the compound (1) represented by the said General formula (1).
Moreover, this invention provides use for the pharmaceutical manufacture of the compound represented by the said General formula (1), its salt, those solvates, or those N-oxides.
Furthermore, the present invention provides a method for treating a thrombus or embolus, which comprises administering an effective amount of the compound represented by the above general formula (1), a salt thereof, a solvate thereof or an N-oxide thereof. Is.

  Since the cyclic diamine derivative of the present invention has a strong inhibitory action on activated blood coagulation factor X, it prevents and / or treats pharmaceuticals, activated blood coagulation factor X inhibitors, blood coagulation inhibitors, thrombi or emboli. Agents, preventive and / or therapeutic agents for thrombotic diseases, as well as cerebral infarction, cerebral embolism, myocardial infarction, angina, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, generalized intravascular coagulation syndrome, Thrombus formation after prosthetic valve / joint replacement, thrombus formation and reocclusion after revascularization, systemic inflammatory response syndrome (SIRS), multiple organ failure (MODS), thrombus formation during extracorporeal circulation or blood clotting during blood collection It is useful as a preventive and / or therapeutic agent.

Below, the substituent in the diamine derivative of this invention represented by General formula (1) is demonstrated.
<For radical Q ^4>
The group Q ⁴ is an aryl group which may have a substituent, an arylalkenyl group which may have a substituent, an arylalkynyl group which may have a substituent, a heteroaryl group which may have a substituent, a substituted group Heteroarylalkenyl group which may have a group, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, saturated or unsaturated bicyclic which may have a substituent Or a tricyclic fused heterocyclic group.
In the group Q ⁴ , examples of the aryl group include aryl groups having 6 to 14 carbon atoms such as a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. The arylalkenyl group means a group composed of an aryl group having 6 to 14 carbon atoms and an alkenylene group having 2 to 6 carbon atoms, and examples thereof include a styryl group. The arylalkynyl group means a group composed of an aryl group having 6 to 14 carbon atoms and an alkynylene group having 2 to 6 carbon atoms, and examples thereof include a phenylethynyl group.
The heteroaryl group means an aromatic monovalent group having at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and has a total number of 5 or 6 heteroaryl groups such as a pyridyl group, Examples include pyridazinyl group, pyrazinyl group, furyl group, thienyl group, pyrrolyl group, thiazolyl group, oxazolyl group, pyrimidinyl group, tetrazolyl group and the like. The heteroarylalkenyl group means a group composed of the above heteroaryl group and an alkenylene group having 2 to 6 carbon atoms, and examples thereof include a thienylethenyl group and a pyridylethenyl group.

Saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group refers to a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon formed as a monovalent group, saturated or Unsaturated bicyclic or tricyclic condensed hydrocarbon is bicyclic or 3 formed by condensing 2 or 3 of the same or different saturated or unsaturated 5 to 6-membered cyclic hydrocarbons. A cyclic condensed hydrocarbon is shown. Examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon in that case include cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, and benzene. Specific examples of the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group include an indenyl group, an indanyl group, a tetrahydronaphthyl group, and a naphthyl group. The position at which the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group is bonded to T ¹ in the general formula (1) is not particularly limited.

Saturated or unsaturated bicyclic or tricyclic fused heterocyclic group refers to a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group formed as a monovalent group. The saturated or unsaturated bicyclic or tricyclic fused heterocyclic ring is represented by the following 1) to 3).
1) a bicyclic or tricyclic condensed heterocyclic ring formed by condensing 2 to 3 of the same or different saturated or unsaturated 5- to 7-membered heterocyclic rings;
2) Bicyclic or tricyclic formed by condensation of one saturated or unsaturated 5- to 7-membered heterocyclic ring with 1 to 2 saturated or unsaturated 5- to 6-membered cyclic hydrocarbons 3) Tricyclic formed by condensation of 2 saturated or unsaturated 5 to 7 membered heterocyclic rings and 1 saturated or unsaturated 5 to 6 membered cyclic hydrocarbon A fused heterocycle of
The position at which the saturated or unsaturated bicyclic or tricyclic fused heterocyclic group is bonded to T ¹ in the general formula (1) is not particularly limited.

  The saturated or unsaturated 5- to 7-membered heterocyclic ring means a heterocyclic ring having at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and furan, pyrrole, thiophene, pyrazole, imidazole , Oxazole, oxazolidine, thiazole, thiadiazole, furazane, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazine, oxadiazine, morpholine, thiazine, thiadiazine, thiomorpholine, tetrazole, triazole, triazine, thiadiazine, oxadiazine, azepine, Specific examples include diazepine, triazepine, thiazepine, oxazepine and the like. The saturated or unsaturated 5- to 6-membered cyclic hydrocarbon is a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon exemplified in the description of the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group. The same thing as a cyclic hydrocarbon is shown. Specific examples of the saturated or unsaturated bicyclic or tricyclic fused heterocyclic group include benzofuryl group, isobenzofuryl group, benzothienyl group, indolyl group, indolinyl group, isoindolyl group, isoindolinyl group, indazolyl group Quinolyl group, dihydroquinolyl group, 4-oxodihydroquinolyl group (dihydroquinolin-4-one), tetrahydroquinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, chromenyl group, chromanyl group, isochromanyl group, 4H- 4-oxobenzopyranyl group, 3,4-dihydro-4H-4-oxobenzopyranyl group, 4H-quinolidinyl group, quinazolinyl group, dihydroquinazolinyl group, tetrahydroquinazolinyl group, quinoxalinyl group, tetrahydroquinoxa Linyl group, cinnolinyl group, tetrahydride Cinnolinyl group, indolizinyl group, tetrahydroindolidinyl group, benzothiazolyl group, tetrahydrobenzothiazolyl group, benzoxazolyl group, benzisothiazolyl group, benzoisoxazolyl group, benzoimidazolyl group, naphthyridinyl group, tetrahydronaphthyridinyl group Group, thienopyridyl group, tetrahydrothienopyridyl group, thiazolopyridyl group, tetrahydrothiazolopyridyl group, thiazolopyridazinyl group, tetrahydrothiazolopyridazinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, tetrahydropyrrolopyridyl group Group, pyrrolopyrimidinyl group, dihydropyrrolopyrimidinyl group, pyridoquinazolinyl group, dihydropyridoquinazolinyl group, pyridopyrimidinyl group, tetrahydropyridopyrimidinyl group, pyranothiazo Group, dihydropyranothiazolyl group, furopyridyl group, tetrahydrofuropyridyl group, oxazolopyridyl group, tetrahydrooxazolopyridyl group, oxazolopyridazinyl group, tetrahydrooxazolopyridazinyl group, pyrrolothiazolyl group, dihydro Pyrrolothiazolyl group, pyrrolooxazolyl group, dihydropyrrolooxazolyl group, thienopyrrolyl group, thiazolopyrimidinyl group, 4-oxotetrahydrocinnolinyl group, 1,2,4-benzothiadiazinyl group, 1, 1-dioxy-2H-1,2,4-benzothiadiazinyl group, 1,2,4-benzooxadiazinyl group, cyclopentapyranyl group, thienofuranyl group, furopyranyl group, pyridooxazinyl group, Pyrazolooxazolyl group, imidazothiazolyl group, imidazopyridyl group, tetrahyd Droimidazopyridyl group, pyrazinopyridazinyl group, benzisoquinolyl group, furocinolyl group, pyrazolothiazolopyridazinyl group, tetrahydropyrazolothiazolopyridazinyl group, hexahydrothiazolopyridazino group Pyridazinyl group, imidazotriazinyl group, oxazolopyridyl group, benzoxepinyl group, benzoazepinyl group, tetrahydrobenzoazepinyl group, benzodiazepinyl group, benzotriazepinyl group, thienoazepinyl group, tetrahydrothie Noazepinyl group, thienodiazepinyl group, thienotriazepinyl group, thiazoloazepinyl group, tetrahydrothiazoloazepinyl group, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyrida Dinyl group, 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopi Dajiniru group, and the like can be mentioned.

  There is no particular limitation on the condensed form of the above condensed heterocyclic group. For example, in the case of a naphthyridinyl group, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7 -A naphthyridinyl group may be used, and in the case of a thienopyridyl group, a thieno [2,3-b] pyridyl group, a thieno [2,3-c] pyridyl group, a thieno [3,2-b] pyridyl group, a thieno [3,2 -C] pyridyl group, thieno [3,4-b] pyridyl group, and thieno [3,4-c] pyridyl group may be used. In the thienopyrrolyl group, thieno [2,3-b] pyrrolyl group, thieno [2 , 3-b] pyrrolyl group, and thiazolopyridyl group includes thiazolo [4,5-b] pyridyl group, thiazolo [4,5-c] pyridyl group, thiazolo [5,4-b] pyridyl group. , Thiazolo [5,4-c] pyridyl group, Any of an azolo [3,4-a] pyridyl group and a thiazolo [3,2-a] pyridyl group may be used. In the thiazolopyridazinyl group, a thiazolo [4,5-c] pyridazinyl group, a thiazolo [4, Any of 5-d] pyridazinyl group, thiazolo [5,4-c] pyridazinyl group, and thiazolo [3,2-b] pyridazinyl group may be used. In pyrrolopyridyl group, pyrrolo [2,3-b] pyridyl group, pyrrolo [ 2,3-c] pyridyl group, pyrrolo [3,2-b] pyridyl group, pyrrolo [3,2-c] pyridyl group, pyrrolo [3,4-b] pyridyl group, pyrrolo [3,4-c] Any pyridyl group may be used, and in the pyridopyrimidinyl group, a pyrido [2,3-d] pyrimidinyl group, a pyrido [3,2-d] pyrimidinyl group, a pyrido [3,4-d] pyrimidinyl group, a pyrido [4, 3-d] Any of a midinyl group, a pyrido [1,2-c] pyrimidinyl group, and a pyrido [1,2-a] pyrimidinyl group may be used. In the pyranothiazolyl group, a pyrano [2,3-d] thiazolyl group, a pyrano [4,3- d] thiazolyl group, pyrano [3,4-d] thiazolyl group, pyrano [3,2-d] thiazolyl group may be used. In the furopyridyl group, furo [2,3-b] pyridyl group, furo [2, 3-c] pyridyl group, furo [3,2-b] pyridyl group, furo [3,2-c] pyridyl group, furo [3,4-b] pyridyl group, furo [3,4-c] pyridyl group In the case of an oxazolopyridyl group, an oxazolo [4,5-b] pyridyl group, an oxazolo [4,5-c] pyridyl group, an oxazolo [5,4-b] pyridyl group, an oxazolo [5,4- c] pyridyl group, oxy Either a sazolo [3,4-a] pyridyl group or an oxazolo [3,2-a] pyridyl group may be used. In the oxazolopyridazinyl group, an oxazolo [4,5-c] pyridazinyl group, oxazolo [4, Any of a 5-d] pyridazinyl group, an oxazolo [5,4-c] pyridazinyl group, and an oxazolo [3,4-b] pyridazinyl group may be used. In the pyrrolothiazolyl group, a pyrrolo [2,1-b] thiazolyl group, a pyrrolo [ 1,2-c] thiazolyl group, pyrrolo [2,3-d] thiazolyl group, pyrrolo [3,2-d] thiazolyl group, pyrrolo [3,4-d] thiazolyl group may be used. In the group, pyrrolo [2,1-b] oxazolyl group, pyrrolo [1,2-c] oxazolyl group, pyrrolo [2,3-d] oxazolyl group, pyrrolo [3,2-d] oxazolyl group , Pyrrolo [3,4-d] oxazolyl group, and benzoazepinyl group may be any of 1H-1-benzoazepinyl group, 1H-2-benzoazepinyl group, 1H-3-benzoazepinyl group, and 4,5- A dihydro-oxo derivative type benzoazepinyl group such as a dihydro-1-oxo-1H-2-benzoazepinyl group may be used, and in the benzodiazepinyl group, a 1H-1,3-benzodiazepinyl group, 1H-1,4- Any of benzodiazepinyl group and 1H-1,5-benzodiazepinyl group, and dihydro-oxo derivatives such as 4,5-dihydro-4-oxo-1H-1,3-benzodiazepinyl group It may be a benzodiazepinyl group of the type, and 1H-1,3,4-benzotriazepinyl group, 1H Any of 1,3,5-benzotriazepinyl groups, and dihydro-oxo derivative type benzotria such as 4,5-dihydro-5-oxo-1H-1,3,4-benzotriazepinyl group It may be a zepinyl group, and in the thienoazepinyl group, a thieno [2,3-b] azepinyl group, a thieno [2,3-c] azepinyl group, a thieno [2,3-d] azepinyl group, a thieno [3,2-c ] Azepinyl group and thieno [3,2-b] azepinyl group, and dihydro- such as 5,6,7,8-tetrahydro-4-oxo-4H-thieno [3,2-c] azepinyl group An oxo derivative type thienoazepinyl group may be used, and a thienodiazepinyl group or a thienotriazepinyl group may be any condensed type, and a dihydro-oxo derivative type. The benzothiazepinyl group may be any of 1H-1-benzothiazepinyl group, 1H-2-benzothiazepinyl group, 1H-3-benzothiazepinyl group, and 4,5 It may be a dihydro-oxo derivative-type benzothiazepinyl group such as a dihydro-1-oxo-1H-2-benzothiazepinyl group. In the benzoxazepinyl group, a 1H-1-benzoxazepinyl group, 1H Any of 2-benzoxazepinyl group and 1H-3-benzoxazepinyl group, and dihydro-oxo derivative type like 4,5-dihydro-1-oxo-1H-2-benzoxazepinyl group The benzoxazepinyl group may be other than these condensed forms.

The above aryl group, heteroaryl group, arylalkenyl group, heteroarylalkenyl group, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group and saturated or unsaturated bicyclic or tricyclic condensed Each of the heterocyclic groups may have 1 to 3 substituents. As the substituents, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a halogen atom of iodine atom, or 1 to 3 halogen atoms. Substituted halogenoalkyl group having 1 to 6 carbon atoms, amino group, cyano group, aminoalkyl group, nitro group, hydroxyalkyl group (for example, hydroxymethyl group, 2-hydroxyethyl group, etc.), alkoxyalkyl group (for example, methoxy group) Methyl group, 2-methoxyethyl group, etc.), carboxyl group, carboxyalkyl group (for example, carboxymethyl group, -Carboxyethyl group etc.), alkoxycarbonylalkyl group (eg methoxycarbonylmethyl group, ethoxycarbonylmethyl group etc.), acyl group (eg alkanoyl group such as formyl group, acetyl group, propionyl group), amidino group, hydroxyamidino Group (amino (hydroxyimino) methyl group), linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (for example, methyl group, ethyl group, etc.), linear, branched or cyclic group C1-C6 alkoxy group (for example, methoxy group, ethoxy group, etc.), linear, branched or cyclic C1-C6 alkyl group substituted amidino group (for example, imino (methylamino) An amidino group substituted by a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms (for example, a methyl group) Amino (methoxyimino) methyl group), linear, branched or cyclic C2-C7 alkoxycarbonyl substituted amidino groups (for example, amino (methoxycarbonylimino) methyl group, amino (ethoxy Carbonylimino) methyl group, etc.), linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms (for example, vinyl group, allyl group, etc.), linear or branched carbon numbers 2 to 6 Alkynyl group (for example, ethynyl group, propynyl group, etc.), linear, branched or cyclic C2-C6 alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, etc.), carbamoyl group, nitrogen A mono- or dialkylcarbamoyl group substituted with a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms on the atom (for example, , Methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl group, ethylmethylcarbamoyl group, etc.), a mono- or dialkylamino group substituted with a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (for example, An ethylamino group, a dimethylamino group, a methylethylamino group) and a 5- to 6-membered nitrogen-containing heterocyclic group (for example, a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group, and the like).
Among the above groups, the group Q ⁴ is preferably the following 12 groups (a) to (l). That is,

[In the group, R ⁵ and R ⁶ are each independently a hydrogen atom, cyano group, halogen atom, alkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, alkoxycarbonyl group. , An alkoxycarbonylalkyl group, or a cyano group, a hydroxyl group, a halogen atom, an alkyl group, or a phenyl group that may be substituted with an alkoxy group, R ⁷ and R ⁸ are each independently a hydrogen atom, a hydroxyl group, a nitro group, Amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl Group, N, N-dialkyl Rubamoiru group, an alkoxycarbonyl group, an amidino group or alkoxycarbonylalkyl group. ],

[In the group, R ⁹ and R ¹⁰ are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group. , An alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group. ],

[In the group, R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group or a hydroxyalkyl group. , Alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. ],

[In the group, X ¹ represents CH ₂ , CH, NH, NOH, N, O or S, and R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, Group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group is shown. ],

[In the group, X ² represents NH, N, O or S, X ³ represents N, C or CH, X ⁴ represents N, C or CH, and R ¹⁷ and R ¹⁸ each independently represent Hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group Carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. The case where X ³ and X ⁴ are a combination of C and CH and the case where both are C or CH are excluded. ],

[In the group, N represents that one or two of the carbon atoms of the ring substituted by R ¹⁹ are substituted with a nitrogen atom, and R ¹⁹ , R ²⁰ and R ²¹ are each independently a hydrogen atom, a hydroxyl group, Nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, An N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group; ],

[In the group, X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N, and Z ³ represents CH ₂ , CH , S, SO ₂ or C═O, X ⁵ —Z ² represents that X ⁵ and Z ² are bonded by a single bond or a double bond, and R ²² and R ²³ each independently represents hydrogen. Atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, A carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group, R ²⁴ represents a hydrogen atom or an alkyl group; Indicates a kill group. ],

[In the group, X ⁶ represents O or S, and R ²⁵ and R ²⁶ independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogeno group, Alkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonyl An alkyl group is shown. ],

[In the group, R ²⁷ and R ²⁸ are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group. , An alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group. ],

[In the group, E ¹ and E ² each independently represent N or CH, and R ²⁹ and R ³⁰ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, or an alkyl group. , Alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxy A carbonyl group, an amidino group or an alkoxycarbonylalkyl group; ],

[In the group, Y ¹ represents CH or N, Y ² represents —N (R ³³ ) — (in the group, R ³³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), O or S R ³¹ and R ³² each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group, An alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group; ],
And the following groups

[In the group, the numbers 1 to 8 indicate positions, and each N is substituted with any one of 1 to 4 carbon atoms and any one of 5 to 8 carbon atoms with one nitrogen atom. R ³⁴ , R ³⁵ and R ³⁶ are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxy group Alkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group . ] Is a preferred group.
Below, explanation is given about these groups.

The halogen atom in the explanation of R ^{5 to} R ³⁶ in the above group represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the alkyl group has a linear, branched or cyclic carbon number of 1-6. An alkenyl group is linear, branched or cyclic having 2 to 6 carbon atoms, an alkynyl group is linear or branched having 2 to 6 carbon atoms, hydroxyalkyl Group represents a C ₁ -C ₆ alkyl group substituted with one hydroxyl group, an alkoxy group represents a linear, branched or cyclic group having 1 to 6 carbon atoms, and an alkoxyalkyl group represents the above the C ₁ -C ₆ alkyl group shows what one C ₁ -C ₆ alkoxy group described above is substituted, the one carboxyalkyl group in which one carboxyl group in C ₁ -C ₆ alkyl group described above is substituted The acyl group is an aryl group having 1 to 6 carbon atoms. (Including formyl) Kanoiru group, an aroyl group or an aryl alkanoyl group C ₆ -C ₁₄ aryl groups of said the C ₁ -C ₆ alkanoyl group described above is substituted, such as benzoyl group and naphthoyl group, N- alkyl The carbamoyl group represents a carbamoyl group in which the above C ₁ -C ₆ alkyl group is substituted on the nitrogen atom, and the N, N-dialkylcarbamoyl group has two C ₁ -C ₆ alkyl groups on the nitrogen atom. A substituted carbamoyl group, an alkoxycarbonyl group is composed of the above C ₁ -C ₆ alkoxy group and a carbonyl group, and an alkoxycarbonylalkyl group is the above C ₁ -C ₆ alkyl group and the above C _1- shows what one C ₆ alkoxycarbonyl group is substituted, halogenoalkyl groups 1 to 3 halogen atoms on the C ₁ -C ₆ alkyl group as described above It shows a material obtained by conversion. In the above description, the substitution position is not particularly limited.
The following group

[In the group, R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as described above, and the numbers 1 to 6 represent positions. In general, R ⁵ and R ⁶ are each independently preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, or a halogenoalkyl group. R ⁵ and R ⁶ are more preferably a hydrogen atom or an alkyl group, and in the case of an alkyl group, a methyl group is preferred. Further, as R ⁷ and R ⁸ , one is preferably a hydrogen atom and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and the other is preferably a hydrogen atom. , A halogen atom, an alkyl group or an alkynyl group is particularly preferable. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Specific examples of the group represented by the above formula include a chlorostyryl group, a fluorostyryl group, a bromostyryl group, an ethynylstyryl group, and the like, and a halogen atom, an alkyl group, or an alkynyl group in these groups. The position at which the group is substituted is not particularly limited, but the 4-position in the above formula is particularly preferable. Specifically, preferred examples include 4-chlorostyryl group, 4-fluorostyryl group, 4-bromostyryl group, 4-ethynylstyryl group and the like.
The following group

[In the group, R ⁹ and R ¹⁰ are the same as described above, and the numbers 1 to 6 represent positions. ], R ⁹ and R ¹⁰ are preferably each independently a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. Furthermore, it is preferable that R ⁹ is a hydrogen atom and R ¹⁰ is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Specific examples of the group represented by the above formula include chlorophenylethynyl group, fluorophenylethynyl group, bromophenylethynyl group, ethynylphenylethynyl group, and the like. The position at which the group or alkynyl group is substituted is not particularly limited, but the 4-position in the above formula is particularly preferable. Specifically, preferred examples include 4-chlorophenylethynyl group, 4-fluorophenylethynyl group, 4-bromophenylethynyl group, 4-ethynylphenylethynyl group, and the like.
The following group

[In the group, R ¹¹ , R ¹² and R ¹³ are the same as described above, and the numbers 1 to 8 represent positions. In general, R ¹¹ , R ¹² and R ¹³ are each independently preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. R ¹¹ is preferably a hydrogen atom, an alkyl group, a halogen atom or a hydroxyl group, and particularly preferably a hydrogen atom. As R ¹² and R ¹³ , one is preferably a hydrogen atom, and the other is preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. Particularly preferred is an atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The naphthyl group is preferably a 2-naphthyl group rather than a 1-naphthyl group, and in the case of a 2-naphthyl group, the position where a halogen atom, an alkyl group or an alkynyl group is substituted should be particularly limited. However, the 6th or 7th position in the above formula is preferred, and the 6th position is most preferred. Further, those in which a chlorine atom, a fluorine atom, a bromine atom, an alkynyl group or the like is substituted on these naphthyl groups are more preferable, and those in which a chlorine atom, a fluorine atom, a bromine atom, an alkynyl group or the like is further substituted are particularly preferable. Specifically, 6-chloro-2-naphthyl group, 6-fluoro-2-naphthyl group, 6-bromo-2-naphthyl group, 6-ethynyl-2-naphthyl group, 7-chloro-2-naphthyl group, Preferred examples include 7-fluoro-2-naphthyl group, 7-bromo-2-naphthyl group, 7-ethynyl-2-naphthyl group and the like.
The following group

[In the group, X ¹ , R ¹⁴ , R ¹⁵ and R ¹⁶ are the same as those described above, and the numbers 4 to 7 represent positions. ], X ¹ is preferably NH, NOH, N, O and S, more preferably NH, O and S. R ¹⁴ is preferably a hydrogen atom, a halogen atom, an acyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group or an alkyl group, and R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, a cyano group or a halogen atom. Atoms, alkyl groups, alkenyl groups, alkynyl groups or halogenoalkyl groups are preferred. As R ¹⁵ and R ¹⁶ , one is a hydrogen atom or a halogen atom, preferably a fluorine atom or a chlorine atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. In some cases, a case where the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group is particularly preferable. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The position at which the halogen atom, alkyl group or alkynyl group is substituted is not particularly limited, but 4-position, 5-position or 6-position in the above formula is preferred. Specific groups represented by the above formula include 5-chloroindolyl group, 5-fluoroindolyl group, 5-bromoindolyl group, 5-ethynylindolyl group, 5-methylindolyl group, 5 -Chloro-4-fluoroindolyl group, 5-chloro-3-fluoroindolyl group, 5-fluoro-3-chloroindolyl group, 5-ethynyl-3-fluoroindolyl group, 5-chloro-3- ( N, N-dimethylcarbamoyl) indolyl group, 5-fluoro-3- (N, N-dimethylcarbamoyl) indolyl group, 5-chloro-3-formylimidyl group, 5-fluoro-3-formylindolyl group, 6 -Chloroindolyl group, 6-fluoroindolyl group, 6-bromoindolyl group, 6-ethynylindolyl group, 6-methylindolyl group, 5-chlorobenzothieni Group, 5-fluorobenzothienyl group, 5-bromobenzothienyl group, 5-ethynylbenzothienyl group, 5-methylbenzothienyl group, 5-chloro-4-fluorobenzothienyl group, 6-chlorobenzothienyl group, 6- Fluorobenzothienyl group, 6-bromobenzothienyl group, 6-ethynylbenzothienyl group, 6-methylbenzothienyl group, 5-chlorobenzofuryl group, 5-fluorobenzofuryl group, 5-bromobenzofuryl group, 5-ethynyl Benzofuryl group, 5-methylbenzofuryl group, 5-chloro-4-fluorobenzofuryl group, 6-chlorobenzofuryl group, 6-fluorobenzofuryl group, 6-bromobenzofuryl group, 6-ethynylbenzofuryl group, A 6-methylbenzofuryl group etc. can be mentioned as a preferable example. The position at which these substituents are bonded to T ¹ is not particularly limited, but is preferably 2-position or 3-position in the above formula (d), specifically 5-chloroindol-2-yl. Group, 5-fluoroindol-2-yl group, 5-bromoindol-2-yl group, 5-ethynylindol-2-yl group, 5-methylindol-2-yl group, 5-chloro-4-fluoroindole 2-yl group, 5-chloro-3-fluoroindol-2-yl group, 3-bromo-5-chloroindol-2-yl group, 3-chloro-5-fluoroindol-2-yl group, 3- Bromo-5-fluoroindol-2-yl group, 5-bromo-3-chloroindol-2-yl group, 5-bromo-3-fluoroindol-2-yl group, 5-chloro-3-formylindole-2 Yl group, 5-fluoro-3-formylindol-2-yl group, 5-bromo-3-formylindol-2-yl group, 5-ethynyl-3-formylindol-2-yl group, 5-chloro-3 -(N, N-dimethylcarbamoyl) indol-2-yl group, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-bromo-3- (N, N-dimethylcarbamoyl) ) Indol-2-yl group, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 6-chloroindol-2-yl group, 6-fluoroindol-2-yl group, 6 -Bromoindol-2-yl group, 6-ethynylindol-2-yl group, 6-methylindol-2-yl group, 5-chloroindol-3-yl group, 5-fluoro Loindol-3-yl group, 5-bromoindol-3-yl group, 5-ethynylindol-3-yl group, 5-methylindol-3-yl group, 5-chloro-4-fluoroindol-3-yl Group, 6-chloroindol-3-yl group, 6-fluoroindol-3-yl group, 6-bromoindol-3-yl group, 6-ethynylindol-3-yl group, 6-methylindol-3-yl Group, 5-chlorobenzothiophen-2-yl group, 5-fluorobenzothiophen-2-yl group, 5-bromobenzothiophen-2-yl group, 5-ethynylbenzothiophen-2-yl group, 5-methylbenzo Thiophen-2-yl group, 5-chloro-4-fluorobenzothiophen-2-yl group, 6-chlorobenzothiophen-2-yl group, 6-fluoroben Thiophen-2-yl group, 6-bromobenzothiophen-2-yl group, 6-ethynylbenzothiophen-2-yl group, 6-methylbenzothiophen-2-yl group, 5-chlorobenzothiophen-3-yl group 5-fluorobenzothiophen-3-yl group, 5-bromobenzothiophen-3-yl group, 5-ethynylbenzothiophen-3-yl group, 5-methylbenzothiophen-3-yl group, 5-chloro-4 -Fluorobenzothiophen-3-yl group, 6-chlorobenzothiophen-3-yl group, 6-fluorobenzothiophen-3-yl group, 6-bromobenzothiophen-3-yl group, 6-ethynylbenzothiophene-3 -Yl group, 6-methylbenzothiophen-3-yl group, 5-chlorobenzofuran-2-yl group, 5-fluorobenzoph N-2-yl group, 5-bromobenzofuran-2-yl group, 5-ethynylbenzofuran-2-yl group, 5-methylbenzofuran-2-yl group, 5-chloro-4-fluorobenzofuran-2-yl group 6-chlorobenzofuran-2-yl group, 6-fluorobenzofuran-2-yl group, 6-bromobenzofuran-2-yl group, 6-ethynylbenzofuran-2-yl group, 6-methylbenzofuran-2-yl group 5-chlorobenzofuran-3-yl group, 5-fluorobenzofuran-3-yl group, 5-bromobenzofuran-3-yl group, 5-ethynylbenzofuran-3-yl group, 5-methylbenzofuran-3-yl group , 5-chloro-4-fluorobenzofuran-3-yl group, 6-chlorobenzofuran-3-yl group, 6-fluorobenzofuran-3-yl group , 6-bromobenzofuran-3-yl group, 6-ethynylbenzofuran-3-yl group, 6-methylbenzofuran-3-yl group and the like; 5-chloroindol-2-yl group, 5-fluoroindole- 2-yl group, 5-bromoindol-2-yl group, 5-ethynylindol-2-yl group, 5-methylindol-2-yl group, 5-chloro-4-fluoroindol-2-yl group, 6 -Chloroindol-2-yl group, 6-fluoroindol-2-yl group, 6-bromoindol-2-yl group, 6-ethynylindol-2-yl group, 6-methylindol-2-yl group, 5 -Chloro-3-fluoroindol-2-yl group, 3-bromo-5-chloroindol-2-yl group, 3-chloro-5-fluoroindol-2-yl group, -Bromo-5-fluoroindol-2-yl group, 5-bromo-3-chloroindol-2-yl group, 5-bromo-3-fluoroindol-2-yl group, 5-chloro-3-formylindole- 2-yl group, 5-fluoro-3-formylindol-2-yl group, 5-bromo-3-formylindol-2-yl group, 5-ethynyl-3-formylindol-2-yl group, 5-chloro -3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-bromo-3- (N, N- Dimethylcarbamoyl) indol-2-yl group, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-chlorobenzothiophen-2-yl 5-fluorobenzothiophen-2-yl group, 5-bromobenzothiophen-2-yl group, 5-ethynylbenzothiophen-2-yl group, 5-methylbenzothiophen-2-yl group, 5-chloro-4 -Fluorobenzothiophen-2-yl group, 6-chlorobenzothiophen-2-yl group, 6-fluorobenzothiophen-2-yl group, 6-bromobenzothiophen-2-yl group, 6-ethynylbenzothiophene-2 -Yl group, 6-methylbenzothiophen-2-yl group, 5-chlorobenzofuran-2-yl group, 5-fluorobenzofuran-2-yl group, 5-bromobenzofuran-2-yl group, 5-ethynylbenzofuran- 2-yl group, 5-methylbenzofuran-2-yl group, 5-chloro-4-fluorobenzofuran-2-yl group, 6-chloro Lobenzofuran-2-yl group, 6-fluorobenzofuran-2-yl group, 6-bromobenzofuran-2-yl group, 6-ethynylbenzofuran-2-yl group and 6-methylbenzofuran-2-yl group are particularly preferable. .
The following group

[In the group, X ² , X ³ , X ⁴ , R ¹⁷ and R ¹⁸ are the same as described above, and the numbers 4 to 7 represent positions. ], X ² is preferably NH, O or S, and one of X ³ and X ⁴ is preferably CH or C, and particularly preferably one is C. R ¹⁷ and R ¹⁸ are each independently preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. As R ¹⁷ and R ¹⁸ , one is preferably a hydrogen atom and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and among them, the other is a hydrogen atom, a halogen atom Particularly preferred is an atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The position at which the halogen atom, alkyl group or alkynyl group is substituted is not particularly limited, but the 5-position or 6-position in the above formula is preferred. Specific groups represented by the above formula include 5-chloroindazolyl group, 5-fluoroindazolyl group, 5-bromoindazolyl group, 5-ethynylindazolyl group, 6-chloroin Dazolyl group, 6-fluoroindazolyl group, 6-bromoindazolyl group, 6-ethynylindazolyl group, 5-chlorobenzoimidazolyl group, 5-fluorobenzoimidazolyl group, 5-bromobenzoimidazolyl group, 5-ethynylbenzimidazolyl Group, 6-chlorobenzoimidazolyl group, 6-fluorobenzoimidazolyl group, 6-bromobenzoimidazolyl group, 6-ethynylbenzimidazolyl group, 5-chlorobenzothiazolyl group, 5-fluorobenzothiazolyl group, 5-bromobenzothiazolyl group Group, 5-ethynylbenzothiazolyl group, 6-chlorobenzothiazolyl Group, 6-fluorobenzothiazolyl group, 6-bromobenzothiazolyl group, 6-ethynylbenzothiazolyl group, 5-chlorobenzoxazolyl group, 5-fluorobenzoxazolyl group, 5-bromo Benzoxazolyl group, 5-ethynylbenzoxazolyl group, 6-chlorobenzoxazolyl group, 6-fluorobenzoxazolyl group, 6-bromobenzoxazolyl group, 6-ethynylbenzoxazolyl group 5-chlorobenzoisothiazolyl group, 5-fluorobenzoisothiazolyl group, 5-bromobenzoisothiazolyl group, 5-ethynylbenzisothiazolyl group, 6-chlorobenzoisothiazolyl group, 6-fluorobenzo Isothiazolyl group, 6-bromobenzoisothiazolyl group, 6-ethynylbenzisothiazolyl group, 5-chlorobenzoisoxy group Zolyl group, 5-fluorobenzoisoxazolyl group, 5-bromobenzoisoxazolyl group, 5-ethynylbenzisoxazolyl group, 6-chlorobenzisoxazolyl group, 6-fluorobenzoisoxazolyl group Group, 6-bromobenzoisoxazolyl group, 6-ethynylbenzisoxazolyl group and the like can be mentioned as preferred examples, and the position where these substituents are bonded to T ¹ is particularly limited Although not 5-chloroindazol-3-yl group, 5-fluoroindazol-3-yl group, 5-bromoindazol-3-yl group, 5-ethynylindazol-3-yl group, 6-chloroindazole-3 -Yl group, 6-fluoroindazol-3-yl group, 6-bromoindazol-3-yl group, 6-ethynylindazol-3-yl group, 5-chloro Nzoimidazol-2-yl group, 5-fluorobenzoimidazol-2-yl group, 5-bromobenzoimidazol-2-yl group, 5-ethynylbenzimidazol-2-yl group, 6-chlorobenzimidazol-2- Yl group, 6-fluorobenzoimidazol-2-yl group, 6-bromobenzoimidazol-2-yl group, 6-ethynylbenzimidazol-2-yl group, 5-chlorobenzothiazol-2-yl group, 5-fluoro Benzothiazol-2-yl group, 5-bromobenzothiazol-2-yl group, 5-ethynylbenzothiazol-2-yl group, 6-chlorobenzothiazol-2-yl group, 6-fluorobenzothiazol-2-yl Group, 6-bromobenzothiazol-2-yl group, 6-ethynylbenzothiazol-2-yl group, 5- Lorobenzoxazol-2-yl group, 5-fluorobenzoxazol-2-yl group, 5-bromobenzoxazol-2-yl group, 5-ethynylbenzoxazol-2-yl group, 6-chlorobenzoxazol-2-yl Yl group, 6-fluorobenzoxazol-2-yl group, 6-bromobenzoxazol-2-yl group, 6-ethynylbenzoxazol-2-yl group, 5-chlorobenzoisothiazol-3-yl group, 5- Fluorobenzoisothiazol-3-yl group, 5-bromobenzoisothiazol-3-yl group, 5-ethynylbenzisothiazol-3-yl group, 6-chlorobenzoisothiazol-3-yl group, 6-fluorobenzo Isothiazol-3-yl group, 6-bromobenzoisothiazol-3-yl group, 6-ethynyl group Nzoisothiazol-3-yl group, 5-chlorobenzoisoxazol-3-yl group, 5-fluorobenzoisoxazol-3-yl group, 5-bromobenzoisoxazol-3-yl group, 5 -Ethynylbenzisoxazol-3-yl group, 6-chlorobenzoisoxazol-3-yl group, 6-fluorobenzoisoxazol-3-yl group, 6-bromobenzoisoxazol-3-yl group , 6-ethynylbenzisoxazol-3-yl group is more preferable, 5-chlorobenzimidazol-2-yl group, 5-fluorobenzoimidazol-2-yl group, 5-bromobenzoimidazol-2-yl group, 5-ethynylbenzimidazol-2-yl group, 6-chlorobenzimidazol-2-yl group, 6-fluorobenzimidazol-2-yl group, 6 Bromobenzimidazol-2-yl group, 6-ethynylbenzimidazol-2-yl group, 5-chlorobenzothiazol-2-yl group, 5-fluorobenzothiazol-2-yl group, 5-bromobenzothiazol-2- Yl group, 5-ethynylbenzothiazol-2-yl group, 6-chlorobenzothiazol-2-yl group, 6-fluorobenzothiazol-2-yl group, 6-bromobenzothiazol-2-yl group, 6-ethynyl Benzothiazol-2-yl group, 5-chlorobenzoxazol-2-yl group, 5-fluorobenzoxazol-2-yl group, 5-bromobenzoxazol-2-yl group, 5-ethynylbenzoxazol-2-yl Group, 6-chlorobenzoxazol-2-yl group, 6-fluorobenzoxazol-2-yl , 6-bromobenzoxazol-2-yl group, 6-ethynylbenzoxazol-2-yl group are particularly preferable, 5-chlorobenzoimidazol-2-yl group, 5-fluorobenzoimidazol-2-yl group, 5- Of these, a bromobenzoimidazol-2-yl group and a 5-ethynylbenzimidazol-2-yl group are more preferable.
The following group

[In the group, N represents that one or two carbon atoms of the ring substituted by R ¹⁹ are substituted with a nitrogen atom, and R ¹⁹ , R ²⁰ and R ²¹ represent the same as above, Numbers 5 to 8 indicate positions. In general, R ¹⁹ , R ²⁰ and R ²¹ are each independently preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. R ¹⁹ is particularly preferably a hydrogen atom, and R ²⁰ and R ²¹ are each a hydrogen atom and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group Among them, the case where the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group is particularly preferable. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The position at which the halogen atom, alkyl group or alkynyl group is substituted is not particularly limited, but the 6th or 7th position in the above formula is preferred. Specific groups represented by the above formula include quinolinyl group, isoquinolinyl group, cinnolinyl group, 6-chloroquinolinyl group, 6-fluoroquinolinyl group, 6-bromoquinolinyl group, 6-ethynylquinolinyl. Group, 6-chloroisoquinolinyl group, 6-fluoroisoquinolinyl group, 6-bromoisoquinolinyl group, 6-ethynylisoquinolinyl group, 7-chlorocinnolinyl group, 7-fluorocin A nolinyl group, a 7-bromocinnolinyl group, a 7-ethynylcinnolinyl group and the like are preferable. 6-chloroquinolin-2-yl group, 6-fluoroquinolin-2-yl group, 6-bromoquinolin-2-yl group, 6-ethynylquinolin-2-yl group, 6-chloroquinolin-3-yl group, 6-fluoroquinolin-3-yl group, 6-bromoquinolin-3-yl group, 6-ethynylquinolin-3-yl group, 7-chloroquinolin-2-yl group, 7-fluoroquinolin-2-yl group, 7-bromoquinolin-2-yl group, 7-ethynylquinolin-2-yl group, 7-chloroquinolin-3-yl group, 7-fluoroquinolin-3-yl group, 7-bromoquinolin-3-yl group, 7-ethynylquinolin-3-yl group, 6-chloroisoquinolin-3-yl group, 6-fluoroisoquinolin-3-yl group, 6-bromoisoquinolin-3-yl group, 6-ethynylisoquinoline-3 Yl group, 7-chloroisoquinolin-3-yl group, 7-fluoroisoquinolin-3-yl group, 7-bromoisoquinolin-3-yl group, 7-ethynylisoquinolin-3-yl group, 7-chlorocinnoline-3 A -yl group, a 7-fluorocinnolin-3-yl group, a 7-bromocinnolin-3-yl group, a 7-ethynylcinnolin-3-yl group and the like are particularly preferable. 6-chloroquinolin-2-yl group, 6-fluoroquinolin-2-yl group, 6-bromoquinolin-2-yl group, 6-ethynylquinolin-2-yl group, 7-chloroquinolin-3-yl group, 7-fluoroquinolin-3-yl group, 7-bromoquinolin-3-yl group, 7-ethynylquinolin-3-yl group, 7-chloroisoquinolin-3-yl group, 7-fluoroisoquinolin-3-yl group, 7-bromoisoquinolin-3-yl group, 7-ethynylisoquinolin-3-yl group, 7-chlorocinnolin-3-yl group, 7-fluorocinnolin-3-yl group, 7-bromocinnoline-3- Of these, an yl group and a 7-ethynylcinnolin-3-yl group are more preferable.
The following group

[In the group, the numbers 5 to 8 represent positions, X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, and Z ² represents CH ₂ , CH, C or N Z ³ represents CH ₂ , CH, S, SO ₂ or C═O, X ⁵ —Z ² represents that X ⁵ and Z ² are bonded by a single bond or a double bond, R ²² , R ²³ and R ²⁴ are the same as described above. In general, R ²² and R ²³ are each independently preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, or a halogenoalkyl group. R ²² and R ²³ are preferably a case where one of them is a hydrogen atom and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. Particularly preferred is a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The position at which the halogen atom, alkyl group or alkynyl group is substituted is not particularly limited, but the 6th or 7th position in the above formula is preferred. R ²⁴ is preferably a hydrogen atom or an alkyl group, and the alkyl group is preferably a methyl group. R ²⁴ is particularly preferably a hydrogen atom. Specific groups represented by the above formula include 4-oxodihydroquinolinyl group, tetrahydroquinolinyl group, 4-oxodihydroquinazolin-2-yl group, 4-oxotetrahydrocinnolinyl group, 4 -Oxobenzopyranyl group, 4-oxobenzothiadiazinyl group, 1,1-dioxy-4-oxobenzothiadiazinyl group, benzoxiadiazinyl group and the like can be mentioned. More specific groups include 6-chloro-4-oxodihydroquinolinyl group, 6-fluoro-4-oxodihydroquinolinyl group, 6-bromo-4-oxodihydroquinolinyl group, 6-ethynyl. -4-oxodihydroquinolinyl group, 7-chloro-4-oxodihydroquinolinyl group, 7-fluoro-4-oxodihydroquinolinyl group, 7-bromo-4-oxodihydroquinolinyl group, 7 -Ethynyl-4-oxodihydroquinolinyl group, 6-chloro-4-oxo-1,4-dihydroquinazolinyl group, 6-fluoro-4-oxo-1,4-dihydroquinazolinyl group, Bromo-4-oxo-1,4-dihydroquinazolinyl group, 6-ethynyl-4-oxo-1,4-dihydroquinazolinyl group, 7-chloro-4-oxo-1,4-dihydroquinazolinyl group Base 7-fluoro-4-oxo-1,4-dihydroquinazolinyl group, 7-bromo-4-oxo-1,4-dihydroquinazolinyl group, 7-ethynyl-4-oxo-1,4-dihydroquina Zolinyl group, 6-chloro-1,2,3,4-tetrahydroquinolinyl group, 6-fluoro-1,2,3,4-tetrahydroquinolinyl group, 6-bromo-1,2,3, 4-tetrahydroquinolinyl group, 6-ethynyl-1,2,3,4-tetrahydroquinolinyl group, 7-chloro-1,2,3,4-tetrahydroquinolinyl group, 7-fluoro-1, 2,3,4-tetrahydroquinolinyl group, 7-bromo-1,2,3,4-tetrahydroquinolinyl group, 7-ethynyl-1,2,3,4-tetrahydroquinolinyl group, 6- Chloro-1,2,3,4-tetrahydro-4-oxo Nonolinyl group, 6-fluoro-1,2,3,4-tetrahydro-4-oxocinnolinyl group, 6-bromo-1,2,3,4-tetrahydro-4-oxocinnolinyl group, 6-ethynyl -1,2,3,4-tetrahydro-4-oxocinnolinyl group, 7-chloro-1,2,3,4-tetrahydro-4-oxocinnolinyl group, 7-fluoro-1,2,3 , 4-tetrahydro-4-oxocinnolinyl group, 7-bromo-1,2,3,4-tetrahydro-4-oxocinnolinyl group, 7-ethynyl-1,2,3,4-tetrahydro-4 -Oxocinnolinyl group, 6-chloro-4H-4-oxobenzopyranyl group, 6-fluoro-4H-4-oxobenzopyranyl group, 6-bromo-4H-4-oxobenzopyranyl group, 6 -Ethynyl-4H-4-Oki Sobenzopyranyl group, 7-chloro-4H-4-oxobenzopyranyl group, 7-fluoro-4H-4-oxobenzopyranyl group, 7-bromo-4H-4-oxobenzopyranyl group, 7-ethynyl-4H -4-oxobenzopyranyl group, 6-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 6-fluoro-1,1-dioxy-2H-1,2,4 -Benzothiadiazinyl group, 6-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 6-ethynyl-1,1-dioxy-2H-1,2,4-benzo Thiadiazinyl group, 7-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 7-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiadi Nyl group, 7-bromo-1,1- Oxy-2H-1,2,4-benzothiadiazinyl group, 7-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 6-chloro-2H-1,2, 4-benzoxiadiazinyl group, 6-fluoro-2H-1,2,4-benzoxiadiazinyl group, 6-bromo-2H-1,2,4-benzoxiazinyl group, 6-ethynyl -2H-1,2,4-benzoxadiazinyl group, 7-chloro-2H-1,2,4-benzoxadiazinyl group, 7-fluoro-2H-1,2,4-benzoxazi Examples include an azinyl group, a 7-bromo-2H-1,2,4-benzoxiadiazinyl group, and a 7-ethynyl-2H-1,2,4-benzoxadiazinyl group. In particular, 6-chloro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-bromo-4-oxo-1 , 4-Dihydroquinolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl group, 7-chloro-4-oxo-1,4-dihydroquinolin-2-yl group 7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl group, 7-bromo-4-oxo-1,4-dihydroquinolin-2-yl group, 7-ethynyl-4-oxo-1 , 4-Dihydroquinolin-2-yl group, 6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl group 6-bromo-4-oxo-1, -Dihydroquinazolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl group, 7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl group, 7 -Fluoro-4-oxo-1,4-dihydroquinazolin-2-yl group, 7-bromo-4-oxo-1,4-dihydroquinazolin-2-yl group, 7-ethynyl-4-oxo-1,4 -Dihydroquinazolin-2-yl group, 6-chloro-1,2,3,4-tetrahydroquinolin-2-yl group, 6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl group, 6 -Bromo-1,2,3,4-tetrahydroquinolin-2-yl group, 6-ethynyl-1,2,3,4-tetrahydroquinolin-2-yl group, 6-chloro-1,2,3,4 -Tetrahydro-4-oxo Nonolin-2-yl group, 6-fluoro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl group, 6-bromo-1,2,3,4-tetrahydro-4-oxocinnoline-2- Yl group, 6-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl group, 7-chloro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl group, 7 -Fluoro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl group, 7-bromo-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl group, 7-ethynyl-1 , 2,3,4-tetrahydro-4-oxocinnolin-2-yl group, 6-chloro-4H-4-oxobenzopyran-2-yl group, 6-fluoro-4H-4-oxobenzopyran-2-yl Group, 6-bromo-4H-4-oxobenzopyran-2-yl group, 6-ethynyl-4H-4-oxobenzopyran-2-yl group, 7-chloro-4H-4-oxobenzopyran-2 -Yl group, 7-fluoro-4H-4-oxobenzopyran-2-yl group, 7-bromo-4H-4-oxobenzopyran-2-yl group, 7-ethynyl-4H-4-oxobenzopyran- 2-yl group, 6-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl group, 6-fluoro-1,1-dioxy-2H-1,2,4 -Benzothiadiazin-3-yl group, 6-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl group, 6-ethynyl-1,1-dioxy-2H -1,2,4-benzothiadiazin-3-yl group, 7-c B-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl group, 7-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazine-3 -Yl group, 7-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl group, 7-ethynyl-1,1-dioxy-2H-1,2,4- Benzothiadiazin-3-yl group, 6-chloro-2H-1,2,4-benzoxadiazin-3-yl group, 6-fluoro-2H-1,2,4-benzoxadiazine-3 -Yl group, 6-bromo-2H-1,2,4-benzoxazin-3-yl group, 6-ethynyl-2H-1,2,4-benzoxazin-3-yl group, 7- Chloro-2H-1,2,4-benzooxadiazin-3-yl group, 7-fluoro-2H-1, , 4-Benzoxadiazin-3-yl group, 7-bromo-2H-1,2,4-benzooxadiazin-3-yl group, 7-ethynyl-2H-1,2,4-benzoxiadia A din-3-yl group and the like are preferable. 6-chloro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-bromo-4-oxo-1, 4-dihydroquinolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl group, 6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-bromo-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-ethynyl-4-oxo-1, A 4-dihydroquinazolin-2-yl group is even more preferred.
The following group

[In the group, X ⁶ represents O or S, R ²⁵ and R ²⁶ represent the same as described above, and the numbers 5 to 8 represent positions. ], X ⁶ is preferably O, and R ²⁵ and R ²⁶ are each independently preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. R ²⁵ and R ²⁶ are preferably a case where one of them is a hydrogen atom and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. Particularly preferred is a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The position at which the halogen atom, alkyl group or alkynyl group is substituted is not particularly limited, but the 6th or 7th position in the above formula is preferred. Specific groups include 6-chloro-2H-chromen-3-yl group, 6-fluoro-2H-chromen-3-yl group, 6-bromo-2H-chromen-3-yl group, 6-ethynyl- 2H-chromen-3-yl group, 7-chloro-2H-chromen-3-yl group, 7-fluoro-2H-chromen-3-yl group, 7-bromo-2H-chromen-3-yl group, 7- Mention may be made of the ethynyl-2H-chromen-3-yl group. 7-chloro-2H-chromen-3-yl group, 7-fluoro-2H-chromen-3-yl group, 7-bromo-2H-chromen-3-yl group, 7-ethynyl-2H-chromen-3-yl The group is particularly preferred.
The following group

[In the group, R ²⁷ and R ²⁸ are the same as described above, and the numbers 1 to 6 represent positions. ], As R ²⁷ and R ²⁸ , one is a hydrogen atom or a halogen atom, and the other is a hydrogen atom, a cyano group, a nitro group, an amino group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group. Alternatively, it is preferably an N, N-dialkylcarbamoyl group, and particularly preferably the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Specific examples of the group represented by the above formula include a phenyl group, a chlorophenyl group, a fluorophenyl group, a bromophenyl group, an ethynylphenyl group, a chlorofluorophenyl group, and the like. The position at which the halogen atom, alkyl group or alkynyl group is substituted is not particularly limited. However, when there is one substituent, the 3-position and 4-position in the above formula are particularly preferred. In the case of two, the combination of 4-position and 2-position or 3-position in the above formula is particularly preferred. Specifically, phenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4-ethynylphenyl group, 3-chlorophenyl group, 3-fluorophenyl group, 3-bromophenyl group, 3- Ethynylphenyl group, 3-chloro-4-fluorophenyl group, 4-chloro-3-fluorophenyl group, 4-chloro-2-fluorophenyl group, 2-chloro-4-fluorophenyl group, 4-bromo-2- Fluorophenyl group, 2-bromo-4-fluorophenyl group, 2,4-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dibromophenyl group, 4-chloro-3-methylphenyl group, 4-fluoro -3-methylphenyl group, 4-bromo-3-methylphenyl group, 4-chloro-2-methylphenyl group, 4-fluoro-2- Butylphenyl group, 4-bromo-2-methylphenyl group, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, may be mentioned as preferred examples of the 3,4-dibromophenyl group.

[In the group, E ¹ , E ² , R ²⁹ and R ³⁰ are the same as described above, and the numbers 1 to 6 represent positions. ], In R ²⁹ and R ³⁰ , one is preferably a hydrogen atom or a halogen atom, and the other is preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, Of these, the case where the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group is particularly preferred. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Specific groups represented by the above formula include a pyridyl group, a pyrimidyl group, a pyridazinyl group, and the like, and the position at which a halogen atom, an alkyl group, or an alkynyl group in those groups is substituted is particularly limited. Although not intended, when the bond with the group T ¹ is the 2-position in the above formula, the 4- and 5-positions in the above formula are particularly preferred. Specifically, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-chloro-2-pyridyl group, 4-fluoro-2-pyridyl group, 4-bromo-2-pyridyl group, 4-ethynyl 2-pyridyl group, 4-chloro-3-pyridyl group, 4-fluoro-3-pyridyl group, 4-bromo-3-pyridyl group, 4-ethynyl-3-pyridyl group, 5-chloro-2-pyridyl group 5-fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5-ethynyl-2-pyridyl group, 4-chloro-5-fluoro-2-pyridyl group, 5-chloro-4-fluoro-2 -Pyridyl group, 5-chloro-3-pyridyl group, 5-fluoro-3-pyridyl group, 5-bromo-3-pyridyl group, 5-ethynyl-3-pyridyl group, 5-chloro-2-pyrimidyl group, 5 -Fluoro-2-pyrimidyl 5-bromo-2-pyrimidyl group, 5-ethynyl-2-pyrimidyl group, 4-chloro-3-pyridazinyl group, 4-fluoro-3-pyridazinyl group, 4-bromo-3-pyridazinyl group, 4-ethynyl- Preferred examples include 3-pyridazinyl group, 6-chloro-3-pyridazinyl group, 6-fluoro-3-pyridazinyl group, 6-bromo-3-pyridazinyl group, 6-ethynyl-3-pyridazinyl group and the like. In particular, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-chloro-2-pyridyl group, 4-fluoro-2-pyridyl group, 4-bromo-2-pyridyl group, 4-ethynyl-2- Pyridyl group, 4-chloro-3-pyridyl group, 4-fluoro-3-pyridyl group, 4-bromo-3-pyridyl group, 4-ethynyl-3-pyridyl group, 5-chloro-2-pyridyl group, 5- Fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5-ethynyl-2-pyridyl group, 4-chloro-5-fluoro-2-pyridyl group, 5-chloro-4-fluoro-2-pyridyl group 5-chloro-3-pyridyl group, 5-fluoro-3-pyridyl group, 5-bromo-3-pyridyl group, 5-ethynyl-3-pyridyl group, 6-chloro-3-pyridazinyl group, 6-fluoro- 3-pyridazinyl group 6-bromo-3-pyridazinyl group, 6-ethynyl-3-pyridazinyl group, 4-chloro-3-pyridazinyl group, 4-fluoro-3-pyridazinyl group, 4-bromo-3-pyridazinyl group, 4-ethynyl-3 -A pyridazinyl group is preferred. Among them, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 5-chloro-2-pyridyl group, 5-fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5-ethynyl-2- Pyridyl group, 5-chloro-4-fluoro-2-pyridyl group, 4-chloro-5-fluoro-2-pyridyl group, 4-chloro-3-pyridazinyl group, 4-fluoro-3-pyridazinyl group, 4-bromo A -3-pyridazinyl group and a 4-ethynyl-3-pyridazinyl group are more preferable.
In addition, the following group

[In the group, Y ¹ , Y ² , R ³¹ and R ³² are the same as described above, and the numbers 1 to 5 represent positions. In general, R ³¹ and R ³² are preferably a hydrogen atom or a halogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, Of these, the case where the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group is particularly preferred. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Specific groups represented by the above formula include a thienyl group, a pyrrolyl group, a furyl group, an oxazolyl group, a thiazolyl group, and the like. Is not particularly limited, but 4-position and 5-position in the above formula are particularly preferable. Specifically, 4-chloro-2-thienyl group, 4-fluoro-2-thienyl group, 4-bromo-2-thienyl group, 4-ethynyl-2-thienyl group, 4-chloro-2-pyrrolyl group, 4-fluoro-2-pyrrolyl group, 4-bromo-2-pyrrolyl group, 4-ethynyl-2-pyrrolyl group, 4-chloro-2-furyl group, 4-fluoro-2-furyl group, 4-bromo-2 -Furyl group, 4-ethynyl-2-furyl group, 5-chloro-2-thienyl group, 5-fluoro-2-thienyl group, 5-bromo-2-thienyl group, 5-ethynyl-2-thienyl group, 5 -Chloro-2-thiazolyl group, 5-fluoro-2-thiazolyl group, 5-bromo-2-thiazolyl group, 5-ethynyl-2-thiazolyl group, 5-chloro-2-oxazolyl group, 5-fluoro-2- Oxazolyl group, 5-bromine 2-oxazolyl group, and a 5-ethynyl-2-oxazolyl group. Particularly preferred are 5-chloro-2-thiazolyl group, 5-fluoro-2-thiazolyl group, 5-bromo-2-thiazolyl group, and 5-ethynyl-2-thiazolyl group.
Furthermore, the following group

[In the group, the numbers 1 to 8 indicate positions, and each N is substituted with any one of 1 to 4 carbon atoms and any one of 5 to 8 carbon atoms with one nitrogen atom. R ^{34 to} R ³⁶ are the same as described above. ], The position of each nitrogen atom may be any positional relationship, R ³⁴ is preferably a hydrogen atom or a halogen atom, one of R ³⁵ and R ³⁶ is a hydrogen atom or a halogen atom, and the other is a hydrogen atom or cyano. The group is preferably a group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and particularly preferably the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. The halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. The position at which the halogen atom, alkyl group or alkynyl group is substituted is not particularly limited, but specific groups represented by the above formula include 6-chloro-1,5-naphthyridine-2. -Yl group, 6-fluoro-1,5-naphthyridin-2-yl group, 6-bromo-1,5-naphthyridin-2-yl group, 6-ethynyl-1,5-naphthyridin-2-yl group, 7 -Chloro-1,5-naphthyridin-2-yl group, 7-fluoro-1,5-naphthyridin-2-yl group, 7-bromo-1,5-naphthyridin-2-yl group, 7-ethynyl-1, 5-naphthyridin-2-yl group, 6-chloro-1,5-naphthyridin-3-yl group, 6-fluoro-1,5-naphthyridin-3-yl group, 6-bromo-1,5-naphthyridine-3 -Yl group, 6-ethynyl 1,5-naphthyridin-3-yl group, 7-chloro-1,5-naphthyridin-3-yl group, 7-fluoro-1,5-naphthyridin-3-yl group, 7-bromo-1,5-naphthyridine -3-yl group, 7-ethynyl-1,5-naphthyridin-3-yl group, 6-chloro-1,7-naphthyridin-2-yl group, 6-fluoro-1,7-naphthyridin-2-yl group 6-bromo-1,7-naphthyridin-2-yl group, 6-ethynyl-1,7-naphthyridin-2-yl group, 6-chloro-1,7-naphthyridin-3-yl group, 6-fluoro- 1,7-naphthyridin-3-yl group, 6-bromo-1,7-naphthyridin-3-yl group, 6-ethynyl-1,7-naphthyridin-3-yl group, 6-chloro-1,8-naphthyridine 2-yl group, 6-fluoro-1,8 Naphthyridin-2-yl group, 6-bromo-1,8-naphthyridin-2-yl group, 6-ethynyl-1,8-naphthyridin-2-yl group, 7-chloro-1,8-naphthyridin-2-yl Group, 7-fluoro-1,8-naphthyridin-2-yl group, 7-bromo-1,8-naphthyridin-2-yl group, 7-ethynyl-1,8-naphthyridin-2-yl group, 6-chloro -1,8-naphthyridin-3-yl group, 6-fluoro-1,8-naphthyridin-3-yl group, 6-bromo-1,8-naphthyridin-3-yl group, 6-ethynyl-1,8- Naphthyridin-3-yl group, 7-chloro-1,8-naphthyridin-3-yl group, 7-fluoro-1,8-naphthyridin-3-yl group, 7-bromo-1,8-naphthyridin-3-yl Group 7-ethynyl-1,8-naphthyl Gin-3-yl group, 6-chloro-2,5-naphthyridin-3-yl group, 6-fluoro-2,5-naphthyridin-3-yl group, 6-bromo-2,5-naphthyridin-3-yl Group, 6-ethynyl-2,5-naphthyridin-3-yl group, 7-chloro-2,5-naphthyridin-3-yl group, 7-fluoro-2,5-naphthyridin-3-yl group, 7-bromo -2,5-naphthyridin-3-yl group, 7-ethynyl-2,5-naphthyridin-3-yl group, 7-chloro-2,6-naphthyridin-3-yl group, 7-fluoro-2,6- Naphthyridin-3-yl group, 7-bromo-2,6-naphthyridin-3-yl group, 7-ethynyl-2,6-naphthyridin-3-yl group, 6-chloro-2,8-naphthyridin-3-yl Group, 6-fluoro-2,8-naphthyridine-3 Yl group, 6-bromo-2,8-naphthyridin-3-yl group, 6-ethynyl-2,8-naphthyridin-3-yl group, 7-chloro-2,8-naphthyridin-3-yl group, 7- Examples include fluoro-2,8-naphthyridin-3-yl group, 7-bromo-2,8-naphthyridin-3-yl group, 7-ethynyl-2,8-naphthyridin-3-yl group, and the like. Particularly preferred are 7-chloro-2,5-naphthyridin-3-yl group, 7-fluoro-2,5-naphthyridin-3-yl group, 7-bromo-2,5-naphthyridin-3-yl group 7-ethynyl-2,5-naphthyridin-3-yl group and the like.

In addition to the 12 groups (a) to (l) above, a thienopyrrolyl group which may have a substituent is also preferred. 1 to 3 substituents may be included, and examples of the substituent include hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group. Groups, alkoxyalkyl groups, carboxyl groups, carboxyalkyl groups, acyl groups, carbamoyl groups, N-alkylcarbamoyl groups, N, N-dialkylcarbamoyl groups, alkoxycarbonyl groups, amidino groups and alkoxycarbonylalkyl groups, Of these, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group and a halogenoalkyl group are preferable. Specifically, 2-chlorothieno [2,3-b] pyrrol-5-yl group, 2-fluorothieno [2,3-b] pyrrol-5-yl group, 2-bromothieno [2,3-b] Preferred examples include a pyrrol-5-yl group and a 2-ethynylthieno [2,3-b] pyrrol-5-yl group.
<About group Q ¹ >
In the present invention, Q ¹ is a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group which may have a substituent, or a saturated or unsaturated 5- to 7-membered heterocyclic ring which may have a substituent. A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a formula group, a substituent, or a saturated or unsaturated bicyclic or tricyclic condensed which may have a substituent Means a heterocyclic group.

Examples of the saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group include a cyclopentyl group, a cyclopentenyl group, a cyclohexyl group, a cyclohexenyl group, a phenyl group, and the like. A cyclopentyl group, a cyclohexyl group, and a phenyl group can be exemplified. Group is preferred, and a phenyl group is more preferred.
Saturated or unsaturated 5- to 7-membered heterocyclic group means that a heterocyclic ring having at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom is a monovalent group, For example, furyl group, pyrrolyl group, thienyl group, pyrazolyl group, imidazolyl group, pyrazolinyl group, oxazolyl group, oxazolinyl group, thiazolyl group, thiazolinyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyrimidyl group, pyridazinyl group, pyrrolidinyl Groups, piperazinyl groups, piperidinyl groups, oxazinyl groups, oxadiazinyl groups, morpholinyl groups, thiazinyl groups, thiadiazinyl groups, thiomorpholinyl groups, tetrazolyl groups, triazolyl groups, triazinyl groups, azepinyl groups, diazepinyl groups and triazepinyl groups. . Of these, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, furazanyl, pyridyl, pyrimidyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, thiadiazinyl and triazolyl Is preferred. Thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrrolidinyl, piperazinyl and piperidinyl are more preferred. Of these heterocyclic groups, a nitrogen-containing heterocyclic group may be an N-oxide.

The saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group includes a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon described in the explanation of Q ^{4 in} the general formula (1). As specific examples, indenyl group, indanyl group, naphthyl group, tetrahydronaphthyl group, anthryl group, phenanthryl group and the like can be mentioned. Indenyl group, indanyl group, naphthyl group and tetrahydro group A naphthyl group is preferred.
The saturated or unsaturated bicyclic or tricyclic fused heterocyclic group includes a saturated or unsaturated bicyclic or tricyclic fused heterocycle described in the explanation of Q ^{4 in} the general formula (1). It means the same as a cyclic group, and specific examples include benzofuryl group, isobenzofuryl group, benzothienyl group, indolyl group, indolinyl group, isoindolyl group, isoindolinyl group, indazolyl group, quinolyl group, dihydroquinolyl. Group, 4-oxo-dihydroquinolyl group (dihydroquinolin-4-one), tetrahydroquinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, chromenyl group, chromanyl group, isochromanyl group, 4H-4-oxobenzopyranyl Group, 3,4-dihydro-4H-4-oxobenzopyranyl group, 4H-quinolidinyl group, quinazolinyl , Dihydroquinazolinyl group, tetrahydroquinazolinyl group, quinoxalinyl group, tetrahydroquinoxalinyl group, cinnolinyl group, tetrahydrocinnolinyl group, indolizinyl group, tetrahydroindolidinyl group, benzothiazolyl group, tetrahydrobenzothiazolyl group , Benzoxazolyl group, benzisothiazolyl group, benzoisoxazolyl group, benzimidazolyl group, naphthyridinyl group, tetrahydronaphthyridinyl group, thienopyridyl group, tetrahydrothienopyridyl group, thiazolopyridyl group, tetrahydrothiazolopyridyl group , Thiazolopyridazinyl group, tetrahydrothiazolopyridazinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, tetrahydropyrrolopyridyl group, pyrrolopyrimidinyl group, dihydropyrrolopyrimidine Nyl group, pyridoquinazolinyl group, dihydropyridoquinazolinyl group, pyridopyrimidinyl group, tetrahydropyridopyrimidinyl group, pyranothiazolyl group, dihydropyranothiazolyl group, furopyridyl group, tetrahydrofuropridyl group, oxazolopyridyl group, Tetrahydrooxazolopyridyl group, oxazolopyridazinyl group, tetrahydrooxazolopyridazinyl group, pyrrolothiazolyl group, dihydropyrrolothiazolyl group, pyrrolooxazolyl group, dihydropyrrolooxazolyl group, thienopyrrolyl group, thia Zolopyrimidinyl group, dihydrothiazolopyrimidinyl group, 4-oxo-tetrahydrocinnolinyl group, 1,2,4-benzothiadiazinyl group, 1,1-dioxy-2H-1,2,4-benzothiadiazinyl group Group 1,2,4-benzoxadia Nyl group, cyclopentapyranyl group, thienofuranyl group, furopyranyl group, pyridooxazinyl group, pyrazolooxazolyl group, imidazothiazolyl group, imidazopyridyl group, tetrahydroimidazopyridyl group, pyrazinopyridazinyl Group, benzisoquinolyl group, furocinolyl group, pyrazolothiazolopyridazinyl group, tetrahydropyrazolothiazolopyridazinyl group, hexahydrothiazolopyridazinopyridazinyl group, imidazotriazinyl group Oxazolopyridyl group, benzoxepinyl group, benzoazepinyl group, tetrahydrobenzoazepinyl group, benzodiazepinyl group, benzotriazepinyl group, thienoazepinyl group, tetrahydrothienoazepinyl group, thienodiazepinyl group, Thienotriazepinyl group, thiazoloazepinyl group, tetra Drothiazoloazepinyl group, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group, 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyrida Examples thereof include a dinyl group. Of these, benzothiazolyl group, tetrahydrobenzothiazolyl group, thienopyridyl group, tetrahydrothienopyridyl group, thienopyrrolyl group, thiazolopyridyl group, tetrahydrothiazolopyridyl group, thiazolopyridazinyl group, tetrahydrothiazolopyridazinyl group Group, pyrrolopyrimidinyl group, dihydropyrrolopyrimidinyl group, pyranothiazolyl group, dihydropyranothiazolyl group, furopyridyl group, tetrahydrofuropridyl group, oxazolopyridyl group, tetrahydrooxazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, tetrahydropyrrolo Pyridyl group, oxazolopyridazinyl group, tetrahydrooxazolopyridazinyl group, pyrrolothiazolyl group, dihydropyrrolothiazolyl group, pyrrolooxazolyl group, dihydropyrrolooxy group Zolyl group, thiazolopyrimidinyl group, dihydrothiazolopyrimidinyl group, benzoazepinyl group, tetrahydrobenzoazepinyl group, thiazoloazepinyl group, tetrahydrothiazoloazepinyl group, thienoazepinyl group, tetrahydrothienoazepinyl group, 4,5 , 6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group and 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group are preferred. Especially tetrahydrobenzothiazolyl group, tetrahydrothienopyridyl group, tetrahydrothiazolopyridyl group, tetrahydrothiazolopyridazinyl group, dihydropyrrolopyrimidinyl group, dihydropyranothiazolyl group, tetrahydrooxazolopyridyl group, dihydropyrrolothiazolyl Group, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group and 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group preferable.

There is no particular limitation on the form of condensation in the above-mentioned condensed heterocyclic group. For example, in thienopyridine, thieno [2,3-b] pyridine, thieno [2,3-c] pyridine, thieno [3,2-b] Any of pyridine, thieno [3,2-c] pyridine, thieno [3,4-b] pyridine, and thieno [3,4-c] pyridine may be used, but thieno [2,3-c] pyridine and thieno [3 , 2-c] pyridine is preferred. The thienopyrrolyl group may be a thieno [2,3-b] pyrrolyl or thieno [3,2-b] pyrrolyl group. In thiazolopyridine, thiazolo [4,5-b] pyridine, thiazolo [4,5-c] pyridine, thiazolo [5,4-b] pyridine, thiazolo [5,4-c] pyridine, thiazolo [3,4] -A] Pyridine and thiazolo [3,2-a] pyridine may be used, but thiazolo [4,5-c] pyridine and thiazolo [5,4-c] pyridine are preferred. Thiazolopyridazine may be any of thiazolo [4,5-c] pyridazine, thiazolo [4,5-d] pyridazine, thiazolo [5,4-c] pyridazine, thiazolo [3,2-b] pyridazine, Thiazolo [4,5-d] pyridazine is preferred. In pyrrolopyridine, pyrrolo [2,3-b] pyridine, pyrrolo [2,3-c] pyridine, pyrrolo [3,2-b] pyridine, pyrrolo [3,2-c] pyridine, pyrrolo [3,4- b] Either pyridine or pyrrolo [3,4-c] pyridine may be used, but pyrrolo [2,3-c] pyridine and pyrrolo [3,2-c] pyridine are preferred. The pyrrolopyrimidine may be any of pyrrolo [3,4-d] pyrimidine, pyrrolo [3,2-d] pyrimidine, and pyrrolo [2,3-d] pyrimidine, but pyrrolo [3,4-d] pyrimidine is preferred. . In pyridopyrimidine, 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 and pyrido [1,2-a] pyrimidine may be used, but pyrido [3,4-d] pyrimidine and pyrido [4,3-d] pyrimidine are preferred. The pyranothiazole may be any of pyrano [2,3-d] thiazole, pyrano [4,3-d] thiazole, pyrano [3,4-d] thiazole, pyrano [3,2-d] thiazole, Pyrano [4,3-d] thiazole and pyrano [3,4-d] thiazole are preferred. In furopyridine, furo [2,3-b] pyridine, furo [2,3-c] pyridine, furo [3,2-b] pyridine, furo [3,2-c] pyridine, furo [3,4-b ] Pyridine and furo [3,4-c] pyridine may be used, but furo [2,3-c] pyridine and furo [3,2-c] pyridine are preferred. In oxazolopyridine, oxazolo [4,5-b] pyridine, oxazolo [4,5-c] pyridine, oxazolo [5,4-b] pyridine, oxazolo [5,4-c] pyridine, oxazolo [3,4] Either -a] pyridine or oxazolo [3,2-a] pyridine may be used, and oxazolo [4,5-c] pyridine and oxazolo [5,4-c] pyridine are preferred. The oxazolopyridazine may be any of oxazolo [4,5-c] pyridazine, oxazolo [4,5-d] pyridazine, oxazolo [5,4-c] pyridazine, oxazolo [3,4-b] pyridazine, Oxazolo [4,5-d] pyridazine is preferred. In pyrrolothiazole, 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 thiazoles may be used, and pyrrolo [3,4-d] thiazole is preferred. In pyrrolooxazole, pyrrolo [2,1-b] oxazole, pyrrolo [1,2-c] oxazole, pyrrolo [2,3-d] oxazole, pyrrolo [3,2-d] oxazole, pyrrolo [3,4- d] Any of oxazoles may be used, but pyrrolo [3,4-d] oxazole is preferred. As the benzoazepine, any of 1H-1-benzoazepine, 1H-2-benzazepine, and 1H-3-benzazepine may be used, but 1H-3-benzoazepine is preferable. The thiazolo [4,5-c] azepine may be any of 4H-thiazolo [4,5-c] azepine, 4H-thiazolo [4,5-d] azepine, 4H-thiazolo [5,4-c] azepine. However, 4H-thiazolo [4,5-d] azepine is preferred. In thieno [2,3-c] azepine, any of 4H-thieno [2,3-d] azepine and 4H-thieno [3,2-c] azepine may be used, but 4H-thieno [2,3-d]. Azepine is preferred.
Of these heterocyclic groups, a nitrogen-containing heterocyclic group may be an N-oxide. The position where the above substituent is bonded to Q ² is not particularly limited.

A saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group, a saturated or unsaturated 5- to 7-membered heterocyclic group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group, Alternatively, each saturated or unsaturated bicyclic or tricyclic fused heterocyclic group may have 1 to 3 substituents, and examples of the substituent include a hydroxyl group, a fluorine atom, a chlorine atom, and bromine. Atom, halogen atom of iodine atom, halogenoalkyl group substituted with 1 to 3 halogen atoms, amino group, cyano group, amidino group, hydroxyamidino group, linear, branched or cyclic carbon number 1-6 Alkyl groups (hereinafter referred to as C ₁ -C ₆ alkyl groups, meaning linear, branched and cyclic groups; for example, linear groups such as methyl, ethyl, isopropyl and tert-butyl groups) Or branched ₁ -C ₆ alkyl group, a cyclopropyl group, cyclobutyl group, cyclopentyl group, C ₃ -C ₆ cycloalkyl group such as 1-methylcyclopropyl group), C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl group ( For example, such cyclopropylmethyl group), a hydroxy C ₁ -C ₆ alkyl group (e.g., hydroxyethyl group, 1,1-dimethyl-2-hydroxyethyl group, etc.), C ₁ -C ₆ alkoxy group (e.g., methoxy group , Ethoxy group, etc.), C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, carboxyl group, C ₂ -C ₆ carboxyalkyl group (eg carboxymethyl group etc.), C ₂ -C ₆ alkoxycarbonyl C _1- C ₆ alkyl group (for example, methoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, etc.), C ₂ -C ₆ alkoxycarbonyl Amidino group substituted with a group, C ₂ -C ₆ alkenyl group (eg, vinyl group, allyl group, etc.), C ₂ -C ₆ alkynyl group (eg, ethynyl group, propynyl group, etc.), C ₂ -C ₆ alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, etc. tert- butoxycarbonyl group), an amino C ₁ -C ₆ alkyl group (e.g., aminomethyl group, such as aminoethyl groups), C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl group (e.g., N- methylaminomethyl group, such as N- ethyl-aminomethyl group), di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl group (e.g., N, N- dimethylamino methyl group, N, N- diethylaminomethyl group, N- and ethyl -N- methylamino ethyl group), C ₂ -C ₆ alkoxycarbonylamino C ₁ -C ₆ A Kill group (e.g., methoxycarbonylamino ethyl group, tert- butoxycarbonylamino ethyl group), C ₁ -C ₆ alkanoyl group (e.g., formyl group, acetyl group, methylpropionyl group, cyclopentanecarbonyl group), C ₁ -C ₆ alkanoylamino C ₁ -C ₆ alkyl group (e.g., acetylamino methyl group), C ₁ -C ₆ alkylsulfonyl group (e.g., methanesulfonyl group), C ₁ -C ₆ alkylsulfonylamino C ₁ - C ₆ alkyl group (eg, methanesulfonylaminomethyl group), carbamoyl group, C ₁ -C ₆ alkyl carbamoyl group (eg, methyl carbamoyl group, ethyl carbamoyl group, isopropyl carbamoyl group, tert-butyl carbamoyl group), N , N- di (C ₁ -C ₆ alkyl) Rubamoiru group (e.g., dimethylcarbamoyl group, diethylcarbamoyl group, such as methyl ethylcarbamoyl group), C ₁ -C ₆ alkylamino group (e.g., N- methylamino group, etc. N- ethylamino group), di (C ₁ - C ₆ alkyl) amino group (eg, N, N-dimethylamino group, N, N-diethylamino group, N-ethyl-N-methylamino group, etc.), aminosulfonyl group, arylsulfonyl group (eg, phenylsulfonyl group, etc.) ) a halogen atom or the like which may be substituted arylcarbonyl groups (benzoyl group, 4-fluoro - benzoyl group), C ₂ -C ₆ alkoxycarbonyl (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl group ( For example, methoxycarbonyl (methyl) aminomethyl group, tert-butoxycarbonyl (methyl) amino Such as a methyl group), C ₁ -C ₆ alkylsulfonyl C ₁ -C ₆ alkyl group (e.g., a methylsulfonylmethyl group), one or homologous or two nitrogen heterogeneous 5-6 containing oxygen or sulfur atom A membered heterocyclic group (for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, pyridyl group, pyrimidinyl group, tetrahydropyranyl group, etc.), the above-mentioned 5- to 6-membered heterocyclic group -C ₁ -C ₄ alkyl group (for example, morpholinomethyl group, etc.) 5-6 membered heterocyclic group-carbonyl group (for example, pyrrolidinocarbonyl group, etc.), 5-6 membered heterocyclic group-amino-C ₁ -C ₄ alkyl group (e.g., N- (oxazol-2-yl) aminomethyl group), said 5-6 membered heterocyclic group - amino group (e.g., pyridylamino group, etc. 5-6 membered heterocyclic group-oxy group (for example, 4-pyridinyloxy group, (1-methyliminopiperidin-4-yl) oxy group, etc.), 3-6 membered heterocyclic group-carbonyl -C ₁ -C ₄ alkyl group (e.g., 4,4-dioxo-thiomorpholin-1-yl) carbonyl, methyl group) and the 5-6 membered heterocyclic group (C ₁ -C ₆ alkyl) amino -C ₁ -C ₄ alkyl group (e.g., N-(4,5-dihydro-1,3-oxazol-2-yl) -N- methylaminomethyl group, etc.), and the like.

If a specific example of Q ¹ is shown, a 5- or 6-membered cyclic hydrocarbon group such as 2-aminosulfonylphenyl group, 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] Pyridin-2-yl group, 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 5-cyclopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 5-carboxymethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 5-butyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 5- (4-pyridyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-yl group, 5-methyl-4,5,6,7-tetrahydrothiazolo [4,5 c] Pyridin-2-yl group, 6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl group, 5-methyl-4,5,6,7-tetrahydro Oxazolo [5,4-c] pyridin-2-yl group, 5-methyl-4,6-dihydro-5H-pyrrolo [3,4-d] thiazol-2-yl group, 5,7-dihydro-6 -Methylpyrrolo [3,4-d] pyrimidin-2-yl group, 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl group, 5,6 -Dimethyl-4,5,6,7-tetrahydrooxazolo [4.5-d] pyridazin-2-yl group, 5-dimethylamino-4,5,6,7-tetrahydrobenzo [d] thiazol-2- Yl group, 5- (4-pyridyl) -4,5,6,7-tetrahydro Bicyclic heterocyclic groups such as thiazolo [5,4-c] pyridin-2-yl group, 6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl group, 4-pyridyl Group, pyridyl group such as 2-pyridyl group, dihydrooxazolyl group such as 4,5-dihydrooxazol-2-yl group, 4- [N- (4,5-dihydrooxazol-2-yl) -N- Methylaminomethyl] thiophen-2-yl group, 4- [N- (4,5-dihydrooxazol-2-yl) -N-methylaminomethyl] -3-chlorothiophen-2-yl group, 5- (N -Methylaminomethyl) thiazol-2-yl group, 5- (N-methylaminomethyl) thiophen-2-yl group, 5- (N, N-dimethylaminomethyl) thiazol-2-yl group, 5- (N , N-dimethylaminomethyl) Thiophene-2-yl group, 5- (N, N- dimethylaminomethyl) can be exemplified 5- to 6-membered heterocyclic group such as pyridine-2-yl group. However, these examples do not limit Q ¹ at all.

<For radical Q ^2>
The group Q ² is a single bond, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, a linear or branched group. C2-C6 alkynylene group, divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, divalent saturated or unsaturated 5 which may have a substituent A 7-membered heterocyclic group, a divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a divalent saturated or optionally substituted group An unsaturated bicyclic or tricyclic fused heterocyclic group is meant.
In the group Q ² , examples of the linear or branched alkylene group having 1 to 6 carbon atoms include a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and the like. Can be mentioned.
Examples of the linear or branched alkenylene group having 2 to 6 carbon atoms include vinylene group, propenylene group, butenylene group, and pentenylene group. The position of the double bond is not particularly limited.
Examples of the linear or branched alkynylene group having 2 to 6 carbon atoms include an ethynylene group, a propynylene group, a butynylene group, a pentynylene group, and a hexynylene group. The position of the triple bond is not particularly limited.
The divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group is divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon described in the description of Q ^{4 in} the general formula (1). Specific examples include cyclohexylene group, cyclohexenylene group, phenylene group and the like, and cyclohexylene group and phenylene group are preferable.

The divalent saturated or unsaturated 5- to 7-membered heterocyclic group is a divalent saturated or unsaturated 5- to 7-membered heterocyclic ring described in the explanation of Q ^{4 in} the general formula (1). Specific examples include furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furazane, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, Oxazine, oxadiazine, morpholine, thiazine, thiadiazine, thiomorpholine, tetrazole, triazole, triazine, azepine, diazepine, triazepine etc. can be mentioned as divalent groups, among them pyrazole, imidazole, oxazole, thiazole, thiadiazole , Frazan, Lysine, it can be mentioned pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, triazole, triazine, azepine, those diazepine and triazepine became divalent group as a preferable example.

Examples of the divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group include a saturated or unsaturated bicyclic or tricyclic group described in the description of Q ^{4 in} the general formula (1). This means that the condensed hydrocarbon is a divalent group, and specific examples include those in which indene, indane, naphthalene, tetrahydronaphthalene, anthracene, phenanthrene and the like are divalent groups. Preferred examples include those in which indane and naphthalene are divalent groups.
Examples of the divalent saturated or unsaturated bicyclic or tricyclic fused heterocyclic group include saturated or unsaturated bicyclic or tricyclic described in the description of Q ^{4 in} the general formula (1). The condensed heterocyclic ring of the above is a divalent group. Specific examples include benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, quinazoline, dihydroquinazoline. , Tetrahydroquinazoline, quinoxaline, tetrahydroquinoxaline, cinnoline, tetrahydrocinnoline, indolizine, tetrahydroindolizine, benzothiazole, tetrahydrobenzothiazole, naphthyridine, tetrahydronaphthyridine, thienopyridine, tetrahydrothienopyridine, thi Zolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine, tetrahydrothiazolopyridazine, pyrrolopyridine, dihydropyrrolopyridine, tetrahydropyrrolopyridine, pyrrolopyrimidine, dihydropyrrolopyrimidine, dihydropyridoquinazoline, pyranothiazole, dihydropyranothiazole, furopyridine, Examples of tetrahydrofuropyridine, oxazolopyridine, tetrahydrooxazolopyridine, oxazolopyridazine, tetrahydrooxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole, pyrroloxazole, dihydropyrrolooxazole, benzoazepine etc. Benzofuran, benzothiophene, indole, indazole, quinoline, isoquinoline, tetrahi Droisoquinoline, benzothiazole, naphthyridine, thienopyridine, thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine, pyrrolopyridine, tetrahydropyrrolopyridine, pyridopyrimidine, pyranothiazole, dihydropyranothiazole, furopyridine, oxazolopyridine, oxa Preferred examples include those in which zolopyridazine, pyrrolothiazole, dihydropyrrolothiazole, pyrrolooxazole and dihydropyrroloxazole are divalent groups. There is no particular limitation on the type of condensation in the above-mentioned condensed heterocyclic group. For example, for naphthyridine, 1,5-, 1,6-, 1,7-, 1,8-, 2,6-, 2,7 -It may be any of naphthyridine, and in thienopyridine, thieno [2,3-b] pyridine, thieno [2,3-c] pyridine, thieno [3,2-b] pyridine, thieno [3,2-c] pyridine, Any of thieno [3,4-b] pyridine and thieno [3,4-c] pyridine may be used. In thiazolopyridine, thiazolo [4,5-b] pyridine, thiazolo [4,5-c] pyridine, and thiazolo. Any of [5,4-b] pyridine, thiazolo [5,4-c] pyridine, thiazolo [3,4-a] pyridine, and thiazolo [3,2-a] pyridine may be used. In thiazolopyridazine, thiazolo [ 4,5-c] pyri Zin, thiazolo [4,5-d] pyridazine, thiazolo [5,4-c] pyridazine, and thiazolo [3,2-b] pyridazine may be used. In pyrrolopyridine, pyrrolo [2,3-b] pyridine, Of pyrrolo [2,3-c] pyridine, pyrrolo [3,2-b] pyridine, pyrrolo [3,2-c] pyridine, pyrrolo [3,4-b] pyridine, pyrrolo [3,4-c] pyridine Any of pyrrolopyrimidines may be used, and any of pyrrolo [3,4-d] pyrimidine, pyrrolo [3,2-d] pyrimidine, and pyrrolo [2,3-d] pyrimidine may be used, and pyrido [2 , 3-d] pyrimidine, pyrido [3,2-d] pyrimidine, and pyrido [3,4-d] pyrimidine. In pyranothiazole, pyrano [2,3-d] thiazole, [4,3-d] thiazole, pyrano [3,4-d] thiazole, and pyrano [3,2-d] thiazole may be used. In furopyridine, furo [2,3-b] pyridine, furo [2 , 3-c] pyridine, furo [3,2-b] pyridine, furo [3,2-c] pyridine, furo [3,4-b] pyridine, furo [3,4-c] pyridine In oxazolopyridine, oxazolo [4,5-b] pyridine, oxazolo [4,5-c] pyridine, oxazolo [5,4-b] pyridine, oxazolo [5,4-c] pyridine, oxazolo [3, 4-a] pyridine and oxazolo [3,2-a] pyridine may be used. In oxazolopyridazine, oxazolo [4,5-c] pyridazine, oxazolo [4,5-d] pyridazine, oxazolo [5 , 4-c] pyridazine and oxazolo [3,4-b] pyridazine, and in pyrrolothiazole, pyrrolo [2,1-b] thiazole, pyrrolo [1,2-c] thiazole, pyrrolo [3,2 -D] thiazole and pyrrolo [3,4-d] thiazole may be used. In pyrroloxazole, pyrrolo [2,1-b] oxazole, pyrrolo [1,2-c] oxazole, pyrrolo [2,3-d Any of oxazole, pyrrolo [3,2-d] oxazole and pyrrolo [3,4-d] oxazole may be used, and those other than these condensed forms may be used.

  The above divalent saturated or unsaturated 5 to 6 membered cyclic hydrocarbon group, divalent saturated or unsaturated 5 to 7 membered heterocyclic group, divalent saturated or unsaturated bicyclic group, or Each of the tricyclic condensed hydrocarbon group and the divalent saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group may have 1 to 3 substituents. As, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a halogen atom of iodine atom, a halogenoalkyl group substituted with 1 to 3 halogen atoms, an amino group, a cyano group, an aminoalkyl group, an amidino group, a hydroxyamidino group A linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (for example, methyl group, ethyl group, etc.), a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms (for example, , Methoxy group, ethoxy Amidino group substituted with a linear, branched or cyclic C2-C7 alkoxycarbonyl group (for example, methoxycarbonylamidino group, ethoxycarbonylamidino group, etc.), linear, branched or A cyclic alkenyl group having 2 to 6 carbon atoms (for example, a vinyl group, an allyl group, etc.), a linear or branched alkynyl group having 2 to 6 carbon atoms (for example, an ethynyl group, a propynyl group, etc.), a straight chain And an alkoxycarbonyl group having 2 to 6 carbon atoms (for example, a methoxycarbonyl group, an ethoxycarbonyl group, etc.) and a carbamoyl group.

Of the above Q ² , a single bond, a divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group that may have a substituent, or a divalent saturated or unsaturated that may have a substituent A 5- to 7-membered heterocyclic group and a divalent saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have a substituent are preferred, and among them, a single bond, a divalent saturated or An unsaturated 5- to 6-membered cyclic hydrocarbon group, a divalent saturated or unsaturated 5- to 7-membered heterocyclic group is more preferable.
Further, the group Q ¹ may be a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a saturated or unsaturated bicyclic or 3 which may have a substituent. In the case of a cyclic fused heterocyclic group, the group Q ² is preferably a single bond. Here, in the above combination, the case where Q ² is a single bond refers to the 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 , R ² , Q ¹ , Q ² , Q ³ , Q ⁴ , T ⁰ and T ¹ are the same as described above. ]
Is represented by the following general formula (1 ′)
^{Q 1 -T 0 -N (R 1} ) -Q 3 -N (R 2) -T 1 -Q 4 (1 ')
[Wherein, Q ¹ represents the above-mentioned bicyclic or tricyclic condensed hydrocarbon group, or bicyclic or tricyclic condensed heterocyclic group, and R ¹ , R ² , Q ³ , Q ⁴ , T ⁰ and T ¹ are the same as described above. ].

More preferably, the group Q ¹ may have a thienopyridyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent, a thiazopyridyl group which may have a substituent, or a substituent. A tetrahydrothiazolopyridyl group, an optionally substituted thiazolopyridazinyl group, an optionally substituted tetrahydrothiazolopyridazinyl group, an optionally substituted pyranothiazolyl group, a substituent Dihydropyranothiazolyl group which may have, flopyridyl group which may have a substituent, tetrahydrofuropyridyl group which may have a substituent, oxazolopyridyl group which may have a substituent, having a substituent A tetrahydrooxazolopyridyl group, a pyrrolopyridyl group that may have a substituent, A dihydropyrrolopyridyl group which may have a substituent, a tetrahydropyrrolopyridyl group which may have a substituent, a pyrrolopyrimidinyl group which may have a substituent, a dihydropyrrolopyrimidinyl group which may have a substituent, a substituent Oxazolopyridazinyl group which may have, tetrahydrooxazolopyridazinyl group which may have substituent, pyrrolothiazolyl group which may have substituent, dihydropyrrolothiazolyl which may have substituent Group, pyrrolooxazolyl group which may have a substituent, dihydropyrrolooxazolyl group which may have a substituent, benzothiazolyl group which may have a substituent, tetrahydrobenzothiazolyl which may have a substituent Group, a thiazolopyrimidinyl group which may have a substituent, A dihydrothiazolopyrimidinyl group which may have a substituent, a benzoazepinyl group which may have a substituent, a tetrahydrobenzoazepinyl group which may have a substituent, a thiazoloazepinyl group which may have a substituent, a substituent Tetrahydrothiazoloazepinyl group which may have, Thienoazepinyl group which may have a substituent, Tetrahydrothienoazepinyl group which may have a substituent, 4,5,6,7- A tetrahydro-5,6-tetramethylenethiazolopyridazinyl group, or a 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group, which may have a substituent, Q ² is preferably a single bond.

In addition, the group Q ¹ may have a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent. If it is, the group Q ² is a divalent sometimes have also divalent saturated or 5- to 6-membered cyclic hydrocarbon group or a substituent unsaturated may have a substituent, saturated or unsaturated And a group Q ¹ -Q ^2- is preferably 4- (4-pyridyl) phenyl group, 4- (2-pyridyl) phenyl group, 5- (4 -Pyridyl) thiazolyl group, 1- (4-pyridyl) piperidyl group, 4- (4-pyridyl) piperidyl group, 4-hydroxy-1- (4-pyridyl) piperidin-4-yl group, biphenylyl group, 4- ( 2-aminosulfonylphenyl) phenyl group, 4- (2-amidinophenyl) phenyl group, 4- (2-methylsulfonylphenyl) phenyl group, 4- (2-aminomethylphenyl) phenyl group, 4- (2-carbamoylphenyl) phenyl group, 4- (2 -Imidazolyl) phenyl group, 4- (1-methyl-2-imidazolyl) phenyl group, 4- (2,3,4,5-tetrahydropyrimidin-2-yl) phenyl group, 4- (1-methyl-2, 3,4,5-tetrahydropyrimidin-2-yl) phenyl group, 4- (5-tetrazolyl) phenyl group, 1- (4-pyridyl) piperidin-4-yl group, 3- (4-piperidyl) isoxazoline- 5-yl group, 3- (4-amidinophenyl) isoxazolin-5-yl group, 3- (4-piperidyl) isoxazolidin-5-yl group, 3- (4-a Dinophenyl) isoxazolidin-5-yl group, 2- (4-piperidyl) -1,3,4-thiadiazol-5-yl group, 2- (4-aminophenyl) -1,3,4-oxadiazole- 5-yl group, 4- (4-piperidyl) piperidin-1-yl group, 4- (4-piperidyl) piperazin-1-yl group, 4- (4-piperazinyl) piperazin-1-yl group, 1- ( 4-pyrimidinyl) piperidin-1-yl group, 1- (2-methylpyrimidin-4-yl) piperidin-4-yl group, 1- (4-pyrimidinyl) pyrrolidin-3-yl group, 1- (4-methyl Pyrimidin-6-yl) piperazin-4-yl group, 1- (2-methylpyrimidin-4-yl) pyrrolidin-4-yl group, 1- (6-chloropyrimidin-4-yl) piperidin-4-yl group , -(4-chlorophenyl) thiophen-2-yl group, 2- (4-chlorophenyl) thiazol-4-yl group, 3- (4-chlorophenyl) -1H-pyrrol-2-yl group, 4- (4-pyrimidinyl) ) Phenyl group, 4- (4-imidazolyl) phenyl group, 5- (pyridin-4-yl) pyrimidin-2-yl group, 2 ′-[(dimethylamino) methyl] [1,1′-biphenyl] -4 -Yl group, 4- [2- (hydroxymethyl) pyridin-4-yl] phenyl group, 4- [2- (aminomethyl) pyridin-4-yl] phenyl group, 2 '-(aminosulfonyl) [1, Preferred examples include 1'-biphenyl] -4-yl group and 4- (3-oxomorpholin-4-yl) phenyl group.
<For radical Q ^3>
Group Q ³ is the following group

[In the group, Q ⁵ represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group — (CH ₂ ) _m —CH ₂ —A—CH ₂ — (CH ₂ ) _n — (in the group , M and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, — NH—NH—, —S—NH—, —SO—NH— or —SO ₂ —NH—, wherein 1 and 2 indicate positions);

R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom or a halogenoalkyl group. Group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, Alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group , Alkoxy carbon An amino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, having a substituent 3 to 6 members A ring carbonyl group, a carbamoylalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, a carbamoyloxy An alkyl group, an N-alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an optionally substituted 3- to 6-membered heterocyclic carbonylalkyl group, and an optionally substituted 3- 6-membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, 3-6 membered heterocyclic group optionally having substituent, 3-6 membered heterocyclic alkyl group optionally having substituent , Alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl Group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, alkoxycarbonylalkyloxy group, Acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group Acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfuric group An aryl group, an alkoxyalkylsulfonyl group, an optionally substituted 3-6 membered heterocyclic sulfonyl group, an optionally substituted 3-6 membered heterocyclic oxy group, an N-alkylaminoacyl group, N, N-dialkylaminoacyl group, N, N-dialkylcarbamoyl acyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group Alkylsulfonylacyl group, N-arylcarbamoyl group, N-3 to 6-membered heterocyclic carbamoyl group, N-alkyl-N-arylcarbamoyl group, N-alkyl-N-3 to 6-membered heterocyclic carbamoyl group, N-arylcarbamoylalkyl group, N-3 to 6-membered heterocyclic carbamoylalkyl group, N-alkyl-N-arylcarbamoylal Group, N-alkyl-N-3 to 6-membered heterocyclic carbamoylalkyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group, alkoxyalkyl (thio Carbonyl) group, alkylthioalkyl group or N-acyl-N-alkylaminoalkyl group, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms Group, a C1-C5 alkylenedioxy group or a carbonyldioxy group. ] Is shown.
The following groups will be described in detail.

[In the group, Q ⁵ , R ³ and R ⁴ are the same as defined above, and 1 and 2 represent positions. ]
The portion of the cyclic structure containing the group Q ⁵ is a 3 to 10-membered divalent cyclic hydrocarbon group which may have one double bond or 5 to 12 having 1 to 2 heteroatoms. A membered divalent heterocyclic group, preferably a 3- to 8-membered divalent cyclic hydrocarbon group or a 5- to 8-membered divalent heterocyclic group, and a 5- to 7-membered divalent cyclic group. A hydrocarbon group or a 5- to 7-membered divalent heterocyclic group is more preferable. Among them, Q ⁵ is an alkylene group having 3 to 6 carbon atoms or a group — (CH ₂ ) _m —CH ₂ —A—CH ₂ — (CH ₂ ) _n — (in the group, m and n are each independently 0 or 1 is preferable, and A is the same as above. In particular, Q ⁵ is preferably an alkylene group having 4 carbon atoms.
In addition, this cyclic hydrocarbon group or heterocyclic group can have a cis and trans structure in the relationship between the 1-position and the 2-position, but in the case of 5 members, trans is preferable, and in the case of 6 to 7 members, Both cis and trans are preferred.

The above substituents R ³ and R ⁴ will be described in detail. A halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Examples of the alkyl group include linear, branched or cyclic C ₁ -C ₆ alkyl groups (for example, methyl group, cyclopropyl group, isobutyl group, etc.), and halogenoalkyl groups include the above alkyl groups. In which 1 to 3 halogen atoms are substituted (for example, chloromethyl group, 1-bromoethyl group, trifluoromethyl group, etc.). Examples of the cyanoalkyl group include those in which one cyano group is substituted on the above C ₁ -C ₆ alkyl group (for example, cyanomethyl group, 1-cyanoethyl group, etc.). Examples of the alkenyl group include linear or branched C 2-6 having one double bond (for example, vinyl group, allyl group, etc.). Examples of the alkynyl group include linear or branched C 2-6 having one triple bond (for example, ethynyl group, propynyl group, etc.). As the acyl group, a C ₁ -C ₆ alkanoyl group (for example, formyl group, acetyl group, etc.), a C ₇ -C ₁₅ aroyl group such as benzoyl group, naphthoyl group, or the above C ₁ -C ₆ alkanoyl group An arylalkanoyl group substituted with one C ₆ -C ₁₄ aryl group (for example, a phenacetyl group) can be mentioned. Examples of the acylalkyl group include those in which one of the above acyl groups is substituted on the above C ₁ -C ₆ alkyl group (for example, an acetylmethyl group). Examples of the alkoxy group include linear, branched or cyclic C ₁ -C ₆ alkoxy groups (for example, methoxy group, cyclopropoxy group, isopropoxy group, etc.). As the alkoxyalkyl group, the above C ₁ -C ₆ which one C ₁ -C ₆ alkoxy groups of the alkyl group is substituted (e.g., methoxymethyl group, ethoxymethyl group). Examples of the hydroxyalkyl group include those in which one hydroxyl group is substituted on the above C ₁ -C ₆ alkyl group (for example, hydroxymethyl group, 1-hydroxyethyl group, etc.). Examples of the carboxyalkyl group include those in which one carboxyl group is substituted on the above C ₁ -C ₆ alkyl group (for example, carboxymethyl group, 1-carboxyethyl group, etc.). Examples of the alkoxycarbonyl group include groups composed of the above C ₁ -C ₆ alkoxy group and a carbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, etc.). Examples of the alkoxycarbonylalkyl group include those in which one of the above alkoxycarbonyl groups is substituted on the above C ₁ -C ₆ alkyl group (for example, methoxycarbonylethyl group, ethoxycarbonylethyl group, etc.). Examples of the carbamoylalkyl group include groups in which the above C ₁ -C ₆ alkyl group is substituted with a carbamoyl group (for example, a carbamoylmethyl group or a carbamoylethyl group).

The 3- to 6-membered heterocyclic group which may have a substituent is a saturated or unsaturated 3- to 6-membered which may contain 1 to 3 heteroatoms (nitrogen atom, oxygen atom, sulfur atom, etc.) Means a heterocyclic group, which may have a substituent such as a hydroxy group, a halogen atom, an amino group, a C ₁ -C ₆ alkyl group, an oxo group, a halogenoalkyl group, etc. As the heterocyclic group, pyrrolyl group, thienyl group, pyrazolyl group, imidazolyl group, pyrazolinyl group, oxazolyl group, oxazolinyl group, oxadiazolyl group, oxazolidinyl group, thiazolyl group, thiazolinyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group , Pyrimidyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl , It can be exemplified thiazinyl group, thiadiazinyl group, Chiorumohoriniru group, tetrazolyl group, a triazolyl group and a triazinyl group. Specifically, thiazolyl group, 4,5-dihydrothiazolyl group, oxazolyl group, 4,5-dihydrooxazolyl group, 5-methyloxazolyl group, imidazolyl group, pyrrolidinyl group, 3-hydroxypyrrolidinyl group Group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxothiomorpholinyl group, tetrahydropyranyl group, pyridyl group, 1,2,4-oxadiazolyl group, 3-methyl-1, 2,4-oxadiazolyl group, 5-methyl-1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 5-methyl-1,3,4-oxadiazolyl group, 5- (trifluoromethyl)- 1,3,4-oxadiazolyl group, 1,3-oxazolyl group, 1,3,4-thiadiazolyl group, 5-methyl-1,3,4-thi Diazolyl group, and a 1,3-oxazolidinyl group, and the like. As the 3- to 6-membered heterocyclic alkyl group which may have a substituent, one in which one of the 3- to 6-membered heterocyclic groups which may have the above-described substituent is substituted with an alkyl group (for example, A thiazolylmethyl group, a 4,5-dihydrothiazolylmethyl group, a morpholinylmethyl group, a 1,1-dioxothiomorpholinylmethyl group, etc. Examples of the aryl group include a phenyl group and a naphthyl group. The aryl group includes the above C ₁ -C ₆ alkyl group, the above C ₁ -C ₆ alkanoyl group, a hydroxyl group, a nitro group, a cyano group, a halogen atom, C ₂ -C ₆ alkenyl group, the above C ₂ -C ₆ alkynyl group, the above C ₁ -C ₆ halogenoalkyl group, the above C ₁ -C ₆ alkoxy group, the carboxy group, the carbamoyl group, the above C _1- C ₆ alkoxycarbonyl 1 to 3 groups which may be substituted selected from and the like. Examples of the aralkyl group, those with one said C ₆ -C ₁₄ aryl group in C ₁ -C ₆ alkyl group described above is substituted (e.g. In the above description, the substitution position is not particularly limited, and the acylamino group which may have a substituent is, for example, the above C ₁ -C ₆ acyl group is an amino group. those substituted with group (e.g., formylamino group, acetylamino and amino group) in addition to the halogen atom on an acyl group, a hydroxyl group, C ₁ -C ₆ alkoxy group, an amino group, N-C ₁ -C ₆ alkylamino Group, N, N-di-C ₁ -C ₆ alkylamino group, carboxyl group, C ₂ -C ₆ alkoxycarbonyl group and one or more substituted acyl groups (for example, 2-methoxyacetylamino group, 3- Ami As the acylaminoalkyl group, the above C ₁ -C ₆ acylamino group is substituted by the above C ₁ -C ₆ alkyl group (for example, formylaminomethyl group, acetylamino group, etc.). Examples of the aminoalkyl group include those obtained by substituting one amino group with the above C ₁ -C ₆ alkyl group (for example, aminomethyl group, 1-aminoethyl group, etc.). The N-alkylaminoalkyl group is a group in which one C ₁ -C ₆ alkyl group is substituted on the nitrogen atom of an amino-C ₁ -C ₆ alkyl group (for example, N-methylaminomethyl group, N-methylamino Ethyl group). As the N, N-dialkylaminoalkyl group, a group in which two C ₁ -C ₆ alkyl groups are substituted on the nitrogen atom of an amino-C ₁ -C ₆ alkyl group (for example, N, N-dimethylaminomethyl group, N-ethyl-N-methylaminoethyl group, etc.). Examples of the N-alkenylcarbamoyl group include those in which a linear or branched C ₂ -C ₆ alkenyl group is substituted with a carbamoyl group (for example, an allylcarbamoyl group). Examples of the N-alkenylcarbamoylalkyl group include those in which the above-mentioned N—C ₂ -C ₆ alkenylcarbamoyl group is substituted with a C ₁ -C ₆ alkyl group (for example, an allylcarbamoylethyl group). Examples of the N-alkenyl-N-alkylcarbamoyl group include those in which a linear or branched C ₁ -C ₆ alkyl group is substituted on the nitrogen atom of the N—C ₂ -C ₆ alkenylcarbamoyl group (for example, And N-allyl-N-methylcarbamoyl group). The N- alkenyl -N- alkylcarbamoyl group, those above N-C ₂ -C ₆ alkenyl carbamoylmethyl alkyl C ₁ -C ₆ alkyl group on the nitrogen atom of the linear or branched group is substituted (For example, N-allyl-N-methylcarbamoylmethyl group and the like). Examples of the N-alkoxycarbamoyl group include those in which a linear or branched C ₁ -C ₆ alkoxy group is substituted with a carbamoyl group (for example, a methoxycarbamoyl group). As the N-alkoxycarbamoylalkyl group, the above-mentioned N—C ₁ -C ₆ alkoxycarbamoyl group is substituted with a linear or branched C ₁ -C ₆ alkyl group (for example, methoxycarbamoylmethyl group, etc.) Is mentioned. The N-alkyl-N-alkoxycarbamoyl group includes a linear or branched C ₁ -C ₆ alkoxy group and a C ₁ -C ₆ alkyl group substituted with a carbamoyl group (for example, N-ethyl-N -Methoxycarbamoyl group, etc.). The N- alkyl -N- alkoxycarbamoyl group, the above-described N-C ₁ -C ₆ alkyl -N-C ₁ -C ₆ alkoxy carbamoyl group a linear or branched C ₁ -C ₆ alkyl group (For example, N-ethyl-N-methoxycarbamoylmethyl group and the like). The carbazoyl group optionally substituted with 1 to 3 alkyl groups includes a carbazoyl group substituted with _{1 to} 3 linear or branched C ₁ -C ₆ alkyl groups in addition to the carbazoyl group. (For example, 1-methylcarbazoyl group, 1,2-dimethylcarbazoyl group, etc.). Examples of the alkylsulfonyl group include linear, branched, or cyclic C ₁ -C ₆ alkylsulfonyl groups (eg, methanesulfonyl group). The alkylsulfonyl group, which C ₁ -C ₆ alkylsulfonyl group described above is substituted with C ₁ -C ₆ alkyl group linear or branched (for example, methanesulfonyl methyl group). Examples of the alkoxyimino group include C ₁ -C ₆ alkoxyimino groups (eg, methoxyimino group, ethoxyimino group, etc.). Examples of the alkoxycarbonylalkylamino group include those obtained by substituting one amino group with the above C ₁ -C ₆ alkoxycarbonylalkyl group (for example, methoxycarbonylmethylamino group, ethoxycarbonylpropylamino group, etc.). Examples of the carboxyalkylamino group include those obtained by substituting one amino group with the above carboxy C ₁ -C ₆ alkyl group (for example, carboxymethylamino group, carboxyethylamino group, etc.). Examples of the alkoxycarbonylamino group include those obtained by substituting one amino group with the above C ₁ -C ₆ alkoxycarbonyl group (for example, methoxycarbonylamino group, tert-butoxycarbonylamino group, etc.). Examples of the alkoxycarbonylaminoalkyl group include those in which the above alkyl group is substituted with one of the above C ₁ -C ₆ alkoxycarbonylamino groups (eg, methoxycarbonylaminomethyl group, tert-butoxycarbonylaminoethyl group, etc.). It is done. May have a substituent N- alkylcarbamoyl group on the alkyl group, hydroxy group, amino group, N-C ₁ -C ₆ alkylamino group, amidino group, a halogen atom, a carboxyl group, a cyano group, a carbamoyl group Linear, branched, which may be substituted with a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkanoyl group, a C ₁ -C ₆ alkanoylamino group, a C ₁ -C ₆ alkylsulfonylamino group, etc. Or a carbamoyl group substituted with a cyclic C ₁ -C ₆ alkyl group, for example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-isopropylcarbamoyl group, N-cyclopropylcarbamoyl group, N- (2 -Hydroxyethyl) carbamoyl group, N- (2-fluoroethyl) carbamoyl group, N- (2-cyanoethyl) carbamoyl group, N- ( - methoxyethyl) carbamoyl group, N- carboxymethyl-methylcarbamoyl group, N- (2- aminoethyl) carbamoyl group, N- (2-Amijinoechiru) such as carbamoyl group, and the like. The N, N-dialkylcarbamoyl group optionally having a substituent on the alkyl group is a hydroxy group, an amino group, an N-C ₁ -C ₆ alkylamino group, an amidino group, a halogen atom, a carboxyl group, or a cyano group. , A carbamoyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkanoyl group, a C ₁ -C ₆ alkanoylamino group, a linear chain optionally substituted by a C ₁ -C ₆ alkylsulfonylamino group, A carbamoyl group substituted with two branched or cyclic C ₁ -C ₆ alkyl groups, for example, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl Group, N-isopropyl-N-methylcarbamoyl group, N- (2-hydroxyethyl) -N-methylcarbamoyl group, N, N-bis (2-hydroxyethyl) Rubamoyl group, N, N-bis (2-fluoroethyl) carbamoyl group, N- (2-cyanoethyl) -N-methylcarbamoyl group, N- (2-methoxyethyl) -N-methylcarbamoyl group, N-carboxymethyl -N-methylcarbamoyl group, N, N-bis (2-aminoethyl) carbamoyl group and the like can be mentioned. As also may N- alkylcarbamoyl group which may have a substituent on the alkyl groups, C ₁ -C on ₆ alkyl group which may have a substituent N- alkylcarbamoyl group mentioned above is a straight-chain or Examples thereof include those substituted with a branched C ₁ -C ₆ alkyl group (for example, N-methylcarbamoylmethyl group, N- (2-hydroxyethyl) carbamoylmethyl group, etc.). N, N-dialkyl optionally having a substituent on the alkyl group




As the rucarbamoylalkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the above C ₁ -C ₆ alkyl group is substituted with a linear or branched C ₁ -C ₆ alkyl group (For example, N, N-dimethylcarbamoylmethyl group, N- (2-hydroxyethyl) -N-methylcarbamoylmethyl group, etc.). The 3- to 6-membered heterocyclic carbonyl group which may have a substituent is a group composed of the above-described 3- to 6-membered heterocyclic group which may have a substituent and a carbonyl group (for example, aziridinyl Rucarbonyl group, azetidinylcarbonyl group, 3-hydroxyazetidinylcarbonyl group, 3-methoxyazetidinylcarbonyl group, pyrrolidinylcarbonyl group, 3-hydroxypyrrolidinylcarbonyl group, 3-fluoropyrrolidinylcarbonyl Group, piperidylcarbonyl group, piperazinylcarbonyl group, morpholinylcarbonyl group, thiomorpholinylcarbonyl group, 1,1-dioxothiomorpholinylcarbonyl group, tetrahydropyranylcarbonyl group, pyridylcarbonyl group, furoyl group Thiophenecarbonyl group, etc.). As the 3- to 6-membered heterocyclic carbonylalkyl group which may have a substituent, one 3- to 6-membered heterocyclic carbonyl group which may have the above substituent is the above-mentioned C ₁ -C _6. Examples thereof include those substituted with an alkyl group (for example, azetidinylcarbonylmethyl group, pyrrolidinylcarbonylethyl group, etc.). The 3- to 6-membered heterocyclic carbonyloxyalkyl group which may have a substituent is a 3- to 6-membered heterocyclic carbonyl group which may have a substituent as described above and an oxygen atom. Examples include one in which one 6-membered heterocyclic carbonyloxy group is substituted with the above C ₁ -C ₆ alkyl group (for example, piperidinylcarbonyloxyethyl group, morpholinylcarbonyloxymethyl group, etc.). As the carbamoyloxyalkyl group, one in which one carbamoyloxy group composed of a carbamoyl group and an oxygen atom is substituted with the above C ₁ -C ₆ alkyl group (for example, carbamoyloxymethyl group, carbamoyloxyethyl group, etc.) is used. Can be mentioned. As the N-alkylcarbamoyloxyalkyl group, _one N-alkylcarbamoyloxy group composed of an oxygen atom and an N-alkylcarbamoyl group which may have a substituent on the above C ₁ -C ₆ alkyl group is Examples thereof include those substituted with the above C ₁ -C ₆ alkyl group (for example, N-methylcarbamoyloxymethyl group, N-methylcarbamoyloxyethyl group, etc.). As the N, N-dialkylcarbamoyloxyalkyl group, an N, N-dialkyl composed of an N, N-dialkylcarbamoyl group which may have a substituent on the C ₁ -C ₆ alkyl group and an oxygen atom. Examples include one in which one carbamoyloxy group is substituted with the above C ₁ -C ₆ alkyl group (for example, N, N-dimethylcarbamoyloxymethyl group, N-ethyl-N-methylcarbamoyloxyethyl group, etc.). Examples of the alkylsulfonylamino group include those in which one alkylsulfonyl group having the above C ₁ -C ₆ alkyl group is substituted with an amino group (for example, methylsulfonylamino group, isopropylsulfonylamino group, etc.). Examples of the arylsulfonylamino group include those in which one arylsulfonyl group having the above aryl group is substituted with an amino group (for example, phenylsulfonylamino group, naphthylsulfonylamino group, etc.). The alkylsulfonylamino group, the above C ₁ -C ₆ which one C ₁ -C ₆ alkylsulfonylamino group described above in the alkyl group is substituted (e.g., methylsulfonyl aminomethyl group, such as methylsulfonyl aminoethyl group ). Examples of the arylsulfonylaminoalkyl group include those in which one of the above arylsulfonylamino groups is substituted on the above C ₁ -C ₆ alkyl group (for example, phenylsulfonylaminomethyl group, naphthylsulfonylaminoethyl group, etc.). Examples of the alkylsulfonylaminocarbonyl group include groups composed of the above C ₁ -C ₆ alkylsulfonylamino group and a carbonyl group (for example, methylsulfonylaminocarbonyl group, isopropylsulfonylaminocarbonyl group, etc.). Examples of the arylsulfonylaminocarbonyl group include groups composed of the above arylsulfonylamino group and a carbonyl group (for example, phenylsulfonylaminocarbonyl group, naphthylsulfonylaminocarbonyl group, etc.). Alkylsulfonyl aminocarbonyl alkyl group, which C ₁ -C ₆ alkylsulfonylamino group described above is substituted by C ₁ -C ₆ alkyl group as described above (e.g., methylsulfonyl aminocarbonyl methyl group, isopropylsulfonyl amino carbonyl methyl Group). Examples of the arylsulfonylaminocarbonylalkyl group include those in which the above arylsulfonylaminocarbonyl group is substituted with the above C ₁ -C ₆ alkyl group (for example, phenylsulfonylaminocarbonylmethyl group, naphthylsulfonylaminocarbonylmethyl group, etc.). It is done. Examples of the alkoxycarbonylalkyloxy group include those in which the above alkoxycarbonyl group is substituted with the above C ₁ -C ₆ alkoxy group (for example, a methoxycarbonylmethyloxy group). The acyloxy group means a group composed of the above acyl group and an oxygen atom (for example, formyloxy group, acetyloxy group, etc.). The acyloxyalkyl group, those in C ₁ -C ₆ alkyl group as described above above acyloxy group is substituted (e.g., formyl oxymethyl group, such as acetyloxy methyl group). Examples of the aralkyloxy group include groups in which the above aryl group is substituted with the above C ₁ -C ₆ alkoxy group (eg, benzyloxy group, naphthylmethoxy group, etc.). Examples of the carboxyalkyloxy group include those in which the above alkoxy group is substituted with a carboxyl group (for example, carboxymethoxy group, carboxyethoxy group, etc.).

Examples of the arylsulfonyl group include C ₆ -C ₁₄ arylsulfonyl groups (eg, phenylsulfonyl group, naphthylsulfonyl group, etc.). Examples of the alkoxycarbonylalkylsulfonyl group include groups composed of the above C ₁ -C ₆ alkoxycarbonylalkyl group and a sulfonyl group (for example, methoxycarbonylethylsulfonyl group, ethoxycarbonylethylsulfonyl group, etc.). Examples of the carboxyalkylsulfonyl group include groups composed of the above carboxyalkyl group and sulfonyl group (for example, carboxymethylsulfonyl group, carboxyethylsulfonyl group, etc.). Examples of the alkoxycarbonylacyl group include groups composed of the above alkoxycarbonylalkyl group and carbonyl group (for example, methoxycarbonylmethylcarbonyl group, ethoxycarbonylmethylcarbonyl group, etc.). Examples of the alkoxyalkyloxycarbonyl group include those in which one C ₁ -C ₆ alkoxy group is substituted with the above alkoxycarbonyl group (for example, a methoxymethyloxycarbonyl group, a methoxyethyloxycarbonyl group, etc.). Examples of the hydroxyacyl group include those in which one hydroxyl group is substituted with the above acyl group (including C ₁ -C ₆ alkanoyl and aroyl) (for example, glycoloyl group, lactoyl group, benzyloyl group, etc.). Examples of the alkoxyacyl group include those in which one of the above C ₁ -C ₆ alkoxy groups is substituted with the above acyl group (for example, a methoxyacetyl group, an ethoxyacetyl group, etc.). Examples of the halogenoacyl group include groups composed of the above-mentioned halogenoalkyl groups and carbonyl groups (for example, chloromethylcarbonyl group, trifluoromethylcarbonyl group, etc.). Examples of the carboxyacyl group include those in which one carboxy group is substituted with the above acyl group (for example, carboxyacetyl group, 2-carboxypropionyl group, etc.). The aminoacyl groups, those with one amino group is substituted with the acyl group (including C ₁ -C ₆ alkanoyl and aroyl) (e.g., aminomethyl group, 1-aminoethyl carbonyl group). Examples of the acyloxyacyl group include groups composed of the above acyloxyalkyl group and carbonyl group (for example, formyloxymethylcarbonyl group, acetyloxymethylcarbonyl group, etc.). Examples of the acyloxyalkylsulfonyl group include groups composed of the above acyloxyalkyl group and a sulfonyl group (for example, formyloxymethylsulfonyl group, acetyloxymethylsulfonyl group, etc.). Examples of the hydroxyalkylsulfonyl group include groups composed of the above C ₁ -C ₆ hydroxyalkyl group and a sulfonyl group (eg, hydroxymethylsulfonyl group, 1-hydroxyethylsulfonyl group, etc.). Examples of the alkoxyalkylsulfonyl group include groups composed of the above C ₁ -C ₆ alkoxyalkyl group and a sulfonyl group (for example, a methoxymethylsulfonyl group, an ethoxyethylsulfonyl group, etc.). The 3- to 6-membered heterocyclic sulfonyl group which may have a substituent includes a group composed of the above-mentioned 3- to 6-membered heterocyclic ring and a sulfonyl group (for example, aziridinyl). Sulfonyl group, azetidinyl sulfonyl group, pyrrolidinyl sulfonyl group, piperidyl sulfonyl group, piperazinyl sulfonyl group, morpholinyl sulfonyl group, tetrahydropyranyl sulfonyl group, etc.). The 3- to 6-membered heterocyclic oxy group which may have a substituent is a group composed of the above-described 3- to 6-membered heterocyclic ring which may have a substituent and an oxygen atom (for example, tetrahydrofuranyl). Oxy group, etc.). N-alkylaminoacyl group is a group in which one of the above C ₁ -C ₆ alkyl groups is substituted on the nitrogen atom of the above aminoacyl group (for example, N-methylaminoacetyl group, N-ethylaminoacetyl group, etc.) Is mentioned. The N, N-dialkylaminoacyl group is a group in which two C ₁ -C ₆ alkyl groups are substituted on the nitrogen atom of the aminoacyl group (for example, N, N-dimethylaminoacetyl group, N-ethyl- N-methylaminoacetyl group and the like). Examples of the N, N-dialkylcarbamoyl acyl group which may have a substituent on the alkyl group include the N, N-dialkylcarbamoyl group which may have a substituent on the above C ₁ -C ₆ alkyl group. Examples include those substituted with the above acyl group (for example, N, N-dimethylcarbamoylacetyl group, N, N-diethylcarbamoylacetyl group, N-ethyl-N-methylcarbamoylacetyl group, etc.). As the N, N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group, the N, N-dialkylcarbamoyl group which may have a substituent on the above C ₁ -C ₆ alkyl group And a group composed of sulfonyl group (for example, N, N-dimethylcarbamoylmethylsulfonyl group, N- (2-hydroxyethyl) -N-methylcarbamoylmethylsulfonyl group, etc.). Examples of the alkylsulfonylacyl group include those in which one alkylsulfonyl group having the above C ₁ -C ₆ alkyl group is substituted with an acyl group (for example, a methylsulfonylacetyl group, an isopropylsulfonylacetyl group, etc.).

Examples of the N-arylcarbamoyl group include those in which the above aryl group is substituted with a carbamoyl group (for example, phenylcarbamoyl group, naphthylcarbamoyl group, etc.). Examples of N-3 to 6-membered heterocyclic carbamoyl groups include those in which the above-described 3 to 6-membered heterocyclic group which may have a substituent is substituted with a carbamoyl group (for example, pyridylcarbamoyl group, thienylcarbamoyl group, etc. ). The N-alkyl-N-arylcarbamoyl group includes a group in which a linear or branched C ₁ -C ₆ alkyl group is substituted on the nitrogen atom of the N-arylcarbamoyl group (for example, N-methyl- N-phenylcarbamoyl group, etc.). The N-alkyl-N-3 to 6-membered heterocyclic carbamoyl group includes linear or branched C ₁ -C ₆ alkyl on the nitrogen atom of the N-3 to 6-membered heterocyclic carbamoyl group. Examples thereof include those substituted with a group (for example, N-methyl-N-thienylcarbamoyl group). Examples of the N-arylcarbamoylalkyl group include those in which the above-mentioned N-arylcarbamoyl group is substituted with a linear or branched C ₁ -C ₆ alkyl group (for example, phenylcarbamoylmethyl group). Examples of the N-3 to 6-membered heterocyclic carbamoylalkyl group include those in which the N-3 to 6-membered heterocyclic carbamoyl group is substituted with a linear or branched C ₁ -C ₆ alkyl group (for example, And pyridylcarbamoylmethyl group). Examples of the N-alkyl-N-arylcarbamoylalkyl group include those in which a linear or branched C ₁ -C ₆ alkyl group is substituted on the nitrogen atom of the N-arylcarbamoylalkyl group (for example, N— Methyl-N-phenylcarbamoylmethyl group, etc.). Examples of the N-alkyl-N-3 to 6-membered heterocyclic carbamoylalkyl group include linear or branched C ₁ -C on the nitrogen atom of the N-3 to 6-membered heterocyclic carbamoylalkyl group. Examples include those substituted with ₆ alkyl groups (for example, N-methyl-N-thienylcarbamoylmethyl group, etc.).
The aminocarbothioyl group is a group represented by —C (═S) —NH ₂ , and the N-alkylaminocarbothioyl group represents an aminothiocarbonyl group substituted with one alkyl group as described above. Examples thereof include (methylamino) carbothioyl group, (ethylamino) carbothioyl group and the like. The N, N-dialkylaminocarbothioyl group represents an aminothiocarbonyl group substituted with two alkyl groups as described above, and examples thereof include (dimethylamino) carbothioyl group, (diethylamino) carbothioyl group, (ethylmethylamino) Examples thereof include a carbochioyl group. As the alkoxyalkyl (thiocarbonyl) group, as the alkylthioalkyl group, a linear, branched or cyclic C ₁ -C ₆ alkylthio group is a linear, branched or cyclic C ₁ -C ₆ alkyl. Examples thereof include those substituted with a group (for example, methylthiomethyl group, 1-methylthioethyl group, etc.). The N- acyl -N- alkylaminoalkyl group, amino -C ₁ -C ₆ those C ₁ -C ₆ alkyl group and an acyl group on the nitrogen atom of the alkyl group is substituted (e.g., N- acetyl -N- Methylaminomethyl group, etc.). The group comprised from said alkoxyalkyl group and thiocarbonyl group is shown, for example, 2-ethoxyethanethioyl group etc. can be mentioned.
The alkylene group means a linear or branched alkylene group having 1 to 5 carbon atoms, and examples thereof include a methylene group, an ethylene group, and a propylene group. The alkenylene group is an alkenylene group having 2 to 5 carbon atoms having one double bond, and examples thereof include a vinylene group and a propenylene group. Examples of the alkylenedioxy group include those having 1 to 5 carbon atoms such as a methylenedioxy group, an ethylenedioxy group, and a propylenedioxy group. A carbonyldioxy group is a group represented by —O—C (═O) —O—. In the above description, the substitution position is not particularly limited.
Of these substituents represented by R ³ and R ⁴ , hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group , Carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, alkyl Base N, N-dialkylcarbamoyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl which may have a substituent on Group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, optionally substituted by 1 to 3 alkyl groups A carbazoyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, an optionally substituted 3-6 membered heterocyclic carbonyl group, an optionally substituted 3-6 membered heterocyclic carbonyloxyalkyl group, Optionally substituted 3- to 6-membered heterocyclic group, carbamoylal Group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on alkyl group, substituted on alkyl group N, N-dialkylcarbamoylalkyl group, alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl which may have a group Group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N, N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, Lucoxyacyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoylacyl group, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N, N - dialkylamino carbothioyl group or an alkoxyalkyl (thiocarbonyl) group and the like are preferred, and alkylene groups R ³ and R ⁴ are taken together, alkenylene group, alkylenedioxy group, a carbonyl dioxy group and the like.

In R ³ and R ⁴ , R ³ is preferably a hydrogen atom, and R ⁴ is preferably the above-described preferred substituents. More preferable groups as R ^{4 in} that case include a hydrogen atom, a hydroxyl group, an alkyl group, a halogen atom, a hydroxyimino group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, and a substituent. An acylamino group, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylamino group, a carbamoyl group, and a substituent on the alkyl group. N-alkylcarbamoyl group which may be substituted, N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkyl Carbamoyl group, N-alke R-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoylalkyl group, optionally substituted with 1 to 3 alkyl groups A carbazoyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, an optionally substituted 3-6 membered heterocyclic carbonyl group, an optionally substituted 3-6 membered heterocyclic carbonyloxyalkyl group, A 3- to 6-membered heterocyclic group which may have a substituent, a carbamoylalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, alkylsulfonyl Amino group, alkylsulfonylaminoalkyl group, acyloxy group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N, N-dialkyl Aminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoylacyl group, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, And N-alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group, alkoxyalkyl (thiocarbonyl) group, and the like. That.

Further, among these groups, particularly preferable groups as R ⁴ include a hydrogen atom, a hydroxyl group, an alkyl group, an N, N-dialkylaminoalkyl group, an optionally substituted acylamino group, an acylaminoalkyl group, Alkoxy group, alkoxyalkyl group, hydroxyalkyl group, alkoxycarbonyl group, alkoxycarbonylamino group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, and a substituent on the alkyl group N, N-dialkylcarbamoyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkyl-N -Alkoxycarbamoyl group, 1-3 al A carbazoyl group optionally substituted with an alkyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, a 3-6 membered heterocyclic carbonyl group which may have a substituent, and 3-6 which may have a substituent Member heterocyclic group, N, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, N, N which may have a substituent on the alkyl group -Dialkylcarbamoylalkyl group, alkylsulfonylamino group, alkylsulfonylaminoalkyl group, acyloxy group, acyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N, N-dialkylaminoacyl group, hydroxyacyl group, alkoxyacyl group, aminocarbo Thioyl group, N-alkylaminocarbothioyl group, N, N- Examples thereof include a dialkylaminocarbothioyl group and an alkoxyalkyl (thiocarbonyl) group.

Examples of preferable specific substituents for R ³ and R ⁴ include hydrogen atom, hydroxyl group, methyl group, ethyl group, isopropyl group, N, N-dimethylaminomethyl group, N, N-dimethylaminoethyl group, N , N-diethylaminomethyl group, acetylamino group, methoxyacetylamino group, acetylaminomethyl group, acetylaminoethyl group, methoxy group, ethoxy group, methoxymethyl group, methoxyethyl group, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxy-1-methylethyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxycarbonylamino group, ethoxycarbonylamino group, N-allylcarbamoyl group, N-allylcarbamoylmethyl group, N-allyl-N-methylcarbamoyl group N-allyl-N-methylcarbamoylmethy Group, N-methoxy-N-methylcarbamoyl group, N, N-dimethylcarbazoyl group, N, N, N'-trimethylcarbazoyl group, methanesulfonyl group, methanesulfonylmethyl group, ethanesulfonylmethyl group, N- Methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group, N-tert-butylcarbamoyl group, N-cyclopropylcarbamoyl group, N-cyclopropylmethylcarbamoyl group, N- (1- Ethoxycarbonylcyclopropyl) carbamoyl group, N- (2-hydroxyethyl) carbamoyl group, N- (2-fluoroethyl) carbamoyl group, N- (2-methoxyethyl) carbamoyl group, N- (carboxymethyl) carbamoyl group, N- (2-aminoethyl) cal Vamoyl group, N- (2-amidinoethyl) carbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group, N-methyl-N-propylcarbamoyl group, N- (2-hydroxyethyl) -N-methylcarbamoyl group, N- (2-fluoroethyl) -N-methylcarbamoyl group, N, N-bis (2-hydroxyethyl) ) Carbamoyl group, N, N-bis (2-fluoroethyl) carbamoyl group, N- (2-methoxyethyl) -N-methylcarbamoyl group, N-carboxymethyl-N-methylcarbamoyl group, N, N-bis ( 2-aminoethyl) carbamoyl group, azetidinocarbonyl group, 3-methoxyazetidinocarbonyl group, 3- Droxyazetidinocarbonyl group, pyrrolidinocarbonyl group, 3-hydroxypyrrolidinocarbonyl group, 3-fluoropyrrolidinocarbonyl group, 3,4-dimethoxypyrrolidinocarbonyl group, piperidinocarbonyl group, piperazinocarbonyl group, Morpholinocarbonyl group, (tetrahydropyran-4-yl) carbonyl group, benzoyl group, pyridylcarbonyl group, thiazolyl group, 4,5-dihydrothiazolyl group, oxazolyl group, 4,5-dihydrooxazolyl group, 5- Methyloxazolyl group, imidazolyl group, pyrrolidinyl group, 3-hydroxypyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxothiomorpholinyl group, tetrahydropyranyl group, pyridyl Group, 1,2,4-oxadi Zolyl group, 3-methyl-1,2,4-oxadiazolyl group, 5-methyl-1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 5-methyl-1,3,4-oxadiazolyl group 5- (trifluoromethyl) -1,3,4-oxadiazolyl group, 1,3-oxazolyl group, 1,3,4-thiadiazolyl group, 5-methyl-1,3,4-thiadiazolyl group, 1,3 -Oxazolidinyl group, N-methylcarbamoylmethyl group, N-methylcarbamoylethyl group, N-ethylcarbamoylmethyl group, N- (2-fluoroethyl) carbamoylmethyl group, N- (2-methoxyethyl) carbamoylmethyl group, N , N-dimethylcarbamoylmethyl group, N, N-dimethylcarbamoylethyl group, N- (2-fluoroethyl) -N-methylcarbonyl Rubamoylmethyl group, N- (2-methoxyethyl) -N-methylcarbamoylmethyl group, N, N-dimethylcarbamoyloxymethyl group, 2- (N-ethyl-N-methylcarbamoyloxy) ethyl group, methylsulfonylamino group, Ethylsulfonylamino group, methylsulfonylaminomethyl group, methylsulfonylaminoethyl group, acetyl group, propionyl group, isobutyryl group, 2-methoxyethoxycarbonyl group, trifluoroacetyl group, N, N-dimethylaminoacetyl group, N-ethyl -N-methylaminoacetyl group, hydroxyacetyl group, 1,1-dimethyl-2-hydroxyethylcarbonyl group, methoxyacetyl group, 1,1-dimethyl-2-methoxyethylcarbonyl group, aminocarbothioyl group, (dimethyl Amino) carbo Oil group, and 2-methoxy-ethane Chi oil group.
As described above, R ³ and R ⁴ are preferably when R ³ is a hydrogen atom and R ⁴ is the above-described specific substituent or the like. In particular, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group is preferable, and among them, a case where it is an N, N-dimethylcarbamoyl group is preferable. However, R ³ and R ⁴ are not limited to these specific substituents.

<For radical T ^0>
The group T ⁰ represents a carbonyl group or a thiocarbonyl group, more preferably a carbonyl group.
<For radical T ^1>
The group T ¹ is a carbonyl group, a sulfonyl group, a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′ )-, Group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(in the group, R ' Represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —A ¹ —N (R ″) — (wherein A ¹ may have a substituent, carbon number 1 . shows the 5 alkylene group, R "is shown hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), group -C (= O) -NH-, group -C (= S) -NH-, group - C (═O) —NH—NH—, group —C (═O) —A ² —C (═O) — (wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms). , group ^{-C (= O) -A 3 -C} (= O) -NH- ( in group, A ³ is carbon Shows the 1-5 alkylene group), group -C (= O) -C (= NOR a) -N (R b) -., Group -C (= S) -C (= NOR a) -N ( R ^b) -. (in group, R ^a represents a hydrogen atom, an alkyl group or an alkanoyl group, R ^b is shown a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), group -C (= O) -N = N-, group -C (= S) -N = N- , group ^{-C (= NOR C) -C (} = O) -N (R d) - ( the radical, R ^C is a hydrogen atom, an alkyl group, It indicates alkanoyl group, an aryl group or an aralkyl group, R ^d represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), group -C (= N-N (R e) (R f)) -. C (= O) —N (R ^g ) — (wherein R ^e and R ^f each independently represents a hydrogen atom, an alkyl group, an alkanoyl group or an alkyl (thiocarbonyl) group). And, R ^g represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), group -C (= O) -NH-C (= O) -., Group -C (= S) -NH-C (= O) -, group -C (= O) -NH-C (= S) -, group -C (= S) -NHC (= S) -, group -C (= O) -NH-SO 2 -, It represents a group —SO ₂ —NH—, a group —C (═NCN) —NH—C (═O) —, a group —C (═S) —C (═O) — or a thiocarbonyl group.
In the above group, the alkylene group having 1 to 5 carbon atoms for A ^1, A ² and A ^3, refers to a linear, branched or cyclic alkylene group having 1 to 5 carbon atoms, e.g., methylene , Ethylene group, propylene group, cyclopropylene group, 1,3-cyclopentylene group and the like. In R ′, R ″, R ^a , R ^b , R ^c , R ^d , R ^e , R ^f, and R ^g , the alkyl group is a linear, branched or cyclic alkyl having 1 to 6 carbon atoms. refers to the group, for example, as a. alkoxy group include a methyl group, an ethyl group, refers to a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, e.g., methoxy, ethoxy Group and the like.
In R ^a , R ^c , R ^e and R ^f , the alkanoyl group means a group composed of a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and a carbonyl group. , An acetyl group, a propionyl group, and the like.

In R ^c , the aryl group means one having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. The aralkyl group means a C1-C6 linear, branched or cyclic alkyl group substituted with a C6-C14 aryl group, and examples thereof include a benzyl group and a phenethyl group. It is done.
The group T ¹ includes a carbonyl group, a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′) —, The group -C (= O) -C (= S) -N (R ')-, the group -C (= S) -C (= S) -N (R')-and the group -C (= O)- CH ₂ —N (R ″) — is preferred, especially a carbonyl group, group —C (═O) —C (═O) —N (R ′) —, group —C (═S) —C (═O). -N (R ')-, the group -C (= O) -C (= S) -N (R')-and the group -C (= S) -C (= S) -N (R ')- preferable.
<Regarding Group R ¹ and Group R ² >
R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, preferably a hydrogen atom or an alkyl group, and more preferably a hydrogen atom.
In R ¹ and R ² , the alkyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group and an ethyl group. The alkoxy group means a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group and an ethoxy group. R ¹ and R ² are preferably each independently a hydrogen atom or an alkyl group, and more preferably both are hydrogen atoms.

When T ¹ is a carbonyl group or a sulfonyl group and Q ⁵ in the group Q ³ is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, Q ⁴ is the above-mentioned 12 kinds of groups (B), (f), (g), (h), (i), (j), (k) and (l) (in the group (f), N is substituted by R ¹⁹ Preferred is a case where two of the ring carbon atoms are substituted with nitrogen atoms.
When T ¹ is a carbonyl group or a sulfonyl group and Q ⁵ in the group Q ³ is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, the substituent on the group Q ⁵ Is preferably an N-alkylcarbamoyl group or an N, N-dialkylcarbamoyl group.
T ¹ is a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′) —, a group —C (= O) —C (═S) —N (R ′) — or a group —C (═S) —C (═S) —N (R ′) —, wherein Q ⁵ in the group Q ³ is the number of carbon atoms. when a 1-8 alkylene group or alkenylene group having 2 to 8 carbon atoms, Q ⁴ is of the 12 kinds of groups of the, (i), preferably it is a (j) and (k).
In addition, T ¹ is a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′) —, or a group —C. (═O) —C (═S) —N (R ′) — or a group —C (═S) —C (═S) —N (R ′) —, wherein Q ⁵ in the group Q ³ is When it is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, the substituent on the group Q ⁵ is preferably an N-alkylcarbamoyl group or an N, N-dialkylcarbamoyl group.

The compound represented by the general formula (1) of the present invention, a salt thereof, a solvate thereof or an N-oxide thereof is characterized by a combination with the group T ¹ and the group Q ³ . There are two ways ((I) and (II)).
(I) T ¹ is a carbonyl group, a sulfonyl group, a group —C (═O) —NH—C (═O) —, a group —C (═S) —NH—C (═O) —, a group —C (═O) —NH—C (═S) —, group —C (═S) —NHC (═S) —, group —C (═O) —NH—SO ₂ —, group —SO ₂ —NH— , A group -C (= NCN) -NH-C (= O)-, a group -C (= S) -C (= O)-or a thiocarbonyl group,
Q ³ is the following group

(In the group, Q ⁵ represents a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n — (in the group, m and n each independently represents an integer of 0, 1 to 3). , A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or — SO ₂ —NH— is shown.)
(II) T ¹ is a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′) —, a group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(in which R 'is a hydrogen atom, A hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —A ¹ —N (R ″) — (wherein A ¹ is an alkylene having 1 to 5 carbon atoms which may have a substituent. R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —NH—, a group —C (═S) —NH—, a group —C (═O ) —NH—NH—, group —C (═O) —A ² —C (═O) — (wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms) group —C ( ^{= O) -A 3 -C (=} O) -NH- ( in group, a ³ is an alkylene group having 1 to 5 carbon atoms Shown), group -C (= O) -C (= NOR a) -N (R b) -., Group -C (= S) -C (= NOR a) -N (R b) - ( in group , R ^a represents a hydrogen atom, an alkyl group or an alkanoyl group, R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group —C (═O) —N═N—, a group —C ( ═S) —N═N—, group —C (═NOR ^C ) —C (═O) —N (R ^d ) — (in which R ^C is a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group) R ^d represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group —C (═N—N (R ^e ) (R ^f )) — C (═O) —N ( R ^g ) — (wherein R ^e and R ^f each independently represents a hydrogen atom, an alkyl group, an alkanoyl group or an alkyl (thiocarbonyl) group, and R ^g represents a hydrogen atom, water, An acid group, an alkyl group or an alkoxy group.), A group —C (═O) —NH—C (═O) —, a group —C (═S) —NH—C (═O) —, a group —C (═O) —NH—C (═S) —, group —C (═S) —NHC (═S) —, group —C (═O) —NH—SO ₂ —, group —SO ₂ —NH— , A group -C (= NCN) -NH-C (= O)-, a group -C (= S) -C (= O)-or a thiocarbonyl group,
Q ³ is the following group

(In the group, Q ⁵ represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n — (in the group , M and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, — NH-NH -, - S- NH -, -.. which the SO-NH- or an -SO ₂ -NH-) shows a) may exhibit.

In the above (I) and (II), the following (i) and (ii) can be mentioned as preferable examples.
(I) The group R ¹ and the group R ² are each independently a hydrogen atom or an alkyl group, and the group Q ¹ may be substituted with a saturated or unsaturated bicyclic or tricyclic condensation A hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent, the group Q ² is a single bond, and in the group Q ³ , In Q ³ , the group Q ⁵ is a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n — (wherein m and n each independently represents 0 or 1, A is the same as above), and the group Q ⁴ is selected from 9 groups (a) to (h) and (l) among the 12 groups, and the group T ⁰ is , A carbonyl group or a thiocarbonyl group, and the group T ¹ is a carbonyl group or a sulfonyl group.
(Ii) In the general formula (1), the groups R ¹ and R ² are each independently a hydrogen atom or an alkyl group, and the group Q ¹ may have a substituent. Or a tricyclic condensed hydrocarbon group, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent, and the group Q ² is a single bond, in Q ^3, in the radical Q ^3, a group Q ^5, alkylene group or a group of 3 to 6 carbon atoms _{- (CH 2) m-CH} 2 -A-CH 2 - (CH 2) n- ( in group , M and n each independently represent 0 or 1, and A is the same as defined above, and the group Q ⁴ is selected from among the 12 groups described above (i), (j) and (k) those selected from the three kinds of groups, group T ⁰ is a carbonyl group or thiocarbonyl group, group T ¹ is a group -C (= O) -C = O) -N (R ')-, group -C (= S) -C (= O) -N (R')-, group -C (= O) -C (= S) -N (R ' )-Or the group -C (= S) -C (= S) -N (R ')-.

  The compound represented by the general formula (1) of the present invention may have stereoisomers or optical isomers derived from asymmetric carbon atoms. These stereoisomers, optical isomers and these isomers may be present. Any of the mixtures are included in the present invention.

  The salt of the compound represented by the general formula (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, hydrochloride, hydrobromide, hydrogen iodide Mineral salts such as acid salts, phosphates, nitrates and sulfates, benzoates, methanesulfonates, organic sulfonates such as 2-hydroxyethanesulfonate and p-toluenesulfonate, and acetates, And organic carboxylates such as propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and mandelate . Further, when the compound represented by the general formula (1) has an acidic group, it may be a salt of an alkali metal ion or an alkaline earth metal ion. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates. Moreover, when a nitrogen atom exists in General formula (1), it may be an N-oxide body.

As the compounds of the present invention, the compounds shown in the examples below, salts of the compounds, and the following compounds and salts thereof are particularly preferable.
1) 3-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) [1,6] naphthyridine-7-carboxamide 2) 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) Carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-fluorocinnoline-3 Carboxamide 3) 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyrid -2-yl) carbonyl] amino} cyclohexyl) -4a, 8a-dihydro-4H-1,2,4-benzooxadiazine-3-carboxamide 4) N-((1S, 2R, 4S) -4- [ (Dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -6-fluoro -4-oxo-1,4-dihydroquinoline-2-carboxamide 5) 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -5-oxo-4,5-dihydro-1H-1,3,4 Ben Triazepine-2-carboxamide 6) 6-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-oxo-3,4-dihydro-2 (1H) -cinnolinecarboxamide 7) 6-chloro-N-(( 1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] amino} cyclohexyl) -1,2,3,4-tetrahydroquinoline-2-carboxamide 8) N-{(1R, 2S, 5S) -2-{[3- (3-chlorophenyl) -2-propinoyl] A Mino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 9) N-{(1R, 2S, 5S) -2-[(4-Chlorobenzoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridine-2-carboxamide 10) N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 6-Methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine-2-carboxamide

11) 5-Chloro-N-[(1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-({[5- (3-pyrrolidinyloxy) thiazol-2-yl] carbonyl} Amino) cyclohexyl] indole-2-carboxamide 12) N ^1- (4-chlorophenyl) -N ² -((1S, 2R) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo) [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 13) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R) -2-{[ (5-methyl-4,5,6,7-tetrahydroisoquinoline thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 14) N ¹ - (5-chloropyridin-2-y ^{) -N 2 - ((1S,} 2R) -2 - {[(5- methyl-5,6-dihydro -4H- pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 15) N ^1- (4-Chlorophenyl) -N ² -((1S, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2- Yl) carbonyl] amino} cyclohexyl) ethanediamide 16) N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R) -2-{[(5-methyl-5,6-dihydro- 4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclopentyl) ethanediamide 17) N ^1- (4-chlorophenyl) -N ² -((1R, 2R) -2-{[(5 -Methyl-5,6-di Mud -4H- pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclopentyl) ethanediamide 18) N ¹ - (4- ^{chlorophenyl) -N 2 - ((1R,} 2R) -2 - {[ (5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cycloheptyl) ethanediamide 19) N ^1- (5-chloropyridine-2- ^{yl) -N 2 - ((1R,} 2R) -2 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} Cycloheptyl) ethanediamide 20) N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3 , 4-d] thiazole- 2-yl) carbonyl] amino} cycloheptyl) ethanediamide

21) N ^1- (4-Chlorophenyl) -N ² -((1R, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2- Yl) carbonyl] amino} cycloheptyl) ethanediamide 22) N ^1- (5-chloro-6-methylpyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl ] -2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 23) N ^1- (5- ^{chloro-3-methyl-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl -4,5,6,7 -Tetrahydrothiazolo [5,4-c] pi 2-yl) carbonyl] amino} cyclohexyl) ethanediamide 24) N ¹ - (5- ^{chloro-4-methyl-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethyl Amino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 25) N ^{1- (4-chloro-3-hydroxyphenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl-4,5,6,7 tetrahydronaphthalene thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 26) N ¹ - (4- chloro-2-hydroxyphenyl) -N ² - ((1S, R, 4S) -4-[(Dimethylamino) carbonyl] -2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] Amino} cyclohexyl) ethanediamide 27) N ^1- [4-chloro-2- (fluoromethyl) phenyl] -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 28) N ^1- [4-chloro-2- (methoxy) Methyl) phenyl] -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyri Gin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 29) N-{(1R, 2S, 5S) -2-({[1- (4-chloroanilino) cyclopropyl] carbonyl} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 30) N ^1- (5-chloropyridin-2-yl) ^{-N 2 - ((1R, 2R} , 4R) -4- ( hydroxymethyl) -2 - {[(5-methyl-4,5,6,7-tetrahydroisoquinoline [5,4-c] pyridin-2 pyridin-2 -Yl) carbonyl] amino} cyclopentyl) ethanediamide

31) N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R, 4S) -4- (hydroxymethyl) -2-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclopentyl) ethanediamide 32) N ¹ -((3R, 4S) -1-acetyl-3-{[(5-methyl- 4,5,6,7-tetrahydronaphthalene thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) -N ² - (5-chloropyridin-2-yl) ethanediamide 33 ) N ^1- (5-chloropyridin-2-yl) -N ² -((3R, 4S) -1- (methylsulfonyl) -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) cal Sulfonyl] amino} piperidin-4-yl) ethanediamide ^{34) N 1 - {(1S} , 2R, 4S) -2 - {[(3- chloro-benzothiophen-2-yl) carbonyl] amino} -4 - [(dimethyl amino) carbonyl] cyclohexyl} -N ² - (5- chloropyridin-2-yl) ethanediamide 35) N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 -[(Dimethylamino) carbothioyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 36 ) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbothioyl] amino} cyclohexyl) ethanediamide 37) N ^1- (5-chloropyridin-2-yl) -N ² — ((3R, 4S) -1- (2-methoxyethanethioyl) -3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino } Piperidin-4-yl) ethanediamide 38) N ^1- (5-chloropyridin-2-yl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbothioyl] amino} piperidin-4-yl) ethanediamide 39) N-[(3R, 4S) -4- ({2-[( -Chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -1- (2-methoxyacetyl) piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridine-2-carboxamide 40) N-[(3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-thioxoacetyl} Amino) -1- (2-methoxyacetyl) piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

41) N ^1- (4-Chlorophenyl) -N ² -((3R, 4S) -1- (2-methoxyethanethioyl) -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide 42) N ^1- (4-chlorophenyl) -N ² -((3R, 4S) -1- ( 2-methoxyacetyl) -3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbothioyl] amino} piperidin-4-yl) ethanediamide 43) N-[(3R, 4S) -4-{[2- (4-chloroanilino) -2-oxoethanethioyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl] -5- Methyl-4,5,6,7- Torahydrothiazolo [5,4-c] pyridine-2-carboxamide 44) N-[(3R, 4S) -4-({2-[(4-chlorophenyl) amino] -2-thioxoacetyl} amino) -1- (2-methoxyacetyl) piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 45) N ¹ -(( 1S, 2R, 4S) -4- (1-azetidinylcarbonyl) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) carbonyl] amino} cyclohexyl) -N ² - (5-chloropyridin-2-yl) ethanediamide 46) N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) - 2-{[(5-methyl-4, , 6,7-tetrahydronaphthalene thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1-pyrrolidinylcarbonyl) cyclohexyl] ethanediamide 47) N ¹ - (5-chloropyridin - ^{2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline thiazolo [5,4-c] pyridin-2-yl) Carbonyl] amino} -4- (1-piperidinylcarbonyl) cyclohexyl] ethanediamide 48) N ^1- (5-chloropyridin-2-yl) -N ² -[(1S, 2R, 4S) -2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (4-morpholinylcarbonyl) cyclohexyl] ethanediamide 49) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(methylamino) carbonyl] -2-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 50) N-{(1R, 2S, 5S) -2-({2-[(6-chloropyridazine) -3-yl) amino] -2-oxoethanethiol} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] Pyridine-2-carboxamide

51) N ^1- (4-Bromophenyl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-C] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide 52) N ^1- (5-chloropyridin-2-yl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[4- (pyridin-4-yl) benzoyl] amino} piperidin-4-yl) ethanediamide 53) N ^1- (5-chloropyridin-2-yl)- ^{N 2 - [(3R, 4S} ) -1- (2- methoxy-acetyl) -3 - ({[2- (pyridin-4-yl) pyrimidin-5-yl] carbonyl} amino) piperidin-4-yl] ethanediamide 54) N ¹ - (5- chloro ^{Lysine-2-yl) -N 2 - [(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - ({[2- (pyridin-4-yl) pyrimidin-5-yl] carbonyl } Amino) cyclohexyl] ethanediamide 55) N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2-oxoethane (methoxy) imidoyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 56) N-{(1R, 2S, 5S) -2-{[2- (4-Chloroanilino) -2- (methoxyimino) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydride Thiazolo [5,4-c] pyridine-2-carboxamide 57) N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2-{[(4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 58) N ^1- (5 - ^{chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(4,4-ethylene-5-methyl-5,6 Dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 59) N-{(1R, 2S, 5S) -2-({[(E) -2- ( 4-chlorophenyl) ete Nyl] sulfonyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 60) N- {(1R, 2S, 5S) -2-{[(4-chlorobenzyl) sulfonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridine-2-carboxamide

61) N-{(1R, 2S, 5S) -2-[(2-{[(4-chlorophenyl) sulfonyl] amino} acetyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 62) N-{(1R, 2S, 5S) -2-({2-[(5-chloropyrimidine-2 -Yl) amino] -2-oxoethanethiol} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridine-2-carboxamide 63) N-{(1R, 2S, 5S) -2-({2-[(5-chloropyrazin-2-yl) amino] -2-oxoethanethiol} amino) -5 [(Jimee Ruamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 64) N-[(1R, 2S, 5S) -5- [ (Dimethylamino) carbonyl] -2-({2-[(5-fluoro-2-thienyl) amino] -2-oxoethanethiol} amino) cyclohexyl] -5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 65) N-{(1R, 2S, 5S) -2-{[2- (3-amino-4-chloroanilino) -2-oxoethanethioyl Amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 66 N ¹ - ^{(4-Chloro-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl -4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 67) N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl]- 2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (3-fluorophenyl) ethanediamide 68) N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl) Carbonyl] amino} cyclohexyl) -N ² -phenylethanediamide 69) N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5, 6,7-tetrahydronaphthalene thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ² - (pyridin-2-yl) ethanediamide 70) N ¹ - (5- chloro-pyridin-2 - ^{yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5,6,6- trimethyl-5,6-dihydro -4H- pyrrolo [3 , 4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

71) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(4,4,5,6 , 6-pentamethyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 72) N ^1- (5-chloropyridin-2-yl ) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(2-methyl-2,3-dihydrothiazolo [
5,4-d] isoxazol-5-yl) carbonyl] amino} cyclohexyl) ethanediamide 73) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4- [(Dimethylamino) carbonyl] -2-{[(2-methyl-2,3-dihydrothiazolo [4,5-d] isoxazol-5-yl) carbonyl] amino} cyclohexyl) ethanediamide 74) N ^1- (5-Chloro-2-furyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 75) N ¹ - (5- ^{chloro-2-yl) -N 2 - ((1S,} 2R, 4 ) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl ) Ethanediamide 76) N ^1- (5-chloro-1H-imidazol-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide 77) N-{(1R, 2S, 5S) -2-{[ 2- (4-Chloroanilino) -1-ethoxyimino-2-oxoethyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydro Azolo [5,4-c] pyridine-2-carboxamide 78) N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -1-phenoxyimino-2-oxoethyl] amino}- 5-[(Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 79) N-{(1R, 2S, 5S ) -2-{[1-Benzyloxyimino-2- (4-chloroanilino) -2-oxoethyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 80) N-{(1R, 2S, 5S) -2-({2- (4-chloroanilino) -1-hydrazono- 2-oxoethyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

81) N-{(1R, 2S, 5S) -2-({2- (4-chloroanilino) -1- (2-methylhydrazono) -2-oxoethyl} amino) -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 82) N-{(1R, 2S, 5S) -2-({2- [(5-chloropyridin-2-yl) amino] -1- (2,2-dimethylhydrazono) -2-oxoethyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 83) N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -1-methylimino -2-Oki Ethyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 84) N-{( 1R, 2S, 5S) -2-{[1- (2-acetylhydrazono) -2- (4-chloroanilino) -2-oxoethyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 85) N-{(1R, 2S, 5S) -2-({2- (4-chloroanilino) ) -1 [(2-ethanethioylhydrazono) -2-oxoethyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl) -5-methyl-4,5,6,7-tetrahydride Thiazolo [5,4-c] pyridine-2-carboxamide 86) N-{(1R, 2S, 5S) -2-{[(E) -3- (5-chloropyridin-2-yl) -2-propenoyl ] Amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide A method for producing the derivative (1) will be described.

[Production Method 1]
The compound represented by the general formula (1), a salt thereof, a solvate thereof, or an N-oxide thereof can be produced, for example, by the following method.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² represent the same as described above, and T ¹ represents a carbonyl group. ]
The compound (4) is produced by inducing the carboxylic acid (3) to a mixed acid anhydride, acid halide, active ester or the like and reacting with the diamine (2). Compound (1) of the present invention can be produced by reacting 5) under the same conditions. In the reaction in each of the above steps, reaction reagents and conditions usually used for peptide synthesis may be applied mutatis mutandis. The above mixed acid anhydride can be produced, for example, by reacting chloroformates such as ethyl chloroformate and isobutyl chloroformate with carboxylic acid (3) in the presence of a base. The acid halide can be produced by treating the carboxylic acid (3) with an acid halide such as thionyl chloride or oxalyl chloride. There are various active esters. For example, phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide, and carboxylic acid (3) are mixed with N, N′-dicyclohexylcarbodiimide or 1-ethyl. It can be produced by reacting with a condensing agent such as -3- (3-dimethylaminopropyl) carbodiimide / hydrochloride. Further, the active ester is a reaction of carboxylic acid (3) with pentafluorophenyl trifluoroacetate, etc., a reaction of carboxylic acid (3) with 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite, carboxylic acid It can also be produced by reaction of (3) with diethyl cyanophosphonate (salt-in method), reaction of carboxylic acid (3) with triphenylphosphine and 2,2′-dipyridyl disulfide (Mukoyama method), and the like. The mixed acid anhydride, acid halide or active ester of carboxylic acid (3) thus obtained is reacted with diamine (2) in the presence of a suitable base in an inert solvent at -78 ° C to 150 ° C. Thus, compound (4) can be produced. Compound (1) of the present invention can be produced by reacting the obtained compound (4) with a mixed acid anhydride, acid halide or active ester of carboxylic acid (5) under the same conditions. The reagents and reaction conditions in the reaction of the compound (4) and the carboxylic acid (5) are the same as the reagents and reaction conditions in the reaction of the diamine (2) and the carboxylic acid (3).

Specific examples of the base used in each of the above steps include alkali metals or alkalis such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride. Earth metal carbonates, alkali metal alkoxides, alkali metal hydroxides or hydrides, or alkyllithiums such as n-butyllithium, organometallic bases represented by dialkylaminolithium such as lithium diisopropylamide, lithium bis Organometallic bases of bissilylamines such as (trimethylsilyl) amide, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diaza , And the like organic bases, such as cyclo [5.4.0] undec-7-ene (DBU).
Examples of the inert solvent used in this reaction include alkyl halide solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, and aromatic solvents such as benzene and toluene. Examples include solvents, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, and in addition to these, sulfoxide solvents such as dimethyl sulfoxide and sulfolane, It is also possible to use ketone solvents such as acetone and methyl ethyl ketone.

[Production Method 2]
Compound (1) of the present invention can also be produced by the following method.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are the same as defined above, T ¹ represents a carbonyl group, Boc represents a tert-butoxycarbonyl group, and Boc-ON Represents 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile. ]
As described above, the diamine (2) was treated with Boc-ON (6) to produce a compound (7) in which one of the two amino groups was protected with a tert-butoxycarbonyl group. Carboxylic acid (5) is reacted to produce compound (8), which is subsequently treated with acid to give compound (9), and then reacted with carboxylic acid (3) to give compound (1) of the present invention. Can be manufactured. Compound (7) can be produced by reacting at −10 ° C. to 40 ° C. in the presence of triethylamine in a solvent such as dichloromethane. Compound (8) can be produced by reacting a mixed acid anhydride, acid halide or active ester of compound (7) and carboxylic acid (5) under the reagents and reaction conditions described in Production Method 1. The resulting compound (8) can be treated with trifluoroacetic acid or the like at −20 ° C. to 70 ° C. to produce amine (9). In the reaction of the obtained amine (9) and carboxylic acid (3), the same reagents and conditions as described in Production Method 1 may be used.
By the way, the tert-butoxycarbonyl group of the compound (7) can be replaced with another amino-protecting group. In that case, it is necessary to use the reaction conditions corresponding to the reagent (6) instead of the other reagent. Other protecting groups for amino groups include alkanoyl groups such as acetyl groups, alkoxycarbonyl groups such as methoxycarbonyl groups and ethoxycarbonyl groups, benzyloxycarbonyl groups, paramethoxybenzyloxycarbonyl groups, para (or ortho) nitrobenzyloxy Examples include arylmethoxycarbonyl groups such as carbonyl groups, arylmethyl groups such as benzyl groups and triphenylmethyl groups, aroyl groups such as benzoyl groups, and arylsulfonyl groups such as 2,4-dinitrobenzenesulfonyl groups and orthonitrobenzenesulfonyl groups. be able to. These protecting groups may be selected according to the properties of the compound protecting the amino group, and reagents and conditions corresponding to the protecting groups may be selected when cleaving these protecting groups.

[Production Method 3]
Compound (1) of the present invention can be produced by reacting diamine (2) with sulfonic acid halide (10) and then condensing with carboxylic acid (5).

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are the same as defined above, T ¹ represents a sulfonyl group, and X represents a halogen atom. ]
Compound (4) can be produced by reacting diamine (2) with sulfonic acid halide (10) in the presence of a base such as triethylamine in an inert solvent at −10 ° C. to 30 ° C. The inert solvent and base may be appropriately selected from those described in Production Method 1 and used. The compound (1) of the present invention can be produced by condensing the obtained (4) with the carboxylic acid (5) using the reagents and conditions described in the production method 1. The sulfonic acid halide (10) can be synthesized in the presence of a suitable base by a known method (WO96 / 10022, WO00 / 09480) or a method analogous thereto.

[Production Method 4]
Compound (1) of the present invention can also be produced by the following method.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and X represent the same as described above, and T ¹ represents a sulfonyl group. ]
That is, compound (1) can be produced by reacting amine (9) with sulfonic acid halide (10) at −10 ° C. to 30 ° C. in an inert solvent in the presence of a base. The inert solvent and base may be appropriately selected from those described in Production Method 1 and used.

[Production Method 5]
In the compound (1) of the present invention, when Q ³ is the following group,

[In the group, R ³ , R ⁴ and Q ⁵ are the same as those described above, and the numbers 1 and 2 represent positions. ]
The relationship between the 1-position and the 2-position exists in the trans-type and cis-type geometric isomers. Below, the manufacturing method of such a cis type and trans type compound (1) is demonstrated.
<Manufacturing method of transformer body>

[Wherein, Q ⁵ , R ³ and R ⁴ are the same as defined above. ]
As an example of production of trans-diol (12a) from cyclic alkene (11), for example, conversion from cyclohexene to trans-cyclohexanediol (Organic Synthesis, 1955, Vol. III, page 217) is known. Further, as a production example of trans-diol (12a) from trans-diol (12a), conversion from trans-cyclopentanediol to trans-cyclopentanediamine (WO 98/30574) has been reported. According to these reports, trans-diamine (2a) can be produced from cyclic alkene (11).
The trans-diamine (2a) produced by the above method can be led to the trans-type compound (1) by the above production methods 1 to 4.
<Method for producing cis-isomer>

[Wherein, Q ⁵ , R ³ and R ⁴ are the same as defined above. ]
As an example of producing cis-diol (12b) from cyclic alkene (11), conversion from cyclohexene to cis-cyclohexanediol (J. Org. Chem., 1998, 63, 6094) is known. . As a production example of cis-diol (2b) from cis-diol (12b), conversion from cis-cyclopentanediol to cis-cyclopentanediamine (WO 98/30574) has been reported. According to these reports, cis-diamine (2b) can be produced.
The cis-diamine (2b) produced by the above method can be led to the cis-type compound (1) by the above production methods 1 to 4.

[Production Method 6]
As described above, the compound (1) of the present invention may have a trans isomer and a cis isomer at the Q ³ portion and have geometric isomers, but each may further have an optical isomer. Below, the manufacturing method of an optically active substance is demonstrated.

[Wherein, Q ⁵ , R ¹ , R ² , R ³ and R ⁴ are the same as defined above, and R ⁵⁰ represents an amino-protecting group. ]
Regarding the process for producing the optically active 1,2-trans type amino alcohol derivative (15), for example, the process for producing the optically active 1,2-trans-2-aminocyclopentanol from cyclopentene oxide or the optical activity from cyclohexene oxide. The preparation of 1,2-trans-2-aminocyclohexanol is known (Tetrahedron: Asymmetry, 1996, 7, 843; J. Org. Chem., 1985, 50, 4154). J. Med. Chem., 1998, 41, 38). The compound (16) can be produced by reacting the amino group of the optically active amino alcohol derivative (15) produced by applying such a known method or the method with an appropriate protecting reagent. . Examples of the protecting group corresponding to R ⁵⁰ in the compound (16) include an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a para Arylmethoxycarbonyl groups such as methoxybenzyloxycarbonyl group, para (or ortho) nitrobenzyloxycarbonyl group, and arylsulfonyl groups such as 2,4-dinitrobenzenesulfonyl group and orthonitrobenzenesulfonyl group are preferred. For example, when protecting with a tert-butoxycarbonyl group, the amino alcohol derivative (15) is reacted with di-tert-butyl dicarbonate at −78 ° C. to 50 ° C. in an inert solvent to give the compound (16). Can be manufactured. The inert solvent may be appropriately selected from those described in Production Method 1 and used.

Compound (17) can be produced by reacting compound (16) with methanesulfonyl chloride in an inert solvent in the presence of a base at −78 ° C. to 50 ° C. The inert solvent may be appropriately selected from those described in Production Method 1 and used. Examples of the base include organic compounds such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU). A base or the like is preferred.
Compound (18) can be produced by reacting compound (17) with sodium azide in an appropriate solvent at −10 ° C. to 150 ° C. Examples of the solvent include amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one, alcohol solvents such as methanol and ethanol, tetrahydrofuran, 1,2-dimethoxyethane, Suitable are ether solvents such as dioxane, benzene solvents such as toluene, halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride, acetone, dimethyl sulfoxide and mixed solvents of these solvents and water.
The method of converting the azide derivative (18) into the compound (7a) includes hydrogenation using a palladium catalyst, Raney nickel catalyst or platinum catalyst, reduction of lithium aluminum hydride, sodium borohydride, zinc borohydride, etc. There are many methods such as a reaction using an agent, a reaction using zinc in the presence of nickel chloride or cobalt chloride, and a reaction using triphenylphosphine, and a suitable reaction condition may be selected according to the properties of the compound. For example, the compound (7a) can be produced by hydrogenating the azide derivative (18) in a suitable solvent at a temperature of −10 ° C. to 70 ° C. using 1 to 20% palladium on carbon as a catalyst. The hydrogen pressure can also be raised above atmospheric pressure. Examples of the solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidine-2- An amide solvent such as ON, an ester solvent such as ethyl acetate, acetic acid, hydrochloric acid, water, or a mixed solvent thereof is suitable.
The optically active amine (7a) produced by the above method can be led to the optically active compound (1) according to the above production method 2. The enantiomer (1) of the optically active substance (1) obtained from the optically active amine (7a) can also be produced by the same method.
Furthermore, there is a method in which the optically active compound (1) is produced by separating the racemate (1) with a column comprising an optically active carrier. Further, the intermediate (2), (4), (7), (8) or (9) for producing the racemate (1) is separated by a column comprising an optically active carrier, and the optically active (2), It is also possible to isolate (4), (7), (8) or (9) and subsequently produce optically active compound (1) according to production methods 1 to 4. As a method of isolating optically active (1), (2), (4), (7), (8) or (9), a method of fractional crystallization of a salt with an optically active carboxylic acid, or Conversely, a method of fractional crystallization of a salt with an optically active base is also possible.

[Production Method 7]
Hereinafter, the compounds of the present invention (1), will be described in detail preparation of compounds (1c) containing a hetero atom in Q ^3.
The compound represented by the general formula (1c), a salt thereof, a solvate thereof, or an N-oxide thereof can be produced, for example, by the following method.

[Wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , A, m and n represent the same as described above, and T ¹ represents a carbonyl group. ]
Carboxylic acid (3) is derived into a mixed acid anhydride, acid halide or active ester, and reacted with compound (2c) to produce compound (4c). To compound (4c) thus obtained, carboxylic acid ( The compound (1c) of the present invention can be produced by reacting 5) under the same conditions.
In the reaction in each of the above steps, reaction reagents and conditions usually used for peptide synthesis may be applied mutatis mutandis. The mixed acid anhydride can be produced by reacting, for example, chloroformate esters such as ethyl chloroformate and isobutyl chloroformate with carboxylic acid (3) in the presence of a base. The acid halide can be produced by treating the carboxylic acid (3) with an acid halide such as thionyl chloride or oxalyl chloride. There are various types of active esters. For example, phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide, and carboxylic acid (3) are mixed with N, N′-dicyclohexylcarbodiimide ( DCC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride or other condensing agent. In addition, active esters include a reaction of carboxylic acid (3) with pentafluorophenyl trifluoroacetate, a reaction of carboxylic acid (3) with 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite, cyanophosphone. It can also be produced by reaction with diethyl acid (salt-in method), reaction of carboxylic acid (3) with triphenylphosphine and 2,2′-dipyridyl disulfide (Mukoyama method), and the like. Reacting the mixed acid anhydride, acid halide or active ester of carboxylic acid (3) thus obtained with compound (2c) in the presence of a suitable base under cooling to heating in an inert solvent. Thus, compound (4c) can be produced. The compound (1c) of the present invention can be produced by reacting the obtained compound (4c) with a mixed acid anhydride, acid halide or active ester of the carboxylic acid (5) under the same conditions. The reagents and reaction conditions in the reaction between the compound (4c) and the carboxylic acid (5) are the same as the reagents and reaction conditions in the reaction between the compound (2c) and the carboxylic acid (3).
Specific examples of bases used in the above steps include alkali metal or alkaline earth metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium ethoxide and potassium butoxide, sodium hydroxide and potassium hydroxide. Alkali metal hydroxides such as sodium hydride, alkali metal hydrides such as sodium hydride and potassium hydride, alkyllithiums such as n-butyllithium, organometallic bases represented by dialkylaminolithium such as lithium diisopropylamide, Organometallic bases of bissilylamines such as trimethylsilyl) amide, or pyridine, 2,6-lutidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [ .4.0] and organic bases such as undec-7-ene (DBU).

Examples of the inert solvent used in this reaction include alkyl halide solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran and 1,4-dioxane, aromatic solvents such as benzene and toluene, N, N- Examples thereof include amide solvents such as dimethylformamide. In addition to these, sulfoxide solvents such as dimethyl sulfoxide, ketone solvents such as acetone, and the like can be used.
In addition, in the above production process, the compound (1c) of the present invention can be produced by appropriately attaching / detaching a protecting group or converting a functional group.
As the protecting group for the amino group, a protecting group which is usually used as a protecting group for an amino group in the synthesis of organic compounds, particularly in peptide synthesis, may be used. Groups such as alkoxycarbonyl groups, benzyloxycarbonyl groups, paramethoxybenzyloxycarbonyl groups, para (or ortho) nitrobenzyloxycarbonyl groups and other arylmethoxycarbonyl groups, benzyl groups, 4-methoxybenzyl groups, triphenylmethyl groups, etc. Alkanoyl groups such as arylmethyl groups, formyl groups, and acetyl groups, aroyl groups such as benzoyl groups, and arylsulfonyl groups such as 2,4-dinitrobenzenesulfonyl groups and orthonitrobenzenesulfonyl groups.
As the hydroxyl-protecting group, a hydroxyl-protecting group usually used for the synthesis of organic compounds may be used. Specifically, alkoxymethyl groups such as methoxymethyl group, benzyl group, 4-methoxybenzyl group, triphenylmethyl An arylmethyl group such as a group, an alkanoyl group such as an acetyl group, an aroyl group such as a benzoyl group, and a tert-butyldiphenylsilyloxy group. The carboxy group can be protected as an ester with an alkyl group such as a methyl group, an ethyl group or a tert-butyl group or an arylmethyl group such as a benzyl group. The above protecting group can be attached or detached according to a conventional method.

The compound in the compound (1c) of the present invention can be led to various derivatives by converting the functional group of the compound. For example, a compound in which A is an unsubstituted nitrogen atom is obtained by acylating an amide compound with a mixed acid anhydride, acid halide, active ester, or the like by a normal organic chemical method, thereby converting a amide compound into a sulfonic acid halide, etc. A carbamate compound can be produced by a method of reacting a sulfonamide compound with an alkyl halide, an N-alkyl compound by reacting with an alkyl halide, an N-aryl compound by reacting with an aryl halide or the like, and an isocyanate. it can. The compound in which A is an unsubstituted nitrogen atom can be produced, for example, by subjecting compound (1c) produced according to production method 7 from diamine (2c) obtained by protecting A with a tert-butoxycarbonyl group by acid treatment. it can.
The compound of the present invention thus produced can be isolated and purified by a known method such as extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization and the like. In addition, the salt of the compound of the present invention can be converted into a desired salt by subjecting it to an ordinary salt formation reaction.
In addition, since the compound of the present invention has an asymmetric carbon, an optical isomer exists. In addition to the method for producing optically active diamines (2c), those optically active isomers used fractionated crystallization by forming salts with optically active amines or acids and optically active carriers. It can be produced by a method such as column chromatography.
Furthermore, in the reaction of the compound (2c) and the carboxylic acid (3), the compound (1c) in which T ¹ is a sulfonyl group is produced by replacing the carboxylic acid (3) with the sulfonic acid halide (10). Can do.

[Production Method 8]
Compound (1c) of the present invention can also be produced by the following method.

[Wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , A, m and n are the same as defined above, T ¹ represents a carbonyl group, R ⁵¹ and R ⁶¹ represent amino group protection] Indicates a group. ]
Compound (21) can be produced by removing protecting group R ⁶¹ of compound (19) obtained by protecting the amino group of compound (2c). Here, the protecting group for the amino group exemplified as R ⁵¹ and R ⁶¹ is not particularly limited as long as it is a group usually used for protecting an amino group, and the amino group described in Production Method 7 is representative. In this case, R ⁵¹ and R ⁶¹ must be protective groups that can be removed by different methods or conditions. For example, a representative combination is a combination in which R ⁵¹ is a tert-butoxycarbonyl group and R ⁶¹ is a benzyloxycarbonyl group. These protecting groups may be selected according to the properties of the compound protecting the amino group, and reagents and conditions corresponding to the protecting groups may be selected when removing these protecting groups.
Moreover, a compound (21) can be manufactured also by converting the hydroxyl group of an amino alcohol body (20) into an amino group. As an example of production of the aminoalcohol (20), for example, conversion of methionine to 3-hydroxy-4-aminothiopyran 1,1-dioxide (Tetrahedron Lett., 37, 7457, 1996) is known. ing.
As a method for converting the hydroxyl group of the amino alcohol form (20) to an amino group, the amino alcohol form (20) is reacted with methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc., and then ammonia, benzyl Primary arylalkylamines such as amine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, secondary arylalkylamines such as dibenzylamine, N-benzylhydroxylamine, N, O-dibenzylhydroxylamine A method of producing diamine (21) by reacting with hydroxylamines such as and the like, and removing benzyl group or the like, if necessary. In addition, by reacting the aminoalcohol (20) with triphenylphosphine and ethyl azodicarboxylate (Mukoyama method) or the like, after reacting with phthalimide or succinimide, etc., by treating with hydrazine or N-methylhydrazine, To the diamine (21). Furthermore, when A in the formula is SO ₂ and n = 0, the amino alcohol form (20) is reacted with methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride and the like. The α, β-unsaturated cyclic sulfone produced by treating with an appropriate base or by directly treating the amino alcohol form (20) with triphenylphosphine and ethyl azodicarboxylate is added with ammonia, benzylamine, p- Methoxybenzylamine, primary arylalkylamines such as 2,4-dimethoxybenzylamine, secondary arylalkylamines such as dibenzylamine, hydroxylamines such as N-benzylhydroxylamine, N, O-dibenzylhydroxylamine Benzyl group if necessary It can be produced diamine (21) by removing the.
The diamine compound (21) thus obtained is reacted with the carboxylic acid (3) to produce the compound (22). Subsequently, the protecting group R ⁵¹ is removed to obtain the compound (4c), and then the carboxylic acid (5) and The compound (1c) of this invention can be manufactured by making it react. In the reaction between the compound (21) and the carboxylic acid (3) and the reaction between the compound (4c) and the carboxylic acid (5), the same reagents and reaction conditions as described in the production method 7 may be used.
Similarly, in the reaction of compound (21) with carboxylic acid (3), compound (1c) in which T ¹ is a sulfonyl group is produced by replacing carboxylic acid (3) with sulfonic acid halide (10). be able to.

[Production Method 9]
A typical production method of the production intermediate (2c) described in the production method 7 will be described.

(In the formula, R ³ , R ⁴ , A, m and n are the same as described above.)
Examples of the production of the diol (23) include, for example, conversion of 1,2,3,6-tetrahydropyridine to 1-benzyloxycarbonyl-3,4-cis-dihydroxypyrrolidine (JP-A-7-138264), L- Conversion of tartaric acid to (R, R) -tetrahydrofurandiol or (R, R) -N-benzylpyrrolidinediol (Tetrahedron: Asymmetry, Vol. 8, 1861, 1997) is known. The diol (23) can be produced by applying such a known method or the method, and removing the protective group or converting the functional group as necessary.
Compound (24) can be produced by reacting diol (23) with methanesulfonyl chloride in an inert solvent in the presence of a base under cooling to room temperature. The inert solvent may be appropriately selected from those described in the production method 7, and is preferably an alkyl halide solvent such as dichloromethane or chloroform, or an ether solvent such as tetrahydrofuran or 1,4-dioxane. . Examples of the base include organic bases such as pyridine, 2,6-lutidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like. Is preferred.
The azide compound (25) can be produced by reacting the compound (24) with sodium azide in an appropriate solvent under cooling to heating. Examples of the solvent include amide solvents such as N, N-dimethylformamide and N-methylpyrrolidin-2-one, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, benzene and toluene. Aromatic solvents such as, alkyl halide solvents such as dichloromethane and chloroform, dimethyl sulfoxide, acetone and the like are suitable. Moreover, said common solvent is good also as a mixture with water.
The method of converting the azide (25) into the compound (2c) is a method of hydrogenation using a palladium catalyst, Raney nickel catalyst or platinum catalyst, a reaction using a reducing agent such as lithium aluminum hydride or sodium borohydride. There are many methods such as a reaction using zinc in the presence of nickel chloride or cobalt chloride and a reaction using triphenylphosphine, and reagents and conditions may be selected according to the properties of the compound. The hydrogen pressure can also be raised above atmospheric pressure. Examples of the solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidin-2-one, and ethyl acetate. An ester solvent, acetic acid, hydrochloric acid, water, or a mixed solvent thereof is suitable. The diamine body (2c) produced by the above method can be led to the present compound (1c) according to the above production method 7.
When the diol (23) is trans-3,4-dihydroxytetrahydrofuran or trans-1-substituted-3,4-dihydroxypyrrolidine, an optically active substance is present. These optically active diols (23) can be led to optically active diamines (2c), and further to optically active compound (1c) of the present invention according to production method 7.

[Manufacturing method 10]
A typical production method for optically active compounds (30), (31) and (32) contained in the compound (19) described in the production method 8 will be described. The coordination of asymmetric carbon shown in the following production route is shown as an example.

[Wherein, m, n, R ³ , R ⁵¹ and R ⁶¹ represent the same as described above, and R ⁷¹ represents a protecting group for a carboxy group. ]
The optically active α, β-unsaturated ester (26) is described in literature (J. Org. Chem., 61, 581, 1996; J. Org. Chem., 57, 6279, 1992, etc.). ), Or by applying the method described above. Diastereomers (27a) and (27b) can be produced by reacting the optically active α, β-unsaturated ester (26) and amine in a suitable solvent under cooling to heating. The amine may be appropriately selected from those described in the above production method 8 and used. As the solvent, an organic solvent that does not react with a substrate, a product, a reagent, or the like, particularly an alcohol solvent such as methanol or ethanol, or an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane is desirable. Further, by applying the method described in the literature (J. Org. Chem., 63, 7263, 1998), organic compounds such as α, β-unsaturated ester (26) and lithium N-benzyl (trimethylsilyl) amide are used. Diastereomers (27a) and (27b) can also be produced by reacting a metal base or the like. By separating this diastereomer, for example, (27a) can be used in the next reaction.
Compound (28) is produced by subjecting compound (27a) to acid treatment in a suitable solvent under cooling to heating. Examples of the acid used include Lewis acids such as hydrochloric acid, sulfuric acid, and boron trifluoride, trifluoroacetic acid, p-toluenesulfonic acid, and the like. Examples of the solvent used for the reaction include alcohol solvents such as water, methanol, and ethanol. Is used. The above solvent may be a mixture with water. In addition, during this reaction, the amino-protecting group R ⁶¹ may be cleaved. In that case, it is necessary to react with an appropriate amino group protecting reagent as necessary.
The optically active compound (30) can be produced by acid-treating the compound (28) in a solvent under cooling to heating. The acid to be used may be appropriately selected from the above acids, and Lewis acids such as boron trifluoride and p-toluenesulfonic acid are particularly preferable. As the solvent used in the reaction, ether solvents such as 1,4-dioxane and tetrahydrofuran, and aromatic solvents such as benzene and toluene are used. Compound (30) can also be produced from an azide isomer (29). Examples of the production of the optically active azide (29) include, for example, conversion of L-aspartic acid to (R, R)-(3S, 4S) -3-amino-4-azido-5-oxotetrahydrofuran (Can. J. Chem., 71, 1407 (1993)). An optically active azide (29) can be produced by applying such a known method or applying the method and removing the protective group or converting the functional group as necessary. After the azide of the azide (29) is reduced to an amino group, it is reacted with a suitable amino group protecting reagent to produce the compound (30). For the reduction of the azide, the same reagents and reaction conditions as described in the method for converting the azide compound (25) of production method 9 to the compound (2c) may be used.
Compound (31) can be produced by converting the hydroxyl group of compound (28) to an amino group and then treating with a base. As a method for converting the hydroxyl group of the compound (28) to an amino group, for example, the production method 8 can be used. Alternatively, the compound (31) can be produced by treating the alcohol form (28) with an oxidizing agent and then reductively aminating the obtained aldehyde form. Specific examples of the oxidizing agent used in the above reaction include pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and sulfur trioxide pyridine complex. Examples of the amine include primary alkylamines such as ammonia, methylamine and ethylamine, and primary arylalkylamines such as benzylamine, p-methoxybenzylamine and 2,4-dimethoxybenzylamine. The reduction method includes a method of hydrogenation using a palladium catalyst, Raney nickel catalyst or platinum catalyst, a reaction using a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, etc. The reagents and conditions may be selected according to the properties of the compound. In addition, the base used in the above steps may be appropriately selected from the bases described in Production Method 7 and used. Compound (31) can be prepared by the method described in the literature (Tetrahedron Lett., 41, 1141, 2000; Heterocycles, 53, 173, 2000) using the above compound (30) and an amine, or It can be manufactured by applying the method. Examples of the amine to be used include primary alkylamines such as ammonia, methylamine and ethylamine, primary arylalkylamines such as benzylamine and p-methoxybenzylamine, and aniline.
The compound (32) can be produced by treating the compound (31) with a reducing agent under cooling to heating in a solvent. Examples of the reducing agent include reducing agents such as borane / tetrahydrofuran complex, borane / methyl sulfide complex, and lithium aluminum hydride, but the reagents and conditions may be selected according to the properties of the compound. As the solvent, an organic solvent that does not react with a substrate, a product, a reagent, or the like, particularly an ether solvent such as tetrahydrofuran or 1,4-dioxane is desirable.
The compounds (30), (31) and (32) produced by the above method can be led to the optically active substance (1c) of the compound of the present invention according to the above production method 8.
The above production process is exemplified for one of the optically active substances. However, optically active substances having different steric coordinations can be produced in the same process if starting materials having different steric coordinations are used. it can.

[Production Method 11]
Compound (1) in which T ¹ is a —CO—CO—N (R ′) — group (wherein R ′ is the same as described above) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above, and T ¹ represents a —CO—CO—N (R ′) — group (in the group , R ′ represents the same as above. ]
That is, compound (4) is produced by derivatizing carboxylic acid (33) into an acid halide or active ester and reacting with diamine (2), and carboxylic acid (5) is added to compound (4) thus obtained. By reacting under the same conditions, the compound (1) of the present invention can be produced. In the reaction in each of the above steps, reaction reagents and conditions usually used for peptide synthesis may be applied mutatis mutandis. The acid halide can be produced by treating the carboxylic acid (33) with an acid halide such as thionyl chloride or oxalyl chloride. There are various active esters. For example, phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide and carboxylic acid (33) are mixed with N, N′-dicyclohexylcarbodiimide or 1-ethyl. It can be produced by reacting with a condensing agent such as -3- (3-dimethylaminopropyl) carbodiimide / hydrochloride. Further, the active ester is a reaction of carboxylic acid (33) with pentafluorophenyl trifluoroacetate or the like, a reaction of carboxylic acid (33) with 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite, carboxylic acid It can also be produced by the reaction of (33) with diethyl cyanophosphonate (salt insertion method), the reaction of carboxylic acid (33) with triphenylphosphine and 2,2′-dipyridyl disulfide (Mukayama method), and the like. The mixed acid anhydride, acid halide or active ester of carboxylic acid (33) thus obtained is reacted with diamine (2) in the presence of a suitable base in an inert solvent at -78 ° C to 150 ° C. Thus, compound (4) can be produced. Compound (1) of the present invention can be produced by reacting the obtained compound (4) with a mixed acid anhydride, acid halide or active ester of carboxylic acid (5) under the same conditions. The reagents and reaction conditions in the reaction of the compound (4) and the carboxylic acid (5) are the same as the reagents and reaction conditions in the reaction of the diamine (2) and the carboxylic acid (33). What is necessary is just to select suitably from the thing described in the manufacturing method 1 as a base and a solvent used for said each process.
Q ³ is the following group

[In the group, R ³ , R ⁴ and Q ⁵ are the same as those described above, and the numbers 1 and 2 represent positions. ]
When the cis-type or trans-type compound (1) is produced between the 1-position and the 2-position, the diamine (2a) or (2b) described in the production method 5 may be used.
Furthermore, when producing compound (1) containing a hetero atom such as a nitrogen atom, oxygen atom or sulfur atom in Q ⁵ , in the reaction of compound (2c) described in Production Method 7 with carboxylic acid (3) The carboxylic acid (3) may be replaced with the carboxylic acid (33). That is, the compound (1) containing a hetero atom in Q ⁵ , that is, the compound (1c) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , R ′, A, m and n are the same as defined above, and T ¹ represents a —CO—CO—N (R ′) — group. (In the group, R ′ is the same as above). ]

[Production Method 12]
Compound (1) in which T ¹ is a —CO—CO—N (R ′) — group (wherein R ′ is the same as described above) can also be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above, and T ¹ represents a —CO—CO—N (R ′) — group (in the group , R ′ represents the same as above. ]
In the reaction of amine (9) and carboxylic acid (33), the same reagents and conditions as described in Production Method 1 may be used.
The amine (9) used here can be produced not only by the route described in Production Method 2, but also by the route shown as the production route of the following amine (41), for example.

[Wherein, R ³ , R ⁴ , Q ¹ , Q ² and Q ⁵ are the same as those described above, and R ⁵² represents an amino-protecting group. ]
The compound (34) in the above production process can be produced by treating a cycloalkene with perbenzoic acid or a derivative thereof in a solvent such as dichloromethane and epoxidizing it. As for the reaction conditions, normal conditions for epoxidizing alkenes may be applied mutatis mutandis. Compound (34) was prepared according to J. Org. Org. Chem. 61, 8687-8691 (1996), or a method analogous thereto.
Compound (34) can be converted to compound (36) by subjecting azide (35) obtained by treatment with sodium azide or the like according to a conventional method to catalytic reduction, and then protecting the amino group. Examples of the amino-protecting group in this case include those described in Production Method 2. Compound (36) can be converted to azide (38) in the same manner as described in Production Method 5, and then the amino-protecting group can be removed to give compound (39). Compound (39) can be converted to compound (41) by reacting with carboxylic acid (5) to give compound (40) and then catalytic reduction.

[Manufacturing method 13]
Compound (1) in which T ¹ is a —CO—CO—N (R ′) — group (wherein R ′ is the same as defined above) is Compound (9) in the route described in Production Method 2 It can also be produced by replacing the reaction of carboxylic acid (3) with the reaction of compound (9) and carboxylic acid (33).

[Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ in the formula are the same as described above, and T ¹ represents a —CO—CO—N (R ′) — group (in the group , R ′ represents the same as described above. ]
The reaction conditions described in Production Method 2 may be applied mutatis mutandis.
Q ³ is the following group

(In the group, R ³ , R ⁴ and Q ⁵ are the same as described above, and the numbers 1 and 2 indicate positions.)
In the case of producing a compound (1) containing a hetero atom such as a nitrogen atom, oxygen atom or sulfur atom in Q ⁵ , the reaction of the compound (21) described in Production Method 8 with the carboxylic acid (3) In this case, the carboxylic acid (3) may be replaced with the carboxylic acid (33). Compound (1) containing a hetero atom in Q ⁵ , that is, compound (1c) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , R ′, A, m and n are the same as defined above, and T ¹ represents a —CO—CO—N (R ′) — group. (Wherein R ′ represents the same as described above), and R ⁵¹ represents an amino-protecting group. ]

[Manufacturing method 14]
T ¹ represents a —CO—A ¹ —N (R ″) — group (wherein R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, and A ¹ may have a substituent having 1 to 1 carbon atoms) Compound (1) is an inert solvent for compound (9) described in Production Method 2 and Q ⁴ —N (R ″) — A ¹ —CO ₂ H (42). In which the reaction is carried out using a condensing agent at −50 to 50 ° C. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl). Examples of the inert solvent include halogenated alkyl solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, and the like. Ether solvents, benzene, may be mentioned aromatic solvents such as toluene, N, amide solvent such such as N- dimethylformamide.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ″ represent the same as described above, and T ¹ represents a —CO—A ¹ —N (R ″) — group (formula R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, and A ¹ represents a C 1-5 alkylene group which may have a substituent.
Compound 42 described in the above production method includes, for example, an arylamine such as 4-chloroaniline and an ester of bromoalkanoic acid in a solvent such as acetonitrile or N, N-dimethylformamide in the presence of a base such as potassium carbonate. After making it react at 40-120 degreeC, it can manufacture by hydrolyzing ester using alkalis, such as lithium hydroxide, potassium hydroxide, sodium hydroxide. As compound 42, a potassium salt or the like may be used in the reaction as it is.

[Production Method 15]
The compound (1) in which T ¹ is a —C (═O) —NH— group or a —C (═S) —NH— group includes the compound (9) described in Production Method 2 and an isocyanate (Q ⁴ —N═ C = O) or isothiocyanate (Q ⁴ —N═C═S) can be produced by reacting at −20 to 50 ° C. in an inert solvent. As an inert solvent, what was described in the manufacturing method 14 can be mentioned as a representative example. The isocyanate and isothiocyanate used here may be produced by a method widely used as a production method of isocyanate or isothiocyanate when a commercially available product cannot be used.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are the same as defined above, and T ¹ represents a —C (═O) —NH— group or —C (═S) — NH-group is shown. ]

[Production Method 16]
Compound (1) wherein T ¹ is a —CO—NH—NH— group is obtained by reacting Compound (9) described in Production Method 2 and Q ⁴ —NH—NH—CO ₂ Ph (43) in an inert solvent. If necessary, it can be produced by reacting at room temperature to 150 ° C. in the presence of a base. As an inert solvent, what was described in the manufacturing method 14 other than acetonitrile and N, N- dimethylformamide can be mentioned as a representative example. Examples of the base include pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU). it can.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are the same as described above, T ¹ represents a —CO—NH—NH— group, and Ph represents a phenyl group. ]
Compound (43) described in the above production method is obtained by, for example, using aryl hydrazine such as 4-chlorophenylhydrazine and diphenyl carbonate, acetonitrile, N, N-dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane. It can manufacture by making it react at room temperature-120 degreeC in solvents, such as a dioxane, benzene, and toluene.

[Production Method 17]
The compound (1) in which T ¹ is a —CO—A ² —CO— group (wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms) is a compound described in Production Method 2 ( 9) and Q ⁴ —CO—A ² —CO ₂ H (44) can be produced by reacting them in an inert solvent at −50 to 50 ° C. using a condensing agent. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride. Examples of the solvent include the solvents described in Production Method 16.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are the same as defined above, and T ¹ represents a —CO—A ² —CO— group (wherein A ² represents a single bond] Or an alkylene group having 1 to 5 carbon atoms.
]
When A ² is a single bond, the compound (44) described in the above production method has, for example, an aromatic hydrocarbon such as chlorobenzene or an aromatic heterocycle such as thiophene and a chlorooxoacetate (eg, ClCO-CO ₂ Et) and Friedel-Crafts compound prepared by the reaction of (production _{^{examples, Q 4 -CO-CO 2 Et}} ) with lithium hydroxide, potassium hydroxide, by hydrolysis with an alkali such as sodium hydroxide can do.
In addition, when A ² is a methylene group, the compound (44) is prepared by, for example, arylcarbonyl chlorides such as 4-chlorobenzoic acid chloride or heteroarylcarbonyl chloride such as thiophenecarbonyl chloride in the presence of magnesium chloride and triethylamine A ketoester derivative (eg, Q ⁴ —CO—CH ₂ —CO ₂ Et) obtained by reacting with a malonic acid monoester monocarboxylic acid potassium salt is used with an alkali such as lithium hydroxide, potassium hydroxide or sodium hydroxide. It can be produced by hydrolysis. In the ketoester induction described above, a carboxylic acid obtained by hydrolyzing the carbonyl group after ethylene ketalization may be used for the reaction with the compound (9). Further, the compound (44) is, A ² is in the case of two or more alkylene groups having carbon, for example, such as aromatic hydrocarbons or thiophene such as benzene and aromatic heterocyclic and alkylene dicarboxylic acid monoester monochloride Produced by hydrolyzing a ketoester derivative (eg, Q ⁴ —CO—A ² —CO ₂ Et) obtained by Friedel-Crafts reaction using an alkali such as lithium hydroxide, potassium hydroxide or sodium hydroxide. be able to.

[Production Method 18]
The compound (1) in which T ¹ is a —CO—A ³ —CO—NH— group (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms) is represented by the compound (9 ) And Q ⁴ —NH—CO—A ³ —CO ₂ H (45) in an inert solvent at −50 to 50 ° C. using a condensing agent. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride. Examples of the inert solvent include halogenated alkyl solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene and toluene, N, Examples include amide solvents such as N-dimethylformamide.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are the same as defined above, and T ¹ represents a —CO—A ³ —CO— group (wherein A ³ represents the number of carbon atoms] Represents an alkylene group of 1 to 5). ]
Compound (45) is a condensing agent comprising an arylamine such as 4-chloroaniline corresponding to Q ⁴ -NH ₂ or a heteroarylamine such as aminopyridine and an alkylene dicarboxylic acid monoester potassium salt in an inert solvent. A compound (eg, Q ⁴ —NH—CO—A ³ —CO ₂ Et) produced by reacting at −50 to 50 ° C. with an alkali such as lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. Can be produced by hydrolysis.

[Production Method 19]
Compound (1) in which T ¹ is a —CS—CO—N (R ′) — group (wherein R ′ is the same as described above) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above, and T ¹ represents a —CS—CO—N (R ′) — group (in the group , R ′ represents the same as above. ]
That is, the compound (1) of the present invention can be produced by dissolving or suspending sodium thiosulfate salt (46) and compound (9) in a solvent and heating. The reaction temperature is preferably from 80 to 200 ° C, particularly preferably around 150 ° C. Solvents used in this reaction include water, alcohols such as methanol and ethanol, basic solvents such as pyridine and N-methylmorpholine, halogenated alkyl solvents such as dichloromethane and chloroform, tetrahydrofuran, 1,2-dimethoxyethane. , Ether solvents such as dioxane, amide solvents such as N, N-dimethylformamide, and the like. These solvents may be used in a suitable mixture. Examples of mixed solvents include a mixture of methanol and dichloromethane. A solvent etc. can be mentioned. In this reaction, it is not always necessary to reflux the solvent. For example, when a mixed solvent of methanol and dichloromethane is used, the reaction liquid (or reaction mixture) is heated to an external temperature of 150 ° C. to distill off the solvent. After that, the residue is continuously heated at the same temperature.

[Production Method 20]
Compound (1) wherein T ¹ is a —CO—CS—N (R ′) — group (wherein R ′ is the same as described above) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above, and T ¹ represents a —CO—CS—N (R ′) — group (in the group , R ′ represents the same as above. ]
That is, after reacting compound (9) with chloroacetic acid chloride in the presence of a base to lead to compound (47), compound (47) is heated in sodium thiosulfate and a solvent to thereby obtain sodium thiosulfate derivative (48). Can be manufactured. The compound (1) of the present invention can be produced by heating (48) thus obtained with an amine, that is, HN (R ′)-Q ⁴ .
The conditions, solvent, etc. for producing the compound (47) from the compound (9) may be applied mutatis mutandis for those used in the reaction of amine and acid chloride. In order to produce the compound (48) from the compound (47), it may be heated and refluxed with sodium thiosulfate for about 1 hour in a solvent such as ethanol. When compound (47) is a salt such as hydrochloric acid, the reaction may be carried out in the presence of a base such as sodium bicarbonate. The production conditions of the compound (48) are not limited to those described here, and the temperature, the type of solvent, and the type of base can be appropriately changed. The reaction conditions for the compound (48) and HN (R ′)-Q ⁴ are the same as those described in Production Method 19.

[Production Method 21]
Compound (1) in which T ⁰ is a thiocarbonyl group (—CS— group) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ and R ² are the same as defined above, and T ¹ represents a —SO ₂ — group, a —CO— group, a —CO—NH— group, —CS— NH— group, —CO—NH—NH— group, —CO—CO—N (R ′) — group (wherein R ′ is the same as described above), —CO—CS—N (R ′ ) -Group (wherein R ′ is the same as above), —CS—CO—N (R ′) — group (wherein R ′ is the same as above), —CS—. CS—N (R ′) — group (wherein R ′ is the same as defined above), —CO—A ¹ —N (R ″) — group (wherein A ¹ and R ″ are as defined above) -CO-A ² -CO- group (in the group, A ² is the same as described above), -CO-A ³ -CO-NH- group (in the group, A ³ is the same meanings as defined above), -. during CO-a ³ -CO- group (group, a ³ is also the same as the Are shown.) Shows the. ]
That is, the compound (49) is dehydrated with the amine (50) in the presence of an acid catalyst such as p-toluenesulfonic acid and led to the compound (51), and then in a solvent such as sulfur powder and methanol / dichloromethane mixture. The compound (1) of the present invention can be produced by heating. As for the conditions for producing the compound (51) from the compound (49) and the amine (50), those generally used for producing a Schiff base may be applied mutatis mutandis. Specifically, it may be heated and refluxed in benzene or toluene in the presence of an acid catalyst under the condition that water is removed from the reaction system using a Dean Stark apparatus or the like. Further, when removing water from the reaction system, a molecular sieve may be used.

[Manufacturing method 22]
Compound (1) in which T ¹ is a —CS—CO—N (R ′) — group (wherein R ′ is the same as described above) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above, and T ¹ represents a —CS—CO—N (R ′) — group (in the group , R ′ represents the same as above. ]
Compound (52) is an arylamine such as 4-chloroaniline corresponding to HN (R ′) Q ⁴ or a heteroarylamine such as aminopyridine and dichloroacetyl chloride, an inert solvent such as N, N-dimethylformamide, or pyridine. In a basic solvent of −78 ° C. to 150 ° C. Alternatively, compound (52) can be produced by reacting dichloroacetic acid with an amine corresponding to HN (R ′) Q ^{4 under} the reagents and conditions described in Production Method 1.
Compound (1) is obtained by suspending compound (52) and sulfur powder in a solvent, adding a base such as diisopropylethylamine or triethylamine and diamine (9), and reacting at a reaction temperature of 0 ° C. to 200 ° C. It can be manufactured efficiently. The amount of sulfur powder used in the reaction is preferably 1 equivalent. The reaction temperature is preferably 60 ° C to 160 ° C, particularly preferably 90 ° C to 140 ° C. Solvents used in this reaction include amide solvents such as N, N-dimethylformamide, basic solvents such as N-methylmorpholine and pyridine, alcohols such as ethanol and butanol, ether solvents such as dioxane, acetonitrile, Water etc. can be mentioned.

[Production Method 23]
Compound (1) in which T ¹ is a —CS—CO—N (R ′) — group (wherein R ′ is the same as described above) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above, and T ¹ represents a —CS—CO—N (R ′) — group (in the group , R ′ represents the same as above. ]
Compound (53) is an arylamine such as 4-chloroaniline corresponding to HN (R ′) Q ⁴ or a heteroarylamine such as aminopyridine and chloroacetyl chloride, an inert solvent such as N, N-dimethylformamide, or pyridine. It can manufacture by reacting at -78 degreeC-150 degreeC in a basic solvent. Alternatively, compound (53) can be produced by reacting chloroacetic acid with an amine corresponding to HN (R ′) Q ^{4 under} the reagents and conditions described in Production Method 1.
Compound (1) is prepared by suspending compound (53) and sulfur powder in a solvent, adding a base such as diisopropylethylamine or triethylamine, stirring for 5 minutes to 8 hours, and then adding diamine (9) and a condensing agent to react. Can be manufactured. The amount of sulfur powder used in the reaction is preferably 2 equivalents or more, and the reaction temperature is preferably 0 ° C to 80 ° C. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride or N, N′-dicyclohexylcarbodiimide. Solvents used in this reaction include amide solvents such as N, N-dimethylformamide, basic solvents such as N-methylmorpholine and pyridine, alkyl halide solvents such as dichloromethane and chloroform, and ether solvents such as dioxane. And acetonitrile. Further, this reaction proceeds even without a condensing agent, and compound (1) can be produced. In that case, alcohols such as methanol and ethanol, water, and the like can be used in addition to the solvents described above.

[Production Method 24]
In the compound (1) in which T ¹ is a —CS—CO—N (R ′) — group (wherein R ′ is the same as described above), T ¹ is —CS—CO—N (R ′ It can also be produced by the following route via compound (4) which is a group (wherein R ′ is the same as above).

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above. T ¹ represents a —CS—CO—N (R ′) — group (wherein R ′ is the same as described above). ]
That is, after reacting the dichloroacetamide compound (52) or chloroacetamide compound (53), sulfur powder and amine (7) in a solvent in the presence of a base, the protecting group is deprotected to give compound (4). The compound (1) of the present invention can be produced by condensing the carboxylic acid (5) to the produced compound (4). Compound (54) is obtained by suspending compound (52) and sulfur powder in a solvent, adding a base such as diisopropylethylamine or triethylamine and amine (7), and reacting at a reaction temperature of 0 ° C. to 200 ° C. It can be manufactured efficiently. The amount of sulfur powder used in the reaction is preferably 1 equivalent. The reaction temperature is preferably 60 ° C to 160 ° C, particularly preferably 90 ° C to 140 ° C. Solvents used in this reaction include amide solvents such as N, N-dimethylformamide, basic solvents such as N-methylmorpholine and pyridine, alcohols such as ethanol and butanol, ether solvents such as dioxane, acetonitrile, Water etc. can be mentioned. Compound (54) is obtained by suspending compound (53) and sulfur powder in a solvent, adding a base such as diisopropylethylamine or triethylamine, stirring for 5 minutes to 5 hours, and then adding amine (7) and a condensing agent. It can be produced by reacting. The amount of sulfur powder used in the reaction is preferably 2 equivalents or more, and the reaction temperature is preferably 0 ° C to 80 ° C. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride or N, N′-dicyclohexylcarbodiimide. Solvents used in this reaction include amide solvents such as N, N-dimethylformamide, basic solvents such as N-methylmorpholine and pyridine, alkyl halide solvents such as dichloromethane and chloroform, and ether solvents such as dioxane. And acetonitrile. Further, this reaction proceeds even without a condensing agent, and compound (54) can be produced. In that case, alcohols such as methanol and ethanol, water, and the like can be used in addition to the solvents described above. Furthermore, compound (54) can also be produced by reacting sodium thiosulfate salt (46) with amine (7) using the reaction conditions described in Production Method 19.
Compound (4) can be produced by treating compound (54) with trifluoroacetic acid or the like at −20 ° C. to 70 ° C.
Carboxylic acid (5) is produced from compound (4) in which T ¹ thus produced is a —CS—CO—N (R ′) — group (wherein R ′ is as defined above). The compound (1) of this invention can be manufactured by making it react by the method described in the method 1.
The tert-butoxycarbonyl group of the compound (7) can be replaced with a protective group for other amino groups as described in Production Method 2. What is necessary is just to select the kind of protecting group according to the property etc. of a compound, and what is necessary is just to select the reagent and conditions according to the protecting group also at the time of the cutting | disconnection of a protecting group.

[Production Method 25]
Compound (1) in which T ¹ is a —CO—N (R ′) — CO— group (wherein R ′ is the same as described above) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above, and T ¹ represents a —CO—N (R ′) — CO— group (in the group , R ′ represents the same as described above. ]
That is, the compound (1) of the present invention comprises an arylamide such as 4-chlorobenzamide corresponding to HN (R ′) COQ ⁴ (55) or a heteroarylamide such as picolinamide via an acyl isocyanate intermediate ( After deprotecting the compound (54) produced by reacting with 7), the obtained compound (4) can be produced by condensing with the carboxylic acid (5).
For example, amide (55) is reacted with oxalyl chloride in an inert solvent at a reaction temperature of 20 ° C. to 100 ° C. to produce an acyl isocyanate derivative, and with amine (7) at a reaction temperature of 0 ° C. to 100 ° C. A compound (54) can be manufactured by making it react. Examples of the inert solvent used in this reaction include alkyl halide solvents such as dichloromethane, chloroform and dichloroethane, ether solvents such as tetrahydrofuran and dioxane, aromatic solvents such as benzene and toluene, N, N-dimethylformamide, Examples thereof include amide solvents such as N, N-dimethylacetamide, acetonitrile and the like.
Compound (4) can be produced by treating compound (54) with trifluoroacetic acid or the like at −20 ° C. to 70 ° C.
Carboxylic acid (5) is produced from compound (4) in which T ¹ thus produced is a —CO—N (R ′) — CO— group (wherein R ′ is the same as described above). The compound (1) of this invention can be manufactured by making it react by the method described in the method 1.
The tert-butoxycarbonyl group of the compound (7) can be replaced with a protective group for other amino groups as described in Production Method 2. What is necessary is just to select the kind of protecting group according to the property etc. of a compound, and what is necessary is just to select the reagent and conditions according to the protecting group also at the time of the cutting | disconnection of a protecting group.

[Production Method 26]
Compound (1) in which T ¹ is a —SO ₂ —N (R ′) — group (wherein R ′ is the same as described above) can be produced by the following route.

[Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R ′ represent the same as described above, and T ¹ represents a —SO ₂ —N (R ′)-group (in the group, R ′ represents the same as above. ]
Compound (1) is an amidosulfuric acid derivative that can be produced by reacting an amine such as 4-chloroaniline corresponding to HN (R ′) Q ⁴ with chlorosulfuric acid in an inert solvent at a reaction temperature of −78 ° C. to 30 ° C. Is activated with a reagent such as phosphorus pentachloride and then reacted with amine (9). As a reagent for activating the amidosulfuric acid derivative, a condensing agent such as 1,1′-carbonyldiimidazole may be used in addition to a halogenating reagent such as phosphorus pentachloride and phosphorus oxychloride. it can. In this reaction, when activated with a halogenating reagent such as phosphorus pentachloride, phosphorus oxychloride, etc., it is preferably heated at 50 ° C. to 120 ° C. Examples of the inert solvent used in this reaction include alkyl halide solvents such as dichloromethane, chloroform and dichloroethane, ether solvents such as tetrahydrofuran and dioxane, aromatic solvents such as benzene and toluene, N, N-dimethylformamide, Examples thereof include amide solvents such as N, N-dimethylacetamide, acetonitrile and the like.
The important intermediates described in the production methods 1 to 21 for the compound (1) in the present invention are described below.
1) The compound represented by the following general formula (4) described in the above production methods 1, 3 and 11 is important as a production intermediate of the compound (1) in the present invention.

[Wherein R ¹ , R ² , Q ³ and Q ⁴ are the same as defined above, and T ¹ represents a carbonyl group, a sulfonyl group or a —CO—CO—N (R ′) — group (in the group, R 'Indicates the same as above. ]
Among the above intermediates, T ¹ represents a group —C (═O) —C (═O) —N (R ′) — (wherein R ′ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group. And T ¹ in the above formula is a carbonyl group, and Q ³ is the following group:

(In the group, R ³ and R ⁴ are the same as above, Q ⁵ is a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n— (in the group, m and n are Each independently represents an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, —NH—NH—, -S-NH -, -. the SO-NH- or an -SO ₂ -NH-)), compound are preferred.
2) The compound represented by the following general formula (9) described in the production methods 2, 4 and 12 is important as a production intermediate of the compound (1) in the present invention.

[Wherein, R ¹ , R ² , Q ¹ , Q ² and Q ³ are the same as described above. ]
Among the above intermediates, Q ³ is the following group

(In the group, R ³ and R ⁴ are the same as above, Q ⁵ is a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n— (in the group, m and n are Each independently represents an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, —NH—NH—, -S-NH -, -. the SO-NH- or an -SO ₂ -NH-)), compound are preferred.
3) The following compound (4c) described in the production methods 7, 11 and 13 is important as a production intermediate of the compound (1) in the present invention.

[Wherein, Q ⁴ , R ³ , R ⁴ , A, m and n are the same as defined above, and T ¹ represents a carbonyl group, a sulfonyl group or a —CO—CO—N (R ′) — group (in the group , R ′ represents the same as described above. ]
Among the above intermediates, a compound in which T ¹ in the above formula is a —CO—CO—N (R ′) — group (wherein R ′ is the same as defined above), and T ¹ is carbonyl a group, a is an oxygen atom, a nitrogen atom, a sulfur _{atom, -SO -, - SO 2 -} , - NH -, - O-NH -, - NH-NH -, - S-NH -, - SO-NH A compound that is — or —SO ₂ —NH— is preferred. 4) The following compound (22) described in the production methods 8 and 13 is important as a production intermediate of the compound (1) in the present invention.

[Wherein, Q ⁴ , R ³ , R ⁴ , A, m and n are the same as defined above, and T ¹ represents a carbonyl group, a sulfonyl group or a —CO—CO—N (R ′) — group (in the group , R ′ represents the same as above, and R ⁵¹ represents an amino-protecting group. ]
Among the above intermediates, a compound in which T ¹ in the above formula is a —CO—CO—N (R ′) — group (wherein R ′ is the same as defined above), and T ¹ is carbonyl a group, a is an oxygen atom, a nitrogen atom, a sulfur _{atom, -SO -, - SO 2 -} , - NH -, - O-NH -, - NH-NH -, - S-NH -, - SO-NH A compound that is — or —SO ₂ —NH— is preferred.
5) The following optically active compound (7a) described in production method 6 is important as a production intermediate of compound (1) in the present invention.

[Wherein, Q ⁵ , R ¹ , R ² , R ³ and R ⁴ are the same as defined above, and R ⁵⁰ represents an amino-protecting group. ]
Among the above intermediates, Q ⁵ in the above formula is a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n— (in which m and n are each independently 0, Represents an integer of 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, —NH—NH—, —S—NH—, -SO-NH- or an -SO ₂ -NH-.) compounds wherein is preferred.
6) The following compound (21) described in the production method 8 is important as a production intermediate of the compound (1) in the present invention.

[Wherein, R ³ , R ⁴ , A, m and n represent the same as described above, and R ⁵¹ represents an amino-protecting group. ]
Among the above intermediates, A in the above formula is an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, —NH—NH—, —S—. Compounds that are NH—, —SO—NH— or —SO ₂ —NH— are preferred.
7) The following compounds described in the production method 10 are important as production intermediates of the compound (1) in the present invention.
That is, the following optically active trans compounds (30), (31) and (32),

[Wherein, R ³ , m and n are the same as defined above, and R ⁵¹ and R ^{61 each} represent an amino-protecting group. ]
Enantiomers (30a), (31a) and (32a) of the above compound produced in the same manner,

[Wherein, R ³ , m and n are the same as defined above, and R ⁵¹ and R ^{61 each} represent an amino-protecting group. ]
Cis-type compounds (30b), (31b) and (32b),

[Wherein, R ³ , m and n are the same as defined above, and R ⁵¹ and R ^{61 each} represent an amino-protecting group. ]
And their enantiomers (30c), (31c) and (32c)

[Wherein, R ³ , m and n are the same as defined above, and R ⁵¹ and R ^{61 each} represent an amino-protecting group. ]
Is important as an intermediate for the production of compound (1) in the present invention.
Since the diamine derivative of the present invention exhibits a potent activated blood coagulation factor X inhibitory action, it is useful for pharmaceuticals for mammals including humans, particularly activated blood coagulation factor X inhibitors, blood coagulation inhibitors, thrombus or Agents for the prevention and / or treatment of emboli, agents for the prevention and / or treatment of thrombotic diseases, as well as cerebral infarction, cerebral embolism, myocardial infarction, angina, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, pancreatic Thrombus formation after prosthetic valve / joint replacement, thrombus formation and reocclusion after revascularization, systemic inflammatory response syndrome (SIRS), multiple organ failure (MODS), thrombus formation during extracorporeal circulation Alternatively, it is useful as a preventive and / or therapeutic agent for blood coagulation during blood collection.
When the compound of the present invention is used as a medicine for the human body, the dosage is in the range of 1 mg to 1 g, preferably 10 mg to 300 mg per day for an adult. The dose for animals varies depending on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and extent of the infectious pathogen, but the daily dose is generally the animal's body weight. The range is 0.1 mg to 200 mg per kg, preferably 0.5 mg to 100 mg. This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above amount if necessary.

A pharmaceutical composition containing the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations commonly used. Examples of the dosage form of the pharmaceutical composition comprising the compound of the present invention as a main ingredient include tablets, powders, granules, capsules, liquids, syrups, elixirs, oily or aqueous suspensions, and the like. .
As injections, stabilizers, preservatives, and solubilizing aids may be used in the preparation. After storing a solution that may contain these adjuvants in a container, it may be prepared as a solid preparation by lyophilization or the like. It is good also as a formulation. Further, a single dose may be stored in one container, and multiple doses may be stored in one container.
Examples of the preparation for external use include liquids, suspensions, emulsions, ointments, gels, creams, lotions, sprays, patches and the like.
The solid preparation includes pharmaceutically acceptable additives together with the compound of the present invention, and includes, for example, fillers, extenders, binders, disintegrants, dissolution accelerators, wetting agents, lubricants and the like. It can be selected and mixed as necessary to prepare a formulation.
Examples of liquid preparations include solutions, suspensions, emulsions, etc., but additives may include suspending agents, emulsifiers, and the like.
Examples of the present compound include the following compounds (A) to (E).
(A) General formula (1)
^{Q 1 -C (= O) -N} (R 1) -Q 2 -N (R 2) -T 1 -Q 3 (1)
[Wherein, R ¹ and R ² each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
Q ¹ is a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group that may have a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic group that may have a substituent, or a substituent. A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent Show;
Q ² is the following group

(In the group, Q ⁴ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n — (in the group , M and n each independently represents an integer of 0, 1 to 3, and A represents an oxygen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, —NH—NH. -, - S-NH -, - SO-NH- or -SO ₂ -NH- are shown, 1 and 2 indicate positions) indicates.;
R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁴ , and each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom or a halogenoalkyl. Group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, Alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group , Alkoxy carbon An amino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, having a substituent 3 to 6 members A ring carbonyl group, a carbamoylalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, a carbamoyloxy An alkyl group, an N-alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an optionally substituted 3- to 6-membered heterocyclic carbonylalkyl group, and an optionally substituted 3- 6-membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylamino Carbonyl group Reelsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkyl Sulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group , An alkoxyalkylsulfonyl group, a 3- to 6-membered heterocyclic sulfonyl group which may have a substituent Nyl group, N-alkylaminoacyl group, N, N-dialkylaminoacyl group, N, N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group, Substituent on the alkyl group An N, N-dialkylcarbamoylalkylsulfonyl group, an alkylsulfonylacyl group, or the like, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, carbon An alkylenedioxy group or a carbonyldioxy group represented by formulas 1 to 5 is shown. );
Q ³ is an aryl group which may have a substituent, an arylalkenyl group which may have a substituent, a heteroaryl group which may have a substituent, a heteroarylalkenyl group which may have a substituent, a substituent A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent ;
T ¹ represents a carbonyl group or a sulfonyl group. Or a salt thereof, a solvate thereof, or an N-oxide thereof.

(B) General formula (1)
^{Q 1 -Q 2 -C (= O} ) -N (R 1) -Q 3 -N (R 2) -T 1 -Q 4 (1)
[Wherein, R ¹ and R ² each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
Q ¹ is a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group that may have a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic group that may have a substituent, or a substituent. A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent Show;
Q ² is a single bond, a divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group that may have a substituent, or a divalent saturated or unsaturated 5 to 6 that may have a substituent. A membered heterocyclic group, a divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated group which may have a substituent A bicyclic or tricyclic fused heterocyclic group of
Q ³ is the following group

(In the group, Q ⁵ represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n — (in the group , M and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, — NH—NH—, —S—NH—, —SO—NH— or —SO ₂ —NH— is indicated);
R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom or a halogenoalkyl group. Group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, Alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group , Alkoxy carbon An amino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, having a substituent 3 to 6 members A ring carbonyl group, a carbamoylalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, a carbamoyloxy An alkyl group, an N-alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an optionally substituted 3- to 6-membered heterocyclic carbonylalkyl group, and an optionally substituted 3- 6-membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylamino Carbonyl group Reelsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkyl Sulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group , An alkoxyalkylsulfonyl group, a 3- to 6-membered heterocyclic sulfonyl group which may have a substituent Nyl group, N-alkylaminoacyl group, N, N-dialkylaminoacyl group, N, N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group, Substituent on the alkyl group An N, N-dialkylcarbamoylalkylsulfonyl group, an alkylsulfonylacyl group, or the like, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, carbon An alkylenedioxy group or a carbonyldioxy group represented by formulas 1 to 5 is shown. );
Q ⁴ represents an aryl group which may have a substituent, an arylalkenyl group which may have a substituent, a heteroaryl group which may have a substituent, a heteroarylalkenyl group which may have a substituent, a substituent A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent ;
T ¹ represents a carbonyl group, a sulfonyl group, or a group —C (═O) —C (═O) —N (R ′) — (wherein R ′ represents a hydrogen atom, a hydroxyl group, an alkyl group, or an alkoxy group. ). Or a salt thereof, a solvate thereof, or an N-oxide thereof.

(C) General formula (1)
^{Q 1 -Q 2 -C (= O} ) -N (R 1) -Q 3 -N (R 2) -T 1 -Q 4 (1)
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group; Q ¹ represents a saturated or unsaturated 5- to 6-membered cyclic ring which may have a substituent Hydrocarbon group, saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent Or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have a substituent;
Q ² is a single bond, a divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group that may have a substituent, or a divalent saturated or unsaturated 5 to 7 that may have a substituent. A membered heterocyclic group, a divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated group which may have a substituent A bicyclic or tricyclic fused heterocyclic group of
Q ³ is the following group

(In the group, Q ⁵ represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n — (in the group , M and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, — NH—NH—, —S—NH—, —SO—NH— or —SO ₂ —NH— is indicated);
R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom or a halogenoalkyl group. Group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, Alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group , Alkoxy carbon An amino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, having a substituent 3 to 6 members A ring carbonyl group, a carbamoylalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, a carbamoyloxy An alkyl group, an N-alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an optionally substituted 3- to 6-membered heterocyclic carbonylalkyl group, and an optionally substituted 3- 6-membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylamino Carbonyl group Reelsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkyl Sulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group , An alkoxyalkylsulfonyl group, a 3- to 6-membered heterocyclic sulfonyl group which may have a substituent Nyl group, N-alkylaminoacyl group, N, N-dialkylaminoacyl group, N, N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group, Substituent on the alkyl group Represents an N, N-dialkylcarbamoylalkylsulfonyl group or an alkylsulfonylacyl group, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, a carbon number 1 to 5 alkylenedioxy groups or carbonyldioxy groups are shown. );
Q ⁴ represents an aryl group that may have a substituent, an arylalkenyl group that may have a substituent, an arylalkynyl group that may have a substituent, a heteroaryl group that may have a substituent, or a substituent. A heteroarylalkenyl group which may have, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, a saturated or unsaturated bicyclic which may have a substituent or Represents a tricyclic fused heterocyclic group;
T ¹ represents a carbonyl group, a sulfonyl group, or a group —C (═O) —C (═O) —N (R ′) — (wherein R ′ represents a hydrogen atom, a hydroxyl group, an alkyl group, or an alkoxy group. ), A group —C (═O) —A ¹ —N (R ″) — (wherein A ¹ represents an optionally substituted alkylene group having 1 to 5 carbon atoms, R ″ represents a hydrogen atom, A hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —NH—, a group —C (═S) —NH—, a group —C (═O) —NH—NH—, a group —C. (═O) —A ² —C (═O) — (wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), a group —C (═O) —A ³ —C ( ═O) —NH— (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms) or a thiocarbonyl group. Or a salt thereof, a solvate thereof, or an N-oxide thereof.

(D) General formula (1)

[Wherein, R ¹ and R ² each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
Q ¹ is a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, a substituent A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent Show;
Q ² is a single bond, a divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group that may have a substituent, or a divalent saturated or unsaturated 5 to 7 that may have a substituent. A membered heterocyclic group, a divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated group which may have a substituent A bicyclic or tricyclic fused heterocyclic group of
Q ³ is the following group

(In the group, Q ⁵ represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group — (CH ₂ ) _m —CH ₂ —A—CH ₂ — (CH ₂ ) _n — (in the group , M and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, — NH—NH—, —S—NH—, —SO—NH— or —SO ₂ —NH— are indicated);
R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom or a halogenoalkyl group. Group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, Alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group , Alkoxy carbon An amino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, having a substituent 3 to 6 members A ring carbonyl group, a carbamoylalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, a carbamoyloxy An alkyl group, an N-alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an optionally substituted 3- to 6-membered heterocyclic carbonylalkyl group, and an optionally substituted 3- 6-membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylamino Carbonyl group Reelsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkyl Sulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group , An alkoxyalkylsulfonyl group, a 3- to 6-membered heterocyclic sulfonyl group which may have a substituent Nyl group, N-alkylaminoacyl group, N, N-dialkylaminoacyl group, N, N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group, Substituent on the alkyl group Represents an N, N-dialkylcarbamoylalkylsulfonyl group or an alkylsulfonylacyl group, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, a carbon number 1 to 5 alkylenedioxy groups or carbonyldioxy groups are shown. );
Q ⁴ represents an aryl group that may have a substituent, an arylalkenyl group that may have a substituent, an arylalkynyl group that may have a substituent, a heteroaryl group that may have a substituent, or a substituent. A heteroarylalkenyl group which may have, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, a saturated or unsaturated bicyclic which may have a substituent or Represents a tricyclic fused heterocyclic group;
T ^O represents a carbonyl group or a thiocarbonyl group;
T ¹ is a carbonyl group, a sulfonyl group, a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′). -, Group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(in which R 'is A hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —A ¹ —N (R ″) — (wherein A ¹ may have a substituent having 1 to 1 carbon atoms; 5 represents an alkylene group, and R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —NH—, a group —C (═S) —NH—, a group —C (═O) —NH—NH—, group —C (═O) —A ² —C (═O) — (wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), Group —C (═O) —A ³ —C (═O) —NH— (wherein A ³ is the number of carbon atoms) 1 to 5 alkylene groups), a group —C (═O) —C (═NOR ^a ) —N (R ^b ) —, a group —C (═S) —C (═NOR ^a ) —N ( R ^b ) — (wherein R ^a represents a hydrogen atom, an alkyl group or an alkanoyl group, and R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group —C (═O) —N═ N-, a group -C (= S) -N = N- or a thiocarbonyl group. Or a salt thereof, a solvate thereof, or an N-oxide thereof.

(E) General formula (1)

[Wherein, R ¹ and R ² each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
Q ¹ is a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, a substituent A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent Show;
Q ² is a single bond, a divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group that may have a substituent, or a divalent saturated or unsaturated 5 to 7 that may have a substituent. A membered heterocyclic group, a divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated group which may have a substituent A bicyclic or tricyclic fused heterocyclic group of
Q ³ is the following group

(In the group, Q ⁵ represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group — (CH ₂ ) m—CH ₂ —A—CH ₂ — (CH ₂ ) n — (in the group , M and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, —SO—, —SO ₂ —, —NH—, —O—NH—, — NH—NH—, —S—NH—, —SO—NH— or —SO ₂ —NH— are shown)));
R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom or a halogenoalkyl group. Group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, Alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group , Alkoxy carbon An amino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, having a substituent 3 to 6 members A ring carbonyl group, a carbamoylalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, a carbamoyloxy An alkyl group, an N-alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an optionally substituted 3- to 6-membered heterocyclic carbonylalkyl group, and an optionally substituted 3- 6-membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylamino Carbonyl group Reelsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkyl Sulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group , An alkoxyalkylsulfonyl group, a 3- to 6-membered heterocyclic sulfonyl group which may have a substituent Nyl group, N-alkylaminoacyl group, N, N-dialkylaminoacyl group, N, N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group, Substituent on the alkyl group Represents an N, N-dialkylcarbamoylalkylsulfonyl group or an alkylsulfonylacyl group, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, a carbon number 1 to 5 alkylenedioxy groups or carbonyldioxy groups are shown. );
Q ⁴ represents an aryl group that may have a substituent, an arylalkenyl group that may have a substituent, an arylalkynyl group that may have a substituent, a heteroaryl group that may have a substituent, or a substituent. A heteroarylalkenyl group which may have, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, a saturated or unsaturated bicyclic which may have a substituent or Represents a tricyclic fused heterocyclic group;
T ^O represents a carbonyl group or a thiocarbonyl group;
T ¹ is a carbonyl group, a sulfonyl group, a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′). -, Group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(in which R 'is A hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —A ¹ —N (R ″) — (wherein A ¹ may have a substituent having 1 to 1 carbon atoms; 5 represents an alkylene group, and R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group —C (═O) —NH—, a group —C (═S) —NH—, a group —C (═O) —NH—NH—, group —C (═O) —A ² —C (═O) — (wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), group ^{-C (= O) -A 3 -C} (= O) -NH- ( in group, A ³ is carbon Shows the 1-5 alkylene group), group -C (= O) -C (= NOR a) -N (R b) -., Group -C (= S) -C (= NOR a) -N ( R ^b ) — (wherein R ^a represents a hydrogen atom, an alkyl group or an alkanoyl group, and R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group —C (═O) —N═ N-, a group -C (= S) -N = N- or a thiocarbonyl group. Or a salt thereof, a solvate thereof, or an N-oxide thereof.

  Next, an Example is given and this invention is demonstrated.

[Reference Example 1] Pyridin-4-ylcarbamic acid tert-butyl ester 4-Aminopyridine (10 g) was dissolved in tetrahydrofuran (500 ml), and di-tert-butyl dicarbonate (25.5 g) was added thereto at room temperature. Stir for a minute. The reaction solution was concentrated under reduced pressure, and the precipitated solid was washed with hexane to obtain the title compound (16.9 g).
¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 6.86 (1H, br. S), 7.30 (2H, dd, J = 1.5, 4.9 Hz), 8 .44 (2H, dd, J = 1.5, 4.9 Hz).
MS (FAB) m / z: 195 (M + H) ^<+> .

[Reference Example 2] 3-sulfanylpyridin-4-ylcarbamic acid tert-butyl ester

The compound (61.6 g) obtained in Reference Example 1 was dissolved in tetrahydrofuran (2000 ml) and stirred at −78 ° C. for 10 minutes. N-Butyllithium (1.59 N hexane solution, 500 ml) was added dropwise to the reaction solution, stirred for 10 minutes, and then stirred for 2 hours under ice cooling. The reaction solution was cooled to -78 ° C, sulfur powder (12.2 g) was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. Water (1000 ml) was added to the reaction solution for liquid separation. 3N hydrochloric acid was added to the aqueous layer to adjust the pH to 3 to 4, and methylene chloride was added to separate the layers. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 1) to obtain the title compound (33.2 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.52 (9H, s), 7.89 (1H, d, J = 6.4 Hz), 7.99 (1H, d, J = 6.4 Hz) , 8.20 (1H, s), 9.91 (1H, br. S).
MS (FAB) m / z: 227 (M + H) ^<+> .

[Reference Example 3] Thiazolo [5,4-c] pyridine

The compound (33.2 g) obtained in Reference Example 2 was dissolved in formic acid (250 ml) and heated to reflux for 3 days. The reaction mixture was concentrated under reduced pressure, and 5N aqueous potassium hydroxide solution (100 ml) and diethyl ether were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to obtain the title compound (9.03 g).
¹ H-NMR (CDCl ₃ ) δ: 8.05 (1H, d, J = 5.4 Hz), 8.70 (1H, d, J = 5.4 Hz), 9.23 (1H, s), 9 .34 (1H, s).
MS (FAB) m / z: 137 (M + H) ^<+> .

[Reference Example 4] 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine

The compound (1.61 g) obtained in Reference Example 3 was dissolved in N, N-dimethylformamide (50 ml), methyl iodide (1.50 ml) was added, and the mixture was heated and stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (100 ml), sodium borohydride (1.53 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and saturated potassium carbonate aqueous solution and diethyl ether were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to obtain the title compound (1.28 g).
¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 2.98 (2H, t, J = 5.9 Hz), 3 .70 (2H, s), 8.63 (1H, s).
MS (FAB) m / z: 155 (M + H) ^<+> .

[Reference Example 5] Lithium salt of 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid

The compound (6.43 g) obtained in Reference Example 4 was dissolved in anhydrous tetrahydrofuran (200 ml), and n-butyllithium (1.47 N hexane solution, 34.0 ml) was added dropwise at −78 ° C. and stirred for 40 minutes. Carbon dioxide was introduced into the reaction solution at −78 ° C. for 1 hour, and then the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound (9.42 g).
¹ H-NMR (DMSO-d ₆ ) 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-dihydrothiazolo [5,4-c] pyridine-5 [4H] -carboxylic acid tert-butyl ester

1-tert-Butoxycarbonyl-4-piperidone (40.0 g) was dissolved in cyclohexane (80 ml), p-toluenesulfonic acid monohydrate (191 mg) and pyrrolidine (17.6 ml) were added, The mixture was heated to reflux for 2 hours while dehydrating. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (60 ml), and sulfur powder (6.42 g) was added. Under ice-cooling, a methanol solution (10 ml) of cyanamide (8.44 g) was slowly added dropwise and stirred at room temperature for 5 hours. The precipitated solid was collected by filtration to obtain the title compound (31.0 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.41 (9H, s), 2.44 (2H, t, J = 5.6 Hz), 3.57 (2H, t, J = 5.6 Hz) , 4.29 (2H, s), 6.79 (2H, s).
MS (EI) m / z: 255 (M ^<+> ).

[Reference Example 7] 2-Bromo-6,7-dihydrothiazolo [5,4-c] pyridine-5 [4H] -carboxylic acid tert-butyl ester

Cupric bromide (1.05 g) was suspended in N, N-dimethylformamide (20 ml), tert-butyl nitrite (0.696 ml) and the compound (1.00 g) obtained in Reference Example 6 under ice cooling. ) Was added, and the reaction mixture was stirred with heating at 40 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 5) to obtain the title compound (568 mg).
¹ H-NMR (CDCl ₃ ) 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-tetrahydrothiazolo [5,4-c] pyridine trifluoroacetate

The compound (890 mg) obtained in Reference Example 7 was dissolved in methylene chloride (2 ml), trifluoroacetic acid (15 ml) was added, and the mixture was stirred at room temperature for 30 seconds. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated solid was collected by filtration to give the title compound (867 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 2.98 (2H, t, J = 6.1 Hz), 3.45 (2H, t, J = 6.1 Hz), 4.35 (2H, s) , 9.53 (2H, br. S).
MS (FAB) m / z: 219 (M + H) ^<+> .

[Reference Example 9] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine

The compound (422 mg) obtained in Reference Example 8 was suspended in methylene chloride (10 ml), dissolved by adding triethylamine (0.356 ml), acetic acid (0.216 ml), aqueous formaldehyde solution (35% solution, 0.202 ml), Sodium triacetoxyborohydride (428 mg) was sequentially added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (100 ml), methylene chloride (100 ml) and a 3N aqueous sodium hydroxide solution (3 ml) were added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain the title compound (286 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H, s), 2.79 (2H, t, J = 5.7 Hz), 2.85-2.93 (2H, m), 3.58 (2H, t, J = 1.8 Hz).
MS (FAB) m / z: 233 (M + H) ^<+> .

[Reference Example 10] Lithium salt of 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid

The compound (531 mg) obtained in Reference Example 9 was dissolved in anhydrous diethyl ether (20 ml), and n-butyllithium (1.54 N hexane solution, 1.63 ml) was added dropwise at −78 ° C. Stir for minutes. Carbon dioxide was introduced into the reaction solution at −78 ° C. for 10 minutes, and then the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound (523 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.64-2.85 (4H, m), 3.54 (2H, s).

[Reference Example 11] 2-[(E) -2-phenylethenyl] oxazole-4-carboxylic acid
Ethyl ester

It was synthesized according to a report by Panek et al. (J. Org. Chem., 1996, 61, 6496). Sodium hydrogen carbonate (22.8 g) and ethyl bromopyruvate (10.5 ml) were added to a solution of cinnamic amide (10.0 g) in tetrahydrofuran (250 ml) at room temperature, and the mixture was heated to reflux for 48 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, and concentrated under reduced pressure to give a residue. To a tetrahydrofuran (30 ml) solution of this residue was added trifluoroacetic anhydride (30 ml) at 0 ° C., and the temperature was gradually raised to room temperature. After stirring for 63 hours, a saturated aqueous sodium hydrogen carbonate solution (500 ml) and ethyl acetate (150 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (150 ml). The organic layers were combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 3: 1). To give the title compound (10.9 g).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.0 Hz), 4.42 (2H, q, J = 7.0 Hz), 6.96 (1H, d, J = 16.6 Hz), 7.30-7.40 (3 H, m), 7.53 (2 H, d, J = 6.8 Hz), 7.63 (1 H, d, J = 16.6 Hz), 8. 20 (1H, s).

[Reference Example 12] 2-[(E) -2-phenylethenyl] oxazole-4-carbaldehyde

Diisobutylaluminum hydride (1.0 N hexane solution, 66 ml) was added dropwise to a solution of the compound obtained in Reference Example 11 (8.57 g) in methylene chloride (80 ml) at −78 ° C. After stirring for 15 minutes, methanol (11 ml) was added dropwise and the temperature was raised to room temperature in 1 hour. The reaction mixture was filtered through Celite, and the resulting pasty material was dissolved in ethyl acetate (200 ml) and saturated aqueous ammonium chloride (200 ml). After separation, the aqueous layer was extracted with methylene chloride (2 × 100 ml). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml), combined with the filtrate during celite filtration and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 5: 1 → methylene chloride: methanol = 10: 1) to obtain the title compound (5.86 g).
¹ H-NMR (CDCl ₃ ) δ: 6.96 (1H, d, J = 16.6 Hz), 7.35-7.45 (3H, m), 7.56 (2H, d, J = 6. 4 Hz), 7.67 (1 H, d, J = 16.6 Hz), 8.26 (1 H, s), 9.98 (1 H, s).
MS (FAB) m / z: 200 (M + H) ^<+> .

[Reference Example 13] 2-[(E) -2-phenylethenyl] -4-vinyloxazole

To a tetrahydrofuran (80 ml) solution of (methyl) triphenylphosphonium bromide (8.16 g), n-butyllithium (1.54 N hexane solution, 14.2 ml) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. . The reaction mixture was cooled again to 0 ° C., a solution of the compound (3.64 g) obtained in Reference Example 12 in tetrahydrofuran (20 ml) was added, and the temperature was raised to room temperature. After stirring for 2 hours, water (200 ml) and ethyl acetate (100 ml) were added for liquid separation, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1) to obtain the title compound (2.84 g).
¹ H-NMR (CDCl ₃ ) δ: 5.33 (1H, dd, J = 1.5, 10.7 Hz), 5.98 (1H, dd, J = 1.5, 17.6 Hz), 6. 56 (1H, dd, J = 10.7, 17.6 Hz), 6.95 (1H, d, J = 16.6 Hz), 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-phenylethenyl] oxazol-4-yl} -1-ethanol

To a solution of the compound (13.0 g) obtained in Reference Example 13 in tetrahydrofuran (500 ml), 9-borabicyclo [3.3.1] nonane (0.5 N tetrahydrofuran solution, 158 ml) was added at 0 ° C. For 15 hours. Water (10 ml), 3N aqueous sodium hydroxide solution (80 ml) and aqueous hydrogen peroxide (80 ml) were successively added dropwise to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 6 hours. Water (600 ml) and ethyl acetate (200 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → ethyl acetate only) to obtain the title compound (14.1 g).
¹ H-NMR (CDCl ₃ ) δ: 2.69 (1H, br.s), 2.80 (2H, t, J = 5.6 Hz), 3.90-3.97 (2H, m), 6 .91 (1H, d, J = 16.6 Hz), 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-phenylethenyl] oxazol-4-yl} ethyl) -1H-isoindole-1,3 (2H) -dione

To a solution of the compound obtained in Reference Example 14 (292 mg) in tetrahydrofuran (15 ml), phthalimide (200 mg), triphenylphosphine (357 mg) and diethyl azodicarboxylate (0.214 ml) were added at room temperature and stirred for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (447 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.98 (2H, t, J = 7.2 Hz), 4.03 (2H, t, J = 7.2 Hz), 6.88 (1H, d, J = 16.6 Hz), 7.28-7.45 (5 H, m), 7.48 (2 H, d, J = 7.3 Hz), 7.71 (2 H, dd, J = 2.9, 5.4 Hz) ), 7.84 (2H, dd, J = 2.9, 5.4 Hz).
MS (FAB) m / z: 345 (M + H) ^<+> .

[Reference Example 16] 2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} ethylcarbamic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 15 (6.40 g) in ethanol (150 ml) was added hydrazine monohydrate (1.50 ml) at room temperature, stirred for 1 hour, and then again hydrazine monohydrate (0.500 ml). ) Was added at room temperature and stirred for 2 hours. To the reaction mixture, methylene chloride (150 ml), saturated aqueous sodium hydrogen carbonate solution (150 ml) and di-tert-butyl dicarbonate (13.4 g) were added at room temperature. After stirring for 30 minutes, liquid separation was performed, and the aqueous layer was extracted with methylene chloride (50 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to obtain the title compound (5.06 g).
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.75 (2H, t, J = 6.6 Hz), 3.46 (2H, dt, J = 5.9, 6. 6Hz), 4.92 (1H, br.s), 6.91 (1H, d, J = 16.6 Hz), 7.29-7.45 (4H, m), 7.48 (1H, d, J = 16.6 Hz), 7.52 (2H, d, J = 7.3 Hz).
MS (FAB) m / z: 315 (M + H) ⁺ , 259 (M-isobutene + H) ⁺ , 315 (M-Boc + H) ⁺ .

[Reference Example 17] 2-[(E) -2-phenylethenyl] -6,7-dihydrooxazolo [5,4-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Paraformaldehyde (54.5 mg) and p-toluenesulfonic acid (7.2 mg) were added to a toluene (15 ml) solution of the compound (190 mg) obtained in Reference Example 16 at room temperature. After heating under reflux for 1 hour, the mixture was allowed to cool, and ethyl acetate (15 ml) and saturated aqueous sodium hydrogen carbonate solution (15 ml) were added to the reaction mixture to separate the layers. The aqueous layer was extracted with ethyl acetate (10 ml), the organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 2: 1) to obtain the title compound (153 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.67 (2H, br. S), 3.73 (2H, br. S), 4.55 (2H, s), 6.90 (1H, d, J = 16.1 Hz), 7.29-7.42 (3H, m), 7.46 (1 H, d, J = 16.1 Hz), 7.52 (2H, d , J = 7.3 Hz).
MS (FAB) m / z: 327 (M + H) ⁺ , 271 (M-isobutene + H) ⁺ , 227 (M-Boc + H) ⁺ .

[Reference Example 18] 2-Formyl-6,7-dihydrooxazolo [5,4-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 17 (803 mg) in tetrahydrofuran (16 ml), acetone (8.0 ml), water (4.0 ml), N-methylmorpholine N-oxide (577 mg) and 0.039 mol osmium tetroxide aqueous solution. (3.20 ml) was added at room temperature and stirred overnight. Acetic acid ethyl ester (50 ml) and 10% aqueous sodium thiosulfate solution (50 ml) were added to the reaction mixture, and the mixture was partitioned. The aqueous layer was extracted with acetic acid ethyl ester (30 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Methanol (8.0 ml), water (8.0 ml), and sodium metaperiodate (790 mg) were added to the remaining tetrahydrofuran (16 ml) solution at room temperature. After stirring for 3 hours, ethyl acetate (30 ml) and water (50 ml) were added to the reaction mixture and the phases were separated, and the aqueous layer was extracted with ethyl acetate (20 ml). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to obtain the title compound (234 mg). Since this aldehyde was unstable, it was immediately used for the next reaction.
¹ H-NMR (CDCl ₃ ) 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-Dihydrooxazolo [5,4-c] pyridine-2,5 (4H) -dicarboxylic acid 5- (tert-butyl) 2-methyl ester

Sodium cyanide (220 mg) and manganese dioxide (780 mg) were added to a solution of the compound obtained in Reference Example 18 (225 mg) in methanol (9.0 ml) at room temperature, stirred for 30 minutes, and then filtered through Celite with ethyl acetate. Did. The filtrate was washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2 → 1: 1) to obtain the title compound (120 mg).
¹ H-NMR (CDCl ₃ ) 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-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid methyl ester

To a solution of the compound obtained in Reference Example 19 (500 mg) in methylene chloride (15 ml) was added trifluoroacetic acid (15 ml) at room temperature and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (20 ml), triethylamine (0.495 ml), acetic acid (205 ml), formalin (0.230 ml) and sodium triacetoxyborohydride (570 mg) were brought to room temperature. Added. After stirring for 15 minutes, methylene chloride (20 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml) were added to the reaction mixture, and after separation, the aqueous layer was extracted with methylene chloride (3 × 20 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1 → 10: 1) to obtain the title compound (257 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 2.72-2.78 (2H, m), 2.78-2.83 (2H, m), 3.61 (2H , T, J = 1.7 Hz), 4.00 (3H, s).
MS (FAB) m / z: 197 (M + H) +, 165 (M-OCH 3) +.

[Reference Example 21] Lithium salt of 5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid

Water (6.0 ml) and lithium hydroxide (99.7 mg) were added to a tetrahydrofuran (24 ml) solution of the compound (800 mg) obtained in Reference Example 20 at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (825 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.47 (2H, t, J = 5.6 Hz), 2.64 (2H, t, J = 5.6 Hz) 3.43 (2H, s).

[Reference Example 22] 5-chloro-6-fluoroindole-2-carboxylic acid methyl ester

A mixture of 3-chloro-4-fluoro-α-azidocinnamic acid methyl ester (JP-A-7-149723) (1.85 g) and xylene (140 ml) was heated under reflux for 1 hour, and then the solvent was distilled off. . The residue was purified by silica gel column chromatography (methylene chloride) to obtain the title compound (491 mg).
¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s), 7.13-7.15 (1H, m), 7.20 (1H, dd, J = 9.3, 0.49 Hz) , 7.71 (1H, d, J = 7.3 Hz), 8.93 (1H, br. S).
MS (FAB) m / z: 227 (M ^<+> ).

[Reference Example 23] 5-Chloro-6-fluoroindole-2-carboxylic acid

The compound (461 mg) obtained in Reference Example 22 was dissolved in a mixed solvent of tetrahydrofuran (15 ml), methanol (10 ml) and water (10 ml), lithium hydroxide (283 mg) was added at room temperature, and the mixture was stirred for 4 hours. The solvent was evaporated under reduced pressure, and 1N hydrochloric acid was added to the residue to make it weakly acidic. The obtained powder was collected by filtration and dried to give the title compound (422 mg).
¹ H-NMR (CDCl ₃ ) δ: 7.08-7.10 (1H, m), 7.34 (1H, d, J = 9.5 Hz), 7.88 (1H, d, J = 7. 6 Hz), 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-tetrahydrothiazolo [5,4-c] pyridine

1) Phosphorous pentasulfide (500 g) was suspended in formamide (3000 ml) under ice cooling and stirred overnight. Water and diethyl ether were added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oily substance. This was dissolved in n-butanol (350 ml), and 3-chloro-4-oxo-1-piperidinecarboxylic acid ethyl ester (150 g) synthesized by a method described in the literature (Tetrahedron, 1983, 39, 3767) was obtained. After the addition, the mixture was stirred at 100 ° C. for 2.5 hours. The reaction solution was filtered through celite, and the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methylene chloride-acetic acid ethyl ester: hexane = 1: 2) to give 6,7-dihydrothiazolo [5,4-c] pyridine-5 (4H). -Carboxylic acid ethyl ester (79.0 g) was obtained.
_{^{1 H-NMR (CDCl 3)}} δ: 1.30 (3H, t, J = 7.3Hz), 2.96 (2H, br.s), 3.82 (2H, br.s), 4.19 (2H, q, J = 7.3 Hz), 4.73 (2H, br.s) 8.68 (1H, s).
MS (FAB) m / z: 213 (M + H) ^<+> .
2) A 3.5N aqueous sodium hydroxide solution (250 ml) was added to the above product (33.5 g), and the mixture was heated to reflux overnight. After cooling the reaction solution to room temperature, di-tert-butyl dicarbonate (103 g) was added under ice cooling, and the mixture was stirred overnight at room temperature. 3N hydrochloric acid was added to the reaction solution to adjust the pH to 1-2, and methylene chloride was added to carry out a liquid separation operation. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2), and 6,7-dihydrothiazolo [5,4-c] pyridine-5 (4H)- Carboxylic acid tert-butyl ester (21.1 g) was obtained.
¹ H-NMR (CDCl ₃ ) 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) To a solution of the compound (5.00 g) obtained in 2) above in methylene chloride (25 ml) was added trifluoroacetic acid (25 ml) at room temperature. After stirring for 10 minutes, the reaction solution was concentrated under reduced pressure. 4-Bromopyridine (5.20 g), N, N-dimethylformamide (30 ml), and triethylamine (15.5 ml) were added to the residue at room temperature, stirred at 150 ° C. for 2 days, and then allowed to cool to room temperature. The resulting colorless precipitate was filtered off, the filtrate was concentrated under reduced pressure, methylene chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution (100 ml) were added, and the aqueous layer was saturated with sodium chloride. After separation, the aqueous layer was extracted with methylene chloride (5 × 30 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 8: 1) to obtain the title compound (2.97 g).
¹ H-NMR (CDCl ₃ ) δ: 3.07 (2H, t, J = 5.9 Hz), 3.81 (2H, t, J = 5.9 Hz), 4.61 (2H, s), 6 .74 (2H, t, J = 6.5 Hz), 8.30 (2H, t, J = 6.5 Hz), 8.70 (1H, s).
MS (ESI) m / z: 218 (M + H) ^<+> .

[Reference Example 25] 2-Chloro-6,7-dihydro-4H-pyrano [4,3-d] thiazole

1) Tetrahydro-4H-pyran-4-one (5.0 g) is dissolved in cyclohexane (20 ml), pyrrolidine (4.35 ml) and p-toluenesulfonic acid monohydrate (48 mg) are added, and the Dean-Stark apparatus is used. The mixture was heated to reflux for 70 minutes while removing water. The reaction solution was cooled to room temperature, and the supernatant was separated and concentrated under reduced pressure. The residue was dissolved in methanol (15 ml), sulfur powder (1.60 g) was added under water cooling, and after 15 minutes, a methanol solution (10 ml) of cyanoamide (2.10 g) was added dropwise over 20 minutes and stirred for 3 days. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 10: 1 → 4: 1), and 6,7-dihydro-4H-pyrano [4,3- d] Thiazol-2-ylamine (3.97 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.66-2.70 (2H, m), 3.97 (2H, t, J = 5.6 Hz), 4.63 (2H, s), 4.94 (2H, br.s).
MS (FAB) m / z: 157 (M + H) ^<+> .
2) Copper (II) chloride (4.10 g) was dissolved in acetonitrile (50 ml), and tert-butyl nitrite (3.93 g) was added at once under water cooling. After 10 minutes, the compound obtained in the above reaction (3.97 g) was added in about 1 hour, and the mixture was stirred at room temperature for 1 hour. Next, the reaction solution was heated to 65 ° C. and stirred for 2 hours. After adding silica gel (20 g) to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: acetic acid ethyl ester = 3: 1) to obtain the title compound (1.78 g). It was.
¹ H-NMR (CDCl ₃ ) δ: 2.85-2.89 (2H, m), 4.02 (2H, t, J = 5.6 Hz), 4.73 (2H, s).
MS (FAB) m / z: 175 (M + H) ^<+> .

[Reference Example 26] Lithium salt of 6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-carboxylic acid

1) The compound (1.78 g) obtained in Reference Example 25 was dissolved in methanol (30 ml), 10% palladium carbon (300 mg) and sodium acetate (830 mg) were added, and the mixture was stirred for 5 days under a hydrogen stream of 5 atm. The catalyst was removed by filtration, the solvent was concentrated, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 6,7-dihydro-4H-pyrano [4,3-d] thiazole (1 .14 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.97-3.01 (2H, m), 4.04 (2H, t, J = 5.6 Hz), 4.87 (2H, s), 8.69 (1H, s).
MS (FAB) m / z: 142 (M + H) ^<+> .
2) The above product (1.14 g) was dissolved in diethyl ether (30 ml), cooled to −78 ° C., 1.6 N butyllithium (6.6 ml) was added, and the mixture was stirred. After 20 minutes, carbon dioxide was introduced for 15 minutes. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the title compound (1.65 g).
¹ H-NMR (DMSO-d ₆ ) δ: 2.83 (2H, t, J = 5.6 Hz), 3.92 (2H, t, J = 5.6 Hz), 4.73 (2H, s) .

[Reference Example 27] Thiazolo [4,5-c] pyridine

3- (tert-Butoxycarbonylamino) -4-mercaptopyridine (JP-A-4-321691) (9.20 g) was dissolved in formic acid (60 ml) and heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and 5N aqueous potassium hydroxide solution (100 ml) and diethyl ether were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration to give the title compound (3.97 g).
¹ H-NMR (CDCl ₃ ) δ: 7.93 (1H, d, J = 5.4 Hz), 8.60 (1H, d, J = 5.4 Hz), 9.07 (1H, s), 9 .46 (1H, s).

[Reference Example 28] 5-Methyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine

In the same manner as in Reference Example 4, the title compound was obtained from the compound obtained in Reference Example 27.
¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 2.77 (2H, t, J = 5.4 Hz), 2.92-3.00 (2H, m), 3.69 (2H, t, J = 2.0 Hz), 8.61 (1H, s).
MS (FAB) m / z: 155 (M + H) ^<+> .

[Reference Example 29] Lithium salt of 5-methyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine-2-carboxylic acid

In the same manner as in Reference Example 5, the title compound was obtained from the compound obtained in Reference Example 28.
¹ H-NMR (DMSO-d ₆ ) δ: 2.38 (3H, s), 2.64 (2H, br. S), 2.80 (2H, br. S), 3.44 (2H, br .S).

[Reference Example 30] 2-Chloro-N, N-dimethyl-4,5,6,7-tetrahydro-benzothiazol-6-amine

2-Chloro-4,7-dihydro-1,3-benzothiazol-6 (5H) -one (Helv. Cim. Acta., 1994, 77, 1256) (2.0 g) in methanol (100 ml) Then, ammonium acetate (8.2 g) and sodium cyanoborohydride (4.0 g) were added, and the mixture was heated to reflux for 20 hours. Hydrochloric acid was added to the reaction solution to decompose excess sodium cyanoborohydride, and the solvent was evaporated under reduced pressure. The solution was made alkaline with 1N sodium hydroxide solution, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil. This oil was dissolved in methanol (50 ml), an aqueous formaldehyde solution (4.29 g) and sodium cyanoborohydride (3.49 g) were added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, methylene chloride was added, the mixture was washed with a saturated sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to obtain the title compound (740 mg).
¹ H-NMR (CDCl ₃ ) 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] Lithium salt of 6- (dimethylamino) -4,5,6,7-tetrahydrobenzothiazole-2-carboxylic acid

The compound (750 mg) obtained in Reference Example 30 was dissolved in diethyl ether (15 ml), cooled to −78 ° C., 1.5 N tert-butyllithium (3.5 ml) was added, and the mixture was stirred for 20 minutes. Introduced for 15 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 [3,4-d] thiazole-5-carboxylic acid tert-butyl ester

1-tert-Butoxycarbonyl-3-pyrrolidone (1.58 g) is dissolved in cyclohexane (10 ml), p-toluenesulfonic acid monohydrate (8.12 mg) and pyrrolidine (607 mg) are added, and the mixture is added using a Dean-Stark apparatus. The mixture was heated to reflux for 1.5 hours while dehydrating. The supernatant was collected and concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), sulfur powder (274 mg) was added, and the mixture was stirred for 15 minutes under ice cooling. To the reaction solution, a methanol solution (2 ml) of cyanamide (377 mg) was slowly added dropwise and stirred overnight at room temperature. The mixture was further heated under reflux for 2 hours, and the reaction mixture was concentrated. Methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 39) to obtain the title compound (248 mg).
¹ H-NMR (CDCl ₃ ) 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).

[Reference Example 33] 2-Bromo-4,6-dihydro-5H-pyrrolo [3,4-d] thiazole-5-carboxylic acid tert-butyl ester

Cupric bromide (445 mg) was suspended in N, N-dimethylformamide, and tert-butyl nitrite (256 mg) was added dropwise at room temperature. Under ice cooling, an N, N-dimethylformamide solution (1 ml) of the compound (400 mg) obtained in Reference Example 32 was added, and the reaction solution was stirred at 60 ° C. for 1.5 hours. Diethyl ether and saturated brine were added to the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (174 mg).
¹ H-NMR (CDCl ₃ ) 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-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt

In the same manner as in Reference Example 10, the title compound was obtained from the compound obtained in Reference Example 7.
¹ H-NMR (DMSO-d ₆ ) δ: 1.42 (9H, s), 2.69-2.77 (2H, m), 3.60-3.68 (2H, m), 4.51 -4.58 (2H, m).

[Reference Example 35] 2-Bromo-4- (2-methoxy-2-oxoethyl) thiazole-5-carboxylic acid methyl ester

Cupric bromide (26.8 g) was added at once to a solution of tert-butyl nitrite (15.5 g) in acetonitrile (500 ml) under ice cooling. To this reaction solution, an acetonitrile solution (500 ml) of 2-amino-5-methoxycarbonyl-4-thiazoleacetic acid methyl ester (Pharmaceutical Journal, 1966, 86, 300) (23.0 g) was added dropwise over 45 minutes. The mixture was stirred for 1 hour under ice cooling and 30 minutes at room temperature. The reaction mixture was concentrated, 10% hydrochloric acid and diethyl ether were added to the residue, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (25.9 g).
¹ H-NMR (CDCl ₃ ) δ: 3.73 (3H, s), 3.87 (3H, s), 4.21 (2H, s).

[Reference Example 36] 2- [5- (hydroxymethyl) thiazol-4-yl] -1-ethanol

Under ice cooling, a tetrahydrofuran (500 ml) solution of the compound (23.4 g) obtained in Reference Example 35 was added dropwise to a suspension of lithium aluminum hydride (9.03 g) in tetrahydrofuran (500 ml) over 1 hour. The mixture was further stirred for 1 hour under ice-cooling, water (9 ml), 35% aqueous sodium hydroxide solution (9 ml) and water (27 ml) were successively added, and the mixture was stirred at room temperature for 1 hour. After adding anhydrous magnesium sulfate to the reaction solution and stirring, insoluble matters were removed by Celite filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 7: 93) to obtain the title compound (8.64 g).
¹ H-NMR (CDCl ₃ ) δ: 3.01 (2H, t, J = 5.5 Hz), 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-{[(methylsulfonyl) oxy] methyl} thiazol-4-yl) ethyl ester

To a solution of the compound obtained in Reference Example 36 (8.64 g) and triethylamine (45.4 ml) in methylene chloride (500 ml) was added a solution of methanesulfonyl chloride (12.6 ml) in methylene chloride at −78 ° C. for 20 minutes. It was dripped over. After stirring at −78 ° C. for 15 minutes and at 0 ° C. for 1 hour, water was added and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (13.4 g).
¹ H-NMR (CDCl ₃ ) δ: 2.93 (3H, s), 3.03 (3H, s), 3.28 (2H, t, J = 6.3 Hz), 4.61 (2H, t , J = 6.3 Hz), 5.44 (2H, s), 8.84 (1H, s).

[Reference Example 38] 5- (1-Methylcyclopropyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine

To the methylene chloride (20 ml) containing the compound (4.46 g) obtained in Reference Example 37 was added 1-methylcyclopropylamine hydrochloride (J. Org. Chem., 1989, 54, 1815) under ice cooling. (1.89 g) was added and stirred at room temperature overnight. Furthermore, 1-methylcyclopropylamine hydrochloride (1.89 g) was added, and the mixture was stirred at room temperature for 20 hours and further heated to reflux for 5 hours. Methylene chloride and water were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 49) to obtain the title compound (944 mg).
¹ H-NMR (CDCl ₃ ) 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 = 5.7 Hz), 3.89 (2H, br.s), 8.60 (1H, s).
MS (ESI) m / z: 195 (M + H) ^<+> .

[Reference Example 39] 5- (1-methylcyclopropyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt

In the same manner as in Reference Example 5, the title compound was obtained from the compound obtained in Reference Example 38.
¹ H-NMR (DMSO-d ₆ ) δ: 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 (2H, br.s).

[Reference Example 40] 2- [6,7-Dihydrothiazolo [5,4-c] pyridin-5 (4H) -yl] -2-methyl-1-propanol

In the same manner as in Reference Example 38, the title compound was obtained from the compound obtained in Reference Example 37 and 2-amino-2-methyl-1-propanol.
¹ H-NMR (CDCl ₃ ) 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 (diphenyl) silyl] oxy} -1,1-dimethylethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine

To a N, N-dimethylformamide (5 ml) solution of the compound obtained in Reference Example 40 (1.24 g), tert-butylchlorodiphenylsilane (1.93 g) and imidazole (994 mg) were added at room temperature and stirred overnight. Water and diethyl ether were added to the reaction solution, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain the title compound (2.46 g).
¹ H-NMR (CDCl ₃ ) 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 (diphenyl) silyl] oxy} -1,1-dimethylethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-carboxylic acid lithium salt

In the same manner as in Reference Example 5, the title compound was obtained from the compound obtained in Reference Example 41.
¹ H-NMR (DMSO-d ₆ ) 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-Tetrahydro-6H-pyrazolo [1,2-a] thiazolo [4,5-d] pyridazine

1) At room temperature, 4,5-dimethylthiazole (5.00 g), N-bromosuccinimide (15.7 g) and α, α′-azobisisobutyronitrile (362 mg) into ethylene dichloride (500 ml). Dissolved and heated to reflux for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: diethyl ether = 1: 4) to obtain 4,5-bis (bromomethyl) thiazole (5.24 g).
¹ H-NMR (CDCl ₃ ) δ: 4.64 (2H, s), 4.74 (2H, s), 8.75 (1H, s).
2) Under cooling with ice, 4,5-bis (bromomethyl) thiazole (1.37 g) and 1,2-trimethylenehydrazine hydrochloride (WO9532965) (732 mg) were suspended in ethanol (15 ml), and triethylamine (2. 82 ml) was added dropwise over 5 minutes. After stirring at room temperature for 2 hours, the solvent was distilled off, methylene chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution were added to the residue, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3: 47) to obtain the title compound (358 mg).
¹ H-NMR (CDCl ₃ ) 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-Tetrahydro-6H-pyrazolo [1,2-a] thiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt

In the same manner as in Reference Example 5, the title compound was obtained from the compound obtained in Reference Example 43.
¹ H-NMR (DMSO-d ₆ ) 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-hexahydropyridazino [1,2-a] thiazolo [4,5-d] pyridazine

In the same manner as in Reference Example 43, the title compound was obtained from 4,5-bis (bromomethyl) thiazole (2.20 g) obtained in 1) of Reference Example 43 and 1,2-tetramethylene hydrazine hydrochloride (US 5726126). It was.
¹ H-NMR (CDCl ₃ ) 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-hexahydropyridazino [1,2-a] thiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt

  In the same manner as in Reference Example 5, the title compound was obtained from the compound obtained in Reference Example 45.

[Reference Example 47] 2- (Methylsulfanyl) -5,7-dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester

1- (tert-Butoxycarbonyl) -3-pyrrolidone (4.57 g) was added N, N-dimethylformamide dimethyl acetal (30 ml) at room temperature, and the mixture was heated at 140 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. Hexane was added to the residue and the precipitated yellow powder was collected by filtration, dissolved in ethanol (100 ml), and methylisothiourea sulfate (9.24 g) and sodium ethoxide (4.52 g) were added to the solution at room temperature. , And refluxed for 24 hours. To the reaction solution are added saturated brine and diethyl ether, and the mixture is separated, and the organic layer is dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 99) to obtain the title compound (1.10 g).
¹ H-NMR (CDCl ₃ ) 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- (Methylsulfonyl) -5,7-dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester

M-Chloroperbenzoic acid (1.99 g) was added to a methylene chloride solution (20 ml) of the compound (1.08 g) obtained in Reference Example 47 under ice-cooling, and the mixture was stirred for 5 hours. A saturated aqueous sodium sulfite solution, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the reaction solution, and the mixture was separated, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, and the precipitated powder was collected by filtration to obtain the title compound (1.09 g).
¹ H-NMR (CDCl ₃ ) 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-5,7-dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 48 (1.05 g) in methylene chloride (30 ml) was added tetrabutylammonium cyanide (1.04 g) at room temperature, and the mixture was stirred at room temperature for 1 hour. 1N sodium hydroxide was added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: acetone = 20: 1) to obtain the title compound (776 mg).
¹ H-NMR (CDCl ₃ ) 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 [3,4-d] pyrimidine-2,6-dicarboxylic acid 6- (tert-butyl) 2-methyl ester

Concentrated hydrochloric acid (5 ml) was added to a solution of the compound obtained in Reference Example 49 (776 mg) in methanol (10 ml) at room temperature, and the mixture was stirred at 100 ° C. for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (10 ml), triethylamine (2.20 ml) and di-tert-butyl dicarbonate (1.37 g) were added at room temperature, and the mixture was stirred for 1 hour. did. After concentration under reduced pressure, methylene chloride and saturated brine were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3: 97) to obtain the title compound (317 mg).
¹ H-NMR (CDCl ₃ ) 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] Lithium salt of 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylic acid

1) 4,5-bis (bromomethyl) thiazole (600 mg) obtained in 1) of Reference Example 43 was dissolved in ethanol (20 ml), and 1,2-dimethylhydrazine hydrochloride (294 mg) was added under ice cooling. Thereafter, triethylamine (1.23 ml) was added in one portion and stirred at room temperature for 30 minutes and at 50 ° C. for 30 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to give 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d]. Pyridazine (90 mg) was obtained.
¹ H-NMR (CDCl ₃ ) 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) In the same manner as in Reference Example 5, the title compound was obtained from 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine.
¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (3H, s), 2.39 (3H, s), 3.66 (2H, br. S), 3.88 (2H, br. S) ).

[Reference Example 52] 5-chloroindole-2-carboxylic acid 4-nitrophenyl ester

5-Chloroindole-2-carboxylic acid (20 g) was suspended in methylene chloride (1500 ml), N, N-dimethylformamide (2 ml) was added, and thionyl chloride (11 ml) was added dropwise at room temperature. The reaction was heated to reflux overnight and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (1000 ml), triethylamine (84.7 ml) was added under ice-cooling, p-nitrophenol (14.2 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate and 0.2 N hydrochloric acid were added to the residue to carry out a liquid separation operation. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (29.9 g).
¹ H-NMR (CDCl ₃ ) δ: 7.35 (1H, dd, J = 9.0, 1.7 Hz), 7.39-7.42 (2H, m), 7.45 (2H, dd, J = 7.3, 1.7 Hz), 7.73 (1H, d, J = 1.0 Hz), 8.35 (2H, dd, J = 7.3, 1.7 Hz), 9.09 (1H , Br.s).
MS (FD) m / z: 316 (M ^<+> ).

[Reference Example 53] 6-Chloro-2-quinolinecarbonitrile

6-Chloroquinoline (2.50 g) was dissolved in methylene chloride (25 ml), m-chloroperbenzoic acid (3.71 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with methylene chloride, washed with an aqueous sodium thiosulfate solution and an aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride (40 ml), trimethylsilyl cyanide (2.0 ml) and N, N-dimethylcarbamoyl chloride (1.50 ml) were added, and the mixture was heated to reflux for 9 hours. Further, trimethylsilyl cyanide (1.0 ml) and N, N-dimethylcarbamoyl chloride (0.80 ml) were added, heated under reflux for 16 hours, diluted with methylene chloride and added with 10% aqueous potassium carbonate (40 ml) for 30 minutes. Stir. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Methylene chloride was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (1.77 g). The mother liquor was further concentrated and purified by silica gel column chromatography (methylene chloride) to give the title compound (0.80 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.94 (1H, dd, J = 9.0, 2.2 Hz), 8.09 (1H, d, J = 8.5 Hz), 8.15 ( 1H, d, J = 9.0 Hz), 8.29 (1H, d, J = 2.2 Hz), 8.63 (1H, d, J = 8.5 Hz).
MS (FAB) m / z: 189 (M + H) ^<+> .

[Reference Example 54] 6-chloro-2-quinolinecarboxylic acid

The compound (1.73 g) obtained in Reference Example 53 was dissolved in concentrated hydrochloric acid (40 ml) and heated to reflux for 19 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with water to give the title compound (1.81 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.87 (1H, dd, J = 9.0, 2.4 Hz), 8.10-8.20 (2H, m), 8.24 (1H, d, J = 2.2 Hz), 8.52 (1H, d, J = 8.5 Hz).
MS (FAB) m / z: 208 (M + H) ^<+> .

[Reference Example 55] 3- (4-Chlorophenyl) -2- (formylamino) propionic acid methyl ester

(±)-(4-Chlorophenyl) alanine methyl ester hydrochloride (2.00 g) was suspended in methylene chloride (20 ml) to give 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.60 g). 1-hydroxybenzotriazole monohydrate (1.23 g), N-methylmorpholine (1.90 ml) and formic acid (0.30 ml) were added and stirred for 15 minutes. Further, the operation of adding formic acid (0.30 ml) and stirring for 15 minutes was repeated three times, and then the reaction solution was diluted with methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain the title compound (1.21 g).
¹ H-NMR (CDCl ₃ ) δ: 3.10 (1H, dd, J = 13.9, 5.6 Hz), 3.18 (1H, dd, J = 13.9, 5.9 Hz), 3. 75 (3H, s), 4.95 (1H, m), 6.07 (1H, br), 7.05 (2H, d, J = 8.3 Hz), 7.27 (2H, d, J = 8.3 Hz), 8.18 (1H, s).
MS (FAB) m / z: 242 (M + H) ^<+> .

[Reference Example 56] 7-Chloro-3-isoquinolinecarboxylic acid methyl ester

The compound (1.45 g) obtained in Reference Example 55 was dissolved in methylene chloride (40 ml), and oxalyl chloride (0.57 ml) was added dropwise. After stirring at room temperature for 30 minutes, ferric chloride (1.17 g) was added at an external temperature of about −10 ° C., and the mixture was stirred at room temperature for 4 days. 1N hydrochloric acid was added, diluted with methylene chloride, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in methanol (38 ml), concentrated sulfuric acid (2 ml) was added, and the mixture was heated to reflux for 20 hours. Aqueous sodium hydrogen carbonate solution was added, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → ethyl acetate) to obtain the title compound (0.25 g).
¹ H-NMR (CDCl ₃ ) δ: 4.07 (3H, s), 7.74 (1H, dd, J = 8.8, 2.0 Hz), 7.94 (1H, d, J = 8. 8 Hz), 8.06 (1 H, d, J = 2.0 Hz), 8.59 (1 H, s), 9.28 (1 H, s).

[Reference Example 57] 7-Chloro-3-isoquinolinecarboxylic acid hydrochloride

The compound (0.23 g) obtained in Reference Example 56 was dissolved in concentrated hydrochloric acid (10 ml) and heated to reflux for 18 hours. The temperature of the reaction solution was lowered to room temperature, and the precipitate was collected by filtration and washed with water to give the title compound (0.21 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.96 (1H, m), 8.29 (1H, d, J = 8.5 Hz), 8.44 (1H, s), 8.72 (1H , S), 9.45 (1H, d, J = 6.6 Hz).
MS (FAB) m / z: 208 (M + H) ^<+> .

[Reference Example 58] (3R) -1-benzyl-3-{[tert-butyl (diphenyl) silyl] oxy} pyrrolidine

(3R) -1-benzyl-3-hydroxypyrrolidine (500 μl) and imidazole (466 mg) were dissolved in N, N-dimethylformamide (15 ml), and tert-butyldiphenylsilyl chloride (1.57 ml) was added under ice cooling. And stirred at room temperature for 9 days. The solvent was distilled off under reduced pressure, methylene chloride and water were added to the residue, and after liquid separation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (1.27 g).
¹ H-NMR (CDCl ₃ ) 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-aminocyclopropyl] -5-chloroindole-2-carboxamide

cis-1,2-cyclopropanediamine hydrochloride (J. Med. Chem., 1998, 41, 4723-4732) (405 mg) and 5-chloroindole-2-carboxylic acid (546 mg) N, N 1-hydroxybenzotriazole monohydrate (377 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (642 mg), and diisopropylethylamine (1.95 ml) were added to a dimethylformamide (10 ml) solution. It added at room temperature and stirred for 50 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution (200 ml) were added, and the precipitated colorless solid was filtered off. The filtrate was separated and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 100: 7 → 10: 1) to obtain the title compound (110 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 0.44 (1H, dd, J = 10.7, 4.4 Hz), 1.11 (1H, dd, J = 14.0, 7.4 Hz), 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, 1.8 Hz), 7.36 (1H, d, J = 8.9 Hz), 7.60 (1H, s), 9.32 (1H, s).
MS (FAB) m / z: 250 (M + H) ^<+> .

[Reference Example 60] N-[(1R ^* , 2S ^* )-2-aminocyclobutyl] -5-chloroindole-2-carboxamide

The title compound was obtained from cis-1,2-cyclobutanediamine hydrochloride (J, Am. Chem. Soc., 1942, 64, 2696-2700) in the same manner as in Reference Example 59.
¹ H-NMR (DMSO-d ₆ ) 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, 2.1 Hz), 7.19 (1H, s), 7.42 (1H, d, J = 8.7 Hz), 7.70 (1H, d, J = 2.1 Hz), 8.36 (1H, d, J = 7.8 Hz), 11.77 (1H, br.s).
MS (ESI) m / z: 264 (M + H) ^<+> .

[Reference Example 61] (1R ^* , 2R ^* )-2-aminocyclopentylcarbamic acid tert-butyl ester

(±) -trans-1,2-cyclopentanediamine (WO98 / 30574) (692 mg) was dissolved in methylene chloride (10 ml), and triethylamine (1.1 ml), 2- (tert-butoxycarbonyloxy) was dissolved at 0 ° C. Imino) -2-phenylacetonitrile (493 mg) was added, and the mixture was stirred at 0 ° C. for 1 hr. Thereafter, 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (493 mg) was added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 9: 1) to obtain the title compound (395 mg).
¹ H-NMR (CDCl ₃ ) 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 = 7.2 Hz), 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-aminocyclopentyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide Hydrochloride salt

The compound (175 mg) obtained in Reference Example 61 was dissolved in N, N-dimethylformamide (3 ml), and 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Carboxylic acid lithium salt (purity 90%, 258 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (252 mg), 1-hydroxybenzotriazole monohydrate (60 mg) was added, and room temperature was maintained for 2 days. Stir. The solvent was distilled off with a pump under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added to the residue for separation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 47: 3). The obtained pale yellow oil was dissolved in ethanol ethanol (5 ml) and stirred at room temperature for 1 hour, ethyl acetate was added, and the solvent was concentrated under reduced pressure. Acetic acid ethyl ester was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (120 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.3 Hz), 11.82-12.01 (1H, m).
MS (ESI) m / z: 281 (M + H) ^<+> .

[Reference Example 63] N-[(1R ^* , 2R ^* )-2-aminocyclopentyl] -5-chloro-1H-indole-2-carboxamide hydrochloride

The compound (1.40 g) obtained in Reference Example 61 was dissolved in N, N-dimethylformamide (15 ml) to give 5-chloroindole-2-carboxylic acid (1.64 g), 1- (3-dimethylaminopropyl). -3-Ethylcarbodiimide hydrochloride (2.68 g) and 1-hydroxybenzotriazole monohydrate (473 mg) were added, and the mixture was stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the precipitate was collected by filtration. The precipitate was washed with acetic acid ethyl ester, methylene chloride and methanol. On the other hand, the filtrate was separated and the organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 19: 1) to obtain a pale yellow solid. The pale yellow solid and the precipitate obtained by filtration were combined and dissolved in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, methylene chloride and 1N aqueous sodium hydroxide solution were added to the residue, and the precipitate was collected by filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. The precipitate collected by filtration was added to this solution, 4N hydrochloric acid dioxane solution (20 ml) was further added, and the solvent was distilled off under reduced pressure. Methylene chloride (10 ml) and 4N hydrochloric acid dioxane solution (10 ml) were added to the residue, and the solvent was distilled off again under reduced pressure. Acetic acid ethyl ester was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (1.83 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.75 (4H, m), 2.05-2.10 (2H, m), 3.49 (1H, q, J = 7. 6 Hz), 4.27 (4 H, quintet, J = 7.6 Hz), 7.17 (1 H, d, J = 8.6 Hz), 7.19 (1 H, s), 7.42 (1 H, d, J = 8.6 Hz), 7.70 (1 H, s), 8.24 (3 H, br. S), 8.85 (1 H, d, J = 7.3 Hz), 11.91 (1 H, s) .
MS (ESI) m / z: 278 (M + H) ^<+> .

[Reference Example 64] (1R ^* , 2R ^* )-2-aminocyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 61, the title compound was obtained from (±) -trans-1,2-cyclohexanediamine.
m. p. 79-81 ° C.
¹ H-NMR (CDCl ₃ ) 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, 3.9 Hz), 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-aminocyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide Tri Fluoroacetate (and hydrochloride)

In the same manner as in Reference Example 62, the title compound was obtained from the compound obtained in Reference Example 64.
¹ H-NMR (DMSO-d ₆ ) 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 = 9.2 Hz).
MS (FAB) m / z: 295 (M + H) ^<+> .
In the same manner, hydrochloride was obtained.

[Reference Example 66] (1R ^* , 2S ^* )-2-Aminocyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 61, the title compound was obtained from cis-1,2-cyclohexanediamine.
¹ H-NMR (CDCl ₃ ) 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-aminocyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide Hydrochloride Salt (and trifluoroacetate)

In the same manner as in Reference Example 62, the title compound was obtained from the compound obtained in Reference Example 66.
¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.90 (8H, m), 2.92 (3H, s), 3.05 to 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) ^<+> .
Similarly, a trifluoroacetate salt was obtained.

[Reference Example 68] (1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 64 (3.00 g) in N, N-dimethylformamide (10 ml), 5-chloroindole-2-carboxylic acid (2.88 g), 1-hydroxybenzotriazole monohydrate (2 0.08 g), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.95 g) were added at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, methylene chloride (30 ml), saturated aqueous sodium hydrogen carbonate solution (150 ml), and water (150 ml) were added to the resulting residue, and the resulting colorless precipitate was collected by filtration. Drying gave the title compound (5.21 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.45 (4H, m), 1.21 (9H, s), 1.68 (2H, d, J = 8.1 Hz), 1 .86 (2H, t, J = 16.2 Hz), 3.22-3.42 (1H, m), 3.69 (1H, br.s), 6.66 (1H, d, J = 8. 5 Hz), 7.02 (1 H, s), 7.15 (1 H, dd, J = 8.5, 2.0 Hz), 7.41 (1 H, d, J = 8.5 Hz), 7.67 ( 1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 8.1 Hz), 11.73 (1H, br.s).
MS (ESI) m / z: 392 (M + H) ^<+> .

[Reference Example 69] N-[(1R ^* , 2R ^* )-2-aminocyclohexyl] -5-chloroindole-2-carboxamide hydrochloride

To a solution of the compound obtained in Reference Example 68 (5.18 g) in methylene chloride (100 ml) was added hydrochloric acid ethanol solution (100 ml) at room temperature. After stirring for 2 days, the reaction mixture was concentrated under reduced pressure, diethyl ether (300 ml) was added to the resulting residue, and the resulting colorless precipitate was collected by filtration and dried to give the title compound (4.30 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.36 (2H, m), 1.36-1.50 (2H, m), 1.60 (2H, br.s), 1 .90 (1H, d, J = 13.0 Hz), 2.07 (1 H, d, J = 13.7 Hz), 3.06 (1 H, br. S), 3.83-3.96 (1H, m), 7.15-7.24 (2H, m), 7.45 (1H, d, J = 8.6 Hz), 7.73 (1H, s), 8.00 (3H, br.s) , 8.60 (1H, d, J = 8.3 Hz), 11.86 (1H, s).
MS (ESI) m / z: 292 (M + H) ^<+> .

[Reference Example 70] (1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 68, the title compound was obtained from the compound obtained in Reference Example 66.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.6 Hz), 7.12 (1H, s), 7.16 (1H, dd, J = 8.8, 2.0 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.69 (1H, d, J = 2.0 Hz), 7.85 ( 1H, d, J = 6.9 Hz), 11.80 (1H, br.s).
MS (ESI) m / z: 392 (M + H) ^<+> .

[Reference Example 71] N-[(1R ^* , 2S ^* )-2-aminocyclohexyl] -5-chloroindole-2-carboxamide hydrochloride

In the same manner as in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 70.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.33 (1H, s), 7.45 (1H, d, J = 8. 7 Hz), 7.60-7.90 (4 H, m), 8.17 (1 H, d, J = 7.1 Hz), 11.91 (1 H, s).
MS (FAB) m / z: 292 (M + H) ^<+> .

[Reference Example 72] (1R ^* , 2R ^* )-1,2-cycloheptanediol

Cycloheptene (3.85 g) was added little by little to 30% aqueous hydrogen peroxide (45 ml) and 88% formic acid (180 ml), stirred at 40-50 ° C. for 1 hour, and then stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and 35% aqueous sodium hydroxide solution was added to the residue to make it alkaline. After stirring this at 40-50 degreeC for 10 minute (s), ethyl acetate was added and liquid-separated and extraction operation was performed 4 times with ethyl acetate from the aqueous layer. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.56 g).
¹ H-NMR (CDCl ₃ ) δ: 1.44 to 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-cycloheptanediamine hydrochloride

The compound (4.56 g) obtained in Reference Example 72 was dissolved in methylene chloride (35 ml), triethylamine (29 ml) was added, and the mixture was cooled to -78 ° C. Methanesulfonyl chloride (8.13 ml) was added dropwise thereto. Methylene chloride (10 ml) was added, and the mixture was stirred at the same temperature for 20 minutes, and then stirred at 0 ° C. for 1.5 hours. Water was added to the reaction solution for liquid separation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oil. This was dissolved in N, N-dimethylformamide (90 ml), sodium azide (13.65 g) was added, and the mixture was stirred at 65 ° C. for 18 hours. Diethyl ether and water were added to the reaction solution for liquid separation, and the diethyl ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oil.
This was dissolved in ethanol (70 ml), 10% palladium carbon (containing 50% water, 4 g) was added, and the mixture was stirred for 4 days in an atmosphere of hydrogen (3.5 atm). 10% palladium carbon was filtered, 1N hydrochloric acid ethanol solution (70 ml) was added to the filtrate, and the solvent was distilled off under reduced pressure. This was dissolved in methanol, ethyl acetate was added, and the solvent was evaporated again under reduced pressure. The resulting precipitate was collected by filtration to give the title compound (3.57 g).
¹ H-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-aminocycloheptyl] -5-chloroindole-2-carboxamide

In the same manner as in Reference Example 59, the title compound was obtained from the compound obtained in Reference Example 73.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.72 (1H, d, J = 2.0 Hz), 7.96 (2H, br.s), 8.75 (1H, d, J = 8.5 Hz), 11.89 (1H, br.s).
MS (ESI) m / z: 306 (M + H) ^<+> .

[Reference Example 75] (1R ^* , 2S ^* )-1,2-cyclooctanediol

Cyclooctene (4.41 g) is dissolved in acetonitrile (45 ml) and water (15 ml), N-methylmorpholine N-oxide (5.15 g), microencapsulated osmium tetroxide (1 g, containing 10% osmium tetroxide) And stirred at 40-50 ° C. for 21 hours. Insoluble microencapsulated osmium was filtered off and washed with acetonitrile. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (4.97 g).
¹ H-NMR (CDCl ₃ ) δ: 1.48-1.58 (6H, m), 1.64-1.75 (4H, m), 1.86-1.96 (2H, m), 2 .28 (2H, d, J = 2.9 Hz), 3.90 (2H, d, J = 8.3 Hz).
MS (FAB) m / z: 145 (M + H) ^<+> .

[Reference Example 76] (1R ^* , 2S ^* )-1,2-diazidocyclooctane

cis-1,2-cyclooctanediol (4.82 g) was dissolved in methylene chloride (60 ml), triethylamine (27.7 ml) was added, the inside of the vessel was purged with argon, and then cooled to -78 ° C. Sulfonyl (7.7 ml, 100 mmol) was added dropwise. After stirring at the same temperature for 1 hour, stirring at 0 ° C for 1 hour, water was added to the reaction solution to separate it, and the organic layer was washed with water, 0.5N hydrochloric acid aqueous solution, water, and saturated aqueous sodium bicarbonate solution. And dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in N, N-dimethylformamide (80 ml), sodium azide (13.0 g) was added, and the mixture was stirred at 65 ° C. for 19 hours. Diethyl ether and water were added to the reaction solution for liquid separation, and the diethyl ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate = 6: 1) to obtain the title compound (4.85 g).
¹ H-NMR (CDCl ₃ ) δ: 1.49-1.64 (6H, m), 1.671-1.78 (2H, m), 1.81-1.97 (4H, m), 3 .74-3.76 (2H, m).

[Reference Example 77] (1R ^* , 2S ^* )-1,2-cyclooctanediamine hydrochloride

The compound (4.85 g) obtained in Reference Example 76 was dissolved in ethanol (55 ml), 10% palladium carbon (containing 50% water, 3.0 g) was added, and the reaction was performed under a hydrogen (4.5 atm) atmosphere for 21 hours. Stir. The catalyst was removed by filtration, 1N hydrochloric acid ethanol solution (50 ml) was added to the filtrate, and the solvent was evaporated under reduced pressure. Acetic acid ethyl ester was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (4.14 g).
¹ H-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-aminocyclooctyl] -5-chloroindole-2-carboxamide

In the same manner as in Reference Example 59, the title compound was obtained from the compound obtained in Reference Example 77. MS (ESI) m / z: 320 (M + H) ^<+> .

[Reference Example 79] (1R ^* , 2R ^* )-4-methoxy-1,2-cyclopentanediol (mixture of stereoisomers at the 4-position)

To a solution of 3-cyclopenten-1-ol (1.68 g) and methyl iodide (1.25 ml) dissolved in tetrahydrofuran (20 ml), 60% sodium hydride (800 mg) was added little by little under ice cooling, and at room temperature. Stir overnight. Water and diethyl ether were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure under ice cooling to obtain crude 4-methoxy-1-cyclopentene.
To the obtained 4-methoxy-1-cyclopentene, 88% formic acid (90 ml) and 30% hydrogen peroxide (3.17 ml) were added at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, 35% aqueous sodium hydroxide solution was added to the residue to make the reaction solution alkaline, and the mixture was stirred at 50 ° C. for 10 minutes. The mixture was cooled to room temperature, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to obtain the title compound (1.21 g).
¹ H-NMR (CDCl ₃ ) δ: 1.65 to 1.85 (2H, m), 2.15 to 2.30 (2H, m), 3.28 (3H, s), 3.90-4 .00 (2H, m), 4.26 (1H, br.s).

[Reference Example 80] (1R ^* , 2R ^* )-1,2-diazido-4-methoxycyclopentane (mixture of stereoisomers at the 4-position)

The compound obtained in Reference Example 79 (1.21 g) and triethylamine (7.66 ml) were dissolved in methylene chloride (20 ml), and methanesulfonyl chloride (2.13 ml) was added dropwise at −78 ° C. over 20 minutes. After completion of dropping, the temperature was raised to 0 ° C. and stirred for 80 minutes to obtain crude (1R ^* , 2R ^* )-1,2-bis (methanesulfonyloxy) -4-methoxycyclopentane. This was dissolved in N, N-dimethylformamide (20 ml), sodium azide (3.57 g) was added, and the mixture was stirred with heating at 65 ° C. for 22 hours. Further, sodium azide (3.57 g) was added and stirred at 70 ° C. for 2 days. The reaction solution was allowed to cool and separated with water and diethyl ether, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (584 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.65 to 1.80 (2H, m), 2.05-2.18 (1H, m), 2.25 to 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-methoxy-1,2-cyclopentanediamine hydrochloride (mixture of stereoisomers at the 4-position)

The compound (584 mg) obtained in Reference Example 80 was dissolved in ethanol, 10% palladium carbon (321 mg) was added, and hydrogenated at room temperature and normal pressure for 2 days. The catalyst was removed by filtration, and the mixture was concentrated. To the residue were added 1N hydrochloric acid ethanol solution and acetic acid ethyl ester, and the mixture was concentrated to give the title compound (488 mg).
¹ H-NMR (CDCl ₃ ) 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-methoxycyclopentyl] -5-chloroindole-2-carboxamide (mixture of stereoisomers at position 4)

  The compound (470 mg) obtained in Reference Example 81 was suspended in N, N-dimethylformamide (5 ml), and triethylamine (0.966 ml) and 5-chloroindole-2-carboxylic acid p-nitrophenyl ester (805 mg) were added. And stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 9) to obtain the title compound (268 mg).

[Reference Example 83] (1R ^* , 2R ^* )-4-[(benzyloxy) methyl] -1,2-cyclopentanediol (mixture of stereoisomers at the 4-position)

In the same manner as in Reference Example 79, 4-hydroxymethyl-1-cyclopentene (J. Heterocycl. Chem., 1989, Vol. 26, page 451) was benzylated with benzyl bromide and then formic acid-peroxygenated. Hydrogen gave the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.44 to 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-cyclopentanediamine (mixture of stereoisomers at the 4-position)

(1R ^* , 2R ^* )-4-benzyloxymethyl-1,2-diazidocyclopentane was obtained from the compound obtained in Reference Example 83 in the same manner as in Reference Example 80. Reference was made without purification. The title compound was obtained in the same manner as in Example 81.

[Reference Example 85] N-{(1R ^* , 2R ^* )-2-amino-4-[(benzyloxy) methyl] cyclopentyl} -5-chloroindole-2-carboxamide (mixture of stereoisomers at position 4)

In the same manner as in Reference Example 59, the title compound was obtained from the compound obtained in Reference Example 84.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.15 (0.5 H, m), 1.26-1.35 (0.5 H, 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 = 8.5 Hz), 7.69 (1H, d, J = 2.2 Hz), 8.34 (1H, t, J = 7.1 Hz).
MS (FAB) m / z: 398 (M + H) ^<+> .

[Reference Example 86] (1R ^* , 3R ^* , 6S ^* )-7-oxabicyclo [4.1.0] heptane-3-carboxylic acid ethyl ester

(1R ^* , 4R ^* , 5R ^* )-4-iodo-6-oxabicyclo [3.2.1] octane-7-one (J. Org. Chem., 1996, 61, 8687) (14 3 g) was dissolved in ethanol (130 ml), 2N aqueous sodium hydroxide solution (34.5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 7 hours. The solvent was distilled off under reduced pressure, water was added to the residue and the mixture was extracted with methylene chloride, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 83: 17) to obtain the title compound (6.54 g).
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz).

[Reference Example 87] (1R ^* , 3S ^* , 4S ^* )-3-Azido-4-hydroxycyclohexanecarboxylic acid ethyl ester

The compound (13.6 g) obtained in Reference Example 86 was dissolved in N, N-dimethylformamide (100 ml), ammonium chloride (6.45 g) and sodium azide (7.8 g) were successively added at room temperature, Stir at 75 ° C. for 12 hours. The solvent was concentrated to about one third, diluted with water and ethyl acetate, and stirred for 3 minutes. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 4) to obtain the title compound (15.8 g).
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz).

[Reference Example 88] (1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl) amino] -4-hydroxycyclohexanecarboxylic acid ethyl ester

The compound (100 mg) and di-tert-butyl dicarbonate (133 mg) obtained in Reference Example 87 were dissolved in acetic acid ethyl ester (12 ml), a catalytic amount of 10% palladium carbon was added, and the mixture was added at room temperature under a hydrogen stream for 12 hours. Stir. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (145 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz), 4.53 (1H, br.s).

[Reference Example 89] (1R ^* , 3S ^* , 4R ^* )-4-azido-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester and (1R ^* , 3S ^* , 4S ^* )-4- Azido-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester

The compound obtained in Reference Example 88 (16 g) and triethylamine (38 ml) were dissolved in methylene chloride (150 ml), cooled to −78 ° C., and methanesulfonyl chloride (13 ml) was added dropwise at the same temperature. After stirring at the same temperature for 15 minutes, the temperature was raised to 0 ° C., followed by stirring for 30 minutes and further at room temperature for 2 hours. After adding 0.1N hydrochloric acid and diluting with methylene chloride, the organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude (1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl) amino] -4-[(methylsulfonyl) oxy] cyclohexanecarboxylic acid ethyl ester. .
The above product was dissolved in N, N-dimethylformamide (100 ml), sodium azide (18 g) was added at room temperature, the temperature was raised to 75 ° C., and the mixture was stirred for 12 hours. The solvent was concentrated to about one third, diluted with water and ethyl acetate, and stirred for 3 minutes. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound [(1R ^* , 3S ^* , 4R ^* )-isomer, 6.74 g] and [(1R ^* , 3S ^* , 4S ^* )-isomer, 1.32 g] was obtained.
(1R ^* , 3S ^* , 4R ^* )-body:
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 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:
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz), 4.67 (1H, br.s).

[Reference Example 90] (1R ^* , 3S ^* , 4R ^* )-4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester

(1R ^* , 3S ^* , 4R ^* )-4-azido-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester (5.4 g) obtained in Reference Example 89 was added to ethanol (10 ml) and ethyl acetate. It melt | dissolved in the mixed solvent of ester (10 ml), 10% palladium carbon of the catalyst amount was added, and it stirred at room temperature under hydrogen stream for 20 hours. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (4.7 g).

[Reference Example 91] (1R ^* , 3S ^* , 4R ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxylate ethyl ester

The compound (4.62 g) obtained in Reference Example 90 was dissolved in methylene chloride (50 ml), and 5-chloroindole-2-carboxylic acid (3.63 g), 1-hydroxybenzotriazole monohydrate ( 2.43 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.45 g) were added and stirred for 12 hours. A 0.1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 2: 3) to obtain the title compound (5.3 g).
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 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-oxabicyclo [4.1.0] heptane-3-carboxylic acid ethyl ester (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3 2.1] Octan-7-one (J. Org. Chem., 1996, 61, 8687) (89.3 g) was suspended in ethanol (810 ml), and 2N aqueous sodium hydroxide solution (213 ml) was suspended. And then stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with methylene chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 17: 3) to obtain the title compound (41.3 g).
[Α] _D ²⁵ = −58 ° (c = 1.0, chloroform).

[Reference Example 93] (1S, 3R, 4R) -3-Azido-4-hydroxycyclohexanecarboxylic acid ethyl ester The compound (41 g) obtained in Reference Example 92 was dissolved in N, N-dimethylformamide (300 ml) and brought to room temperature. Ammonium chloride (19.3 g) and sodium azide (23.5 g) were sequentially added, and the mixture was stirred at 76 ° C. for 13 hours. The reaction solution was filtered, the filtrate was concentrated, the previous filtrate was put into the residue, and water was added to dissolve. Extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (51.5 g).
[Α] _D ²⁵ = + 8 ° (c = 1.0, chloroform)

[Reference Example 94] (1S, 3R, 4R) -3-[(tert-butoxycarbonyl) amino] -4-hydroxycyclohexanecarboxylic acid ethyl ester Compound (51.2 g) obtained in Reference Example 93 and di-tert- Butyl dicarbonate (68.1 g) was dissolved in acetic acid ethyl ester (1000 ml), 5% palladium carbon (5.0 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen pressure of 7 kg / cm ² . The insoluble material was filtered off, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1), solidified by adding hexane, and the title compound (46. 9 g) was obtained.
[Α] _D ²⁵ = + 25 ° (c = 1.0, chloroform).

[Reference Example 95] (1S, 3R, 4S) -4-azido-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester and (1S, 3R, 4R) -4-azido-3-[( tert-Butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester The compound (53.5 g) obtained in Reference Example 94 and triethylamine (130 ml) were dissolved in methylene chloride (500 ml), and chlorinated with cooling to -10 to -15 ° C. Methanesulfonyl (42 ml) was added dropwise over 20 minutes. After stirring for 20 minutes at the same temperature, the temperature was raised to room temperature over 2 hours. The reaction mixture was cooled to 0 ° C., 0.5N hydrochloric acid (800 ml) was added dropwise, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude (1S, 3R, 4R) -3-[(tert-butoxycarbonyl) amino] -4-[(methylsulfonyl) oxy] cyclohexanecarboxylic acid ethyl ester.
The crude compound was dissolved in N, N-dimethylformamide (335 ml), sodium azide (60.5 g) was added, and the mixture was stirred at 67 to 75 ° C. for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and 250 ml of the solvent was distilled off. The residue and the previous filtered product were combined, dissolved in water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 4) to give (1S, 3R, 4S) -form (18.4 g) of the title compound and (1S, 3R, 4R)- Body (3.3 g) was obtained. (1S, 3R, 4S) -form: [α] _D ²⁵ = + 62 ° (c = 1.0, chloroform).
(1S, 3R, 4R) -form: [α] _D ²⁵ = −19 ° (c = 1.0, chloroform).

[Reference Example 96] (1S, 3R, 4S) -4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester The compound (4.0 g) obtained in Reference Example 95 was ethanol (150 ml). And 5% palladium on carbon (0.5 g) was added and stirred for 17 hours at room temperature in a hydrogen atmosphere (5 kg / cm ² ). The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to give the title compound (4.2 g).

[Reference Example 97] (1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester

The compound (4.2 g) obtained in Reference Example 96 was dissolved in methylene chloride (50 ml), and 5-chloroindole-2-carboxylic acid (3.33 g), 1-hydroxybenzotriazole monohydrate ( 2.52 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.15 g) were added and stirred for 12 hours. A 0.1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 1) to obtain the title compound (4.36 g).
[Α] _D = −27 ° (c = 1.0, chloroform).

[Reference Example 98] (1R ^* , 3S ^* , 4R ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester

  In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 90 and the compound obtained in Reference Example 10.

[Reference Example 99] 3-Cyclohexene-1-carboxylic acid benzyl ester

(±) -3-Cyclohexene-1-carboxylic acid (50 g) was dissolved in N, N-dimethylformamide (550 ml), triethylamine (170 ml) and benzyl bromide (61 ml) were added under ice cooling, and the mixture was stirred at room temperature for 12 hours. . Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (70.8 g).
¹ H-NMR (CDCl ₃ ) 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-oxabicyclo [4.1.0] heptane-3-carboxylic acid benzyl ester

The compound (40 g) obtained in Reference Example 99 was dissolved in methylene chloride (500 ml), m-chloroperbenzoic acid (86 g) was added under ice cooling, and the mixture was stirred for 2 hours. After adding 10% aqueous sodium thiosulfate solution and stirring for 20 minutes, the organic layer was separated, washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give the title compound (23.4 g) and (1R ^* , 3R ^* , 6S ^* )-7. -Oxabicyclo [4.1.0] heptane-3-carboxylic acid benzyl ester (12.1 g) was obtained.
¹ H-NMR (CDCl ₃ ) 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, 4.9 Hz), 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-hydroxycyclohexanecarboxylic acid benzyl ester

The compound (52.3 g) obtained in Reference Example 100 was dissolved in N, N-dimethylformamide (1000 ml), ammonium chloride (21.9 g) and sodium azide (18.1 g) were added, and the mixture was heated to 70 ° C. Stir for 24 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (61.8 g).
¹ H-NMR (CDCl ₃ ) 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-hydroxycyclohexanecarboxylic acid benzyl ester

The compound (5.27 g) obtained in Reference Example 101 was dissolved in tetrahydrofuran (25 ml), triphenylphosphine (5.53 g) and water (0.55 ml) were added, and the mixture was stirred at room temperature for 20 hours. Di-tert-butyl dicarbonate (4.82 g) was added to the reaction solution, and stirring was further continued for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (6.22 g).
¹ H-NMR (CDCl ₃ ) 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 = 12.5 Hz), 7.30-7.38 (5H, m).
MS (FAB) m / z: 350 (M + H) ^<+> .

[Reference Example 103] (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-hydroxycyclohexanecarboxylic acid methyl ester

The compound (2.54 g) obtained in Reference Example 102 was dissolved in ethyl acetate (15 ml), a catalytic amount of 10% palladium carbon was added, and the mixture was stirred at room temperature for 20 hours under a hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-hydroxycyclohexanecarboxylic acid as a colorless oil. . This was dissolved in a mixed solution of methanol (8 ml) and toluene (15 ml), 2N trimethylsilyldiazomethanehexane solution (10 ml) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (1.82 g).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.6-2.32 (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-azido-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester and (1R ^* , 3S ^* , 4S ^* )-3- Azido-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester

The compound (1.81 g) obtained in Reference Example 103 was dissolved in methylene chloride (36 ml), triethylamine (4.6 ml) and methanesulfonyl chloride (1.63 ml) were added at −78 ° C., and after 30 minutes 0 ° C. The mixture was heated up to 30 minutes and further stirred for 30 minutes. 1N Hydrochloric acid was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-[(methylsulfonyl) oxy] cyclohexanecarboxylic acid methyl ester. .
The crude compound was dissolved in N, N-dimethylformamide (23 ml), sodium azide (1.29 g) was added, and the mixture was heated to 70 ° C. and stirred for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 17) to give (1R ^* , 3S ^* , 4S ^* )-3-azido-4-[(tert- Butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester (85 mg) and (1R ^* , 3R ^* , 4S ^* )-3-azido-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester (590 mg) were obtained. It was.
(1R ^* , 3R ^* , 4S ^* )-isomer: ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.35 to 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 ^* )-isomer: ¹ H-NMR (CDCl ₃ ) 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] cyclohexanecarboxylic acid methyl ester

The (1R ^* , 3R ^* , 4S ^* ) compound (230 mg) obtained in Reference Example 104 was dissolved in acetic acid ethyl ester (8 ml), a catalytic amount of 10% palladium carbon was added, and the mixture was stirred under a hydrogen stream for 20 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (220 mg).

[Reference Example 106] (1R ^* , 3R ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 105 and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) 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-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxylate methyl ester

In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 105.
¹ H-NMR (CDCl ₃ ) 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-oxabicyclo [4.1.0] heptane-3-carboxylic acid benzyl ester 1) In the same manner as in Reference Example 99, (1R) -3-cyclohexene (1R) -3-cyclohexene-1-carboxylic acid benzyl ester was obtained from -1-carboxylic acid (J. Am. Chem. Soc, 1978, 100, 5199). 2) In the same manner as in Reference Example 100, the title compound was obtained from the above product.
MS (FAB) m / z: 233 (M + H) ^<+> .

[Reference Example 109] (1R, 3S, 4S) -4-[(tert-butoxycarbonyl) amino] -3-hydroxycyclohexanecarboxylic acid benzyl ester 1) Obtained in Reference Example 108 in the same manner as in Reference Example 101 (1R, 3S, 4S) -4-azido-3-hydroxycyclohexanecarboxylic acid benzyl ester was obtained from the compound.
2) The title compound was obtained from the above product in the same manner as in Reference Example 102.
MS (FAB) m / z: 350 (M + H) ^<+> .

[Reference Example 110] (1R, 3R, 4S) -3-Azido-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid benzyl ester

In the same manner as in Reference Example 104, the title compound was obtained from the compound obtained in Reference Example 109.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.52-1.66 (2H, m), 1.83 to 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 = 12.2 Hz), 7.33-7.38 (5H, m).
MS (FAB) m / z: 375 (M + H) ^<+> .

[Reference Example 111] (1R, 3R, 4S) -3-Azido-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester

The compound (3.5 g) obtained in Reference Example 110 was dissolved in tetrahydrofuran (130 ml) and water (16 ml), lithium hydroxide (291 mg) was added under ice cooling, and after 10 minutes, the mixture was returned to room temperature and stirred for 20 hours. The residue obtained after evaporation of the solvent under reduced pressure was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 20) to give (1R, 3R, 4S) -3-azido-4-[(tert-butoxycarbonyl). ) Amino] cyclohexanecarboxylic acid (3.34 g) was obtained as a pale yellow oil. This was dissolved in methanol (18 ml) and toluene (64 ml), 2 mol trimethylsilyldiazomethanehexane solution (6.1 ml) was added under ice cooling, and after 10 minutes, the temperature was returned to room temperature and stirred for 2 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 4) to obtain the title compound (3.35 g).
¹ H-NMR (CDCl ₃ ) 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-tetrahydrothiazolo [5,4- c] Pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester

1) (1R, 3R, 4S) -3-Amino-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester was obtained from the compound obtained in Reference Example 111 in the same manner as in Reference Example 105. It was.
2) In the same manner as in Reference Example 106, the title compound was obtained from the above product and the compound obtained in Reference Example 10.
MS (FAB) m / z: 453 (M + H) ^<+> .

[Reference Example 113] (1R ^* , 2S ^* , 5S ^* )-5-aminocarbonyl-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester

The compound obtained in Reference Example 91 (590 mg) was dissolved in a mixed solvent of ethanol (3 ml) and tetrahydrofuran (6 ml), 1N aqueous sodium hydroxide solution (2.5 ml) was added at room temperature, and the mixture was stirred for 12 hours. The solvent was distilled off and (1R ^* , 3S ^* , 4R ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxylic acid The sodium salt was obtained. This was suspended in N, N-dimethylformamide (4 ml), di-tert-butyl dicarbonate (654 mg) and ammonium hydrogen carbonate (1 g) were added at room temperature, and the mixture was stirred for 18 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3) to obtain the title compound (82 mg).
MS (ESI) m / z: 435 (M + H) ^<+> .

[Reference Example 114] (1R, 6S) -6-{[(Benzyloxy) carbonyl] amino} -3-cyclohexen-1-ylcarbamic acid benzyl ester

4-Cyclohexene-1,2-diamine hydrochloride (4.0 g) was dissolved in a mixed solvent of water (20 ml) and acetonitrile (20 ml), benzyl chloroformate (7.66 ml), potassium carbonate (14.9 g). And stirred at room temperature for 3 days. The reaction solution was poured into water, extracted with methylene chloride, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride) to obtain the title compound (8.22 g).
¹ H-NMR (CDCl ₃ ) δ: 2.03 (2H, m), 2.53 (2H, d, J = 17.1 Hz), 3.77 (2H, m), 5.03 (2H, q , J = 12.3 Hz), 5.09 (2H, q, J = 12.3 Hz), 5.59 (2H, s), 7.32 (10 H, m).
MS (ESI) m / z: 381 (M + H) ^<+> .

[Reference Example 115] (1R ^* , 2S ^* )-2-{[(benzyloxy) carbonyl] amino} -5-hydroxycyclohexylcarbamic acid benzyl ester

The compound (10 g) obtained in Reference Example 114 was dissolved in anhydrous tetrahydrofuran (70 ml), borane dimethyl sulfide complex (7.4 ml) was added at 0 ° C., the temperature was gradually raised to room temperature, and the mixture was stirred for 14 hours. Ice was added to the reaction solution to decompose excess borane, 1N aqueous sodium hydroxide solution (80 ml) and 30% aqueous hydrogen peroxide (80 ml) were added, and the mixture was stirred as it was for 1 hour. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 2: 1) to obtain the title compound (9.2 g).
¹ H-NMR (CDCl ₃ ) 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-oxocyclohexylcarbamic acid benzyl ester

Under cooling and stirring at −60 ° C., dimethyl sulfoxide (8.2 ml) was added to a solution of oxalyl chloride (9.9 ml) dissolved in methylene chloride (90 ml), and the compound (9.2 g) obtained in Reference Example 115 was further added. Tetrahydrofuran (90 ml) solution was added in one portion. After 1 hour, the temperature was raised to −40 ° C., and triethylamine (26 ml) was added all at once. The temperature was raised to room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 1) to obtain the title compound (8.0 g).
¹ H-NMR (CDCl ₃ ) δ: 2.27-2.43 (4H, m), 2.78 (1H, dd, J = 14.4, 3.9 Hz), 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-dimethoxycyclohexylcarbamic acid benzyl ester

The compound (3.89 g) obtained in Reference Example 116 was dissolved in a mixed solvent of methanol (15 ml) and tetrahydrofuran (15 ml), and 2,2-dimethoxypropane (10.7 ml) and p-toluenesulfonic acid (187 mg) were added. The mixture was further stirred at room temperature for 3 hours. The solution was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 2) to obtain the title compound (3.54 g).
¹ H-NMR (CDCl ₃ ) 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 = 12.5 Hz), 5.09 (2H, q, J = 12.5 Hz), 7. 32 (10H, s).

[Reference Example 118] N-[(1R ^* , 2S ^* )-2-amino-4,4-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide and N-[(1R ^* , 2S ^* )-2- Amino-5,5-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide

The compound (1.45 g) obtained in Reference Example 117 was dissolved in methanol (12 ml), 10% palladium carbon (290 mg) was added, and the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. Further, 10% palladium carbon (290 mg) and methanol (10 ml) were added, and the mixture was stirred for 8 hours. The reaction solution was filtered through Celite, and the mother liquor was concentrated. The residue was dissolved in N, N-dimethylformamide (10 ml), and 5-chloroindole-2-carboxylic acid (320 mg), 1- (3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (377 mg), 1-hydroxybenzotriazole monohydrate (301 mg) and N-methylmorpholine (360 ml) were added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, separated and purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 93: 7), and N-[(1R ^* , 2S ^* )-2-amino-4,4- Dimethoxycyclohexyl] -5-chloroindole-2-carboxamide (or N-[(1R ^* , 2S ^* )-2-amino-5,5-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide) (98 mg) and N-[(1R ^* , 2S ^* )-2-amino-5,5-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide (or N-[(1R ^* , 2S ^* )-2-amino-4, 4-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide) (105 mg) was obtained.
N-[(1R ^* , 2S ^* )-2-amino-4,4-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide:
¹ H-NMR (CDCl ₃ ) δ: 1.45-1.50 (2H, m), 2.06-2.10 (2H, m), 2.34 (1H, d, J = 13.1 Hz) 2.78 (1H, dt, J = 2.9, 13.1 Hz), 3.18 (3H, s), 3.23 (3H, s), 3.75-3.77 (1H, m) , 6.24 (1H, d, J = 8.3 Hz), 6.79 (1H, s), 7.23 (1H, dd, J = 8.8, 2.0 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.60 (1H, d, J = 8.8 Hz), 9.53 (1H, br.s).
MS (ESI) m / z: 352 (M + H) ^<+> .
N-[(1R ^* , 2S ^* )-2-amino-5,5-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide:
¹ H-NMR (CDCl ₃ ) δ: 1.83 to 1.87 (1H, m), 1.97-2.01 (1H, m), 2.39 (1H, br, J = 13.2 Hz) 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 = 8.5 Hz), 7.37 (1H, d, J = 8.5 Hz), 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} -1,4-dioxaspiro [4.5] dec-8-ylcarbamic acid benzyl ester

The compound (4.0 g) obtained in Reference Example 116 was dissolved in anhydrous tetrahydrofuran (30 ml), ethylene glycol (5.6 ml) and p-toluenesulfonic acid (192 mg) were added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 1) to obtain the title compound (4.23 g).
¹ H-NMR (CDCl ₃ ) 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 = 12.2 Hz), 5.08 (2H, q, J = 12.2 Hz), 7. 32 (10H, s).
MS (ESI) m / z: 441 (M + H) ^<+> .

[Reference Example 120] N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindole-2-carboxamide and N-[( 7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindole-2-carboxamide

N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl]-from the compound obtained in Reference Example 119 by a method similar to that of Reference Example 118 5-chloroindole-2-carboxamide (or N-[(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindole-2-carboxamide ) And N-[(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindole-2-carboxamide (or N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindole-2-carboxamide).
N-[(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindole-2-carboxamide (or N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindole-2-carboxamide):
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.81 (4H, m), 2.11 (2H, m), 2.87 (1H, td, J = 3.9, 11.2 Hz) , 3.77 (1H, m), 3.97 (4H, s), 6.27 (1H, d, J = 7.6 Hz), 6.80 (1H, s), 7.24 (1H, d) , J = 9.0 Hz), 7.35 (1H, d, J = 9.0 Hz), 7.61 (1H, s), 9.47 (br. S, 1H).
MS (ESI) m / z: 350 (M + H) ^<+> .
N-[(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindole-2-carboxamide (or N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindole-2-carboxamide):
¹ H-NMR (CDCl ₃ ) δ: 1.65 (2H, m), 1.88 (1H, m), 1.96 (1H, m), 2.31 (1H, dd, J = 12.9) , 3.2 Hz), 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, 2.0 Hz), 7.37 (1H, d, J = 8.8 Hz), 7.62 ( 1H, d, J = 2.0 Hz), 9.49 (1H, br.s).
MS (ESI) m / z: 350 (M + H) ^<+> .

[Reference Example 121] (1R, 6S) -6-[(tert-butoxycarbonyl) amino] -3-cyclohexen-1-ylcarbamic acid tert-butyl ester

Cis-4-cyclohexene-1,2-diamine hydrochloride (4.0 g) was dissolved in water (40 ml) and acetonitrile (40 ml), and di-tert-butoxycarbonate (11.8 g) and triethylamine (12 ml) were dissolved. The mixture was further stirred at room temperature for 4.5 hours. The reaction solution was poured into water and extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 4) to obtain the title compound (6.12 g).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (18H, s), 1.98 (2H, dd, J = 9.3, 15.9 Hz), 2.48 (2H, br.d, J = 15.9 Hz), 3.66 (2H, br.s), 4.88 (2H, br.s), 5.58 (2H, d, J = 2.7 Hz).

[Reference Example 122] (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl) amino] -5-hydroxycyclohexylcarbamic acid tert-butyl ester (mixture of stereoisomers)

The compound (6.1 g) obtained in Reference Example 121 was dissolved in anhydrous tetrahydrofuran (40 ml), borane-dimethyl sulfide complex (2.22 ml) was added under ice cooling, and the temperature was gradually raised to room temperature for 16 hours. Stir. Ice was added to the reaction mixture, 1N aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide (50 ml) were added, and the mixture was stirred as it was at room temperature for 2 hr. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2 → 2: 1) to obtain the title compound (6.1 g).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.43 (9H, s), 1.83 to 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 = 9.0 Hz) , 5.02 (1H, q, J = 9.0 Hz).
MS (ESI) m / z: 331 (M + H) ^<+> .

[Reference Example 123] (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl) amino] -5-oxocyclohexylcarbamic acid tert-butyl ester

Oxalyl chloride (8.2 ml) and dimethyl sulfoxide (6.8 ml) were dissolved in methylene chloride (100 ml), cooled to −60 ° C., and the compound obtained in Reference Example 122 (mixture of stereoisomers) (6.32 g). ) In tetrahydrofuran (80 ml) was added in one portion and stirred for 1 hour. The temperature was raised to −40 ° C., triethylamine (21 ml) was added, the temperature was raised to room temperature, and the mixture was poured into water after 3 hours. After extraction with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 1) to obtain the title compound (3.8 g).
¹ H-NMR (CDCl ₃ ) 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, 2.9 Hz), 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) cyclohexylcarbamic acid tert-butyl ester

The compound (1.5 g) obtained in Reference Example 123 was dissolved in methanol (30 ml), O-methylhydroxylamine hydrochloride (572 mg) and pyridine (737 ml) were added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 4) to obtain the title compound (1.52 g).
¹ H-NMR (CDCl ₃ ) 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 (diphenyl) silyl] oxy} cyclohexylcarbamic acid tert-butyl ester (stereoisomer) A)

In the same manner as in Reference Example 58, the title compound was obtained from the compound (mixture of stereoisomers) obtained in Reference Example 122. In addition, (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl) amino] -5-hydroxycyclohexylcarbamic acid tert-butyl ester (stereoisomer B) was recovered.
¹ H-NMR (CDCl ₃ ) 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-methylcyclohexylcarbamic acid benzyl ester

Anhydrous cerium chloride (6.4 g) was suspended in tetrahydrofuran (50 ml) and cooled to −78 ° C. under an argon stream. A methyllithium solution (1.14 N diethyl ether solution, 22.5 ml) was added to the suspension, and the mixture was stirred at -78 ° C for 30 minutes. A tetrahydrofuran solution (50 ml) of the compound (3.0 g) obtained in Reference Example 116 was added dropwise at −78 ° C. and stirred for 30 minutes. The reaction solution was poured into a 3% aqueous acetic acid solution (100 ml), diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified twice by silica gel column chromatography (methanol: chloroform = 0: 100-1: 19) to give the title compound (stereoisomer A) (780 mg) and the title compound (stereoisomer). Isomer B) (1.1 g) was obtained.
Stereoisomer A:
¹ H-NMR (CDCl ₃ ) 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:
¹ H-NMR (CDCl ₃ ) 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-diamino-1-methylcyclohexanol (stereoisomer A)

10% Palladium carbon (350 mg) was suspended in a methanol solution (100 ml) of the compound (stereoisomer A) (780 mg) obtained in Reference Example 126 and stirred for 5 hours under a hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride (100 ml) and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (stereoisomer A) (190 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.25-2.48 (11 H, m), 2.62 (1 H, br. S), 2.78 (1 H, br .S).

[Reference Example 128] N-[(1R ^* , 2S ^* )-2-amino-4-hydroxy-4-methylcyclohexyl] -5-chloroindole-2-carboxamide (stereoisomer A) and N-[(1R ^* , 2S ^* )-2-amino-5-hydroxy-5-methylcyclohexyl] -5-chloroindole-2-carboxamide (stereoisomer A)

In the same manner as in Reference Example 59, the title compound was obtained from the compound (stereoisomer A) obtained in Reference Example 127 and 5-chloroindole-2-carboxylic acid.
¹ H-NMR (CDCl ₃ ) 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-Chloroindol-2-yl) carbonyl] amino} -5- (hydroxymethyl) cyclohexylcarbamic acid tert-butyl ester

1) (1R ^* , 3S ^* , 4S ^* )-3-[(tert-) from the (1R ^* , 3S ^* , 4S ^* ) isomer obtained in Reference Example 89 in the same manner as described in Reference Examples 90-91. Butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester was obtained.
¹ H-NMR (CDCl ₃ ) 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 = 8.8 and 2.0 Hz), 7.33 (1H, d, J = 8. 8 Hz), 7.52-7.57 (1 H, m), 7.59 (1 H, d, J = 2.0 Hz), 9.24 (1 H, s).
MS (ESI) m / z: 464 (M + H) ^<+> .
2) The above product (735 mg) was dissolved in methylene chloride (10 ml), diisobutylaluminum hydride 1N hexane solution (5 ml) was added at −78 ° C., and the mixture was stirred for 3 hours and then stirred at 0 ° C. for 30 minutes. . A saturated aqueous ammonium chloride solution was added at −78 ° C., and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 19: 1) to obtain the title compound (480 mg).
¹ H-NMR (CDCl ₃ ) 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- (methoxymethyl) oxabicyclo [4.1.0] heptane

1) (1R ^* , 4R ^* , 5R ^* )-4-iodo-6-oxabicyclo [3.2.1] octan-7-one (2.8 g) mixed with tetrahydrofuran (27 ml) and water (3 ml) Dissolved in the solvent, concentrated hydrochloric acid (0.1 ml) was added, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain (1R ^* , 3R ^* , 4R ^* )-3-hydroxy-4-iodocyclohexanecarboxylic acid (3.23 g) as a colorless solid.
2) The product (3.22 g) obtained in the above reaction was dissolved in tetrahydrofuran (50 ml), borane-dimethyl sulfide complex (2 molar tetrahydrofuran solution, 47 ml) was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. did. The solvent was distilled off under reduced pressure, the residue was dissolved in isopropanol (10 ml), 1N aqueous sodium hydroxide solution (12 ml) was added at room temperature, and the mixture was stirred for 12 hours. The solvent was concentrated to about 1/5, diluted with water and methylene chloride, and stirred for 10 minutes. The organic layer was separated, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2), and (1R ^* , 3R ^* , 6S ^* )-7-oxabicyclo [4.1.0]. ] Hept-3-ylmethanol (1.25 g) was obtained as a colorless oil.
3) The product (4.63 g) obtained in the reaction 2) above was dissolved in tetrahydrofuran (50 ml), and potassium bis (trimethylsilyl) amide (0.5 N toluene solution, 80 ml) was added at -78 ° C. After stirring at the same temperature for 10 minutes, methyl iodide (2.93 ml) was added. The mixture was heated to 0 ° C. and stirred for 1 hour, and a saturated aqueous ammonium chloride solution was added, and the mixture was diluted with diethyl ether. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 4) to obtain the title compound (3.7 g).
¹ H-NMR (CDCl ₃ ) 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-azido-4- (methoxymethyl) cyclohexanol

In the same manner as in Reference Example 87, the title compound was obtained from the compound obtained in Reference Example 130.
¹ H-NMR (CDCl ₃ ) δ: 1.45-1.70 (5H, m), 1.77-1.95 (2H, m), 1.98-2.08 (1H, m), 3 .30 (2H, d, J = 6.8 Hz), 3.35 (3H, s), 3.45-3.65 (2H, m).

[Reference Example 132] (1R ^* , 2R ^* , 5S ^* )-2-hydroxy-5- (methoxymethyl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 88, the title compound was obtained from the compound obtained in Reference Example 131.
¹ H-NMR (CDCl ₃ ) δ: 1.35 to 2.01 (16H, m), 3.05 (1H, br.s), 3.32 (2H, d, J = 7.1 Hz), 3 .34 (3H, s), 3.44-3.62 (2H, m), 4.59 (1H, br. S).

[Reference Example 133] (1R ^* , 2S ^* , 5S ^* )-2-azido-5- (methoxymethyl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 89, the title compound was obtained from the compound obtained in Reference Example 132 via its methanesulfonic acid ester.
¹ H-NMR (CDCl ₃ ) δ: 1.31-1.93 (16H, m), 3.27 (2H, d, J = 6.4 Hz), 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- (methoxymethyl) cyclohexylcarbamic acid tert-butyl ester

  In the same manner as in Reference Example 90, the title compound was obtained from the compound obtained in Reference Example 133.

[Reference Example 135] (1R ^* , 2S ^* , 5S ^* )-2-{[(5-Chloroindol-2-yl) carbonyl] amino} -5- (methoxymethyl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 134 and 5-chloroindole-2-carboxylic acid.
¹ H-NMR (CDCl ₃ ) 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). .8 Hz), 7.33 (1 H, d, J = 8.8 Hz), 7.60 (1 H, s), 8.09 (1 H, br. S), 9.42 (1 H, br. S).
MS (ESI) m / z: 436 (M + H) ^<+> .

[Reference Example 136] (1R ^* , 2S ^* , 5S ^* )-2-{[(5-Chloroindol-2-yl) carbonyl] amino} -5- (hydroxymethyl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 91 by a method similar to that of Reference Example 129.
¹ H-NMR (CDCl ₃ ) 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- (azidomethyl) -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester

  In the same manner as in Reference Example 80, the title compound was obtained from the compound obtained in Reference Example 136.

[Reference Example 138] 3-Cyclohexen-1-ylcarbamic acid tert-butyl ester

3-Cyclohexene-1-carboxylic acid (25.3 g) was dissolved in tert-butanol (250 ml), triethylamine (28 ml) and diphenylphosphoryl azide (43.0 ml) were added, and the mixture was further heated to 90 ° C. for 1 hour at room temperature. And stirred for 2 days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride) and then re-purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give the title compound (24.9 g). It was.
¹ H-NMR (CDCl ₃ ) 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-dihydroxycyclohexylcarbamic acid tert-butyl ester

The compound (1.24 g) obtained in Reference Example 138 was dissolved in a mixed solvent of acetonitrile (15 ml) and water (5 ml), and N-methylmorpholine N-oxide (0.90 g), microencapsulated 10% osmium tetroxide. (1 g) was added and stirred at about 80 ° C. for 1 day. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to give the title compound (1.28 g).
¹ H-NMR (CDCl ₃ ) 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-diazidocyclohexylcarbamic acid tert-butyl ester (stereoisomer A and stereoisomer B)

In the same manner as in Reference Example 80, the title compounds (stereoisomer A and stereoisomer B) were obtained from the compound obtained in Reference Example 139.
Stereoisomer A:
¹ H-NMR (CDCl ₃ ) 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:
¹ H-NMR (CDCl ₃ ) 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] (1S, 3R, 4S) -4-{[(Benzyloxy) carbonyl] amino} -3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester

The compound (3.10 g) obtained in Reference Example 96 was dissolved in tetrahydrofuran (50 ml), and saturated aqueous sodium hydrogen carbonate solution (50 ml) was added. Benzyloxycarbonyl chloride (1.71 ml) was added dropwise to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 4 days. Acetic acid ethyl ester (200 ml) and water (200 ml) were added to the reaction solution, and a liquid separation operation was performed. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The precipitated solid was collected by filtration to give the title compound (3.24 g).
¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1 Hz), 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] cyclohexanecarboxylic acid

The compound (620 mg) obtained in Reference Example 141 was dissolved in tetrahydrofuran (20 ml), an aqueous solution (10 ml) of lithium hydroxide monohydrate (93 mg) was added, and the mixture was stirred at room temperature for 16 hours. Lithium hydroxide monohydrate (217 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours, neutralized with 1N aqueous hydrochloric acid solution, and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (600 mg).
¹ H-NMR (CDCl ₃ ) 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] cyclohexylcarbamic acid benzyl ester

The compound (600 mg) obtained in Reference Example 142 and dimethylamine hydrochloride (240 mg) were suspended in methylene chloride (50 ml), and an appropriate amount of tetrahydrofuran was added to prepare a solution. To this solution, triethylamine (0.41 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (422 mg) and 1-hydroxybenzotriazole monohydrate (338 mg) were added and stirred at room temperature for 1 hour. did. Dimethylamine hydrochloride (480 mg) and triethylamine (0.82 ml) were added to the reaction mixture, and the mixture was further stirred at room temperature for 18 hours. The reaction solution was poured into water, the organic layer was separated, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3: 47 → 2: 23) to obtain the title compound (620 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.50 (2H, m), 1.44 (9H, s), 1.50-2.10 (4H, m), 2.60 (1H , Br.t, J = 11.6 Hz), 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] cyclohexylcarbamic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 143 (190 g) in methanol (8000 ml) was added 10% palladium carbon (57 g), and the mixture was stirred under hydrogen at 7 atm for 3 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Toluene was added to the residue and concentrated under reduced pressure, hexane (2500 ml) was added and solidified, and the residue was collected by filtration and dried to obtain the title compound (121 g).
¹ H-NMR (CDCl ₃ ) 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-Chloroquinolin-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 54 by a method similar to that in Reference Example 91.
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 7.84 (1H, s), 8. 00 (1H, d, J = 8.8 Hz), 8.19 (1H, d, J = 8.6 Hz), 8.30 (1H, d, J = 8.6 Hz).
MS (FAB) m / z: 475 (M + H) ^<+> .

[Reference Example 146] (1R, 2S, 5S) -2-{[(7-chloroquinolin-3-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 57 by a method similar to that in Reference Example 91.
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Reference Example 147] 2-Bromo-5-isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine

In the same manner as in Reference Example 9, the title compound was obtained from the compound obtained in Reference Example 8.
¹ H-NMR (CDCl ₃ ) δ: 1.13 (6H, d, J = 6.5 Hz), 2.86 (4H, s), 2.89-3.00 (1H, m), 3.70 (2H, s).

[Reference Example 148] 5-isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt

In the same manner as in Reference Example 10, the title compound was obtained from the compound obtained in Reference Example 147.
¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (6H, d, J = 6.4 Hz), 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-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid 4-nitrophenyl ester

In the same manner as in Reference Example 52, the title compound was obtained from the compound obtained in Reference Example 10 and p-nitrophenol.
¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H, s), 2.88 (2H, t, J = 5.7 Hz), 3.06-3.12 (2H, m), 3.80 (2H, s), 7.46 (2H, d
, J = 9.3 Hz), 8.32 (2H, d, J = 9.3 Hz).
MS (ESI) m / z: 320 (M + H ^< + ^> ).

[Reference Example 150] 3-Oxocyclobutanecarboxylic acid benzyl ester

To a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., 53, 3841-3843, 1981) (995 mg) in tetrahydrofuran (5.0 ml) was added triethylamine (2.0 ml) and benzyl bromide (1 2 ml) and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid aqueous solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to obtain the title compound (886 mg).
¹ H-NMR (CDCl ₃ ) 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-Hydroxycyclobutanecarboxylic acid benzyl ester

To a mixed solution of the compound obtained in Reference Example 150 (781 mg) in tetrahydrofuran (10 ml) and methanol (0.5 ml) was added sodium borohydride (76 mg) at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with acetic acid ethyl ester, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (770 mg).
¹ H-NMR (CDCl ₃ ) 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-Hydroxycyclobutanecarboxylic acid

To a solution of the compound obtained in Reference Example 151 (706 mg) in ethanol (10 ml) was added 10% palladium carbon (108 mg), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (399 mg).
¹ H-NMR (CD ₃ OD) δ: 2.00-2.21 (2H, m), 2.41-2.61 (3H, m), 4.01-4.13 (1H, m).

[Reference Example 153] 3-Methoxycyclobutanecarboxylic acid benzyl ester

Methyl iodide (194 μl) and silver oxide (237 mg) were added to a solution of the compound (317 mg) obtained in Reference Example 151 in N, N-dimethylformamide (3.0 ml), and the mixture was stirred at 45 ° C. for 1 hour. Methyl iodide (194 μl) and silver oxide (226 mg) were further added to the reaction solution, followed by stirring at 45 ° C. for 16 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to obtain the title compound (152 mg).
¹ H-NMR (CDCl ₃ ) 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-Methoxycyclobutanecarboxylic acid

In the same manner as in Reference Example 152, the title compound was obtained from the compound obtained in Reference Example 153.
¹ H-NMR (CDCl ₃ ) 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-methoxy-2- (methoxymethyl) propionic acid methyl ester

Sodium methoxide (1.21 g) was added to a methanol (10 ml) solution of 2- (bromomethyl) acrylic acid methyl ester (1.0 ml), and the mixture was heated to reflux for 26 hours. The reaction mixture was cooled, diluted with diethyl ether, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (726 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.90-2.96 (1H, m), 3.34 (6H, s), 3.57 (2H, dd, J = 9.3, 5.9 Hz) 3.64 (2H, dd, J = 9.3, 6.6 Hz), 3.73 (3H, s).
¹³ C-NMR (CDCl ₃ ) δ: 172.71, 70.31, 59.91, 46.49.
MS (ESI) m / z: 163 (M + H ^< + ^> ).

[Reference Example 156] Tetrahydro-2H-pyran-4-carboxylic acid

20% hydrochloric acid (20 ml) was added to tetrahydro-4H-pyran-4,4-dicarboxylic acid dimethyl ester (4.04 g), and the mixture was heated to reflux for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was solidified with hexane, and the obtained solid was collected by filtration and washed to obtain the title compound (2.63 g).
¹ H-NMR (CDCl ₃ ) 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 (diphenyl) silyl] oxy} -2,2-dimethylpropionic acid methyl ester

In the same manner as in Reference Example 41, the title compound was obtained from 2,2-dimethyl-3-hydroxypropionic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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 (diphenyl) silyl] oxy} -2,2-dimethylpropionic acid

Water (0.24 ml) was added to a suspension of potassium tert-butoxide (5.32 g) and diethyl ether (100 ml) under ice cooling, and the mixture was stirred for 5 minutes. To this was added the compound (2.22 g) obtained in Reference Example 157 and stirred overnight at room temperature. Water was added to the reaction solution, acidified with 1N aqueous hydrochloric acid solution, and extracted three times with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to obtain the title compound (735 mg). It was.
¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, d, J = 0.7 Hz), 1.22 (6H, s), 3.65 (2H, s), 7.36-7.45 (6H, m), 7.64-7.66 (4H, m).

[Reference Example 159] 3-methoxy-2,2-dimethylpropionic acid methyl ester

Tetrahydrofuran of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (25.0 g) under ice-cooling to a suspension consisting of 60% sodium hydride (8.32 g) in oil suspension and tetrahydrofuran (100 ml) (300 ml) The solution was added dropwise and stirred at 60 ° C. for 1 hour. Methyl iodide (53.7 g) was added to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. Water was carefully added and extracted twice with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained oil was distilled to obtain the title compound (12.8 g).
Boiling point: 140-142 ° C. (normal pressure).
¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 1.0 Hz), 3.33 (3H, d, J = 1.0 Hz), 3.38 (2H, d, J = 1.0 Hz), 3.69 (3H, d, J = 1.0 Hz).

[Reference Example 160] 3-Methoxy-2,2-dimethylpropionic acid

The compound obtained in Reference Example 159 was treated in the same manner as in Reference Example 158 to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 0.7 Hz), 3.38 (3H, d, J = 0.7 Hz), 3.40 (2H, d, J = 0.7 Hz).

[Reference Example 161] 1- (methoxycarbonyl) cyclopropanecarboxylic acid

1,1-Cyclopropanedicarboxylic acid dimethyl ester (25 g) was dissolved in methanol (250 ml) and cooled on ice. Then, 1N aqueous sodium hydroxide solution (158 ml) was added dropwise, and the mixture was returned to room temperature and stirred overnight. Methanol was distilled off, washed with chloroform, the aqueous layer was ice-cooled, adjusted to pH 2 with concentrated aqueous hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (16 0.8 g) was obtained.
¹ H-NMR (CDCl ₃ ) 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) cyclopropanecarboxylic acid methyl ester

The compound obtained in Reference Example 161 (9.0 g) and triethylamine (9.7 ml) were dissolved in tetrahydrofuran (180 ml), cooled to −10 ° C., and isobutyl chloroformate (9.1 ml) was added dropwise and stirred for 1 hour. . On the other hand, sodium borohydride (7.1 g) was dissolved in tetrahydrofuran (100 ml) -water (25 ml) and ice-cooled. The previous solution was added dropwise while removing insolubles, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a cold 10% aqueous citric acid solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 2: 1) to obtain the title compound (4.25 g).
¹ H-NMR (CDCl ₃ ) 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) cyclopropanecarboxylic acid methyl ester

Triphenylphosphine (10 g) and carbon tetrabromide (16 g) were added to a methylene chloride solution (168 ml) of the compound (4.20 g) obtained in Reference Example 162 under a nitrogen atmosphere at room temperature, and saturated after 2 minutes. Aqueous sodium bicarbonate was added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19) to obtain the title compound (2.15 g).
¹ H-NMR (CDCl ₃ ) 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-Ethoxy-3-oxo-1-propenyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester

(4R) -4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (11.7 g), (carboethoxymethylene) triphenylphosphorane (20.7 g) and toluene (100 ml) was mixed with heating at 100 ° C. for 18 hours. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (17 g).
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 6.6 Hz), 1.43-1.56 (15H, m), 3.80 (1H, dd, J = 9. 0, 2.4 Hz), 4.09 (1H, dd, J = 9.0, 6.6 Hz), 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-ethoxy-3-oxopropyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester

A mixed solution consisting of the compound (22.2 g) obtained in Reference Example 164, benzylamine (16 g) and ethanol (100 ml) was heated to reflux for 2 days. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 8: 1) to obtain the title compound (26 g).
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 6.6 Hz), 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-ethoxy-3-oxopropyl) -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester

To a solution of the compound (13.6 g) obtained in Reference Example 165 in ethanol (200 ml) was added 10% palladium carbon (10 g), and the mixture was stirred for 2 days in a hydrogen atmosphere. Insoluble material was removed by filtration through a Celite pad, and the filtrate was concentrated under reduced pressure to give the title compound (10.5 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (1.5 H, t, J = 6.6 Hz), 1.20 (1.5 H, t, J = 6.6 Hz), 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 .8 Hz), 4.08 (2H, q, J = 6.6 Hz), 4.20-4.30 (1 H, m).

[Reference Example 167] (4S) -4- (1-{[(Benzyloxy) carbonyl] amino} -3-ethoxy-3-oxopropyl) -2,2-dimethyl-1,3-oxazolidine-3-carvone Acid tert-butyl ester

The compound (3.0 g) obtained in Reference Example 166 was suspended in 9% aqueous sodium hydrogen carbonate solution (56 ml), and N- (benzyloxycarbonyloxy) succinimide (2.3 g) in dioxane (12 ml) was cooled with ice. ) The solution was added dropwise and stirred for 3 hours while gradually returning to room temperature. The reaction solution was diluted with ethyl acetate, washed with water, 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (3.8 g).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 6.6 Hz), 1.48 (9H, s), 1.56 (6H, s), 2.40-2.51 (2H, m), 2.62-2.70 (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-hydroxyvaleric acid ethyl ester (low polarity compound) and ( 3R, 4S) -3-{[(Benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] -5-hydroxyvaleric acid ethyl ester (high polarity compound)

To a methylene chloride (100 ml) solution of the compound (30 g) obtained in Reference Example 167 was added dropwise trifluoroacetic acid (100 ml) under ice cooling, and the mixture was stirred for 3 hours while gradually returning to room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in methylene chloride (100 ml). To this solution, a solution of triethylamine (20 ml) and di-tert-butyl dicarbonate (19 g) in methylene chloride (100 ml) was added dropwise in this order, and the mixture was stirred for 4 hours while gradually returning to room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title low-polar compound (7.6 g) and the title high-polar compound ( 10 g) was obtained.
Low polarity compounds :
¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 6.6 Hz), 1.42 (9H, s), 2.63 (2H, d, J = 4.4 Hz), 3 .30-3.41 (1H, m), 3.50 (1H, t, J = 9.7 Hz), 3.65 (1H, t, J = 9.7 Hz), 3.75 (1H, d, J = 11.7 Hz), 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).
High polarity compounds :
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 6.6 Hz), 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-[(methylsulfonyl) oxy] tetrahydro-3-furanyl ester

To a solution of 1,4-anhydroerythritol (5.0 g) in methylene chloride (50 ml), triethylamine (12.0 ml) and methanesulfonyl chloride (3.6 ml) were successively added dropwise under ice cooling, and the mixture was added with ice cooling for 10 minutes. Stir. The reaction mixture was diluted with methylene chloride and washed with 10% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (9.2 g).
¹ H-NMR (CDCl ₃ ) δ: 3.15 (6H, s), 3.99 (2H, dd, J = 11.2, 2.5 Hz), 4.16 (2H, dd, J = 1.11. 2, 4.6 Hz), 5.10-5.20 (2H, m).

[Reference Example 170] (3R, 4S) -3,4-diazidetetrahydrofuran

The compound (9.2 g) obtained in Reference Example 169 was dissolved in N, N-dimethylformamide (50 ml), sodium azide (18 g) was added, and the mixture was heated with stirring at 100 ° C. for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (3.8 g).
¹ H-NMR (CDCl ₃ ) δ: 3.83 (2H, dd, J = 8.6, 2.0 Hz), 3.96-4.12 (4H, m).

[Reference Example 171] (3R, 4S) -Tetrahydro-3,4-furandiamine dihydrochloride

The compound (3.8 g) obtained in Reference Example 170 was dissolved in ethanol (50 ml), 10% palladium carbon (1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere for 18 hours. Insoluble material was removed by filtration through a Celite pad, and the filtrate was concentrated under reduced pressure. 1N Hydrochloric acid ethanol solution was added to the resulting residue to make hydrochloride, then recrystallized from a mixed solvent of ethanol and diethyl ether to obtain the title compound (2.0 g).
¹ H-NMR (CDCl ₃ ) δ: 3.90 (2H, dd, J = 9.0, 3.7 Hz), 4.01-4.13 (4H, m), 8.84 (6H, s) .

[Reference Example 172] N-[(3R ^* , 4S ^* )-4-aminotetrahydro-3-furanyl] -5-chloroindole-2-carboxamide

To a solution of the compound (0.5 g) obtained in Reference Example 171 in N, N-dimethylformamide (10 ml) at room temperature, 5-chloroindole-2-carboxylic acid (0.29 g) and 1-hydroxybenzotriazole (0. 2 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.6 g) were sequentially added, and the mixture was heated and stirred at 50 ° C. for 1 day. The reaction mixture was concentrated, and the resulting residue was diluted with a mixed solvent of chloroform: methanol (9: 1) and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain the title compound (0.2 g). It was.
¹ H-NMR (CDCl ₃ ) δ: 1.80-1.92 (1H, m), 3.62 (1H, dd, J = 9.3, 4.2 Hz), 3.68-3.80 ( 2H, m), 4.06 (1H, dd, J = 9.3, 5.6 Hz), 4.21 (1H, dd, J = 9.3, 6.8 Hz), 4.36-4.52 (2H, m), 6.87 (1H, s), 7.24 (1H, dd, J = 8.8, 2.0 Hz), 7.36 (1H, d, J = 8.8 Hz), 7 .44-7.56 (1H, m), 7.62 (1H, d, J = 2.0 Hz), 9.41 (1H, s).

[Reference Example 173] (4R) -4-[(E) -3-Ethoxy-3-oxo-1-propenyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester

In the same manner as in Reference Example 164, the title compound was obtained from (4S) -4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 6.6 Hz), 1.40-1.60 (15H, m), 3.80 (1H, dd, J = 9. 0, 2.4 Hz), 4.09 (1H, dd, J = 9.0, 6.6 Hz), 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-ethoxy-3-oxopropyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester

In the same manner as in Reference Example 165, the title compound was obtained from the compound obtained in Reference Example 173.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 6.6 Hz), 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-Chloroindol-2-yl) carbonyl] amino} -3-ethoxy-3-oxopropyl) -2,2-dimethyl-1,3 -Oxazolidine-3-carboxylic acid tert-butyl ester

In the same manner as in Reference Example 166, the compound obtained in Reference Example 174 was subjected to catalytic reduction to remove the benzyl group, and then condensed in the same manner as in Reference Example 172 with 5-chloroindole-2-carboxylic acid. The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (1.5 H, t, J = 6.6 Hz), 1.25 (1.5 H, t, J = 6.6 Hz), 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, 5.5 Hz), 3.80-3.90 (0.5 H, m), 4.00-4.31 (5 H, m), 4.41-4.67 (0.5 H) M), 6.85 (0.5 H, s), 6.87 (0.5 H, s), 7.10-7.20 (1 H, m), 7.34 (0.5 H, d, J = 8.8 Hz), 7.38 (0.5 H, d, J = 8.8 Hz), 7.57 (0.5 H, s), 7.63 (0.5 H, s), 7.88 (0 .5H, d, J = 7.6 Hz), 8.54 (0.5H, d, J = 7.6 Hz), 9.40 (0.5 H, s), 9.54 (0.5 H, s).

[Reference Example 176] (3R, 4R) -4-{[(5-Chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester (low Polar compounds) and (3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester (high polarity) Compound)

To a solution of the compound (1.0 g) obtained in Reference Example 175 in ethanol (20 ml) was added 1N aqueous sodium hydroxide solution (4.0 ml), and the mixture was stirred for 4 hours. Citric acid was added to the reaction solution to adjust the pH to 4.0, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (50 ml), toluenesulfonic acid monohydrate (0.1 g) was added, and the mixture was stirred for 18 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1) to give the title low-polar compound (0.3 g). ) And a highly polar compound (0.3 g) were obtained.
Low polarity compounds :
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.70 (1H, dd, J = 16.5, 4.9 Hz), 2.85 (1H, dd, J = 16.6. 5, 4.6 Hz), 3.50-3.61 (1H, m), 3.71-3.81 (2H, m), 4.30-4.40 (1 H, m), 5.30 ( 1H, d, J = 9.5 Hz), 6.89 (1H, s), 7.23 (1H, dd, J = 8.8, 2.0 Hz), 7.38 (1H, d, J = 8) .8 Hz), 7.62 (1 H, d, J = 2.0 Hz), 7.93 (1 H, d, J = 9.5 Hz), 9.30 (1 H, s).
High polarity compounds :
¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 2.75 (1H, dd, J = 16.5, 4.9 Hz), 2.82 (1H, dd, J = 16.6. 5, 4.6 Hz), 3.41-3.52 (2H, m), 3.71-3.82 (1 H, m), 3.85-3.94 (1 H, m), 5.03 ( 1H, d, J = 9.3 Hz), 6.99 (1H, s), 7.22-7.31 (1H, m), 7.34 (1H, d, J = 8.8 Hz), 7. 61 (1H, d, J = 2.0 Hz), 7.83 (1H, d, J = 9.3 Hz), 9.28 (1H, s).

[Reference Example 177] 1,1,3, -Trioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

A solution of N-tert-butoxycarbonyl-L-methionine sulfonemethyl ester (60.2 g) in tetrahydrofuran (900 ml) was cooled to −78 ° C., and 0.5 M potassium bis (trimethylsilyl) amide (toluene solution, 900 ml) was added dropwise. The mixture was stirred at -78 ° C for 2 hours and at room temperature for 4 hours and a half. 1M ammonium chloride aqueous solution was added and stirred. After separating the reaction solution, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was collected by filtration to give the title compound (12.4 g). The previously separated aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Furthermore, the aqueous layers used for washing were combined, extracted again with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The ethyl acetate extracts were combined, dried and concentrated under reduced pressure to give the title compound (27.7 g) (total amount of the title compound: 40.1 g).
¹ H-NMR (CDCl ₃ ) 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, 3.7 Hz), 4.14 (1H, d, J = 13.5 Hz), 4.38-4.44 ( 1H, m), 5.46 (1H, br).
MS (ESI) m / z: 262 (M-H) ^- .

[Reference Example 178] (3R ^* , 4R ^* )-3-hydroxy-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

Sodium borohydride (2.17 g) was added to a suspension of the compound (10.1 g) obtained in Reference Example 177 in methanol (200 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Acetic acid ethyl ester and saturated aqueous sodium hydrogen carbonate solution were added to the residue. After separation, the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (9.96 g).
¹ H-NMR (CDCl ₃ ) 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-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester (low polarity compound) and (3R ^* , 4S ^* )-3-Amino-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester (high polarity compound)

To a solution of the compound (9.66 g) obtained in Reference Example 178 and triphenylphosphine (10.5 g) in tetrahydrofuran (150 ml) was added diethyl azodicarboxylate (6.96 g), and the mixture was stirred at room temperature for 4 hours and a half. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the resulting solid was collected by filtration. The solid collected by filtration was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3), and 1,1-dioxo-1,2,3,4-tetrahydrothiopyran-4-ylcarbamic acid tert- A mixture containing butyl ester (7.25 g) was obtained as a colorless solid. Further, the mother liquor was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain 1,1-dioxo-1,2,3,4-tetrahydrothio. A mixture (9.18 g) containing pyran-4-ylcarbamic acid tert-butyl ester was obtained as a colorless solid (total amount: 16.4 g). The obtained mixture was dissolved in dioxane (60 ml), 28% aqueous ammonia (60 ml) was added, and the mixture was stirred in a sealed tube at 60 ° C. for 4 and a half hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure. Dioxane was distilled off, followed by extraction with methylene chloride five times. The organic layers were combined and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (methylene chloride: methanol = 96: 4) to obtain the title low-polar compound (2.31 g) and high-polar compound (4.31 g). .
Low polarity compounds :
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.14-2.28 (2H, m), 3.01-3.08 (3H, m), 3.23 (1H , Dd, J = 13.8, 3.9 Hz), 3.47-3.49 (1H, m), 3.71-3.76 (1H, m), 5.32 (1H, d, J = 7.3 Hz).
MS (ESI) m / z: 265 (M + H ^< + ^> ).
High polarity compounds :
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.94-2.01 (1H, m), 2.37-2.44 (1H, m), 2.91 (1H , Dd, J = 11.2, 14.1 Hz), 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 ^< + ^> ).

[Reference Example 180] (2S, 3S) -2,3-bis (methoxymethoxy) -1,4-butanediol

To a mixed solution consisting of diethyl L-tartrate (8.6 g), diisopropylethylamine (40 ml) and methylene chloride (40 ml) was added dropwise chloromethyl methyl ether (4.8 ml) under ice-cooling, while gradually returning to room temperature. Stir for 18 hours. The reaction mixture was concentrated, and the resulting residue was diluted with ethyl acetate and washed with 10% aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran. The above solution was added dropwise to a tetrahydrofuran suspension of lithium aluminum hydride (2.2 g) under ice cooling, and the mixture was stirred for 2 hours under ice cooling. Under ice-cooling, 10% aqueous sodium hydrogensulfate solution was carefully added, stirred for 1 hour, diluted with saturated brine, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (3.0 g).
¹ H-NMR (CDCl ₃ ) δ: 1.55-1.64 (2H, m), 3.44 (6H, s), 3.70-3.81 (6H, m), 4.70 (2H , D, J = 6.9 Hz), 4.76 (2H, d, J = 6.9 Hz).

[Reference Example 181] (3S, 4S) -3,4-bis (methoxymethoxy) tetrahydrofuran

Diethyl azodicarboxylate (2.64 ml) was added dropwise to a mixed solution consisting of the compound obtained in Reference Example 180 (3.0 g), triphenylphosphine (4.5 g), tetrahydrofuran (10 ml) and toluene (40 ml). And stirred at room temperature for 4 days. The reaction mixture was concentrated, a mixed solvent (160 ml) consisting of hexane: diethyl ether (1: 1) was added to the resulting residue, and the resulting insoluble matter was filtered off after stirring for 3 hours. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (1.95 g).
¹ H-NMR (CDCl ₃ ) δ: 3.38 (6H, s), 3.80 (2H, dd, J = 9.2, 1.7 Hz), 4.00 (2H, dd, J = 9. 2, 4.4 Hz), 4.23 (2H, dd, J = 4.4, 1.7 Hz), 4.67 (2H, d, J = 6.9 Hz), 4.71 (2H, d, J = 6.9 Hz).

[Reference Example 182] (3S, 4S) tetrahydro-3,4-furandiol

Concentrated hydrochloric acid (2.1 ml) was added to a methanol (6.0 ml) solution of the compound (1.95 g) obtained in Reference Example 181, and the mixture was stirred for 18 hours. The reaction mixture was concentrated, and the resulting residue was diluted with chloroform, dried over potassium carbonate, and the solvent was evaporated under reduced pressure to give the title compound (0.52 g).
¹ H-NMR (CDCl ₃ ) δ: 1.77 (2H, d, J = 4.7 Hz), 3.73 (2H, d, J = 10.2 Hz), 4.08 (2H, dd, J = 10.2, 3.7 Hz), 4.18-4.34 (2H, m).

[Reference Example 183] (3S, 4S) tetrahydro-3,4-furandiamine

The title compound was obtained from the compound obtained in Reference Example 182 in the same manner as in the methods described in Reference Examples 169 to 171.
¹ H-NMR (CDCl ₃ ) δ: 1.35 to 1.46 (4H, m), 3.19 (2H, dd, J = 5.6, 4.1 Hz), 3.50 (2H, dd, J = 9.0, 4.1 Hz), 4.09 (2H, dd, J = 9.0, 5.6 Hz).

[Reference Example 184] (2R, 3R) -2,3-bis (methoxymethoxy) -1,4-butanediol

In the same manner as in Reference Example 180, the title compound was obtained from diethyl D-tartrate.
¹ H-NMR: consistent with Reference Example 180 which is an enantiomer.

[Reference Example 185] (3R, 4R) -3,4-bis (methoxymethoxy) tetrahydrofuran

In the same manner as in Reference Example 181, the title compound was obtained from the compound obtained in Reference Example 184.
¹ H-NMR: consistent with Reference Example 181, which is an enantiomer.

[Reference Example 186] (3R, 4R) tetrahydro-3,4-furandiol

In the same manner as in Reference Example 182, the title compound was obtained from the compound obtained in Reference Example 185.
¹ H-NMR: consistent with Reference Example 182 which is an enantiomer.

[Reference Example 187] (3R, 4R) tetrahydro-3,4-furandiamine

In the same manner as in Reference Example 183, the title compound was obtained from the compound obtained in Reference Example 186.
¹ H-NMR: consistent with Reference Example 183, which is an enantiomer.

[Reference Example 188] (3R, 4R) -1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione

L-tartaric acid (30 g) and benzylamine (22 ml) were added to xylene (150 ml), and the mixture was heated to reflux at 150 ° C. for 3 hours using a Dean-Stark dehydrator. The reaction solution was allowed to cool overnight, and the crystals were collected by filtration and washed with acetone. The obtained crude product was recrystallized from ethanol to obtain the title compound (23.2 g).
¹ H-NMR (DMSO-d ₆ ) δ: 4.36-4.40 (2H, m), 4.55 (each 1H, AB type d, J = 15 Hz), 6.26-6.30 (2H M), 7.25-7.35 (5H, m).

[Reference Example 189] (3S, 4S) -1-benzyl-3,4-pyrrolidinediol

The compound (11 g) obtained in Reference Example 188 was dissolved in tetrahydrofuran (110 ml), and lithium aluminum hydride (5.69 g) was added little by little under ice cooling. The temperature was raised to room temperature, and the mixture was further heated to reflux for 1 hour and overnight. After standing to cool, the mixture was cooled on ice, water (5.7 ml), 15% aqueous sodium hydroxide solution (5.7 ml) and water (17.1 ml) were added in this order, and the mixture was returned to room temperature and stirred for 1 hr. The precipitate was filtered through Celite, the mother liquor was concentrated, and recrystallized from ethyl acetate to give the title compound (6.35 g).
¹ H-NMR (CDCl ₃ ) δ: 2.40-2.44 (2H, m), 2.88-2.92 (2H, m), 3.58 (each 1H, AB type d, J = 7 .8 Hz), 4.04 (2H, t, J = 4.2 Hz), 7.25-7.34 (5H, m).

[Reference Example 190] Methanesulfonic acid (3S, 4S) -1-benzyl-4-[(methylsulfonyl) oxy] pyrrolidinyl ester

In the same manner as in Reference Example 169, the title compound was obtained from the compound obtained in Reference Example 189.
¹ H-NMR (CDCl ₃ ) δ: 2.76 (2H, dd, J = 11, 4.6 Hz), 3.08 (6H, s), 3.64 (2H, d, J = 2.5 Hz) 3.68-3.75 (2H, m), 5.12-5.15 (2H, m), 7.27-7.35 (5H, m).

[Reference Example 191] (3S, 4S) -3,4-bis [(methylsulfonyl) oxy] -1-pyrrolidinecarboxylic acid tert-butyl ester

The compound (1.57 g) obtained in Reference Example 190 was dissolved in 1,2-dichloroethane (16 ml), 1-chloroethyl chloroformate (0.73 ml) was added at room temperature, and the mixture was heated to reflux for 4 hours. After distilling off the solvent under reduced pressure, methanol (16 ml) was added to the obtained residue, heated under reflux for 1 hour, allowed to cool, concentrated, and crystals were collected by filtration from ethyl acetate (3S, 4S) -3, 4-Bis-[(methylsulfonyl) oxy] pyrrolidine hydrochloride (1.30 g) was obtained as colorless crystals. To a solution of the obtained hydrochloride and triethylamine (1.40 ml) in methylene chloride (26 ml), di-tert-butyl dicarbonate (1.15 ml) was added and stirred overnight at room temperature. After concentration, the mixture was diluted with acetic acid ethyl ester, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9-1: 1) to give the title compound (1.40 g).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.12 (6H, s), 3.70-3.73 (2H, m), 3.79 (1H, d, J = 4.5 Hz), 3.82 (1H, d, J = 4.5 Hz), 5.19 (2H, br).

[Reference Example 192] (3R, 4R) -3,4-diazide-1-pyrrolidinecarboxylic acid tert-butyl ester

In the same manner as in Reference Example 170, the title compound was obtained from the compound obtained in Reference Example 191.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.37-3.46 (2H, m), 3.64-3.71 (2H, m), 3.96 (2H , T, J = 3.2 Hz).

[Reference Example 193] (3R, 4R) -3-Amino-4-{[(5-chloroindol-2-yl) carbonyl] amino} pyrrolidine-1-carboxylic acid tert-butyl ester

In the same manner as in Reference Examples 171 and 172, the title compound was obtained from the compound obtained in Reference Example 192.
¹ H-NMR (DMSO-d ₆ ) δ: 1.39 (9H, s), 2.95-3.00 (1H, m), 3.09-3.13 (1H, m), 3.52 (1H, dd, J = 10, 6.5 Hz), 3.68 (1H, dd, J = 10, 7.8 Hz), 4.04-4.09 (2H, m), 7.16 (1H, s), 7.18 (1H, s), 7.42 (1H, d, J = 8.5 Hz), 7.69 (1H, d, J = 1.5 Hz), 8.50 (1H, d, J = 6.5 Hz), 11.77 (1H, br).

[Reference Example 194] (3S) -5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester

To a solution of (3S)-(−)-tetrahydro-5-oxo-3-furanylcarbamic acid benzyl ester (3.3 g) in tetrahydrofuran (20 ml) was added di-tert-butyl dicarbonate (4.1 g) and 10%. Palladium on carbon (0.4 g) was added and stirred for 1 day under a hydrogen atmosphere. Insoluble material was removed by filtration through a Celite pad, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (1.5 g). Got.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.45 (1H, dd, J = 17.8, 2.7 Hz), 2.86 (1H, dd, J = 17.1. 8, 7.3 Hz), 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-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester

1M lithium bis (trimethylsilyl) amide (tetrahydrofuran solution, 8.65 ml) was added dropwise at −78 ° C. to a solution of the compound obtained in Reference Example 194 (0.87 g) in tetrahydrofuran (20 ml) and stirred for 30 minutes. Next, a solution of p-toluenesulfonyl azide (1.02 g) in tetrahydrofuran (10 ml) was added, and after stirring for 5 minutes, trimethylchlorosilane (1.7 ml) was added, and the mixture was stirred for 2 hours while gradually returning to room temperature. The reaction mixture was diluted with diethyl ether, washed with 10% aqueous hydrochloric acid, 5% saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (0.62 g).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 4.09 (1H, dt, J = 15.3, 7.6 Hz), 4.12-4.23 (1H, m) 4.37-4.50 (1H, m), 4.54 (1H, dd, J = 9.0, 7.6 Hz), 4.81-4.90 (1H, m).

[Reference Example 196] (3S, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester

In the same manner as in Reference Examples 90 and 91, the title compound was obtained from the compound obtained in Reference Example 195.
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 7.61 (1H, s), 9.27 (1H, s).

[Reference Example 197] (3S, 4S) -4-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -5 -Oxotetrahydro-3-furanylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 90, (3S, 4S) -4-amino-5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester was obtained from the compound obtained in Reference Example 195. The title compound was obtained by reacting the compound obtained in Reference Example 10 according to the reaction conditions.
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.52 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 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-chloroindol-2-yl) carbonyl] amino} -4-hydroxybutanoyl) Amino] acetic acid ethyl ester

The compound obtained in Reference Example 196 (0.4 g), glycine ethyl ester hydrochloride (1.0 g) and triethylamine (1.0 ml) were added to ethanol (20 ml), and the mixture was heated and stirred at 60 ° C. for 18 hours. The reaction mixture was diluted with chloroform and washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to obtain the title compound (0.31 g). It was.
¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (3H, t, J = 7.0 Hz), 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 = 7.0 Hz), 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 = 9.5 Hz), 6.80 ( 0.6H, d, J = 9.5 Hz), 7.10-7.22 (2H, m), 7.42 (1H, d, J = 8.8 Hz), 7.72 (0.4 H, d) , J = 2.0 Hz), 7.73 (0.6 H, d, J = 2.0 Hz), 8.23-8.31 (0.6 H, 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-chloroindol-2-yl) carbonyl] amino} -2-oxopyrrolidin-1-yl) acetic acid ethyl ester hydrochloride

The compound obtained in Reference Example 198 was converted to a pyrrolidone derivative using the reaction conditions described in Reference Example 181, and then the tert-butoxycarbonyl group was removed in the same manner as in Reference Example 69 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (2H, t, J = 7.0 Hz), 1.23 (1H, t, J = 7.0 Hz), 3.31-3.40 ( 0.6H, m), 3.57 (0.4H, d, J = 11.2 Hz), 3.90-4.23 (4H, m), 4.42 (0.6H, dd, J = 12) 0.0, 6.1 Hz), 4.50-4.60 (0.4 H, m), 4.62 (0.6 H, dd, J = 12.0, 3.9 Hz), 5.12-5. 23 (0.4H, m), 7.17 (0.4H, s), 7.20 (0.4H, dd, J = 8.8, 2.0 Hz), 7.28 (0.6H, dd) , J = 8.8, 2.0 Hz), 7.30 (0.6 H, s), 7.44 (0.4 H, d, J = 8.8 Hz), 7.50 (0.6 H, d, J = 8.8 Hz), 7.75 (1H, d, J = 2) 0.0Hz), 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-Chloroindol-2-yl) carbonyl] amino} -1-methyl-5-oxopyrrolidin-3-ylcarbamic acid tert-butyl ester

The compound obtained in the reaction of the compound obtained in Reference Example 196 and methylamine (40% methanol solution) in the same manner as in Reference Example 198 was treated under the same conditions as in Reference Example 181 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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-oxopyrrolidin-3-yl] -5-chloroindole-2-carboxamide

The compound obtained in Reference Example 200 was treated in the same manner as in Reference Example 69 to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.95 (3H, d, J = 5.1 Hz), 3.91-3.93 (1H, m), 4.19 (1H, d, J = 3. 7 Hz), 4.36 (1 H, dd, J = 11, 1.7 Hz), 4.48 (1 H, dd, J = 11, 2.0 Hz), 6.90-6.97 (2 H, m), 7.21-7.33 (2H, m), 7.62 (1H, d, J = 2.0 Hz), 8.90 (1H, s)

[Reference Example 202] 3,6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (6.55 g) was added to a mixture of 1,2,3,6-tetrahydropyridine (2.50 g) and 10% aqueous sodium carbonate solution (3.0 ml), and the mixture was stirred at room temperature for 20 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.08 g). Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.12 (2H, br.s), 3.48 (2H, t, J = 5.6 Hz), 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-piperidinecarboxylic acid tert-butyl ester

The compound (18.45 g) obtained in Reference Example 202 was dissolved in acetonitrile (200 ml), water (38 ml), 0.039 mol osmium tetroxide aqueous solution (82 ml), N-methylmorpholine N-oxide (23.13 g). And stirred at room temperature for 17 hours. Excess oxidizing agent was treated with saturated aqueous sodium sulfite and extracted with ethyl acetate. The organic layer was washed successively with water, 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3) to give the title compound (15.0 g).
¹ H-NMR (CDCl ₃ ) 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, 3.4 Hz) 3.50-3.62 (2H, m), 3.77 (1H, brs), 3.81-3.92 (1H, m).

[Reference Example 204] (3R ^* , 4S ^* )-3,4-bis [(methylsulfonyl) oxy] -1-piperidinecarboxylic acid tert-butyl ester

In the same manner as in Reference Example 169, the title compound was obtained from the compound obtained in Reference Example 203.
¹ H-NMR (CDCl ₃ ) 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-diazide-1-piperidinecarboxylic acid tert-butyl ester

In the same manner as in Reference Example 170, the title compound was obtained from the compound obtained in Reference Example 204.
¹ H-NMR (CDCl ₃ ) 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-diamino-1-piperidinecarboxylic acid tert-butyl ester

In the same manner as in Reference Example 171, the title compound was obtained from the compound obtained in Reference Example 205.
¹ H-NMR (CDCl ₃ ) 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, 2.7 Hz), 3.74 (1H, dd, J = 13. 6, 4.2 Hz), 3.81 (1H, s).

[Reference Example 207] (3R ^* , 4S ^* )-3-Amino-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-piperidinecarboxylic acid tert-butyl ester

The compound (3.23 g) obtained in Reference Example 206 was dissolved in N, N-dimethylformamide (100 ml), triethylamine (2.08 ml) and the compound (3.80 g) obtained in Reference Example 52 were added, and at room temperature. Stir for 3 days. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 to 10: 1) to obtain the title compound (2.70 g).
¹ H-NMR (DMSO-d ₆ ) 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. 4 Hz), 3.79 (1 H, br. S), 4.04-4.12 (1 H, m), 7.17 (1 H, dd, J = 8.7, 1.9 Hz), 7.21 ( 1H, s), 7.42 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 1.9 Hz), 8.00 (1H, br.d, J = 7.6 Hz) ), 11.80 (1H, s).

[Reference Example 208] (3R ^* , 4S ^* )-3-amino-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] amino} -1-piperidinecarboxylic acid tert-butyl ester

The compound (3.23 g) obtained in Reference Example 206 was dissolved in N, N-dimethylformamide (100 ml), and triethylamine (2.08 ml) was added. Subsequently, the compound (3.83 g) obtained in Reference Example 149 was added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was separated by silica gel column chromatography (methylene chloride: methanol = 10: 1 to 5: 1) to obtain the title compound (2.27 g).
¹ H-NMR (CDCl ₃ ) 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 = 5.9 Hz), 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-fluoroindol-2-yl) carbonyl] amino} -1-piperidinecarboxylic acid tert-butyl ester

In the same manner as in Reference Example 172, the title compound was obtained from the compound obtained in Reference Example 206 and 5-fluoroindole-2-carboxylic acid.
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 7 .07-7.20 (1H, br), 7.27 (1H, dd, J = 9.0, 2.4 Hz), 7.35 (1H, d, J = 9.0, 4.4 Hz), 9.25-9.50 (1H, br).
MS (ESI) m / z: 377 (M + H) ^<+> .

[Reference Example 210] (3S, 4R) -5-azido-3-{[(benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] valeric acid ethyl ester

To a solution of (3S, 4S) -compound (low polarity compound) (7.1 g) obtained in Reference Example 168 in methylene chloride (100 ml) was added triethylamine (4.80 ml) and methanesulfonyl chloride (1.55 ml) under ice cooling. Were sequentially added dropwise and stirred for 30 minutes under ice-cooling. The reaction solution was diluted with chloroform and washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a methanesulfonyl compound (9.20 g). A mixed solution consisting of the obtained methanesulfonyl compound, sodium azide (5.64 g) and N, N-dimethylformamide (100 ml) was stirred at 80 ° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (5.42 g).
¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1 Hz), 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-oxopiperidin-4-ylcarbamic acid benzyl ester

A Lindlar catalyst (2.71 g) was added to a mixed solution of the compound obtained in Reference Example 210 (5.42 g) in ethanol (150 ml) and tetrahydrofuran (10.0 ml), and the mixture was stirred under a hydrogen atmosphere for 3 hours. Stir for 14 hours. Insoluble material was removed by filtration through a Celite pad, and the filtrate was concentrated under reduced pressure. The obtained residue was made into a tetrahydrofuran (30 ml) solution, triethylamine (3.0 ml) was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 25: 1) to obtain the title compound (2.50 g). It was.
¹ H-NMR (CDCl ₃ ) 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-ylcarbamic acid benzyl ester

To a solution of the compound obtained in Reference Example 211 (2.49 g) in tetrahydrofuran (70 ml) was added dropwise 1 mol borane / tetrahydrofuran complex (tetrahydrofuran solution, 34.0 ml) under ice cooling, and the mixture was stirred for 20 hours while gradually returning to room temperature. . Methanol (100 ml) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethanol (45 ml), water (5 ml), and triethylamine (10 ml) were added to the resulting residue, and the mixture was heated to reflux for 24 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol: water = 7: 3: 1, lower layer) to obtain the title compound (1.61 g).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.65-1.72 (2H, m), 2.67 (1H, t, J = 12.0 Hz), 2.82 (12H, d, J = 12.0 Hz), 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-4-{[(benzyloxy) carbonyl] amino} piperidin-3-ylcarbamic acid tert-butyl ester

The compound obtained in Reference Example 212 was reacted with acetyl chloride in the presence of triethylamine in methylene chloride to give the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 14.2 Hz), 3.65-4.05 (3H, m), 4.38-4.47 (0.5 H, br.d, J = 13.0 Hz), 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-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-ylcarbamic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 213 (745 mg) in ethanol (50 ml) was added 10% palladium carbon (532 mg), and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. The insoluble material was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was treated with 5-chloroindole-2-carboxylic acid (467 mg) in the same manner as in Reference Example 68 to give the title compound (650 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.60-1.80 (2H, m), 2.12 (1H, s), 2.16 (2H, s), 2.30-2.45 (0.5 H, m), 2.67-2.82 (0.3 H, m), 2.89 (0.7 H, d, J = 13.7 Hz), 3.23 (0.7 H, t, J = 12.9 Hz), 3.37 (0.3 H, d, J = 13.7 Hz), 3.81-3.95 (1 H, m), 4.05-4. 33 (2H, m), 4.62-4.72 (0.3 H, br), 4.77 (0.7 H, d, J = 13.7 Hz), 5.10-5.27 (1 H, m ), 6.81 (0.3 H, br. S), 6.85 (0.7 H, s), 7.21 (1 H, br. D, J = 8.8 Hz), 7.34 (1 H, d , J = 8.8 Hz), 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-azido-3-{[(benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] valeric acid ethyl ester

In the same manner as in Reference Example 210, the title compound was obtained from the (3R, 4S) -compound (high polarity compound) obtained in Reference Example 168.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 6.6 Hz), 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-oxopiperidin-4-ylcarbamic acid benzyl ester

The compound obtained in Reference Example 215 was treated in the same manner as in Reference Example 211 to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 (9H, s), 2.19 (1H, dd, J = 17.4, 9.1 Hz), 2.41-2.51 (1H, m), 2.97 (1H, t, J = 9.1 Hz), 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 (1 H, 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-ylcarbamic acid benzyl ester

The compound obtained in Reference Example 216 was treated in the same manner as in Reference Example 212 to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 2.05 (2H, d, J = 12.9 Hz), 2.40 (1H, t, J = 11.0 Hz), 2 .63 (1H, t, J = 12.0 Hz), 3.09 (1H, d, J = 12.0 Hz), 3.31 (1H, d, J = 11.0 Hz), 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-4-{[(benzyloxy) carbonyl] amino} piperidin-3-ylcarbamic acid tert-butyl ester

The compound obtained in Reference Example 217 was treated in the same manner as in Reference Example 213 to give the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 12.0 Hz), 2.78 (1H, t, J = 12.0 Hz), 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-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-ylcarbamic acid tert-butyl ester

The compound obtained in Reference Example 218 was treated in the same manner as in Reference Example 214 to give the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 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-methoxyacetyl) piperidin-4-ylcarbamic acid benzyl ester

The title compound was obtained in the same manner as in Reference Example 213 from the compound obtained in Reference Example 212 and methoxyacetyl chloride.
¹ H-NMR (CDCl ₃ ) 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-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 214, the title compound was obtained from the compound obtained in Reference Example 220.
¹ H-NMR (CDCl ₃ ) 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 (total 3H, each), 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, 2.0 Hz), 7.33 (1H, d, J = 8.7 Hz), 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-methoxyacetyl) piperidin-4-ylcarbamic acid benzyl ester

In the same manner as in Reference Example 213, the title compound was obtained from the compound obtained in Reference Example 217 and methoxyacetyl chloride.
¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.45 to 1.67 (1H, m), 2.01-2.14 (1H, m), 2.63 (1H , T, J = 12.0 Hz), 2.75 (1H, t, J = 12.0 Hz), 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-Chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 214, the title compound was obtained from the compound obtained in Reference Example 222 and 5-chloroindole-2-carboxylic acid.
¹ H-NMR (CDCl ₃ ) 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 (0.5 H, s), 6.93 (0.5 H, s), 7.23 (1 H, dd, J = 8.8, 2.0 Hz), 7.33 (1 H, d, J = 8.8 Hz), 7.59 (1 H, s), 9.37 (0.5 H, s), 9.54 (0.5 H, s).

[Reference Example 224] (3R, 4S) -3-{[(Benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] -5-{[tert-butyl (diphenyl) silyl] oxy} Valeric acid ethyl ester

To a solution of (3R, 4S) -compound (high polarity compound) (0.74 g) obtained in Reference Example 168 in N, N-dimethylformamide (30 ml), triethylamine (0.47 ml) and imidazole (0. 19 g) and tert-butylchlorodiphenylsilane (0.7 ml) were sequentially added, and the mixture was stirred for 4 days while gradually returning to room temperature. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous citric acid solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain the title compound (0.85 g).
¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.19 (3H, t, J = 7.4 Hz), 1.40 (9H, s), 2.40-2.50 (1H, m), 2.60 (1H, dd, J = 15.9, 4.5 Hz), 3.56-3.67 (1H, m), 3.74 (1H, dd, J = 1.11. 2, 4.5 Hz), 3.78-3.89 (1 H, m), 4.08 (2 H, q, J = 7.4 Hz), 4.21-4.30 (1 H, 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 (diphenyl) silyl] oxy} -3-{[(5-chloroindol-2-yl ) Carbonyl] amino} valeric acid ethyl ester

In the same manner as in Reference Example 214, the benzyloxycarbonyl group of the compound obtained in Reference Example 224 was removed and condensed with 5-chloroindole-2-carboxylic acid to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.20 (3H, t, J = 7.4 Hz), 1.32 (9H, s), 2.40-2.52 (1H, m), 2.71 (1H, dd, J = 15.9, 4.5 Hz), 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, 2.0 Hz), 7.32 (1 H, d, J = 8.8 Hz), 7.40-7.50 (6 H, m), 7.58 (1 H, d, J = 8.5 Hz), 7. 63-7.74 (5H, m), 9.01-9.14 (1H, m).

[Reference Example 226] (3R ^* , 4R ^* )-3-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 68, the title compound was obtained from the (3R ^* , 4R ^* )-compound (low polarity compound) obtained in Reference Example 179 and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) 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-dioxohexahydro-1-thiopyran-3-yl] -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 226 was treated in the same manner as in Reference Example 69 to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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-chloroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 68, the title compound was obtained from the (3R ^* , 4R ^* )-compound (low polarity compound) obtained in Reference Example 179 and 5-chloroindole-2-carboxylic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (9H, s), 2.09 (2H, br), 3.07 (1H, d, J = 12.6 Hz), 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 = 8.7 Hz), 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-dioxohexahydro-1-thiopyran-3-yl] -5-chloroindole-2-carboxamide hydrochloride

The compound obtained in Reference Example 228 was treated in the same manner as in Reference Example 69 to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz) , 7.72 (1H, d, J = 1.7 Hz), 8.39 (2H, br), 8.58 (1H, d, J = 6.8 Hz), 11.93 (1H, s).
MS (ESI) m / z: 342 (M + H ^< + ^> ).

[Reference Example 230] (3R ^* , 4S ^* )-3-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 98, the title compound was obtained from the (3R ^* , 4S ^* )-compound (high polarity compound) obtained in Reference Example 179 and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) 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 = 13.4 Hz), 3.68 (1H, d, J = 15.5 Hz), 3.72 (1H, d, J = 15.5 Hz), 3.86-3.88 (1H, m) , 4.45-4.53 (1H, m), 4.75 (1H, d, J = 8.5 Hz), 7.76 (1H, d, J = 8.3 Hz).
MS (ESI) m / z: 445 (M + H) ^<+> .

[Reference Example 231] N-[(3R ^* , 4S ^* )-4-amino-1,1-dioxohexahydro-1-thiopyran-3-yl] -5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 230 was treated in the same manner as in Reference Example 69 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 2.03-2.12 (1H, m), 2.51 (1H, br), 2.93 (3H, s), 3.14 (2H, d , J = 12.2 Hz), 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-fluoroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 68, the title compound was obtained from the (3R ^* , 4R ^* )-compound (low polarity compound) obtained in Reference Example 179 and 5-fluoroindole-2-carboxylic acid.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 7.41 (1H, dd, J = 8.8, 4.5 Hz), 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-dioxohexahydro-1-thiopyran-3-yl] -5-fluoroindole-2-carboxamide hydrochloride

The compound obtained in Reference Example 232 was treated in the same manner as in Reference Example 69 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 9.0 Hz), 7.44 (1H, dd, J = 8.8, 4.4 Hz), 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-oxovaleric acid ethyl ester

Sulfur trioxide at room temperature in a mixed solvent consisting of (3R, 4S) -compound (highly polar compound) (0.5 g), dimethyl sulfoxide (6.8 ml), and triethylamine (2.6 ml) obtained in Reference Example 168 Pyridine complex salt (1.5 g) was gradually added and stirred for 20 minutes. The reaction solution was poured into water and extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (0.51 g). Got.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.4 Hz), 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-oxopiperidin-4-ylcarbamic acid benzyl ester

To a solution of the compound (0.51 g) obtained in Reference Example 234 in ethanol (10 ml), acetic acid (0.27 ml) and 2M methylamine (tetrahydrofuran solution, 1.0 ml) were successively added under ice cooling, and the temperature was gradually returned to room temperature. After stirring for 1 hour, sodium cyanoborohydride (0.15 g) was added and stirred for 18 hours. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in toluene (20 ml). To this solution, triethylamine (2 ml) was added and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to give the title compound. (0.28 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (3.6 H, s), 1.38 (5.4 H, s), 2.22-2.43 (1 H, m), 2.44 -2.61 (1 H, m), 2.72 (1.2 H. s), 2.80 (1.8 H. s), 3.10 (0.5 H, 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 (1 H, m), 4.94 (1 H, d, J = 8.1 Hz), 5.00 (1.2 H. s), 5.01 (0.8 H, s), 6.89-7. 02 (0.5 H, m), 7.23-7.44 (5.5 H, m).

[Reference Example 236] (4R) -4-{[(5-Chloroindol-2-yl) carbonyl] amino} -1-methyl-6-oxopiperidin-3-ylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 214, the title compound was obtained from the compound obtained in Reference Example 235 and 5-chloroindole-2-carboxylic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (5.4 H, s), 1.35 (3.6 H, s), 2.43-2.56 (2 H, 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 = 8.1 Hz), 7.08 (1H, s), 7.16 (1H, dd, J = 8.8, 2.0 Hz), 7.42 (1H, d, J = 8.8 Hz) ), 7.69 (1H, d, J = 2.0 Hz), 8.30 (0.4 H, s), 8.36 (0.4 H, d, J = 7.3 Hz), 8.43 (0 .6H, d, J = 8.3 Hz), 11.75 (0.6H, s), 11.78 (0.4H, s).

[Reference Example 237] 4- (Pyridin-4-yl) benzoic acid hydrochloride

4-Bromopyridine hydrochloride (11.7 g) and 4-carboxyphenylboronic acid (10.0 g) were dissolved in a mixed solvent of toluene (250 ml) -water (250 ml), and tetrakis (triphenylphosphine) palladium (0). (5.0 g) and anhydrous sodium carbonate (25.4 g) were sequentially added, and the mixture was heated to reflux at 120 ° C. for 19 hours. After cooling to room temperature, ethyl acetate was added and extracted with water, and the aqueous layer was acidified with concentrated hydrochloric acid. The aqueous layer was washed with ethyl acetate, and then the aqueous layer was concentrated and the precipitated solid was collected by filtration to obtain the title compound (8.37 g).
¹ H-NMR (DMSO-d ₆ ) δ: 8.11 (2H, d, J = 8.8 Hz), 8.14 (2H, dJ = 8.8 Hz), 8.35 (2H, d, J = 6.6 Hz), 8.97 (2H, d, J = 6.6 Hz).
MS (FAB) m / z: 200 (M + H) ^<+> .

[Reference Example 238] 4- (Pyridin-4-yl) benzoic acid methyl ester

The compound (12.4 g) obtained in Reference Example 237 was dissolved in methanol (200 ml), concentrated sulfuric acid (5 ml) was added at room temperature, and the mixture was heated to reflux for 3 hours. After completion of the reaction, the solvent was distilled off, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with acetic acid ethyl ester and dried over anhydrous sodium sulfate. The solvent was distilled off, and hexane was added to the residue to solidify to obtain the title compound (9.86 g).
¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 7.54 (2H, d, J = 5.9 Hz), 7.71 (2H, dJ = 8.3 Hz), 8.16 (2H, d, J = 8.3 Hz), 8.71 (2H, d, J = 5.9 Hz).

[Reference Example 239] 4- [4- (methoxycarbonyl) phenyl] pyridine N-oxide

The compound (1.49 g) obtained in Reference Example 238 was dissolved in methylene chloride (30 ml), 70% m-chloroperbenzoic acid (3.46 g) was added, and the mixture was stirred at room temperature for 1 hour. An aqueous sodium sulfite solution was added for liquid separation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.33 g).
¹ H-NMR (DMSO) δ: 3.88 (3H, s), 7.86 (2H, d, J = 7.2 Hz), 7.94 (2H, d, J = 8.3 Hz), 8. 05 (2H, d, J = 8.3 Hz), 8.30 (2H, d, J = 7.2 Hz).
MS (FAB) m / z: 230 (M + H) ^<+> .

[Reference Example 240] 4- (4-Carboxyphenyl) pyridine N-oxide

The compound (802 mg) obtained in Reference Example 239 was dissolved in dioxane (20 ml), 1N aqueous sodium hydroxide solution (5 ml) was added, the mixture was refluxed for 1 hour, and stirred at room temperature for 2 hours. 1N Hydrochloric acid aqueous solution (5 ml) was added for neutralization, water (5 ml) was further added, and the resulting precipitate was collected by filtration to give the title compound (627 mg).
¹ H-NMR (DMSO) δ: 7.85 (2H, d, J = 7.2 Hz), 7.91 (2H, d, J = 8.3 Hz), 8.03 (2H, d, J = 8) .3 Hz), 8.30 (2H, d, J = 7.2 Hz).

[Reference Example 241] 2- (4-Carboxyphenyl) -1-pyridine N-oxide

The title compound was obtained from 2-bromopyridine in the same manner as in Reference Examples 237, 238, 239, and 240.
¹ H-NMR (DMSO-d ₆ ) δ: 7.41-7.45 (2H, m), 7.65-7.69 (1H, m), 7.94 (2H, d, J = 8. 3 Hz), 8.02 (2H, d, J = 8.3 Hz), 8.34-8.38 (1 H, m), 13.09 (1 H, s).
MS (FAB) m / z: 216 (M + H) ^<+> .

[Reference Example 242] 2- (4-Chloroanilino) -2-oxoacetic acid ethyl ester

To a solution of 4-chloroaniline (1.16 g) and methylene chloride (26 ml), triethylamine (1.52 ml) and chlorooxoacetic acid ethyl ester (1.11 ml) were successively added under ice cooling, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was partitioned. The organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, hexane was added to the residue to precipitate crystals, which were collected by filtration and dried to obtain the title compound (1.89 g).
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.1 Hz), 4.42 (2H, q, J = 7.1 Hz), 7.34 (2H, d, J = 8.8 Hz), 7.60 (2H, d, J = 8.8 Hz), 8.86 (1 H, br.s).
MS (ESI) m / z: 228 (M + H) ^<+> .

[Reference Example 243] 2-[(5-Chloropyridin-2-yl) amino] -2-oxoacetic acid methyl ester

2-Amino-5-chloropyridine (1.16 g) and triethylamine (1.51 ml) were dissolved in methylene chloride (26 ml), and chlorooxoacetic acid ethyl ester (1.10 ml) was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. Stir. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was separated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1). The obtained pale yellow solid was dissolved in methanol (20 ml) and stirred at 50 ° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and dried to give the title compound (0.43 g).
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.73 (1H, dd, J = 8.8, 2.2 Hz), 8.24 (1H, d, J = 8. 8 Hz), 8.31 (1 H, d, J = 2.2 Hz), 9.39 (1 H, br. S).
MS (ESI) m / z: 215 (M + H) ^<+> .

[Reference Example 244] (1S) -3-cyclohexene-1-carboxylic acid

(1S) -3-Cyclohexene-1-carboxylic acid (R)-(+)-α-methylbenzylamine salt (J. Am. Chem. Soc., 1978, 100, 5199-5203) (95 0.0 g) is dissolved in acetic acid ethyl ester (1.6 l) and 2N hydrochloric acid (1.6 l), the organic layer is separated, and the aqueous layer is extracted with acetic acid ethyl ester (500 ml × 2 times). Were washed with saturated brine (300 ml × 2 times), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (200 ml), and the organic layer was washed with saturated brine (100 ml). All organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (48 .3 g) was obtained.
[Α] ²⁵ _D = −104 ° (c = 1, chloroform).
¹ H-NMR (CDCl ₃ ) 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).

[Reference Example 245] (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one

To a mixture of the compound obtained in Reference Example 244 (48.0 g), methylene chloride (580 ml), potassium iodide (82.1 g), sodium hydrogen carbonate (42.0 g) and water (530 ml) at an internal temperature of 5 ° C. Iodine (125.4 g) was added and stirred at room temperature for 3 hours. 1N Aqueous sodium thiosulfate solution (800 ml) was added to the reaction mixture, and the mixture was extracted with methylene chloride (1 L, 500 ml). The organic layer was extracted with aqueous sodium hydrogen carbonate solution (300 ml), water (500 ml) and saturated brine (300 ml). The extract was washed with, dried over anhydrous magnesium sulfate, and concentrated. The precipitated crystals were collected by filtration, washed with hexane and dried to give the title compound (89.5 g).
Melting point: 130-131 ° C.
[Α] ²⁵ _D = −41 ° (c = 1, chloroform)
¹ H-NMR (CDCl ₃ ) δ: 1.78-1.96 (2H, m), 2.12 (1H, dd, J = 16.5 Hz, 5.2 Hz), 2.35-2.50 ( 2H, m), 2.65-2.70 (1H, m), 2.80 (1H, d, J = 12.2 Hz), 4.45-4.55 (1H, m), 4.77- 4.87 (1H, m).

[Reference Example 246] (1S, 3S, 6R) -7-oxabicyclo [4.1.0] heptane-3-carboxylic acid ethyl ester

To a suspension of the compound (89.3 g) obtained in Reference Example 245 in ethanol (810 ml) was added 2N aqueous sodium hydroxide solution (213 ml) with stirring at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure at a bath temperature of 35 ° C., water (500 ml) was added to the obtained oil, and the mixture was extracted with methylene chloride (500 ml and 300 ml). The organic layer was washed with water (300 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15) to give the title compound (41.3 g).
[Α] ²⁵ _D = −58 ° (c = 1, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.2 Hz), 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 = 7.2 Hz).

[Reference Example 247] (1S, 3R, 4R) -3-Azido-4-hydroxycyclohexanecarboxylic acid ethyl ester

A mixture of the compound obtained in Reference Example 246 (41.0 g), N, N-dimethylformamide (300 ml), ammonium chloride (19.3 g) and sodium azide (23.5 g) was stirred at 76 ° C. for 13 hours. The insoluble material was collected by filtration, and the filtrate was concentrated under reduced pressure without drying. The previous filtered product was added to the residue and dissolved in water (500 ml). Extraction with ethyl acetate (500 ml, 300 ml), washing with water, saturated brine, drying over anhydrous magnesium sulfate, and concentration yielded the title compound (51.5 g).
[Α] ²⁵ _D = + 8 ° (c = 1, chloroform)
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 1.37-1.64 (3H, m), 1.86-1.95 (1H, m) 2.04-2.16 (1H, m), 2.32-2.41 (1H, m), 2.44 (1H, br.s), 2.68-2.78 (1H, m) 3.45-3.60 (2H, m), 4.17 (2H, q, J = 7.1 Hz).

[Reference Example 248] (1S, 3R, 4R) -3-[(tert-butoxycarbonyl) amino] -4-hydroxycyclohexanecarboxylic acid ethyl ester

A mixture of the compound obtained in Reference Example 247 (51.2 g), di-tert-butyl dicarbonate (68.1 g), 5% palladium carbon (5.0 g) and ethyl acetate (1000 ml) was added with hydrogen pressure ( The mixture was stirred overnight at room temperature under 7 kg / cm ² ). The reaction mixture was filtered and concentrated to obtain an oily substance, which was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1). Crystallization from hexane gave the title compound (46.9 g). Furthermore, the mother liquor was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to obtain the title compound (6.74 g).
[Α] ²⁵ _D = + 25 ° (c = 1, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 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-azido-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester

To a solution of the compound obtained in Reference Example 248 (53.5 g), methylene chloride (500 ml) and triethylamine (130 ml), methanesulfonyl chloride (42 ml) was added dropwise at −10 ° C. to −15 ° C. over 20 minutes. The temperature was raised to room temperature over 2 hours and stirred for 2 hours. 0.5N Hydrochloric acid (800 ml) was added dropwise to the reaction mixture at 0 ° C. to make it acidic, and the mixture was extracted with methylene chloride (500 ml, 300 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crystals were dissolved in N, N-dimethylformamide (335 ml), sodium azide (60.5 g) was added, and the mixture was stirred at 67 to 75 ° C. for 16 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to distill off 250 ml of the solvent. The residue and the previous filtrate were combined, dissolved in water (500 ml), and extracted with ethyl acetate (1 l and 300 ml). The organic layer was washed with saturated brine (400 ml, 200 ml), dried over anhydrous magnesium sulfate, and concentrated. The resulting crystals were purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title Compound (18.4 g) was obtained.
[Α] ²⁵ _D = + 62 ° (c = 1, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.35-2.00 (15H, s), 2.60-2.68 (1H, m) 3.80-3.96 (2H, m), 4.15 (2H, q, J = 7.1 Hz), 4.61 (1H, br.s).

[Reference Example 250] (1S, 3R, 4S) -4-azido-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid

To a solution of the compound (1.0 g) obtained in Reference Example 249 in tetrahydrofuran (25 ml) was added lithium hydroxide (102 mg) and water (5 ml), and the mixture was stirred for 17 hours, and further lithium hydroxide (50 mg) was added. Stir for 4 hours. To the reaction solution was added 1N aqueous hydrochloric acid solution (6.3 ml), and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure to obtain the title compound (980 mg).
¹ H-NMR (CDCl ₃ ) 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-azido-5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

The compound (4.77 g) obtained in Reference Example 250 was dissolved in methylene chloride (150 ml), and dimethylamine hydrochloride (3.26 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4 .60 g), 1-hydroxybenzotriazole monohydrate (3.24 g) and N-methylmorpholine (8.09 g) were added and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for liquid separation, the organic layer was dried, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 50) to obtain the title compound (4.90 g).
¹ H-NMR (CDCl ₃ ) 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-azido-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridine-2-carboxamide

The compound (9.13 g) obtained in Reference Example 251 was dissolved in methylene chloride (100 ml), hydrochloric acid ethanol solution (100 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in N, N-dimethylformamide (200 ml) to obtain the compound (7.75 g) obtained in Reference Example 10, 1-hydroxybenzotriazole monohydrate ( 4.47 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.2 g) and triethylamine (2.02 ml) were added and stirred overnight at room temperature. Furthermore, the compound (2.38 g) obtained in Reference Example 10 and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.60 g) were added and stirred for 3 days. The reaction solution was concentrated under reduced pressure, methylene chloride and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue for liquid separation, and the resulting organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3) to obtain the title compound (7.38 g).
¹ H-NMR (CDCl ₃ ) 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 = 15.4 Hz), 3.74 (1H, d, J = 15.4 Hz), 3.86-3.93 (1H, m) 4.54 to 4.60 (1H, m), 7.25 (1H, d, J = 7.6 Hz).

[Reference Example 253] N-{(1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridine-2-carboxamide

To a solution of the compound obtained in Reference Example 252 (9.0 g) in methanol (300 ml) was added 10% palladium on carbon (6.0 g), and the mixture was vigorously stirred at room temperature under 4 atmospheres of hydrogen for 11 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give the title compound (7.67 g).
¹ H-NMR (CDCl ₃ ) 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 = 6.1 Hz).

[Reference Example 254] 2- (4-Fluoroanilino) -2-oxoacetic acid methyl ester

In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-fluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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-Bromoanilino) -2-oxoacetic acid methyl ester

In the same manner as in Reference Example 242, the title compound was obtained from 4-bromoaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 7.49 (2H, d, J = 9.0 Hz), 7.55 (2H, d, J = 9.0 Hz), 8 .85 (1H, br.s).
MS (FAB) m / z: 258M ^<+> .

[Reference Example 256] 2- (4-Chloro-2-methylanilino) -2-oxoacetic acid methyl ester

In the same manner as described in Reference Example 242, the title compound was obtained from 4-chloro-2-methylaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.99 (3H, s), 7.15-7.30 (2H, m), 7.98 (1H, d, J = 8.8 Hz), 8.77 (1H, br).
MS (FAB) m / z: 228 (M + H) ^<+> .

[Reference Example 257] 2-[(4-Chloro-3-methylanilino) -2-oxoacetic acid methyl ester

In the same manner as in Reference Example 242, the title compound was obtained from 4-chloro-3-methylaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s), 3.98 (3H, s), 7.33 (1H, d, J = 12.5 Hz), 7.44 (1H, dd , J = 12.5, 2.5 Hz), 7.53 (1H, d, J = 2.5 Hz), 8.81 (1H, br.s).
MS (ESI) m / z: 228 (M + H) ^<+> .

[Reference Example 258] 2- (4-Chloro-2-fluoroanilino) -2-oxoacetic acid methyl ester

In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-chloro-2-fluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.15-7.24 (2H, m), 8.33 (1H, t, J = 8.4 Hz), 9.05 (1H, br.s).
MS (ESI) m / z: 232 (M + H) ^<+> .

[Reference Example 259] 2- (2,4-Difluoroanilino) -2-oxoacetic acid methyl ester

In the same manner as described in Reference Example 242, the title compound was obtained from 2,4-difluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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: 215 M ⁺ .

[Reference Example 260] 2- (3,4-Difluoroanilino) -2-oxoacetic acid methyl ester

In the same manner as described in Reference Example 242, the title compound was obtained from 3,4-difluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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: 215 M ⁺ .

[Reference Example 261] 2-Oxo-2- (pyridin-4-ylamino) acetic acid methyl ester

In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-aminopyridine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.58 (2H, dd, J = 4.8, 1.6 Hz), 8.60 (2H, dd, J = 4. 8, 1.6 Hz), 9.04 (1H, br.s).
MS (ESI) m / z: 181 (M + H) ^<+> .

[Reference Example 262] 2-[(5-Bromopyridin-2-yl) amino] -2-oxoacetic acid methyl ester

In the same manner as in Reference Example 242, the title compound was obtained from 2-amino-5-bromopyridine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.87 (1H, dd, J = 8.8, 2.4 Hz), 8.19 (1H, d, J = 8. 8 Hz), 8.41 (1 H, d, J = 2.4 Hz), 9.38 (1 H, br. S).
MS (FAB) m / z: 259M ^<+> .

[Reference Example 263] 2-[(6-Chloropyridin-3-yl) amino] -2-oxoacetic acid ethyl ester

5-Amino-2-chloropyridine (386 mg) was dissolved in N, N-dimethylformamide (8 ml) to give potassium 2-ethoxy-2-oxoacetate (469 mg), 1- (3-dimethylaminopropyl) -3. -Ethylcarbodiimide hydrochloride (863 mg) and 1-hydroxybenzotriazole monohydrate (203 mg) were added, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added for liquid separation. The organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and then purified by silica gel flash column chromatography (hexane: acetic acid ethyl ester = 2: 1) to obtain a residue (200 mg) containing the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.2 Hz), 4.44 (2H, q, J = 7.2 Hz), 7.36 (1H, d, J = 8.7 Hz), 8.24 (1H, dd, J = 8.7, 2.7 Hz), 8.55 (1H, d, J = 2.7 Hz), 9.03 (1H, br.s).

[Reference Example 264] 2-[(6-Chloropyridazin-3-yl) amino] -2-oxoacetic acid methyl ester

3-Amino-6-chloropyridazine (516 mg) was dissolved in pyridine (26 ml), triethylamine (665 μl) and chlorooxoacetic acid methyl ester (441 μl) were successively added under ice cooling, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (748 mg).
¹ H-NMR (CDCl ₃ ) δ: 4.03 (3H, s), 7.59 (1H, d, J = 9.3 Hz), 8.52 (1H, d, J = 9.3 Hz), 9 .88 (1H, br.s).
MS (FAB) m / z: 215 M ^<+> .

[Reference Example 265] 2-[(5-chlorothiazol-2-yl) amino] -2-oxoacetic acid methyl ester

In the same manner as described in Reference Example 242, the title compound was obtained from 2-amino-5-chlorothiazole and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetic acid lithium salt

To a solution of the compound (1.12 g) obtained in Reference Example 243 in tetrahydrofuran (20 ml), water (5.0 ml) and lithium hydroxide (128 mg) were added at room temperature and stirred for 5 hours. The solvent was evaporated under reduced pressure, hexane (30 ml) was added to the resulting white solid, and the mixture was stirred for 30 minutes. The solid was collected by filtration and dried to give the title compound (1.02 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.90 (1H, dd, J = 8.9, 2.6 Hz), 8.12 (1H, d, J = 8.9 Hz), 8.34 ( 1H, d, J = 2.6 Hz), 10.18 (1H, s).

[Reference Example 267] 2- (4-Chloroanilino) acetic acid ethyl ester

4-Chloroaniline (2.0 g) was dissolved in acetonitrile (20 ml), ethyl bromoacetate (2.1 g) and potassium carbonate (2.2 g) were added, and the mixture was stirred at 60 ° C. for 2 days. The reaction solution was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: chloroform = 2: 1) to obtain the title compound (2.3 g).
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 3.86 (2H, s), 4.24 (2H, q, J = 7.3 Hz), 4 26-4.35 (1H, m), 6.53 (2H, dd, J = 6.6, 2.2 Hz), 7.14 (2H, dd, J = 6.6, 2.2 Hz).

[Reference Example 268] 2- (4-Chloro-2-fluoroanilino) acetic acid ethyl ester

The title compound was obtained from 4-chloro-2-fluoroaniline and bromoacetic acid ethyl ester in the same manner as described in Reference Example 267.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 3.91 (2H, s), 4.22 (2H, q, J = 7.3 Hz), 4 .42-4.51 (1H, m), 6.49 (1H, t, J = 8.8 Hz), 6.98 (1H, dt, J = 8.8, 2.5 Hz), 7.01 ( 1H, dd, J = 11.3, 2.5 Hz).

[Reference Example 269] 2-[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] -2-oxoacetic acid ethyl ester

The compound (1.5 g) obtained in Reference Example 253 was dissolved in N, N-dimethylformamide (15 ml), and 2-ethoxy-2-oxoacetic acid potassium salt (962 mg), 1- (3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (1.18 g) and 1-hydroxybenzotriazole monohydrate (277 mg) were added, and the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue for separation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 47: 3) to obtain the title compound (1.13 g). .
¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 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 = 15.5 Hz), 3.73 (1H , D, J = 15.5 Hz), 4.06-4.13 (1H, m), 4.32 (2H, q, J = 7.1 Hz), 4.60-4.63 (1H, m) 7.39 (1H, d, J = 8.3 Hz), 7.83 (1H, d, J = 7.6 Hz).
MS (ESI) m / z: 466 (M + H) ^<+> .

[Reference Example 270] 2-[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] Pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] -2-oxoacetic acid lithium salt

The compound (1.13 g) obtained in Reference Example 269 was dissolved in tetrahydrofuran (20 ml), methanol (10 ml) and water (10 ml), lithium hydroxide (58 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (1.10 g).
¹ H-NMR (DMSO-d ₆ ) 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-{(1R, 2S, 5S) -2-azido-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-5,6-dihydro-4H-pyrrolo [3,4 d] Thiazole-2-carboxamide

In the same manner as in the method described in Reference Example 252, the title compound was obtained from the compound obtained in Reference Example 293 and the compound obtained in Reference Example 251.
¹ H-NMR (CDCl ₃ ) 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 [3,4 d] Thiazole-2-carboxamide

In the same manner as in Reference Example 253, the title compound was obtained from the compound obtained in Reference Example 271.
¹ H-NMR (CDCl ₃ ) 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).

[Reference Example 273] 5-Chloro-4-fluoroindole-2-carboxylic acid methyl ester

Ethanol (100 ml) was added to sodium hydride (containing 60%, 4.7 g) at 0 ° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. 2-Nitropropane (11 ml) was added to the reaction solution and stirred for 10 minutes, 1- (bromomethyl) -3-chloro-2-fluorobenzene (10 g) was added, and the mixture was stirred at room temperature for 3.5 hours. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water, and the organic layer was washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale yellow oily compound. . Methanol (20 ml) was added to sodium hydride (containing 60%, 1.6 g) at 0 ° C. in an argon atmosphere and stirred for 10 minutes. The reaction solution was cooled to −20 ° C., and a solution of crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and 2-azidoacetic acid methyl ester (5.0 g) in methanol (10 ml) was added within 20 minutes. The reaction mixture was warmed to 0 ° C. and stirred for 2.5 hours, and water (40 ml) was added. The reaction solution was concentrated under reduced pressure, and the residue was extracted with a mixture of methylene chloride and ethyl ester. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography (toluene: hexane = 3: 17), and crude 2-azido-3-[(3-chloro-2-fluoro) phenyl] acrylic acid methyl ester ( 2.6 g) was obtained. This was dissolved in xylene (50 ml) and stirred at 130-140 ° C. for 3 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (methylene chloride) and crystallized from diethyl ether-hexane to obtain the title compound (440 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 4.08 (3H, s), 7.20 (1H, s), 7.31-7.38 (2H, m).
MS (FAB) m / z: 228 (M + H) ^<+> .

[Reference Example 274] 5-Chloro-4-fluoroindole-2-carboxylic acid

The compound (440 mg) obtained in Reference Example 273 was dissolved in tetrahydrofuran (10 ml), an aqueous solution (5 ml) of lithium hydroxide (160 mg) was added, and the mixture was stirred at room temperature for 3 hours. An aqueous solution (5 ml) of lithium hydroxide (240 mg) was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was neutralized with 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (390 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 6.79 (1H, s), 7.16-7.26 (2H, m)
MS (FAB) m / z: 214 (M + H) ^<+> .

[Reference Example 275] 1-benzyl-5-chloroindole-2-carboxylic acid ethyl ester

5-Chloroindole-2-carboxylic acid ethyl ester (1.4 g) was dissolved in N, N-dimethylformamide (30 ml), and potassium carbonate (2.9 g) and benzyl chloride (2.4 ml) were added. The mixture was heated and stirred at a bath temperature of 100 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was poured into ice water and extracted with acetic acid ethyl ester. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 19) and crystallized from diethyl ether-hexane to give the title compound (1.6 g).
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1 Hz), 4.33 (2H, q, J = 7.1 Hz), 5.83 (2H, s), 7 .00-7.02 (2H, d), 7.20-7.38 (6H, m), 7.67 (1H, d, J = 1.7 Hz).

[Reference Example 276] 1-benzyl-5-chloro-3-fluoroindole-2-carboxylic acid ethyl ester

1-Fluoro-2,6-dichloropyridinium triflate (4.4 g) was added to a methylene chloride solution (30 ml) of the compound (2.2 g) obtained in Reference Example 275, and the mixture was heated to reflux for 3 days. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 24) to obtain the crude title compound (2.8 g). A portion of this was purified by preparative silica gel thin layer chromatography to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 7.1 Hz), 4.29 (2H, q, J = 7.1 Hz), 5.77 (2H, s) 6.97-6.99 (2H, m), 7.18-7.28 (3H, m), 7.39 (1H, dd, J = 9.0, 2.1 Hz), 7.69 ( 1H, dd, J = 9.0, 2.1 Hz), 7.78 (1H, d, J = 2.1 Hz)

[Reference Example 277] 5-chloro-3-fluoroindole-2-carboxylic acid ethyl ester

The crude compound (1.4 g) obtained in Reference Example 276 was dissolved in anisole (30 ml), and aluminum chloride (2.9 g) was added little by little under ice cooling. The reaction solution was stirred at room temperature for 30 minutes, further added with aluminum chloride (2.9 g), and stirred for 18 hours. Aluminum chloride (8.0 g) was added to the reaction solution and stirred for 5 hours, and water was added. The reaction solution was extracted with ethyl acetate, and the combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride) to obtain the title compound (470 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.2 Hz), 4.45 (2H, q, J = 7.2 Hz), 7.25-7.31 (2H, m), 7.66 (1H, d, J = 0.73 Hz), 8.53 (1H, br. s).
MS (FAB) m / z: 242 (M + H) ^<+> .

[Reference Example 278] 5-chloro-3-fluoroindole-2-carboxylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 277.
¹ H-NMR (DMSO-d ₆ ) δ: 7.31 (1H, dd, J = 8.8, 1.9 Hz), 7.42 (1H, dd, J = 8.8, 1.9 Hz), 7.70 (1H, d, J = 1.9 Hz), 11.78 (1H, s)
MS (FAB) m / z: 214 (M + H) ^<+> .

[Reference Example 279] (1R, 2S, 5S)-{[(5-Chloro-3-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 97, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 278.
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Reference Example 280] 3-Bromo-5-chloroindole-2-carboxylic acid ethyl ester

To a solution of 5-chloroindole-2-carboxylic acid ethyl ester (500 mg) in N, N-dimethylformamide (10 ml) was added N-bromosuccinimide (440 mg) under ice cooling. The reaction solution was stirred at room temperature for 18 hours, and the solvent was distilled off under reduced pressure. The residue was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9), and the resulting white powder was washed with hexane to obtain the title compound (680 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.42-1.48 (3H, m), 4.43-4.49 (2H, m), 7.30-7.32 (2H, m), 7 .65 (1H, d, J = 0.74 Hz), 9.11 (1H, s)
MS (FAB) m / z: 303 (M + H) ^<+> .

[Reference Example 281] 3-Bromo-5-chloroindole-2-carboxylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 280.
¹ H-NMR (DMSO-d ₆ ) δ: 7.35 (1H, dd, J = 8.8, 2.0 Hz), 7.48-7.53 (2H, m), 12.33 (1H, s)
MS (FAB) m / z: 275 (M + H) ^<+> .

[Reference Example 282] (1R, 2S, 5S) -2-{[(3-Bromo-5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert- Butyl ester

In the same manner as in Reference Example 97, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 281.
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Reference Example 283] 3-Chloro-5-fluoroindole-2-carboxylic acid ethyl ester

5-Fluoroindole-2-carboxylic acid ethyl ester (2.0 g) was dissolved in N, N-dimethylformamide (20 ml), and N-chlorosuccinimide (1.4 g) in N, N-dimethyl was added under ice cooling. A formamide (10 ml) solution was added dropwise and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (1.9 g).
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.4 Hz), 4.46 (2H, q, J = 7.4 Hz), 7.14 (1H, dt, J = 8.0, 2.7 Hz), 7.32-7.36 (2H, m), 8.91 (1H, br).

[Reference Example 284] 3-Chloro-5-fluoroindole-2-carboxylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 283.
¹ H-NMR (DMSO-d ₆ ) δ: 7.20 (1H, dt, J = 8.8, 2.4 Hz), 7.31 (1H, dd, J = 8.8, 2.4 Hz), 7.46 (1H, dd, J = 8.8, 4.4 Hz), 12.12 (1H, br).

[Reference Example 285] 5-Chloro-3-formylindole-2-carboxylic acid ethyl ester

Phosphorus oxychloride (2.0 ml) was added to N-methylformanilide (2.9 g), and after stirring for 15 minutes, 1,2-dichloroethane (50 ml) and 5-chloroindole-2-carboxylic acid ethyl ester (4. 0 g) was added and heated to reflux for 1 hour. Under ice-cooling, the reaction solution was poured into an aqueous solution (28 ml) of sodium acetate (14 g), stirred for 18 hours, and insolubles were collected by filtration. This was washed successively with water and diethyl ether to give the title compound (3.56 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.38 (3H, t, J = 7.1 Hz), 4.44 (2H, q, J = 7.1 Hz), 7.38 (1H, dd, J = 8.0, 1.4 Hz), 7.56 (1H, d, J = 8.0 Hz), 8.19 (1H, d, J = 1.4 Hz), 10.53 (1H, s).

[Reference Example 286] 5-Chloro-3-formylindole-2-carboxylic acid

The compound (1.0 g) obtained in Reference Example 285 was dissolved in ethanol (10 ml), 1N aqueous sodium hydroxide solution (10 ml) was added dropwise, and the mixture was heated with stirring at 50 ° C. for 2 hr. 1N Hydrochloric acid aqueous solution (11 ml) was added to the reaction mixture, and after stirring, the precipitated insoluble material was collected by filtration to give the title compound (0.86 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.39 (1H, d, J = 8.0 Hz), 7.55 (1H, d, J = 8.0 Hz), 8.20 (1H, s) , 10.58 (1H, s), 12.90 (1H, br).

[Reference Example 287] 5-Chloro-2-ethoxycarbonylindole-3-carboxylic acid

The compound (1.5 g) and sulfamic acid (1.7 g) obtained in Reference Example 286 were dissolved in tert-butanol (30 ml) -water (30 ml), sodium chlorite (1.6 g) was added, and the mixture was stirred for 8 hours. did. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with 1N aqueous hydrochloric acid and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent consisting of isopropyl ether-hexane to obtain the title compound (0.7 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (3H, t, J = 7.1 Hz), 4.38 (2H, q, J = 7.1 Hz), 7.33 (1H, dd, J = 8.0, 1.4 Hz), 7.52 (1H, d, J = 8.0 Hz), 7.97 (1H, d, J = 1.4 Hz), 12.75 (1H, br).

[Reference Example 288] 5-Chloro-3-[(dimethylamino) carbonyl] indole-2-carboxylic acid ethyl ester

The compound (0.7 g) obtained in Reference Example 287 was dissolved in N, N-dimethylformamide (10 ml), dimethylamine hydrochloride (0.26 g), 1-hydroxybenzotriazole monohydrate (0.43 g). , 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.0 g) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate and washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent consisting of isopropyl ether-hexane to obtain the title compound (0.6 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (3H, t, J = 7.1 Hz), 2.78 (3H, s), 3.04 (3H, s), 4.30 (2H , Q, J = 7.1 Hz), 7.31 (1H, dd, J = 8.0, 1.4 Hz), 7.45 (1H, d, J = 1.4 Hz), 7.48 (1H, d, J = 8.0 Hz), 12.29 (1H, s).

[Reference Example 289] 5-Chloro-3-[(dimethylamino) carbonyl] indole-2-carboxylic acid

In the same manner as in Reference Example 286, the title compound was obtained from the compound obtained in Reference Example 288.
¹ H-NMR (DMSO-d ₆ ) δ: 2.91 (6H, s), 7.29 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz) 7.47 (1H, s), 12.16 (1H, s).

[Reference Example 290] 5- (Phenylsulfonyl) -5,6-dihydro-4H-pyrrolo [3,4-d] thiazole

Under ice-cooling, benzenesulfonamide (638 mg) and 4,5-bis (bromomethyl) thiazole (M. Al. Hariri, O. Galley, F. Paulet, H. Filion, Eur. J. Org. Chem. 1998, 593). -594.) (1.10 g) was dissolved in N, N-dimethylformamide (10 ml), sodium hydride (60% oily, 357 mg) was added at once and stirred at room temperature for 3 hours. Water and methylene chloride were added for liquid separation, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (methylene chloride: acetic acid ethyl ester = 9: 1) to give the title compound (137 mg )
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Reference Example 291] 5,6-dihydro-4H-pyrrolo [3,4-d] thiazole dihydrobromide

A mixture of the compound obtained in Reference Example 290 (800 mg), phenol (800 μl) and 47% aqueous hydrobromic acid solution (5.00 ml) was heated to reflux for 2 hours. After cooling to room temperature, ethyl acetate and water were added for liquid separation, and the aqueous layer was evaporated under reduced pressure. Acetic acid ethyl ester was added to the residue, and the precipitate was collected by filtration and dried to give the title compound (521 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 4.42 (2H, brs), 4.56 (2H, brs), 9.14 (1H, s).
MS (FAB) m / z: 127 (M + H) ^<+> .

[Reference Example 292] 5-Methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole

The title compound was obtained from the compound obtained in Reference Example 291 by a method similar to that described in Reference Example 9.
¹ H-NMR (CDCl ₃ ) 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 [3,4-d] thiazole-2-carboxylic acid lithium salt

In the same manner as in Reference Example 5, the title compound was obtained from the compound obtained in Reference Example 292.
¹ H-NMR (DMSO-d ₆ ) δ: 2.52 (3H, s), 3.73 (2H, t, J = 3.2 Hz), 3.87 (2H, t, J = 3.2 Hz) .

[Reference Example 294] (1R, 2S, 5S) -2-[(6-Chloro-2-naphthoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 97, from the compound obtained in Reference Example 144 and 6-chloronaphthalene-2-carboxylic acid (Eur. J. Chem-Chim. Ther., 1984, 19, pp. 205-214) The title compound was obtained.
¹ H-NMR (CDCl ₃ ) 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 = 9.0 Hz), 7.70-7.95 (5H, m), 8.31 (1H, s).
MS (FAB) m / z: 474 (M + H) ^<+> .

[Reference Example 295] (E) -3- (morpholin-4-yl) -2-acrylic acid ethyl ester

Propionic acid ethyl ester (2.0 ml) was dissolved in methylene chloride (20 ml), and morpholine (1.70 ml) was added dropwise under ice cooling. The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to obtain the title compound (3.72 g).
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 3.21 (4H, t, J = 5.1 Hz), 3.71 (4H, t, J = 5.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.70 (1H, d, J = 13.4 Hz), 7.36 (1H, d, J = 13.4 Hz).
MS (FAB) m / z: 186 (M + H) ^<+> .

[Reference Example 296] 3-Chlorobenzenediazonium tetrafluoroborate

  3-Chloroaniline (2.0 g) was dissolved in a mixed solvent of water (30 ml) and concentrated hydrochloric acid (3.5 ml), sodium nitrite (1.30 g) was added under ice cooling, and the mixture was stirred for 10 minutes. Concentrated hydrochloric acid (5.3 ml) and sodium tetrafluoroborate (6.90 g) were added, and the mixture was stirred for 30 minutes under ice-cooling. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether to give the title compound ( 2.63 g) was obtained. It used for next reaction as it was.

[Reference Example 297] 7-chlorocinnoline-3-carboxylic acid ethyl ester

The compound (1.45 g) obtained in Reference Example 295 was dissolved in acetonitrile (100 ml), the compound (1.73 g) obtained in Reference Example 296 was added and stirred at room temperature for 1 hour, and then heated to reflux for 7 days. . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride → methylene chloride: ethyl acetate = 10: 1, then hexane: ethyl acetate = 4: 1 → 1: 1). (0.25 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.53 (3H, t, J = 7.1 Hz), 4.62 (2H, q, J = 7.1 Hz), 7.80 (1H, dd, J = 8.8, 2.0 Hz), 7.95 (1H, d, J = 8.8 Hz), 8.64 (1H, s), 8.68 (1H, d, J = 2.0 Hz).

[Reference Example 298] 7-chlorocinnoline-3-carboxylic acid

In the same manner as in Reference Example 286, the title compound was obtained from the compound obtained in Reference Example 297.
¹ H-NMR (DMSO-d ₆ ) δ: 8.02 (1H, dd, J = 8.8, 2.0 Hz), 8.34 (1H, d, J = 8.8 Hz), 8.70 ( 1H, s), 8.90 (1H, s).
MS (FAB) m / z: 209 (M + H) ^<+> .

[Reference Example 299] (1R, 2S, 5S) -2-{[(7-chlorocinnolin-3-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 298 by a method similar to that of Reference Example 97.
¹ H-NMR (CDCl ₃ ) 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 = 3.7 Hz), 4.30-4.45 (2H, m), 4.87 (1H, br), 7.77 ( 1H, dd, J = 8.8, 2.0 Hz), 7.96 (1H, d, J = 8.8 Hz), 8.59 (2H, br), 8.72 (1H, s).
MS (FAB) m / z: 476 (M + H) ^<+> .

[Reference Example 300] (1R, 2S, 5S) -2-{[(5-Chloro-1H-benzimidazol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert- Butyl ester

To a solution of the compound (235 mg) obtained in Reference Example 143 in tetrahydrofuran (5.0 ml) was added 10% palladium carbon (50 mg), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered and the product obtained by concentrating the filtrate and N of chlorobenzimidazole-2-carboxylic acid (Bull. Chem. Soc. Jpn., 1989, 62, 2668) (165 mg) , N-dimethylformamide (5.0 ml) solution was added 1-hydroxybenzotriazole monohydrate (100 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (171 mg) at room temperature. Stir for 4 days. The reaction mixture was concentrated, methylene chloride, aqueous sodium hydrogen carbonate solution and water were added to separate the mixture, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 10: 1) to obtain the title compound (250 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 6.6 Hz), 7.31 (1H, d , J = 8.5 Hz), 7.62 (2H, br.s), 8.47 (1H, d, J = 8.5 Hz), 13.46 (1H, br.s).
MS (ESI) m / z: 466 (M + H) ^<+> .

[Reference Example 301] 3- (4-Fluorophenyl) -2-{[(4-methylphenyl) sulfonyl] amino} propionic acid methyl ester

2-amino-3- (4-fluorophenyl) propionic acid methyl ester (2.01 g), p-toluenesulfonyl chloride (2.25 g), 4-dimethylaminopyridine (309 mg) were dissolved in chloroform (30 ml), Pyridine (3.0 ml) was added and heated to reflux for 4.5 hours. Furthermore, p-toluenesulfonyl chloride (2.20 g) was added, and the mixture was heated to reflux for 3.5 hours. The reaction mixture was poured into ice and 1N hydrochloric acid (17 ml), and the phases were separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 2: 1) to obtain the title compound (2.89 g).
¹ H-NMR (CDCl ₃ ) 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 = 9.0 Hz), 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) ^<+> .

[Reference Example 302] 7-Fluoro-2-[(4-methylphenyl) sulfonyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester

The compound obtained in Reference Example 301 (1.50 g) and paraformaldehyde (207 mg) were dissolved in chloroform (40 ml) and purged with argon. Next, trifluoroborane-diethyl ether complex (1.20 ml) was added, and the mixture was stirred at room temperature for 7.5 hours. The reaction solution was poured into ice and saturated aqueous sodium hydrogen carbonate solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (1.45 g).
¹ H-NMR (CDCl ₃ ) δ: 2.42 (3H, s), 3.15 (2H, d, J = 3.9 Hz), 3.46 (3H, s), 4.45 (1H, d , J = 15.9 Hz), 4.69 (1H, d, J = 15.9 Hz), 5.01 (1H, t, J = 4.4 Hz), 6.70-6.80 (1H, m) 6.80-6.90 (1H, m), 7.00-7.10 (1H, m), 7.29 (2H, d, J = 8.1 Hz), 7.72 (2H, d, J = 8.3 Hz).
MS (ESI) m / z: 364 (M + H) ^<+> .

[Reference Example 303] 7-Fluoroisoquinoline-3-carboxylic acid methyl ester

The compound (1.45 g) obtained in Reference Example 302 was dissolved in N, N-dimethylformamide (40 ml). Oxygen was introduced into the reaction solution and stirred at 100 ° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue for separation. The organic layer was washed successively with a 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (0.59 g).
¹ H-NMR (CDCl ₃ ) 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-Fluoroisoquinoline-3-carboxylic acid hydrochloride

The compound (1.45 g) obtained in Reference Example 303 was dissolved in concentrated hydrochloric acid (18 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound (0.46 g).
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

[Reference Example 305] 7-Chloro-2H-chromene-3-carboxylic acid ethyl ester

4-Chloro-2-hydroxybenzaldehyde (Acta. Chem. Scand., 1999, 53 卷, 258 pages) (510 mg) was dissolved in tetrahydrofuran (40 ml), and sodium hydride (60% oily, 157 mg) was added to room temperature. For 2 hours. A tetrahydrofuran solution (10 ml) of 2-diethylphosphonoacrylic acid ethyl ester (J. Org. Chem. 1978, 43, 1256) (769 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours and then heated to reflux overnight. did. After cooling the reaction solution to room temperature, water and diethyl ether were added to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound (247 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (3H, t, J = 7.1 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.99 (2H, d, J = 1.2 Hz), 6.85 (1H, d, J = 1.2 Hz), 6.89 (1H, dd, J = 8.1, 2.0 Hz), 7.04 (1H, d, J = 8.1 Hz), 7.38 (1H, d, J = 1.0 Hz).
MS (EI) m / z: 238 (M ^<+> ).

[Reference Example 306] 7-Chloro-2H-chromene-3-carboxylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 305.
¹ H-NMR (DMSO-d ₆ ) δ: 4.92 (1H, d, J = 2.0 Hz), 6.95 (1H, d, J = 2.0 Hz), 7.01 (1H, dd, J = 8.1, 2.2 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.44 (1H, s). MS (EI) m / z: 210 (M) ^<+> .

[Reference Example 307] (1R, 2S, 5S) -2-{[(E) -3- (4-chlorophenyl) -2-propenoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert- Butyl ester

The title compound was obtained from the compound obtained in Reference Example 144 and 4-chlorocinnamic acid in the same manner as in Reference Example 97.
¹ H-NMR (CDCl ₃ ) 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 = 15.6 Hz), 7.02 (1H, s), 7.31 (2H, d, J = 8.5 Hz), 7 .40 (2H, d, J = 8.5 Hz), 7.52 (1H, d, J = 15.6 Hz).
MS (ESI) m / z: 450 (M + H) ^<+> .

[Reference Example 308] 6-Chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid methyl ester

Acetylenedicarboxylic acid dimethyl ester (13.5 ml) was added to a solution of 4-chloroaniline (12.76 g) in methanol (150 ml), and the mixture was heated to reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in diphenyl ether (70 ml) and stirred with heating at 240 ° C. for 4 hours. After cooling the reaction mixture, a mixed solvent of hexane and diethyl ether was added and the precipitated crystals were collected by filtration and washed to give the title compound (11.09 g).
¹ H-NMR (DMSO-d ₆ ) δ: 3.97 (3H, s), 7.76 (1H, dd, J = 9.0, 2.5 Hz), 7.90-8.05 (2H, m), 12.28 (1H, br.s).
MS (ESI) m / z: 238 (M + H) ^<+> .

[Reference Example 309] 6-Chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid

In the same manner as in Reference Example 286, the title compound was obtained from the compound obtained in Reference Example 308.
¹ H-NMR (DMSO-d ₆ ) 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-Chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

Water (10 ml) and lithium hydroxide (263 mg) were added to a solution of the compound obtained in Reference Example 97 (5.00 g) in tetrahydrofuran (40 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was concentrated, and the resulting residue and a solution of dimethylamine hydrochloride (1.85 g) in N, N-dimethylformamide (100 ml) were added to 1-hydroxybenzotriazole monohydrate (1. 75 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.32 g), and diisopropylethylamine (11.3 ml) were added at room temperature and stirred for 2 days. The reaction mixture was concentrated, methylene chloride, aqueous sodium hydrogen carbonate solution and water were added to separate the mixture, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: acetone = 2: 1 → 1: 1) to obtain the title compound (4.59 g).
¹ H-NMR (CDCl ₃ ) 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, 1.9 Hz), 7.36 (1H, d, J = 8.8 Hz), 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-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

1) Similar to Reference Example 91, from the compound obtained in Reference Example 96 and 5-fluoroindole-2-carboxylic acid, (1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4- {[(5-Fluoroindol-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.52 (9H, s), 1.67-2.41 (7H, m), 3.97 (1H, br.s), 4.15 (2H, q, J = 7.1 Hz), 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) The title compound was obtained from the above compound in the same manner as in Reference Example 310.
¹ H-NMR (CDCl ₃ ) 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, 9.0 Hz), 7.24 (1H, br.s), 7.35 (1H, dd, J = 9.0, 4.3 Hz), 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-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid ethyl ester

Under an argon stream, copper (I) cyanide (918 mg) was suspended in tetrahydrofuran (50 ml) and cooled to −20 ° C., and then n-butyllithium (1.56 N hexane solution, 6.41 ml) was added dropwise over 5 minutes. And stirred at −20 ° C. for 30 minutes. After cooling this reaction liquid to -50 degreeC, diisobutylaluminum hydride (1.00 mol hexane solution) was dripped in 20 minutes, and it stirred at -50 degreeC for 1 hour. 2,2-Dimethyl-5-oxo-5,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester (Helv. Chim. Acta, 1998, 81, 303) (986 mg) was added to this reaction solution. A solution containing tetrahydrofuran (5 ml) was added dropwise over 5 minutes, and the mixture was stirred at −50 ° C. for 2 hours. After raising the temperature to −20 ° C., bromine (4.90 ml) was added dropwise at once, and the mixture was stirred at −20 ° C. for 30 minutes. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was washed with a saturated aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was dissolved in N, N-dimethylformamide (10 ml), thiourea (760 mg) was added, and the mixture was stirred at 50 ° C. overnight. After the solvent was distilled off, methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added for liquid separation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to obtain the title compound (412 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 1.54 (6H, s), 2.65-2.67 (2H, m), 4.09 (2H, q, J = 7.1 Hz), 4.44-4.46 (2H, m), 4.78 (2H, br. S).

[Reference Example 313] 2-Bromo-6,6-dimethyl-6,7-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid ethyl ester

Cupric bromide (431 mg) was suspended in acetonitrile (8 ml), and tert-butyl nitrite (249 mg) was added dropwise at room temperature. To the reaction solution was added an acetonitrile solution (8 ml) of the compound (412 mg) obtained in Reference Example 312 under ice-cooling, the temperature was raised to 50 ° C., and the mixture was stirred for 15 minutes. The solvent was distilled off, diethyl ether and 10% hydrochloric acid were added to the residue and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain the title compound (151 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.55 (6H, s), 2.79-2.81 (2H, m), 4.10 (2H, q, J = 7.1 Hz), 4.65-4.67 (2H, m).
MS (ESI) m / z: 319 (M + H) ^<+> .

[Reference Example 314] 6,6-Dimethyl-6,7-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid ethyl ester

N-Butyllithium (1.56 N hexane solution, 1.04 ml) was added to a diethyl ether solution (5 ml) of the compound (432 mg) obtained in Reference Example 313 at -78 ° C, and the mixture was stirred at -78 ° C for 30 minutes. Water and diethyl ether were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (307 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 1.55 (6H, s), 2.90 (2H, s), 4.12 (2H, q , J = 7.1 Hz), 4.75 (2H, m), 8.63 (1H, s).

[Reference Example 315] 6,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine

The compound (307 mg) obtained in Reference Example 314 was dissolved in a mixed solvent of water (5 ml), ethanol (5 ml) and dioxane (5 ml). Lithium hydroxide (598 mg) was added to the reaction mixture, and the mixture was heated to reflux for 7 days. . After allowing to stand to room temperature, water and methylene chloride were added for liquid separation, and the aqueous layer was further extracted six times with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain the title compound (207 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, s), 2.61-2.73 (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-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester

The compound (207 mg) obtained in Reference Example 315 was dissolved in methylene chloride (5 ml), and di-tert-butyl dicarbonate (404 mg) and 4- (N, N-dimethylamino) pyridine (151 mg) were added to room temperature. For 2 hours. Di-tert-butyl dicarbonate (404 mg) was further added and stirred overnight at room temperature, and di-tert-butyl dicarbonate (1.00 g) was added again and stirred for 1 hour. Methylene chloride and 10% aqueous hydrochloric acid solution were added for liquid separation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (95.4 mg).
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Reference Example 317] 4-Chloro-5- (1,3-dioxolan-2-yl) thiazole-2-carboxylic acid lithium salt

  2,4-dichlorothiazole-5-carbaldehyde ethylene acetal (J. Chem. Soc. Perkin Trans. 1, 1992, page 973) (2.26 g) was dissolved in tetrahydrofuran (15 ml) and dried ice-acetone. Under cooling, n-butyllithium (1.5 N hexane solution, 6.8 ml) was added and stirred for 20 minutes, and then carbon dioxide gas was introduced at the same temperature. After gradually warming to room temperature over 1.5 hours, the mixture was concentrated under reduced pressure, hexane was added to form a powder, filtered, and then suspended in acetic acid ethyl ester. The powder was again collected by filtration to give the title compound (1 .65 g) was obtained.

[Reference Example 318] 4-Chloro-5- (1,3-dioxolan-2-yl) thiazole-2-carboxylic acid ethyl ester

The compound (242 mg) obtained in Reference Example 317 and ethanol (0.2 ml) were dissolved in N, N-dimethylformamide (2 ml) to give 1-hydroxybenzotriazole monohydrate (136 mg), 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (250 mg) was added and stirred overnight at room temperature. The solvent was concentrated under reduced pressure, diethyl ether and dilute hydrochloric acid were added, and the organic layer was separated. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (170 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.3 Hz), 4.00-4.10 (2H, m), 4.10-4.20 (2H, m) 4.48 (2H, q, J = 7.3 Hz), 6.15 (1H, s).
MS (ESI) m / z: 264 (M + H) ^<+> .

[Reference Example 319] 4-Chloro-5-formylthiazole-2-carboxylic acid ethyl ester

The compound (132 mg) obtained in Reference Example 318 was dissolved in diethyl ether (5 ml), 20% aqueous hydrochloric acid (0.3 ml) was added, and the mixture was stirred at room temperature for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (110 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, t, J = 7.1 Hz), 4.52 (2H, q, J = 7.1 Hz), 10.12 (1H, s).

[Reference Example 320] 4-Azido-5-formylthiazole-2-carboxylic acid ethyl ester

The compound (5.15 g) obtained in Reference Example 319 was dissolved in dimethyl sulfoxide (30 ml), sodium azide (1.52 g) was added, and the mixture was stirred at room temperature for 2.5 hours. Ice water was added to the reaction solution, extracted with diethyl ether, washed twice with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to obtain the title compound (1.78 g).
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.1 Hz), 4.50 (2H, q, J = 7.1 Hz), 9.95 (1H, s).

[Reference Example 321] 6-Methyl-6,7-dihydrothiazolo [4,5-d] pyrimidine-2-carboxylic acid ethyl ester

The compound (1.56 g) obtained in Reference Example 320 was dissolved in methylene chloride (20 ml), acetic acid (2 ml), methylamine (2N tetrahydrofuran solution, 21 ml) and sodium triacetoxyborohydride (2.98 g) were added. Added and stirred. One hour later, sodium triacetoxyborohydride (2.98 g) was added, and stirring was further continued for 4.5 hours. The reaction solution was made alkaline by adding a 0.5 N aqueous sodium hydroxide solution (100 ml), extracted with methylene chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a brown oil (1.43 g). This oily substance was dissolved in ethanol (50 ml), 10% palladium carbon (2.0 g) was added, and the mixture was subjected to a hydrogenation reaction at normal temperature and pressure. After 2.5 hours, the catalyst was filtered off, the filtrate was concentrated, the residue was dissolved in methylene chloride (30 ml), trimethyl orthoformate (0.7 ml) and boron trifluoride-diethyl ether complex (0.3 ml). ) And stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3) to obtain the title compound (100 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1 Hz), 2.95 (3H, s), 4.44 (2H, q, J = 7.1 Hz), 4 .87 (2H, s), 7.06 (1H, s).
MS (ESI) m / z: 226 (M + H) ^<+> .

[Reference Example 322] Lithium salt of 6-methyl-6,7-dihydrothiazolo [4,5-d] pyrimidine-2-carboxylic acid

The compound (463 mg) obtained in Reference Example 321 was dissolved in tetrahydrofuran (20 ml), lithium hydroxide (54.1 mg) and water (4 ml) were added, and the mixture was stirred at room temperature for 4.5 hours. The solvent was distilled off under reduced pressure and dried with a vacuum pump to obtain the title compound (460 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 2.86 (3H, s), 4.71 (2H, s), 7.03 (1H, s).

[Reference Example 323] (1R, 2S, 5S) -2-azido-5-{[ethyl (methyl) amino] carbonyl} cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by condensing the compound obtained in Reference Example 250 with ethylmethylamine.
¹ H-NMR (CDCl ₃ ) δ: 1.08, 1.18 (3H, each t, J = 7.1 Hz), 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, each), 3.32, 3.39 ( 2H, each q, J = 7.1 Hz), 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-Chloroisoquinolin-3-yl) carbonyl] amino} -5-{[ethyl (methyl) amino] carbonyl} cyclohexylcarbamic acid tert-butyl ester

The compound (1.44 g) obtained in Reference Example 323 was dissolved in methanol (20 ml), 10% palladium carbon (150 mg) was added, and the mixture was stirred under a hydrogen stream. After 24 hours, the catalyst was removed by filtration, and the solvent was concentrated under reduced pressure to obtain a colorless oil, which was directly used in the next reaction.
The above oil was dissolved in methylene chloride (30 ml), and the compound obtained in Reference Example 57 (850 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.27 g), 1-hydroxybenzo Triazole monohydrate (900 mg) and N-methylmorpholine (1.34 g) were added, and the mixture was stirred at room temperature. After 17 hours, methylene chloride and a saturated sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 50) to obtain the title compound (1.61 g).
¹ H-NMR (CDCl ₃ ) δ: 1.10, 1.22 (3H, each t, J = 7.1 Hz), 1.43 (9H, s), 1.84-2.17 (6H, m ), 2.66 (1H, br.s), 2.92, 3.03 (3H, each), 3.35-3.44 (2H, m), 4.20-4.30 (2H, m), 5.30 (1H, br.s), 7.70 (1H, d, J = 8.6 Hz), 7.92 (1H, d, J = 8.6 Hz), 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-chloroisoquinolin-3-yl) carbonyl] -4-{[ethyl (methyl) amino] carbonyl} cyclohexyl) -7-chloroisoquinoline-3-carboxamide

The compound (1.60 g) obtained in Reference Example 324 was dissolved in hydrochloric acid ethanol solution (25 ml) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and methylene chloride and 1N aqueous sodium hydroxide solution were added to the residue for separation. The aqueous layer was extracted with methylene chloride, the combined organic layers were dried over potassium carbonate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the precipitate was collected by filtration to give the title compound (1.22 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.10, 1.23 (3H, each, J = 7.1 Hz), 1.26 (2H, br.s), 1.69-2.11. (6H, m), 2.89 (1H, br.s), 2.93, 3.05 (3H, each), 3.38-3.45 (2H, m), 3.52 (1H, s), 4.18 (1H, br.s), 7.70 (1H, dd, J = 8.8, 2.0 Hz), 7.94 (1H, d, J = 8.8 Hz), 8. 02 (1H, d, J = 2.0 Hz), 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 (diphenyl) silyl] oxy} cyclohexanecarboxylic acid ethyl ester

The compound (28.0 g) obtained in Reference Example 88 was dissolved in N, N-dimethylformamide (500 ml), and tert-butyldiphenylsilyl chloride (63.5 ml) and imidazole (19.9 g) were added. After stirring at room temperature for 10 hours, ethyl acetate and water were added to the reaction solution and the phases were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed twice with water. After drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 1: 0 → 47: 3), and N, N-dimethylformamide was reduced to 0.00. The title compound (52.5 g) mixed with 4 molecules was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.27 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz), 4.32 (1H) , D, J = 8.1 Hz), 7.34-7.46 (6H, m), 7.65-7.73 (4H, m).

[Reference Example 327] (1R ^* , 2R ^* , 5S ^* )-2-{[tert-butyl (diphenyl) silyl] oxy} -5- (hydroxymethyl) cyclohexanecarbamic acid tert-butyl ester

Under argon substitution, lithium aluminum hydride (7.11 g) was suspended in dry diethyl ether (100 ml) at 0 ° C., and a solution of the compound obtained in Reference Example 326 (52.5 g) in diethyl ether (500 ml) was added over 30 minutes. And dripped. After stirring at 0 ° C. for 30 minutes, methanol (100 ml) was added dropwise to the reaction solution. The resulting slurry was filtered off through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (29.6 g).
¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.32-1.74 (16H, m), 1.87 (1H, t, J = 10.4 Hz), 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 (diphenyl) silyl] oxy} cyclohexyl) methyl ester

The compound (29.5 g) obtained in Reference Example 327 was dissolved in methylene chloride (200 ml) and pyridine (20 ml), methanesulfonyl chloride (9.5 ml) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed twice with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (29.8 g).
¹ H-NMR (CDCl ₃ ) 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 = 5.4 Hz), 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 (diphenyl) silyl] oxy} -5- (cyanomethyl) cyclohexanecarbamic acid tert-butyl ester

The compound (29.8 g) obtained in Reference Example 328 was dissolved in N, N-dimethylformamide (400 ml), sodium cyanide (3.64 g) was added, and the mixture was stirred at 80 ° C. for 11 hours. To the reaction solution were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (20.6 g).
¹ H-NMR (CDCl ₃ ) 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 = 7.1 Hz), 3.77 (1H, br.s), 3.82 (1H, br) S), 4.32 (1H, br.d, J = 6.8 Hz), 7.35-7.45 (6H, m), 7.65-7.71 (4H, m).

[Reference Example 330] (1R ^* , 2R ^* , 5S ^* )-2-{[tert-butyl (diphenyl) silyl] oxy} -5- (2-oxoethyl) cyclohexanecarbamic acid tert-butyl ester

The compound (2.00 g) obtained in Reference Example 329 was dissolved in anhydrous methylene chloride (20 ml), substituted with argon, and then cooled to -78 ° C. Diisobutylaluminum hydride (0.95 M hexane solution, 8.55 ml) was added dropwise thereto, and then the mixture was warmed to room temperature and stirred for 3 hours. The reaction solution was cooled to 0 ° C., and methanol (10 ml) was added dropwise. The resulting slurry was filtered off through Celite, the filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 1: 0 → 49: 1) to give the title compound (1.45 g). Got.
¹ H-NMR (CDCl ₃ ) 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 = 1.7 Hz) ).
MS (FAB) m / z: 496 (M + H) ^<+> .

[Reference Example 331] 2-((1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[tert-butyl (diphenyl) silyl] oxy} cyclohexyl) acetic acid

The compound (8.40 g) obtained in Reference Example 330 was dissolved in a mixed solvent of water (33 ml) and tert-butanol (120 ml), and 2-methyl-2-butene (8.08 ml), sodium dihydrogen phosphate 2 Hydrate (2.64 g) and sodium chlorite (3.45 g) were added, and the mixture was stirred at room temperature for 1.5 hr. The reaction solution was diluted with methylene chloride and water, and the aqueous layer was adjusted to pH 4 with 1N aqueous hydrochloric acid. The solution was separated and extracted from the aqueous layer twice with methylene chloride. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to obtain the title compound (7.62 g).
¹ H-NMR (CDCl ₃ ) 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 (diphenyl) silyl] oxy} -5- [2- (dimethylamino) -2-oxoethyl] cyclohexanecarbamic acid tert- Butyl ester

The compound (7.62 g) obtained in Reference Example 331 was dissolved in N, N-dimethylformamide (150 ml), dimethylamine hydrochloride (6.07 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. Hydrochloric acid salt (8.56 g), 1-hydroxybenzotriazole monohydrate (1.01 g) and triethylamine (10.3 ml) were added and stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added to the residue for separation. The aqueous layer was extracted with methylene chloride, and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). The solvent was distilled off, hexane was added, and the resulting white precipitate was collected by filtration to obtain the title compound (6.42 g).
¹ H-NMR (CDCl ₃ ) 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-oxoethyl] -2-hydroxycyclohexanecarbamic acid tert-butyl ester

The compound (6.36 g) obtained in Reference Example 332 was dissolved in tetrahydrofuran (50 ml), tetrabutylammonium fluoride (1N tetrahydrofuran solution, 17.85 ml) was added, and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 24: 1) to obtain the title compound (3.49 g).
¹ H-NMR (CDCl ₃ ) 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-oxoethyl] cyclohexyl ester

The compound (8.05 mg) obtained in Reference Example 333 was dissolved in methylene chloride (50 ml), cooled to −78 ° C. under an argon atmosphere, and methanesulfonyl chloride (2.70 ml) was added dropwise. The temperature was raised to 0 ° C. and stirred for 30 minutes, and then stirred at room temperature for 2 hours. Water was added to the reaction solution for liquid separation, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate = 1: 1 → 0: 1) to obtain the title compound (3.63 g).
¹ H-NMR (CDCl ₃ ) 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-azido-5- [2- (dimethylamino) -2-oxoethyl] cyclohexanecarbamic acid tert-butyl ester

The compound (3.62 g) obtained in Reference Example 334 was dissolved in N, N-dimethylformamide (20 ml), sodium azide (3.11 g) was added, and the mixture was stirred at 75 ° C. for 17 hours. The reaction solution was poured into a mixture of water and ethyl acetate and separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (acetic acid ethyl ester) to obtain the title compound (1.30 g).
¹ H-NMR (CDCl ₃ ) δ: 1.14 to 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 ^* , 4R ^* )-2-amino-4- [2- (dimethylamino) -2-oxoethyl] cyclohexyl} -5-chloroindole-2-carboxamide hydrochloride

In the same manner as in Reference Example 324, the product obtained by catalytic reduction of the compound obtained in Reference Example 335 and then condensation with 5-chloroindole-2-carboxylic acid was treated in the same manner as in Reference Example 69. The title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.6-1.19 (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 (1 H, dd, J = 8.7, 1.7 Hz), 7 .35 (1H, s), 7.44 (1H, d, J = 8.7 Hz), 7.69 (1H, d, J = 1.7 Hz), 8.22 (3H, br.s), 8 .62 (1H, d, J = 7.1 Hz), 11.91 (1H, s).
MS (ESI) m / z: 377 (M + H) ^<+> .

[Reference Example 337] (1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (hydroxymethyl) cyclohexanecarbamic acid tert-butyl ester

  The title compound was obtained from the compound obtained in Reference Example 97 by a method similar to that of Reference Example 129 2).

[Reference Example 338] Methanesulfonic acid ((1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) methyl ester

The compound (500 mg) obtained in Reference Example 337 and triethylamine (329 ml) were suspended in tetrahydrofuran (8 ml) -methylene chloride (8 ml) and cooled to -78 ° C. After dropwise addition of methanesulfonyl chloride (138 ml) to this solution, the liquid temperature was gradually raised to −5 ° C. and stirred at the same temperature for 15 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted 3 times with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (654 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.57 (9H, s), 1.84 to 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 .8 Hz), 7.34 (1 H, d, J = 8.8 Hz), 7.60 (1 H, s), 8.02 (1 H, br. S), 9.27 (1 H, br. S).
MS (ESI) m / z: 500 (M + H) ^<+> .

[Reference Example 339] (1R, 2S, 5S) -2-{[(5-Chloroindol-2-yl) carbonyl] amino} -5-[(methylsulfanyl) methyl] cyclohexanecarbamic acid tert-butyl ester

The compound (654 mg) obtained in Reference Example 338 was dissolved in N, N-dimethylformamide (8 ml), 15% aqueous sodium thiomethoxide solution (1.8 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to obtain the title compound (492 mg).
¹ H-NMR (CDCl ₃ ) 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, 1.2 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.57 (1H, s), 9.82 (1H, br. S).
MS (ESI) m / z: 452 (M + H) ^<+> .

[Reference Example 340] (1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(methylsulfonyl) methyl] cyclohexanecarbamic acid tert-butyl ester

The compound (300 mg) obtained in Reference Example 339 was dissolved in methylene chloride (10 ml), and m-chloroperbenzoic acid (70%, 400 mg) was added with stirring at 0 ° C. After stirring for 1 hour, the reaction mixture was poured into water and extracted three times with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1), and partitioned with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was concentrated to give the title compound (254 mg).
¹ H-NMR (CDCl ₃ ) 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, 2.0 Hz) 7.34 (1H, d, J = 8.8 Hz), 7.60 (1H, br.s), 9.54 (1H, br.s).

[Reference Example 341] (5-Chlorothien-3-yl) methanol

5-Chlorothiophene-3-carboxylic acid (Monatsh. Chem., 1989, 120 卷, p. 53) (6.93 g) was dissolved in tetrahydrofuran (750 ml), triethylamine (27.3 ml), ethyl chloroformate ( 18.7 ml) was added and stirred at room temperature for 2.5 hours. Further, an aqueous solution (41 ml) of sodium borohydride (19.3 g) was added dropwise over 10 minutes, and then stirred at room temperature for 18.5 hours. Acetic acid was added to the reaction solution to make it acidic, and then the solvent was distilled off under reduced pressure. Water and methylene chloride were added to the residue, and after separation, the organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (acetic acid ethyl ester: hexane = 1: 4) to obtain the title compound (5.17 g).
¹ H-NMR (CDCl ₃ ) δ: 1.63 (1H, t, J = 5.8 Hz), 4.59 (2H, d, J = 5.3 Hz), 6.91 (1H, d, J = 1.7 Hz), 6.98-6.99 (1 H, m).

[Reference Example 342] 5-Chlorothiophene-3-carbaldehyde

The compound (5.17 g) obtained in Reference Example 341 was dissolved in methylene chloride (400 ml), manganese dioxide (51.3 g) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure to give the title compound (2.84 g).
¹ H-NMR (CDCl ₃ ) δ: 7.35 (1H, d, J = 1.7 Hz), 7.88 (1H, d, J = 1.7 Hz), 9.75 (1H, s).

[Reference Example 343] 2-Azido-3- (5-chlorothien-3-yl) acrylic acid ethyl ester

Ethanol (15 ml) was added to a 20% sodium ethoxide ethanol solution (10.7 ml), cooled to 0 ° C., and then the compound obtained in Reference Example 342 (1.01 g) and azidoacetic acid ethyl ester (3.55 g). The mixture was added dropwise over 30 minutes and stirred at 0 ° C. for 3 hours. A cold aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with diethyl ether. The organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (acetic acid ethyl ester: hexane = 1: 49) to obtain the title compound (1.04 g).
¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.1 Hz), 4.34 (2H, q, J = 7.1 Hz), 6.75 (1H, s), 7 .39 (1H, d, J = 1.7 Hz), 7.54 (1H, d, J = 1.7 Hz).

[Reference Example 344] 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid ethyl ester

The compound (0.97 g) obtained in Reference Example 343 was dissolved in xylene (20 ml) and heated to reflux for 30 minutes. After allowing to cool, the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the resulting solid was collected by filtration to give the title compound (0.608 g).
¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.0 Hz), 4.35 (2H, q, J = 7.0 Hz), 6.90 (1H, s), 7 .00 (1H, d, J = 1.9 Hz), 9.32 (1H, br).

[Reference Example 345] 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 344.
¹ H-NMR (CD ₃ OD) 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-dibromovinyl) benzene

4-Chlorobenzaldehyde (2.81 g) was dissolved in methylene chloride (300 ml), carbon tetrabromide (13.3 g) and triphenylphosphine (21.0 g) were added, and the mixture was stirred at room temperature for 90 minutes. The precipitated insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the title compound (5.54 g).
¹ H-NMR (CDCl ₃ ) δ: 7.33 (2H, d, J = 8.5 Hz), 7.43 (1H, s), 7.47 (2H, d, J = 8.5 Hz).
MS (EI) m / z: 296 (M ^<+> ).

[Reference Example 347] 3- (4-Chlorophenyl) -2-propiolic acid

The compound (1.0 g) obtained in Reference Example 346 was dissolved in tetrahydrofuran (30 ml), and n-butyllithium (1.59 N hexane solution, 4.46 ml) was added dropwise at −78 ° C. under an argon stream. The reaction was warmed to room temperature and stirred for 1 hour. The reaction solution was cooled again to −78 ° C., stirred for 2 minutes in a carbon dioxide gas stream, and then warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and then saturated brine and ethyl acetate were added to the residue for separation. 3N Hydrochloric acid was added to the aqueous layer to make it acidic, and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (453 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 7.55 (2H, d, J = 8.5 Hz), 7.66 (2H, d, J = 8.5 Hz), 13.90 (1H, br. s).
MS (EI) m / z: 180 (M ^<+> ).

[Reference Example 348] 6-Chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylic acid ethyl ester

To a solution of 2-amino-5-chlorobenzamide (2.50 g) in pyridine (15 ml) was added oxoacetic acid ethyl ester (2.0 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in acetic acid (50 ml), acetic anhydride (5.0 ml) was added, and the mixture was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure, ethanol was added to the residue, and the precipitated crystals were collected by filtration and washed to give the title compound (2.71 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 (3H, t, J = 7.1 Hz), 4.38 (2H, q, J = 7.1 Hz), 7.85 (1H, d, J = 8.6 Hz), 7.91 (1H, dd, J = 8.6, 2.3 Hz), 8.10 (1H, d, J = 2.3 Hz), 12.85 (1H, br.s) ).
MS (ESI) m / z: 253 (M + H) ^<+> .

[Reference Example 349] 6-chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylic acid

Lithium hydroxide (263 mg) was added to a mixed solution of the compound (1.26 g) obtained in Reference Example 348 in water (5 ml) -tetrahydrofuran (15 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized with 1N hydrochloric acid (11 ml) under ice cooling and stirred for 1 hour. The precipitated crystals were collected by filtration and washed with water to give the title compound (0.96 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.50-8.20 (3H, m), 12.44 (1H, br.s).
MS (ESI) m / z: 265 (M + H + CH 3 CN) +.

[Reference Example 350] 2-Chloro-N- (4-chlorophenyl) acetamide

p-Chloroaniline (3.82 g) was dissolved in acetic acid ethyl ester (30 ml), chloroacetyl chloride (2.39 ml) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was heated and stirred at 60 ° C. for 3.5 hours, and the precipitated crystals were collected by filtration to give the title compound (4.78 g). Further, the filtrate was concentrated to about 1/4, and the precipitated crystals were collected by filtration to obtain the title compound (1.01 g).
¹ H-NMR (CDCl ₃ ) δ: 4.19 (2H, s), 7.33 (2H, d, J = 9.0 Hz), 7.51 (2H, d, J = 9.0 Hz), 8 .22 (1H, br.s).

[Reference Example 351] S- [2- (4-Chloroanilino) -2-oxoethyl] thiosulfate sodium salt

The compound (5.79 g) obtained in Reference Example 350 was dissolved in ethanol (140 ml), and an aqueous solution (140 ml) of sodium thiosulfate pentahydrate (7.04 g) was added all at once at 70 ° C. with stirring. Heated to reflux for 5 hours. The reaction mixture was concentrated to about 1/10, and the precipitated powder was collected by filtration to give the title compound (8.20 g).
¹ H-NMR (DMSO-d ₆ ) δ: 3.73 (2H, s), 7.35 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz) , 10.30 (1H, s).

[Reference Example 352] 2-Chloro-N- (5-chloropyridin-2-yl) acetamide hydrochloride

2-Amino-5-chloropyridine (3.85 g) was dissolved in ethyl acetate (60 ml), chloroacetyl chloride (2.39 ml) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was heated and stirred at 60 ° C. for 30 minutes, chloroacetyl chloride (0.5 ml) was added, and the mixture was further stirred at 60 ° C. for 1 hour. The precipitated powder was collected by filtration to obtain the title compound (6.18 g).
¹ H-NMR (DMSO-d ₆ ) δ: 4.36 (2H, s), 7.94 (1H, dd, J = 8.8, 2.7 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.40 (1 H, d, J = 2.7 Hz), 11.03 (1 H, s).

[Reference Example 353] S- {2-[(5-chloropyridin-2-yl) amino] -2-oxoethyl} thiosulfate sodium salt

To a solution of the compound obtained in Reference Example 352 (6.18 g) in ethanol (130 ml), sodium thiosulfate pentahydrate (6.35 g) and sodium hydrogen carbonate (2.15 g) were stirred at 80 ° C. Aqueous solution (130 ml) was added all at once and heated under reflux at an external temperature of 110 ° C. for 2 hours. The mixture was concentrated to dryness under reduced pressure, ethanol (500 ml) was added to the residue, heated and extracted twice. The extract was concentrated to about 1/20, diethyl ether was added, and the precipitated insoluble material was collected by filtration to obtain the title compound (6.65 g).
¹ H-NMR (DMSO-d ₆ ) δ: 3.77 (2H, s), 7.89 (1H, dd, J = 9.0, 2.7 Hz), 8.09 (1H, d, J = 9.0 Hz), 8.34 (1 H, d, J = 2.7 Hz), 10.57 (1 H, s).

[Reference Example 354] N-{(1R, 2S, 5S) -2-[(2-chloroacetyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (100 mg) obtained in Reference Example 253 was dissolved in ethyl acetate (10 ml), chloroacetyl chloride (21.6 μl) was added, and the mixture was stirred with heating at 60 ° C. for 30 min. After allowing to cool, the insoluble material was collected by filtration and dissolved in methylene chloride-methanol, and the solvent was evaporated under reduced pressure to give the crude title compound (112 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.50 (1H, m), 1.55 to 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 = 12.9 Hz), 4.00-4.15 (1 H, m), 4.02 (1 H, d, J = 12.9 Hz), 4.45-4, 70 (2 H, m), 7.85. −8.00 (1H, br), 8.12 (1H, d, J = 7.3 Hz), 8.35 (1H, d, J = 8.3 Hz).
MS (ESI) m / z: 442 (M + H) ^<+> .

[Reference Example 355] S- {2-[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo) [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] -2-oxoethyl} thiosulfate sodium salt

An aqueous solution in which the compound (106 mg) obtained in Reference Example 354 was dissolved in ethanol (1.5 ml) and sodium thiosulfate pentahydrate (55 mg) and sodium hydrogen carbonate (18.6 mg) were dissolved at 90 ° C. with stirring. (1.5 ml) was added all at once and heated to reflux for 1 hour. The mixture was concentrated to dryness under reduced pressure, ethanol (10 ml) was added to the residue, and extraction was performed during heating. The extract was concentrated to about ½, isopropyl ether (10 ml) was added, and the precipitated insoluble material was collected by filtration to give the title compound (72 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 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 = 14.2 Hz), 3.50 (1H, d , J = 14.2 Hz), 3.68 (2H, s), 3.75-3.90 (1H, m), 4.45-4.50 (1H, m), 8.01 (1H, d) , J = 7.4 Hz), 8.15 (1H, d, J = 8.3 Hz).

[Reference Example 356] 2-[(5-chlorothien-2-yl) amino] -2-oxoacetic acid methyl ester

Triethylamine (1.25 ml) and diphenylphosphoryl azide (1.55 ml) were added to a suspension of 5-chlorothiophene-2-carboxylic acid (0.99 g) in toluene (20 ml), and the mixture was stirred at 80 ° C. for 1 hour. . The reaction mixture was cooled to room temperature, tert-butanol (2 ml) was added, and the mixture was heated to reflux for 19 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride (200 ml) was added to the resulting residue, and the mixture was washed successively with distilled water, 10% aqueous citric acid solution, distilled water, saturated aqueous sodium bicarbonate solution and saturated brine, and then anhydrous sodium sulfate. And dried. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 5-chloro-2-thienylcarbamic acid tert-butyl ester (1.05 g). .
¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 6.21 (1H, d, J = 3.1 Hz), 6.60 (1H, d, J = 3.1 Hz), 6 .91 (1H, br.s).
MS (ESI) m / z: 234 (M + H) ^<+> .
The above product (1.87 g) was added to 4N dioxane hydrochloride solution (40 ml) and stirred at room temperature for 4 hours, and then the solvent was evaporated under reduced pressure. The residue was suspended in tetrahydrofuran (50 ml), sodium hydrogen carbonate (2.02 g) and chlorooxoacetic acid methyl ester (0.883 ml) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and water and methylene chloride were added to the residue for liquid separation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 3: 1), and the solvent was distilled off to obtain the title compound (1.44 g).
¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 6.61 (1H, d, J = 4.2 Hz), 6.75 (1H, d, J = 4.2 Hz), 9 .42 (1H, br.s).
MS (FAB) m / z: 220 (M + H) ^<+> .

[Reference Example 357] 2-[(5-Fluoropyridin-2-yl) amino] -2-oxoacetic acid methyl ester

In the same manner as in Reference Example 242, the title compound was obtained from 2-amino-5-fluoropyridine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.48-7.53 (1H, m), 8.21 (1H, d, J = 2.9 Hz), 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 ester

In the same manner as described in Reference Example 242, the title compound was obtained from 4-chloro-2-trifluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 4.01 (3H, s), 7.58 (1H, dd, J = 8.8, 2.2 Hz), 7.65 (1H, d, J = 2. 2 Hz), 8.34 (1 H, d, J = 8.8 Hz), 9.30 (1 H, br. S).
MS (EI) m / z: 281 (M + H) ^<+> .

[Reference Example 359] 2- [4-Chloro-2- (trifluoromethyl) anilino] -2-oxoacetic acid

Lithium hydroxide (28 mg) was added to a mixed solution of the compound obtained in Reference Example 358 (297 mg) in tetrahydrofuran (7 ml) -water (3 ml), and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (8 ml) and methylene chloride (20 ml) were added to the reaction solvent, and a liquid separation operation was performed. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure and dried to obtain the title compound (291 mg).
¹ H-NMR (CDCl ₃ ) δ: 7.61 (1H, dd, J = 8.8, 2.5 Hz), 7.68 (1H, d, J = 2.5 Hz), 8.26 (1H, d, J = 8.8 Hz), 9.36 (1H, br.s).
MS (ESI, anion) m / z: 267 (M-H) ^- .

[Reference Example 360] 5-Chloro-N, N-dimethyl-2-nitrobenzamide

5-Chloro-2-nitrobenzoic acid and dimethylamine were condensed in the same manner as in Reference Example 143 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 2.86 (3H, s), 3.16 (3H, s), 7.38 (1H, d, J = 2.2 Hz), 7.51 (1H, dd , J = 8.8, 2.2 Hz), 8.15 (1H, d, J = 8.8 Hz).

[Reference Example 361] 2-Amino-5-chloro-N, N-dimethylbenzamide

To a mixed solution of the compound obtained in Reference Example 360 (2.8 g) in N, N-dimethylformamide (80 ml) -water (40 ml), iron (III) chloride hexahydrate (9.93 g), zinc dust (8 .01 g) was added and heated to reflux for 20 minutes. The reaction solution was filtered through Celite 545, ethyl acetate (200 ml) was added to the filtrate, and a liquid separation operation was performed. The aqueous layer was washed with acetic acid ethyl ester (100 ml × 2), and the combined organic layers were washed with distilled water (100 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (methylene chloride: hexane = 1: 1 → 1: 0 → methanol: methylene chloride = 1: 100) to give the title compound (2 .41 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.13 (6H, s), 4.33 (2H, br), 6.65 (1H, d, J = 8.5 Hz), 7.07 (1H, d , J = 2.2 Hz), 7.11 (1H, dd, J = 8.5, 2.2 Hz).
MS (ESI) m / z: 240 (M + MeCN) ^<+> .

[Reference Example 362] 2- {4-Chloro-2-[(dimethylamino) carbonyl] anilino} -2-oxoacetic acid methyl ester

In the same manner as in the method described in Reference Example 242, the title compound was obtained from the compound obtained in Reference Example 361 and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.09 (6H, br), 3.96 (3H, s), 7.30 (1H, d, J = 2.4 Hz), 7.41 (1H, d , J = 8.8, 2.4 Hz), 8.34 (1H, d, J = 8.8 Hz), 10.46 (1H, br).
MS (ESI) m / z: 285 (M + H) ^<+> .

[Reference Example 363] 4-Chloro-2-methoxyaniline

The title compound was obtained from 5-chloro-2-nitroanisole in the same manner as described in Reference Example 361.
¹ H-NMR (CDCl ₃ ) δ: 3.65-3.95 (2H, br), 3.87 (3H, s), 6.61 (1H, d, J = 8.8 Hz), 6.74 -6.78 (2H, m).
MS (ESI) m / z: 199 (M + MeCN + H) ^<+> .

[Reference Example 364] 2- (4-Chloro-2-methoxyanilino) -2-oxoacetic acid methyl ester

In the same manner as in the method described in Reference Example 242, the title compound was obtained from the compound obtained in Reference Example 363 and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.92 (3H, s), 3.97 (3H, s), 6.90 (1H, d, J = 2.2 Hz), 6.98 (1H, dd , J = 8.8, 2.2 Hz), 8.35 (1H, d, J = 8.8 Hz), 9.33-9.44 (1H, br).
MS (ESI) m / z: 244 (M + H) ^<+> .

[Reference Example 365] 2- (4-Chloroanilino) -2- (hydroxyimino) acetic acid ethyl ester

In the same manner as described in the literature (Gilchrist, TL; Peek, ME; Rees, CW; J. Chem. Soc. Chem. Commun., 1975, 913.), 4-chloro The title compound was obtained from aniline (3.03 g) and 2-chloro-2-hydroxyiminoacetic acid ethyl ester.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.60-1.80 (1H, br), 4.28 (2H, q, J = 7. 1 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.24 (2H, d, J = 8.6 Hz), 8.15-8.45 (1H, br).
MS (ESI) m / z: 243 (M + H) ^<+> .

[Reference Example 366] (1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2- (hydroxyimino) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert- Butyl ester

The compound (597 mg) obtained in Reference Example 144 was added to an ethanol (5.0 ml) solution of the compound (350 mg) obtained in Reference Example 365 and stirred at 70 ° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1) to give the title compound (180 mg).
¹ H-NMR (CD ₃ OD) 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 = 8.8 Hz), 7.18 (2H, d, J = 8.8 Hz).
MS (ESI) m / z: 504 (M + Na) ^<+> .

[Reference Example 367] (3R, 4S) -4-{[2- (4-Chloroanilino) -2-oxoacetyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 374 and the compound obtained in Reference Example 220 in the same manner as in the method described in Reference Example 214.
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -1- (2-methoxyacetyl) piperidine-3 -Ilcarbamic acid tert-butyl ester

From the compound obtained in Reference Example 266 and the compound obtained in Reference Example 220, the title compound was obtained in the same manner as in the method described in Reference Example 214.
¹ H-NMR (CDCl ₃ ) 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 = 8.7 Hz) ), 7.95-8.05 (0.3 H, br), 8.19 (1 H, br d, J = 8.8 Hz), 8.31 (1 H, 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-bromopyridin-2-yl) amino] -2-oxoacetyl} amino) -1- (2-methoxyacetyl) piperidine-3 -Ilcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 375 and the compound obtained in Reference Example 220 in the same manner as in the method described in Reference Example 214.
¹ H-NMR (CDCl ₃ ) 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, 2.2 Hz), 8.16 (1H, d, J = 8.8 Hz), 8. 30-8.55 (1H, br), 8.40 (1H, d, J = 2.2 Hz), 9.68 (1H, br. S).

[Reference Example 370] 3- (4-Chloroanilino) -3-oxopropionic acid ethyl ester

To a solution of 4-chloroaniline (2.0 g) in N, N-dimethylformamide (20 ml) at room temperature, ethyl potassium malonate (3.2 g), 1-hydroxybenzotriazole (2.1 g), and 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.5 g) was sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.0 g).
¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.3 Hz), 3.47 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 7 .29 (2H, d, J = 8.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 9.32 (1H, br.s).

[Reference Example 371] 3- (4-Chloroanilino) -3-oxopropionic acid

To a solution of the compound obtained in Reference Example 370 (1.0 g) in ethanol (10 ml) was added dropwise 1N aqueous sodium hydroxide solution (10 ml) at room temperature, and the mixture was stirred for 2 hours. A 1N aqueous hydrochloric acid solution (10 ml) was added to the reaction mixture, and after stirring, the precipitated insoluble material was collected by filtration to give the title compound (0.5 g).
¹ H-NMR (DMSO-d ₆ ) δ: 3.34 (2H, s), 7.35 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz) , 10.26 (1H, s), 12.66 (1H, br. S).

[Reference Example 372] 3- (3-Chloroanilino) -3-oxopropionic acid ethyl ester

In the same manner as described in Reference Example 370, the title compound was obtained by condensing 3-chloroaniline and ethyl potassium malonate.
¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.3 Hz), 3.47 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 7 .09 (1H, d, J = 8.8 Hz), 7.22-7.26 (1H, m), 7.39 (1H, d, J = 8.8 Hz), 7.69 (1H, s) , 9.35 (1H, br. S).

[Reference Example 373] 3- (3-Chloroanilino) -3-oxopropionic acid

In the same manner as described in Reference Example 371, the title compound was obtained from the compound obtained in Reference Example 372.
¹ H-NMR (DMSO-d ₆ ) δ: 3.35 (2H, s), 7.11 (1H, d, J = 8.8 Hz), 7.33 (1H, t, J = 8.8 Hz) 7.39 (1H, d, J = 8.8 Hz), 7.78 (1 H, s), 10.31 (1 H, s), 12.67 (1 H, br. S).

[Reference Example 374] 2- (4-Chloroanilino) -2-oxoacetic acid

In the same manner as in the method described in Reference Example 359, the title compound was obtained from the compound obtained in Reference Example 242.
¹ H-NMR (DMSO-d ₆ ) δ: 7.37 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 10.66 (1H, s) .

[Reference Example 375] 2-[(5-Bromopyridin-2-yl) amino] -2-oxoacetic acid

In the same manner as in Reference Example 359, the title compound was obtained from the compound obtained in Reference Example 262.
¹ H-NMR (DMSO-d ₆ ) δ: 7.95-8.00 (1H, m), 8.08 (1H, dd, J = 8.8, 2.0 Hz), 8.50 (1H, d, J = 2.0 Hz), 10.74
(1H, s).

[Reference Example 376] 4-Chloro-3-fluorobenzoic acid

To a mixed solution of 4-chloro-3-fluorobenzaldehyde (10 g), amidosulfuric acid (18 g), tert-butyl alcohol (50 ml), and water (50 ml), sodium chlorite (17 g) was added in small portions under ice-cooling. The mixture was stirred for 4 days while gradually returning to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water, 1N aqueous hydrochloric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from a mixed solvent consisting of diisopropyl ether and hexane to obtain the title compound (11.2 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.72 (1H, dt, J = 8.3, 1.5 Hz), 7.77 (1H, dt, J = 8.3, 1.6 Hz), 7.82 (1H, dt, J = 9.7, 1.5 Hz), 13.45 (1H, s).

[Reference Example 377] 2- (4-Chloro-3-fluoroanilino) -2-oxoacetic acid methyl ester

In the same manner as in Reference Example 356, the compound obtained in Reference Example 376 was subjected to a Curtius rearrangement reaction and then condensed with chlorooxoacetic acid methyl ester to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.25-7.27 (1H, m), 7.39 (1H, t, J = 8.5 Hz), 7.72 (1H, dd, J = 10.4, 2.4 Hz), 8.90 (1H, br.s).

[Reference Example 378] 2- (4-Chloro-3-fluoroanilino) -2-oxoacetic acid

In the same manner as in Reference Example 359, the title compound was obtained from the compound obtained in Reference Example 377.
¹ H-NMR (DMSO-d ₆ ) δ: 7.52 (1H, t, J = 8.8 Hz), 7.63 (1H, dd, J = 8.8, 2.2 Hz), 7.88 ( 1H, dd, J = 12.0, 2.2 Hz), 10.83 (1H, br.s).

[Reference Example 379] 3- (4-Chlorophenyl) -3-oxopropionic acid ethyl ester

To a suspension of ethyl potassium malonate (8.2 g) in ethyl acetate (100 ml) were added triethylamine (17 ml) and magnesium chloride (5.5 g) under ice cooling, and the mixture was stirred for 18 hours while gradually returning to room temperature. On the other hand, a suspension of 4-chlorobenzoic acid (5.0 g), thionyl chloride (12 ml), N, N-dimethylformamide (1 drop), and toluene (100 ml) was heated to reflux for 1 hour, and then reacted. The liquid was concentrated. The obtained residue was dissolved in ethyl acetate, added dropwise to the reaction solution under ice cooling, and stirred for 18 hours while gradually returning to room temperature. A 10% aqueous citric acid solution was added to the reaction solution, and after stirring for 30 minutes, the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (6.4 g).
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 3.96 (2H, s), 4.21 (2H, q, J = 7.3 Hz), 7 .46 (2H, d, J = 8.8 Hz), 7.89 (2H, d, J = 8.8 Hz).

[Reference Example 380] 3- (4-Chlorophenyl) -3-hydroxypropionic acid ethyl ester

To a solution of the compound (1.0 g) obtained in Reference Example 379 in tetrahydrofuran (10 ml) was added sodium borohydride (0.2 g) little by little under ice cooling, and the mixture was stirred for 2 hours while gradually returning to room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (0.56 g).
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.70 (1H, d, J = 7.8 Hz), 2.71 (1H, d, J = 3.4 Hz), 3.37 (1 H, d, J = 3.4 Hz), 4.18 (2 H, q, J = 7.3 Hz), 5.09-5.13 (1 H, m), 7. 30-7.35 (5H, m).

[Reference Example 381] 3- (4-Chlorophenyl) -3-hydroxypropionic acid

In the same manner as in Reference Example 359, the title compound was obtained from the compound obtained in Reference Example 380.
¹ H-NMR (DMSO-d ₆ ) 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 (MH) ^- .

[Reference Example 382] (1R, 2S, 5S) -2-{[3- (4-Chlorophenyl) -3-hydroxypropanoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 91, the title compound was obtained by condensing the compound obtained in Reference Example 144 and the compound obtained in Reference Example 381.
¹ H-NMR (CDCl ₃ ) 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-Chlorophenyl) -3-oxopropanoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

To a 1,4-dioxane (20 ml) solution of the compound (0.5 g) obtained in Reference Example 382, manganese dioxide (0.47 g) was added at room temperature and stirred for 4 days. Insoluble material was removed by filtration through a Celite pad, and the obtained filtrate was concentrated under reduced pressure to give the title compound (0.46 g).
¹ H-NMR (DMSO-d ₆ ) 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, 1.7 Hz).
MS (ESI, anion) m / z: 464 (MH) ^- .

[Reference Example 384] (1S, 3R, 4R) -4-azido-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester

In the same manner as in Reference Example 249, the title compound was obtained from the compound obtained in Reference Example 248.
[Α] _D ²⁵ + 62 ° (c = 1, chloroform)
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz), 4.58 (1H, br.s),

[Reference Example 385] (1R, 2R, 5S) -2-azido-5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 250 and Reference Example 251, the title compound was obtained from the compound obtained in Reference Example 384.
¹ H-NMR (CDCl ₃ ) 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) .2 Hz).

[Reference Example 386] (1R, 2R, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(dimethylamino) carbonyl] Cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 90, the azide group of the compound obtained in Reference Example 385 was converted to an amino group, and then obtained in Reference Example 266 in the same manner as described in Reference Example 91. Condensation with the compound gave the title compound.
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 8 .03 (1H, br.s), 8.21 (1H, d, J = 8.8 Hz), 8.29 (1H, d, J = 2.4 Hz), 9.71 (1H, s).
MS (ESI) m / z: 468 (M + H) ^<+> .

[Reference Example 387] N-{(1R, 2R, 5S) -2-azido-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridine-2-carboxamide

In the same manner as in Reference Example 252, the title compound was obtained from the compound obtained in Reference Example 385 and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) 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-Methoxy-2-oxoacetyl) amino] piperidine-1-carboxylic acid tert-butyl ester

In the same manner as in the method described in Reference Example 242, the title compound was obtained from (4-amino-N-tert-butoxycarbonyl) piperidine and chlorooxoacetic acid methyl ester. ¹ H-NMR (DMSO-d ₆ ) 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-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl } Amino) -2-oxoacetyl] amino} piperidine-1-carboxylic acid tert-butyl ester

In the same manner as in the method described in Example 191, the title compound was obtained from the compound obtained in Reference Example 310 and the compound obtained in Reference Example 388.
¹ H-NMR (DMSO-d ₆ ) 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-chloropyridin-2-yl) (methyl) amino] -2-oxoacetic acid methyl ester

In the same manner as in Reference Example 242, the title compound was obtained from 5-chloro-N-methyl-2-pyridinamine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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-[(5-Chloro-pyrimidin-2-yl) amino] -2-oxoacetic acid methyl ester

In the same manner as described in Reference Example 242, the title compound was obtained from 2-amino-5-chloropyrimidine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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-azido-5-{[ethyl (methyl) amino] carbonyl} cyclohexyl) -5-methyl-5,6-dihydro-4H-pyrrolo [3 , 4-d] thiazole-2-carboxamide

In the same manner as in the method described in Reference Example 252, the title compound was obtained from the compound obtained in Reference Example 323 and the compound obtained in Reference Example 293.
¹ H-NMR (CDCl ₃ ) δ: 1.08, 1.15 (3H, each t, J = 7.1 Hz), 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, 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 = 7.6 Hz).
MS (ESI) m / z: 392 (M + H) ^<+> .

[Reference Example 393] 2- (4-Chloro-3-methoxyanilino) -2-oxoacetic acid methyl ester

In the same manner as described in Reference Example 361, 2-chloro-5-nitroanisole was reduced to obtain an amino compound, and then condensed with chlorooxoacetic acid methyl ester in the same manner as described in Reference Example 242. The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 3.98 (3H, s), 7.00 (1H, dd, J = 8.5, 2.4 Hz), 7.33 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 2.4 Hz), 8.89 (1H, br.s).

[Reference Example 394] 2- (4-Chloro-3-methoxyanilino) -2-oxoacetic acid

The title compound was obtained by hydrolyzing the compound obtained in Reference Example 393 in the same manner as described in Reference Example 359.
¹ H-NMR (DMSO-d ₆ ) δ: 3.81 (3H, s), 7.36 (1H, d, J = 8.7 Hz), 7.43 (1H, d, J = 8.7 Hz) , 7.65 (1H, d, J = 2.2 Hz), 10.79 (1H, s).
MS (ESI, anion) m / z: 228 (M−H) ⁻ .

[Reference Example ^{395] N 1 - {(1S} , 2R, 4S) -2- amino-4 - [(dimethylamino) carbonyl] cyclohexyl} -N ² - (4-chloro-3-methoxyphenyl) ethanediamide

In the same manner as described in Reference Example 97, the compound obtained in Reference Example 144 and the compound obtained in Reference Example 394 were condensed, and then treated with hydrochloric acid in the same manner as described in Reference Example 69. The title compound was obtained by neutralization with aqueous sodium hydroxide.
¹ H-NMR (CDCl ₃ ) 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, 2.2 Hz), 7 .32 (1H, d, J = 8.5 Hz), 7.56 (1H, d, J = 2.2 Hz), 8.05 (1H, d, J = 8.5 Hz), 9.43 (1H, br.s).
MS (ESI) m / z: 397 (M ^<+> ).

[Reference Example 396] 2- (4-Ethynylanilino) -2-oxoacetic acid methyl ester

In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-ethynylaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.09 (1H, s), 3.98 (3H, s), 7.50 (2H, d, J = 8.4 Hz), 7.62 (2H, d , J = 8.4 Hz), 8.89 (1H, br.s).

[Reference Example 397] 2- (4-Ethynylanilino) -2-oxoacetic acid sodium salt

The title compound was obtained by hydrolyzing the compound obtained in Reference Example 396 with sodium hydroxide in the same manner as described in Reference Example 266.
¹ H-NMR (DMSO-d ₆ ) δ: 4.06 (1H, s), 7.39 (2H, d, J = 8.4 Hz), 7.80 (2H, d, J = 8.4 Hz) , 10.33 (1H, br.s).

[Reference Example 398] 2-[(5-Chloropyrazin-2-yl) amino] -2-oxoacetic acid methyl ester

2-amino-5-chloropyrazine and chlorooxo synthesized according to the literature (Sato, Nobuhiro et al., J. Heterocycl. Chem. 1982, 19 (3), 673-4) in the same manner as described in Reference Example 242. The title compound was obtained from acetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 4.02 (3H, s), 8.35 (1H, d, J = 1.5 Hz), 9.37 (1H, d, J = 1.5 Hz), 9 .41 (1H, br.s).
MS (FAB) m / z: 216 (M + H) ^<+> .

[Reference Example 399] 2-[(5-Chloropyrazin-2-yl) amino] -2-oxoacetic acid

In the same manner as in the method described in Reference Example 359, the title compound was obtained from the compound obtained in Reference Example 398.
¹ H-NMR (DMSO-d ₆ ) δ: 8.62 (1H, s), 9.02 (1H, br. S), 11.30 (1H, s).
MS (EI) m / z: 201 M ⁺ .

[Reference Example 400] 2- (4-Chloro-3-nitroanilino) -2-oxoacetic acid

In the same manner as described in Reference Example 242, 4-chloro-3-nitroaniline and chlorooxoacetic acid methyl ester were condensed and then hydrolyzed in the same manner as described in Reference Example 359 to obtain the title compound. .
¹ H-NMR (DMSO-d ₆ ) δ: 7.76 (1H, dd, J = 8.8 Hz), 8.04 (1H, dd, J = 8.8, 2.4 Hz), 8.55 ( 1H, d, J = 2.4 Hz), 11.24 (1H, s). The proton of carboxylic acid is not visible.
MS (EI) m / z: 244M ^<+> .

[Reference Example 401] 2- (4-Chloro-2-nitroanilino) -2-oxoacetic acid sodium salt

In the same manner as described in Reference Example 242, 4-chloro-2-nitroaniline and chlorooxoacetic acid methyl ester were condensed and then hydrolyzed in the same manner as described in Reference Example 266. The title compound was obtained by dissolving in methanol, adding 1N aqueous sodium hydroxide solution and collecting the resulting precipitate by filtration.
¹ H-NMR (DMSO-d ₆ ) δ: 7.84 (1H, dd, J = 9.0, 2.5 Hz), 8.20 (1H, d, J = 2.5 Hz), 8.67 ( 1H, d, J = 9.0 Hz), 11.89 (1H, s).

[Reference Example 402] 6-Chloro-4-methyl-3-pyridinamine

2-Chloro-4-methyl-5-nitropyridine (173 mg) was dissolved in ethanol (5 ml), a catalytic amount of Raney nickel was added, and the mixture was stirred at room temperature for 9 hours in a hydrogen atmosphere. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give the title compound (113 mg).
¹ H-NMR (CDCl ₃ ) 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] N ¹ - (2- aminophenyl) -N ² - (4-chlorophenyl) ethanediamide

In the same manner as described in Reference Example 59, 1,2-benzenediamine and the compound obtained in Reference Example 374 were condensed to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 5.00 (2H, s), 6.59-6.63 (1H, m), 6.78 (1H, dd, J = 8.1, 1. 2 Hz), 6.96-7.01 (1 H, m), 7.25 (1 H, dd, J = 7.8, 1.2 Hz), 7.44 (2 H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 10.04 (1H, s), 10.91 (1H, s).
MS (FAB): 290 (M + H) ^<+> .

[Reference Example 404] N-((1R, 2S, 5S) -2-azido-5-{[ethyl (methyl) amino] carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

In the same manner as described in Reference Example 252, the compound obtained in Reference Example 323 was treated with hydrochloric acid, deprotected, and condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.08 (1/2 of 3H, t, J = 7.2 Hz), 1.14 (1/2 of 3H, t, J = 7.2 Hz), 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 (1 H, d, J = 13.4 Hz), 3.73 (1 H, d, J = 13.4 Hz), 3.87-3.95 (1 H, m ), 4.55-4.62 (1H, m), 7.26 (1H, d, J = 7.6 Hz).

[Reference Example 405] 2- (4-Chlorophenyl) -1-hydrazinecarboxylic acid phenyl ester

(4-Chlorophenyl) hydrazine hydrochloride (3.00 g) is dissolved in tetrahydrofuran (50 ml), diethyl ether (50 ml) and saturated aqueous sodium hydrogen carbonate solution, the organic layer is separated, dried over anhydrous sodium sulfate and concentrated. Gave (4-chlorophenyl) hydrazine as a brown solid. This was dissolved in benzene (15 ml) and then heated to reflux, and a solution of diphenyl carbonate (5.22 g) in benzene (8.0 ml) was added dropwise over 30 minutes. After refluxing for 19 hours, allowing to cool to room temperature, concentrating, adding benzene (15 ml), suspending with ultrasonic waves, adding hexane (50 ml), stirring for 30 minutes, filtering insolubles, drying, title compound (1.05 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 5.86 (1H, br.s), 6.83-6.92 (3H, m), 7.17 (1H, br.s), 7.20-7 .32 (4H, m), 7.37 (2H, t, J = 7.7 Hz).
MS (ESI) m / z: 263 (M + H) ^<+> .

[Reference Example 406] Lithium salt of 5-tert-butoxycarbonyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxylic acid

In the same manner as described in Reference Example 10, the title compound was obtained from the compound obtained in Reference Example 33.
¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (9H, s), 4.30-4.70 (4H, m).

[Reference Example 407] 1-hydroxycyclopropanecarboxylic acid benzyl ester

Triethylamine (1.0 ml) and benzyl bromide (650 μl) were added to a solution of 1-hydroxycyclopropanecarboxylic acid (409 mg) in tetrahydrofuran (3.0 ml), and the mixture was stirred at room temperature for 23 hours. Methylene chloride and 1N aqueous hydrochloric acid were added to the reaction solution to form two layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (607 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.16 (2H, dd, J = 7.9, 4.9 Hz), 1.32 (2H, dd, J = 7.9, 4.9 Hz), 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-methoxycyclopropanecarboxylic acid benzyl ester

60% oily sodium hydride (345 mg) and methyl iodide (900 μl) were added to a solution of the compound (600 mg) obtained in Reference Example 407 in tetrahydrofuran (5.0 ml), and the mixture was refluxed for 28 hours. Acetic acid ethyl ester and saturated aqueous ammonium chloride solution were added to the reaction solution to form two layers. The organic layer was washed with saturated brine and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound (340 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.16 (2H, dd, J = 7.9, 4.8 Hz), 1.31 (2H, dd, J = 7.9, 4.8 Hz), 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-methoxycyclopropanecarboxylic acid

In the same manner as in Reference Example 152, the title compound was obtained from the compound obtained in Reference Example 408.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (2H, dd, J = 8.0, 4.9 Hz), 1.38 (2H, dd, J = 8.0, 4.9 Hz), 3. 45 (3H, s), 8.80-9.00 (1H, br).

[Reference Example 410] (3R, 4S) -4-{[(7-chloroisoquinolin-3-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

In the same manner as in the method described in Reference Example 214, the title compound was obtained from the compound obtained in Reference Example 220 and the compound obtained in Reference Example 57.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, brs), 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, 2.0 Hz), 7.94 (1H, d, J = 8.8 Hz), 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- (4-Chloro-3-fluoroanilino) -2-oxoacetyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl Carbamic acid tert-butyl ester

In the same manner as in Reference Example 214, the title compound was obtained by condensing the compound obtained in Reference Example 220 and the compound obtained in Reference Example 377.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.60-1.75 (1H, m), 1.92-2.08 (1H, m), 2.68-2 .80 (0.5 H, m), 2.88-3.03 (0.5 H, m), 3.06-3.24 (0.5 H, 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 = 12.9 Hz), 7.35 (1H, t, J = 8.3 Hz), 7.72 (1H, dd, J = 8.3, 2.3 Hz), 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-[(5-chloro-2-thienyl) amino] -2-oxoacetyl} amino) -1- (2-methoxyacetyl) piperidine-3- Illcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 214, the title compound was obtained from the lithium salt of carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 220 and the compound obtained in Reference Example 356.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.55-1.75 (1H, br), 1.90-2.10 (1H, br), 2.68-1 .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 = 3.9 Hz), 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 [3,4-d] thiazolo-2-carboxylic acid ethyl ester

1) 2-Thioxoacetic acid ethyl ester (26.75 g) was added to a solution of 3-bromo-2-butanone (26.36 g) in ethanol (250 ml), and the mixture was refluxed for 14 hours. The reaction mixture was cooled and concentrated under reduced pressure, and ethyl acetate and saturated brine were added to the residue to form two layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain 4,5-dimethylthiazole-2-carboxylic acid ethyl ester (19.53 g).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 2.42 (3H, s), 2.44 (3H, s), 4.45 (2H, q , J = 7.1 Hz).
2) N-bromosuccinimide (62.42 g) and 2,2′-azobisisobutyronitrile (227 mg) were added to a solution of the above product (19.53 g) in 1,2-dichloroethane (500 ml), Refluxed for 42 hours. After cooling the reaction mixture, water and methylene chloride were added to form two layers, and the organic layer was washed with saturated brine and concentrated under reduced pressure to give a crude product (40.54 g) as a dark brown oil. To an acetonitrile solution (400 ml) of the obtained crude product (8.41 g), triethylamine (8.0 ml) and 2 mol methylamine tetrahydrofuran solution (11.0 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and methylene chloride and saturated brine were added to the residue to form two layers. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (270 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.1 Hz), 3.91 (3H, s), 4.48 (2H, q, J = 7.1 Hz), 6 .73 (1H, d, J = 1.7 Hz), 7.30 (1H, d, J = 1.7 Hz).
MS (ESI) m / z: 211 (M + H) ^<+> .

[Reference Example 414] 6-Chloro-4-oxo-4H-chromene-2-carboxylic acid ethyl ester

Under argon substitution, oily about 60% sodium hydride (1.68 g) was added to ethanol (10 ml), and the mixture was stirred at room temperature for 10 minutes. After adding oxalic acid diethyl ester (3.36 ml), an ethanol solution (20 ml) of 5′-chloro-2′-hydroxyacetophenone (2.82 g) was added dropwise, and ethanol (40 ml) was added for 1 hour. The mixture was stirred at 50 ° C. for 14 hours at half reflux. Concentrated sulfuric acid (1.5 ml) and ethanol (10 ml) were added to the mixture, and the mixture was refluxed for 4 hours. After cooling, the solvent was reduced to half by concentration under reduced pressure, and toluene and 1N aqueous sodium hydroxide solution (15 ml) were added to the concentrated solution. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1). The obtained solid was washed with hexane to obtain the title compound (1.20 g).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.1 Hz), 4.47 (2H, q, J = 7.1 Hz), 7.12 (1H, s), 7 .58 (1H, d, J = 9.0 Hz), 7.69 (1H, dd, J = 9.0, 2.7 Hz), 8.16 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 293 (M + MeCN + H) ^<+> .

[Reference Example 415] 6-Chloro-4-oxo-4H-chromene-2-carboxylic acid

The title compound was obtained from the compound obtained in Reference Example 414 in a manner similar to that described in Reference Example 359.
¹ H-NMR (CDCl ₃ ) δ: 7.12 (1H, s), 7.60 (1H, d, J = 8.8 Hz), 7.69 (1H, dd, J = 8.8, 2. 7 Hz), 8.15 (1H, d, J = 2.7 Hz).
MS (FAB) m / z: 225 (M + H) ^<+> .

[Reference Example 416] (1S, 3R, 4S) -4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester

In the same manner as described in Reference Example 90, the title compound was obtained from the compound obtained in Reference Example 249.
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.80 (4H, m), 1.25 (3H, t, J = 7.3 Hz), 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 = 7.3 Hz), 4.75 (1H, br s).

[Reference Example 417] (1R, 2S, 5S) -2-{[(6-Chloro-4-oxo-4H-chromen-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamine Acid tert-butyl ester

N, N-dimethylformamide (0.02 ml) was added to a solution of the compound obtained in Reference Example 415 (213 mg) in thionyl chloride (2.0 ml), and the mixture was refluxed for 15 minutes. The reaction mixture was concentrated under reduced pressure, the residue was made into a tetrahydrofuran (4.0 ml) solution, triethylamine (500 μl) and the compound (294 mg) obtained in Reference Example 144 were added, and the mixture was stirred at room temperature for 15 min. Acetic acid ethyl ester and 10% aqueous citric acid solution were added to the reaction solution to form two layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1) to obtain the title compound (230 mg).
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 7.66 (1H, dd, J = 8) .8, 2.4 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.77-8.92 (1H, br).
MS (ESI) m / z: 492 (M + H) ^<+> .

[Reference Example 418] (3R, 4S) -4-{[(7-chlorocinnolin-3-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 214, the title compound was obtained from the lithium salt of carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 220 and the ester described in Reference Example 297.
¹ H-NMR (CDCl ₃ ) δ: 1.38 (9H, s), 1.65-1.90 (1H, m), 1.90-2.15 (1H, m), 2.80-3 0.00 (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 (0.6 H, br s), 7.78 (1 H, d, J = 8.8 Hz), 7 .97 (1H, d, J = 8.8 Hz), 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(dimethylamino) carbonyl] Cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 68, the compound obtained in Reference Example 144 and the compound obtained in Reference Example 266 were condensed to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.35 to 1.65 (1H, m), 1.45 (9H, s), 1.65 to 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, 2.6 Hz), 7.83 (1H, br s), 8.14 (1 H, br d, J = 7.8 Hz), 8.30 (1 H, s), 9 .72 (1H, s).
MS (ESI) m / z: 468 (M + H) ^<+> .

[Reference Example ^{420] N 1 - {(1S} , 2R, 4S) -2- amino-4 - [(dimethylamino) carbonyl] cyclohexyl} -N ² - (5-chloropyridin-2-yl) ethanediamide hydrochloride

In the same manner as in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 419.
¹ H-NMR (DMSO-d ₆ ) 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, 2.5 Hz), 8.07 (1H, d, J = 9.0 Hz), 8.34 (3H, br s), 8 .46 (1H, d, J = 2.5 Hz), 8.96 (1 H, d, J = 6.6 Hz), 10.34 (1 H, s).
MS (ESI) m / z: 368 (M + H) ^<+> .

[Reference Example 421] 2-[({(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} amino) carbonyl] -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester

The compound obtained in Reference Example 420 was condensed with 5- (tert-butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid (WO 94/21599) to give the title A compound was obtained.
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 8.13 (1H, d, J = 9.0 Hz), 8.13-8.25 (1H, m ), 8.28 (1H, d, J = 2.4 Hz), 9.75 (1H, s). MS (ESI) m / z: 633 (M + H) ^<+> .

[Reference Example 422] 2-Chloro-N- (4-fluorophenyl) acetamide

The title compound was obtained from p-fluoroaniline in the same manner as described in Reference Example 350.
¹ H-NMR (CDCl ₃ ) δ: 4.19 (2H, s), 7.05 (2H, t, J = 8.6 Hz), 7.51 (2H, dd, J = 9.1, 4. 7 Hz), 8.19 (1H, br s).

[Reference Example 423] S- [2- (4-Fluoroanilino) -2-oxoethyl] thiosulfate sodium salt

In the same manner as in the method described in Reference Example 351, the title compound was obtained from the compound obtained in Reference Example 422.
¹ H-NMR (DMSO-d ₆ ) δ: 3.72 (2H, s), 7.14 (2H, t, J = 9.0 Hz), 7.56 (2H, dd, J = 9.0, 5.1 Hz), 10.21 (1 H, s).

[Reference Example 424] (1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-{[2- (4-fluoroanilino) -2-oxoethanethioyl] amino} cyclohexylcarbamic acid tert -Butyl ester

The compound (1.1 g) obtained in Reference Example 144 and the compound (1.24 g) obtained in Reference Example 423 are dissolved in N-methylmorpholine (20 ml), and the bath temperature is increased from room temperature to 140 ° C. over 15 minutes. The mixture was heated and stirred at the same temperature for 15 minutes. After allowing to cool, ice water was added to the reaction solution, and insoluble matter was collected by filtration. It was purified by silica gel column chromatography (methylene chloride: methanol = 200: 1 → 197: 3) to give the title compound (1.43 g).
¹ H-NMR (CDCl ₃ ) 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 = 8.5 Hz), 7.50-7.70 (2H, m), 9.75-9.95 (1H, m), 10.13 (1H, s) ).
MS (ESI) m / z: 467 (M + H) ^<+> .

[Reference Example 425] 2-Chloro-N- (5-fluoropyridin-2-yl) acetamide hydrochloride

The title compound was obtained from 2-amino-5-fluoropyridine in the same manner as described in Reference Example 352.
¹ H-NMR (DMSO-d ₆ ) δ: 4.35 (2H, s), 7.74-7.82 (1H, m), 8.10 (1H, dd, J = 9.0, 4. 2 Hz), 8.36 (1 H, d, J = 2.9 Hz), (1 H, br s).
MS (ESI) m / z: 188 (M + H) ^<+> .

[Reference Example 426] S- {2-[(5-fluoropyridin-2-yl) amino] -2-oxoethyl} thiosulfate sodium salt

In the same manner as in Reference Example 353, the title compound was obtained from the compound obtained in Reference Example 425.
¹ H-NMR (DMSO-d ₆ ) δ: 3.75 (2H, s), 7.67-7.77 (1H, m), 8.07 (1H, dd, J = 9.2, 4. 2 Hz), 8.28 (1 H, d, J = 2.9 Hz), 10.48 (1 H, s).

[Reference Example 427] (1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-fluoropyridin-2-yl) amino] -2-oxoethanethiol} Amino) cyclohexylcarbamic acid tert-butyl ester

A solution of the compound (1.20 g) obtained in Reference Example 144 in pyridine (70 ml) was heated to 120 ° C., the compound (2.42 g) obtained in Reference Example 426 was added, stirred for 30 minutes, and allowed to cool to room temperature. The solvent was distilled off under reduced pressure. To the obtained residue were added methylene chloride (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml), and water (50 ml), and the mixture was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: tetrahydrofuran = 1: 1). The obtained solid was slurried with isopropyl ether (40 ml) for 1 hour, collected by filtration and dried to give the title compound (920 mg).
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[(dimethylamino) Carbonyl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 427, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 353.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.65 to 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, brs), 6.92 (1 / 2H, brs), 7.69. (1H, dd, J = 8.9, 2.6 Hz), 7.95-8.20 (1H, br), 8.29 (1H, s), 9.67 (1 / 2H, br s), 9.93 (1 / 2H, br s), 10.54 (1 H, br s).

[Reference Example 429] 2-Chloro-4,5,6,7-tetrahydrobenzothiazol-6-ylformamide

A solution of 2-chloro-5-oxo-4,5,6,7-tetrahydrobenzo [d] thiazole (Helv. Cim. Acta., 1994, 77, 1256) (4.53 g) in methanol (200 ml) To the mixture, ammonium acetate (18.58 g) and sodium cyanoborohydride (10.68 g) were added and heated to reflux. After 19 hours, hydrochloric acid was added to decompose excess reagent, and the reaction solution was concentrated under reduced pressure, made alkaline with 1N aqueous sodium hydroxide solution, and methylene chloride was added to separate the layers. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 20: 1), and the solvent was distilled off to obtain a pale yellow oil (2.42 g). This oil was dissolved in methylene chloride (100 ml) and formic acid (530 μl), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.68 g), 1-hydroxybenzotriazole (2.60 g) , N-methylmorpholine (3.88 g) was added and stirred at room temperature. After 20 hours, methylene chloride and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, followed by liquid separation. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 20: 1) to give the title compound (2.21 g). .
¹ H-NMR (CDCl ₃ ) 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, 4.4 Hz), 4.46-4.48 (1 H, m), 5.76 (1 H, br s), 8.17 (1 H, s).

[Reference Example 430] N- (2-chloro-4,5,6,7-tetrahydrobenzothiazol-6-yl) -N-methylcarbamic acid tert-butyl ester

To a solution of the compound (2.11 g) obtained in Reference Example 429 in tetrahydrofuran (50 ml), 1M borane-tetrahydrofuran complex tetrahydrofuran solution (14.6 ml) was added and heated to reflux. After 15 hours, a 1M borane-tetrahydrofuran complex tetrahydrofuran solution (6.0 ml) was added, and the mixture was heated to reflux. After 4 hours, ethanol (10 ml) and 1N hydrochloric acid (15 ml) were added and heated to reflux. After 3 hours, the reaction solution was concentrated under reduced pressure, a 1N aqueous sodium hydroxide solution and methylene chloride were added, and the mixture was separated. The obtained residue was dissolved in methylene chloride (50 ml), triethylamine (1.28 g) and di-tert-butyl dicarbonate (2.21 g) were added, and the mixture was stirred at room temperature. After 30 minutes, methylene chloride and 1N hydrochloric acid were added for liquid separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (2.26 g).
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5 -[(Dimethylamino) carbonyl] cyclohexyl} amino) carbonyl] -4,5,6,7-tetrahydrobenzothiazol-6-yl) -N-methylcarbamic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 430 (1.0 g) in diethyl ether (10 ml) -tetrahydrofuran (5 ml) was added 1.6 N tert-butyllithium pentane solution (3.1 ml) after cooling to −78 ° C. 20 Carbon dioxide gas was introduced for 20 minutes after stirring for 20 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure to obtain lithium 6-[(tert-butoxycarbonyl) (methyl) amino] -4,5,6,7-tetrahydrobenzothiazole-2-carboxylic acid lithium salt.
To a solution of the compound obtained in Reference Example 420 (490.5 mg) in N, N-dimethylformamide (20 ml), lithium carboxylate (350.2 mg) obtained by the above reaction, 1- (3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (287.6 mg), 1-hydroxybenzotriazole (202.7 mg), and N-methylmorpholine (0.319 ml) were added, and the mixture was stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and water and methylene chloride were added to the residue for liquid separation, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (methylene chloride: methanol = 40: 1 → 20: 1) to obtain the title compound (323.9 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.48, 1.49 (total 9H, each), 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 (total 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 = 8.6 Hz) 7.68 (1H, dt, J = 8.8, 2.6 Hz), 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-chloroindole-2-carboxamide hydrochloride

In the same manner as in Reference Example 69, the compound obtained in Reference Example 310 was deprotected to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.56 (0.5 H, m), 1.72-1.97 (4.5 H, m), 2.82 (3 H, 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, 8.8 Hz), 7.29 (1H, d, J = 2.0 Hz), 7.45 ( 1H, d, J = 8.8 Hz), 7.72 (1H, s), 8.07 (3H, br), 8.47 (1H, m), 11.85 (1H, br).

[Reference Example 433] 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid lithium salt

Chlorooxoacetic acid methyl ester (78.7 ml) was added dropwise at 0 ° C. to a suspension of 2-amino-5-chloropyridine (100 g) and sodium hydrogen carbonate (78.4 g) in tetrahydrofuran (2000 ml) at room temperature. Stir for hours. The reaction mixture was added to a mixture of diethyl ether (2000 ml), ammonium chloride (62.4 g) and water (1000 ml) with stirring, and the layers were separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was dried to give 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid methyl ester (162 g). Got. Water (450 ml) and lithium hydroxide (18.2 g) were added to a solution of this ester (160 g) in tetrahydrofuran (1800 ml). After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, hexane (3000 ml) was added to the resulting residue, and the mixture was stirred for 3 hours. The solid was collected by filtration and dried. Acetonitrile (1000 ml) was added to the obtained solid (190 g), and the mixture was stirred for 1 hour. The resulting solid was collected by filtration, washed with diethyl ether (500 ml) and dried to give the title compound. (158 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 7.92 (1H, dd, J = 9.1, 2.7 Hz), 8.13 (1H, dd, J = 9.1, 0.5 Hz), 8.36 (1H, dd, J = 2.7, 0.5 Hz), 10.19 (1H, s).

[Reference Example 434] (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(dimethylamino) carbonyl] Cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 433.
¹ H-NMR (CDCl ₃ ) 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 (0.7 H, br), 5.70-6.00 (0.3 H, br), 7.70 (1 H, dd, J = 8.8, 2.4 Hz) , 7.75-8.00 (1H, br), 8.16 (1H, br d, J = 8.8 Hz), 8.30 (1H, d, J = 2.4 Hz), 9.73 (1H , S).
MS (ESI) m / z: 468 (M + H) ^<+> .

[Reference Example ^{435] N 1 - {(1S} , 2R, 4S) -2- amino-4 - [(dimethylamino) carbonyl] cyclohexyl} -N ² - (5-chloropyridin-2-yl) ethanediamide hydrochloride

In the same manner as in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 434.
¹ H-NMR (DMSO-d ₆ ) 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, 2.5 Hz), 8.07 (1H, d, J = 9.1 Hz), 8.15-8.40 (3H, br), 8.45 (1H, d, J = 2.5 Hz), 8.96 (1H, d, J = 6.6 Hz), 10.33 (1H, s).

[Reference Example 436] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4-[(methylamino) carbonyl] cyclohexylcarbamic acid benzyl ester

In the same manner as in Reference Example 143, the title compound was obtained from the compound obtained in Reference Example 142 and methylamine hydrochloride.
¹ H-NMR (DMSO-d ₆ ) 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 = 4.6 Hz), 3.48 (1H, br. S), 3 .80-3.91 (1H, m), 5.01 (1H, 1 / 2ABq, J = 12.1 Hz), 5.03 (1H, 1 / 2ABq, J = 12.1 Hz), 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(methylamino) carbonyl] Cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 144, the compound obtained in Reference Example 436 was deprotected, and then the obtained amine was converted into the compound obtained in Reference Example 433 in the same manner as described in Reference Example 91. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 4.6 Hz), 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, 1.0 Hz), 8.67 (1 H, d, J = 7.6 Hz), 10.26 (1 H, s).
MS (ESI: negative) m / z: 452 [(M−H) ⁻ , Cl ³⁵ ], 454 [(M−H) ⁻ , Cl ³⁷ ].

[Reference Example 438] 2-Chloro-N- (5-methylpyridin-2-yl) acetamide hydrochloride

The title compound was obtained from 2-amino-5-picoline in the same manner as described in Reference Example 425.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 4.40 (2H, s), 7.83 (1H, d, J = 8.8 Hz), 7.91 (1H , D, J = 8.5 Hz), 8.21 (1H, s), 11.40 (1H, s).

[Reference Example 439] S- {2-[(5-Methylpyridin-2-yl) amino] -2-oxoethyl} thiosulfate sodium salt

In the same manner as described in Reference Example 353, the title compound was obtained from the compound obtained in Reference Example 438.
¹ H-NMR (DMSO-d ₆ ) δ: 2.24 (3H, s), 3.74 (2H, s), 7.59 (1H, d, J = 8.5 Hz), 7.94 (1H , D, J = 8.3 Hz), 8.12 (1H, s), 10.26 (1H, s).

[Reference Example 440] (1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-methylpyridin-2-yl) amino] -2-oxoethanethiol} Amino) cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 427, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 439.
¹ H-NMR (CDCl ₃ ) 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, 2.0 Hz), 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-Chloroanilino) -2-oxoethanethioyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert- Butyl ester

The compound obtained in Reference Example 220 was deprotected by catalytic reduction in the same manner as described in Reference Example 214, and the resulting amine was obtained in Reference Example 351 in the same manner as described in Reference Example 427. Condensation with the obtained compound gave the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 8.6 Hz), 7.61 (2H, d, J = 8.6 Hz), 10.12 ( 1H, s), 10.19-10.33 (1H, br).
MS (FAB) m / z: 485 [(M + H) ⁺ , Cl ³⁵ ], 487 [(M + H) ⁺ , Cl ³⁷ ].

[Reference Example 442] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4-[(dimethylamino) carbonyl] cyclohexylcarbamic acid 9H-fluoren-9-ylmethyl ester

The compound (856 mg) obtained in Reference Example 144 was dissolved in acetone (10 ml), pentafluorophenylcarbamic acid 9-fluorenylmethyl ester (1.34 g) and sodium bicarbonate (302 mg) were added, and the mixture was stirred at room temperature for 2.5 hours. Stir. Further, pentafluorophenylcarbamic acid 9-fluorenylmethyl ester (609 mg) and sodium hydrogen carbonate (151 mg) were added, and the mixture was heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (SI-40B, methylene chloride: methanol = 93: 7) using silica gel as a carrier to obtain the title compound (1.47 g).
¹ H-NMR (CDCl ₃ ) 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 = 7.3 Hz), 7.39 (2H, t, J = 7.3 Hz), 7.57 (2H, d, J = 7.3 Hz), 7.75 (2H, d, J = 7.3 Hz).
MS (ESI) m / z: 508 (M + H) ^<+> .

[Reference Example 443] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4-[(dimethylamino) carbothioyl] cyclohexylcarbamic acid 9H-fluoren-9-ylmethyl ester

The compound (1.26 g) obtained in Reference Example 442 was dissolved in toluene (50 ml), Lawesson's reagent (1.00 g) was added, and the mixture was stirred at 60 (C for 1 hour. Insoluble materials were removed by filtration, and the solvent was removed under reduced pressure. The residue was dissolved in ethanol (50 ml), di-tert-butyl dicarbonate (541 mg) and sodium hydrogen carbonate (208 mg) were added, and the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (hexane: ethyl acetate = 1: 1 → methylene chloride: methanol = 9: 1) to give the title compound (609 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) 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 = 7.3 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.55 ( 2H, br.s), 7.75 (2H, d, J = 7.3 Hz).

[Reference Example 444] (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(dimethylamino) carbotyoyl] Cyclohexylcarbamic acid tert-butyl ester

The compound (1.11 g) obtained in Reference Example 443 was dissolved in N, N-dimethylformamide (30 ml), piperazine (3.0 ml) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation. The aqueous layer was extracted twice with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This residue was condensed with the compound obtained in Reference Example 433 in the same manner as described in Reference Example 91 to give the title compound (629 mg).
¹ H-NMR (CDCl ₃ ) 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 (1 H, dd, J = 8.8, 2.7 Hz), 7.85 (1 H, br. S), 8.16 (1 H, d, J = 8.8 Hz), 8.30 (1 H, d , J = 2.7 Hz), 9.73 (1H, s).
MS (FAB) m / z: 484 [(M + H) ⁺ , Cl ³⁵ ], 486 [(M + H) ⁺ , Cl ³⁷ ].

[Reference Example ^{445] N 1 - {(1S} , 2R, 4S) -2- amino-4 - [(dimethylamino) carbothioyl] cyclohexyl} -N ² - (5-chloropyridin-2-yl) ethanediamide dihydrochloride

In the same manner as in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 444.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.2 Hz), 9.06 (1H, d, J = 6.8 Hz), 10.34 (1H, s).
MS (FAB) m / z: 384 [(M + H) ⁺ , Cl ³⁵ ], 386 [(M + H) ⁺ , Cl ³⁷ ].

[Reference Example 446] (3R, 4S) -3-[(tert-butoxycarbonyl) amino] -1- (2-methoxyacetyl) piperidin-4-ylcarbamic acid 9H-fluoren-9-ylmethyl ester

The compound obtained in Reference Example 220 was deprotected by catalytic reduction in the same manner as described in Reference Example 214, and the resulting amine was treated in the same manner as described in Reference Example 442 to give the title compound. Obtained.
¹ H-NMR (CDCl ₃ ) 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 = 7.6 Hz), 7.55-7.65 (2H, m) , 7.76 (2H, d, J = 7.6 Hz).
MS (FAB) m / z: 510 (M + H) ^<+> .

[Reference Example 447] (3R, 4S) -3-[(tert-butoxycarbonyl) amino] -1- (2-methoxyethanethioyl) piperidin-4-ylcarbamic acid 9H-fluoren-9-ylmethyl ester

In the same manner as in Reference Example 443, the title compound was obtained from the compound obtained in Reference Example 446.
¹ H-NMR (CDCl ₃ ) 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 = 7.3 Hz), 7.55-7.68 (2H, m), 7.77 (2H, d, J = 7.3 Hz).
MS (FAB) m / z: 526 (M + H) ^<+> .

[Reference Example 448] (3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -1- (2-methoxyethanethioyl) piperidine -3-ylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 444, the compound obtained in Reference Example 447 was treated with diethylamine and deprotected, and then condensed with the compound obtained in Reference Example 433 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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, 2.0 Hz), 8.21 (1H, d, J = 8.5 Hz), 8.31 (1H, d, J = 2.0 Hz), 8.42-8. 60 (1H, br), 9.72 (1H, br. S).
MS (ESI) m / z: 486 [(M + H) ⁺ , Cl ³⁵ ], 488 [(M + H) ⁺ , Cl ³⁷ ].

[Reference Example 449] (1S, 3R, 4S) -4-{[(allyloxy) carbonyl] amino} -3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester

To a mixed solution of the compound (10.0 g) obtained in Reference Example 141 in tetrahydrofuran (40 ml) and ethanol (40 ml) was added 10% palladium carbon catalyst (10.2 g), and the mixture was stirred at room temperature for 63 hours in a hydrogen atmosphere. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained colorless oil was dissolved in tetrahydrofuran (25 ml), pyridine (2.3 ml) was added at room temperature, allyl chloroformate (2.70 ml) was added dropwise at 0 ° C., and the mixture was stirred for 20 min. Ice and ethyl acetate were added to the reaction mixture, and the mixture was stirred for 5 minutes, and acidified with 10% aqueous citric acid solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain the title compound (6.03 g).
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz), 4.49-4.59 (2H, m), 4.60-4.75 (1H, m), 5.20 (1H, d, J = 10.5 Hz), 5.22-5.32 (1H, br), 5.29 (1H, dd, J = 17.1, 1.7 Hz), 5.85-5.97 (1 H, m).
MS (ESI) m / z: 371 (M + H) ^<+> .

[Reference Example 450] (1S, 3R, 4S) -4-{[(allyloxy) carbonyl] amino} -3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 142, the title compound was obtained from the compound obtained in Reference Example 449.
¹ H-NMR (CDCl ₃ ) 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 = 10.3 Hz), 5.29 (1H, dd, J = 17.1, 1.5 Hz), 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] cyclohexanecarboxylic acid 2,2,2-trichloroethyl ester

To a solution of the compound obtained in Reference Example 450 (5.93 g) in N, N-dimethylformamide (40 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.99 g), 1-hydroxy Benzotriazole (2.81 g), 2,2,2-trichloroethanol (4.15 ml) and 4-dimethylaminopyridine (4.15 g) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain the title compound (8.88 g).
¹ H-NMR (CDCl ₃ ) δ: 1.35 to 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 = 11.8 Hz), 4.77 (1H, d, J = 1.11. 8 Hz), 5.18-5.34 (1 H, br), 5.20 (1 H, d, J = 10.5 Hz), 5.30 (1 H, dd, J = 17.4, 1.0 Hz), 5.86-5.97 (1H, m).
MS (ESI) m / z: 473 [(M + H) ⁺ , 3 × Cl ³⁵ ], 475 [(M + H) ⁺ , 2 × Cl ³⁵ , Cl ³⁷ ], 477 [(M + H) ⁺ , Cl ³⁵ , 2 × Cl ³⁷ ].

[Reference Example 452] (1S, 3R, 4S) -4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid 2,2,2-trichloroethyl ester

Diethylamine (20 ml) and tetrakis (triphenylphosphine) palladium (719 mg) were added to a solution of the compound (8.83 g) obtained in Reference Example 451 in tetrahydrofuran (35 ml), and the mixture was stirred at room temperature for 2.5 hours under argon. The reaction mixture was acidified with 10% aqueous citric acid solution (250 ml), and diethyl ether was added. The aqueous layer was washed with diethyl ether, basified with sodium carbonate, and extracted with methylene chloride. The methylene chloride layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (4.35 g).
¹ H-NMR (CDCl ₃ ) 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 = 12.0 Hz), 4.75-4.85 (1H, br) , 4.78 (1H, d, J = 12.0 Hz).
MS (ESI) m / z: 389 [(M + H) ⁺ , 3 × Cl ³⁵ ], 391 [(M + H) ⁺ , 2 × Cl ³⁵ , Cl ³⁷ ], 393 [(M + H) ⁺ , Cl ³⁵ , 2 × Cl ³⁷ ].

[Reference Example 453] (1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} Amino) cyclohexanecarboxylic acid 2,2,2-trichloroethyl ester

In the same manner as in Reference Example 91, the compound obtained in Reference Example 452 and the compound obtained in Reference Example 433 were condensed to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 12.0 Hz), 4.78 (1H, d, J = 12.0 Hz), 7.70 (1H, dd, J = 8.8, 2.4 Hz), 7.90-8.07 (1 H, br), 8.18 (1 H, d, J = 8.8 Hz), 8.31 (1 H, d, J = 2.4 Hz) ), 9.72 (1H, br.s).
MS (ESI) m / z: 571 [(M + H) ⁺ , 3 × Cl ³⁵ ], 573 [(M + H) ⁺ , 2 × Cl ³⁵ , Cl ³⁷ ], 575 [(M + H) ⁺ , Cl ³⁵ , 2 × Cl ³⁷ ].

[Reference Example 454] 2-[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] -2- (methoxyimino) acetic acid methyl ester

The compound (435 mg) obtained in Reference Example 144 and 2- (methoxyimino) -2- (methylsulfonyl) acetic acid methyl ester (WO99 / 67209) (233 mg) were dissolved in tetrahydrofuran (5 ml), and triethylamine ( 332 μl) was added and stirred at 70 ° C. overnight. The reaction solution was concentrated under reduced pressure, methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was separated. The oil layer was dried over anhydrous sodium sulfate. After concentration, the obtained residue was purified by silica gel chromatography (methylene chloride: methanol = 91: 9) to obtain the title compound (111 mg).
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 7.25-7.30 (1H, m).
MS (ESI) m / z: 481 (M + H) ^<+> .

[Reference Example 455] N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} ^{cyclohexyl) -N 2 - {5- [2-} ( trimethylsilyl) ethynyl] pyridin-2-yl} ethanediamide

The compound (658 mg) obtained in Example 204 was dissolved in tetrahydrofuran (10 ml), N, N-dimethylformamide (10 ml), triethylamine (20 ml), triphenylphosphine (87 mg), trimethylsilylacetylene (471 μl), palladium acetate ( 50 mg) was added, and the mixture was stirred at 80 C for 14 hours under an argon atmosphere. The reaction solution was filtered through Celite and washed well with methylene chloride. Water was added to the filtrate for liquid separation, and the organic layer was separated with activated carbon (about 3 g). After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7) to give the title compound (360 mg) Got.
¹ H-NMR (CDCl ₃ ) 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 = 15.4 Hz), 3.73 (1H, d, J = 15.4 Hz), 4.08-4.15. (1H, m), 4.66-4.69 (1H, m), 7.42 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4, 2.. 1 Hz), 8.03 (1 H, d, J = 8.1 Hz), 8.13 (1 H, d, J = 8.8 Hz), 8.43 (1 H, d, J = 2.1 Hz), 9. 74 (1H, s).
MS (ESI) m / z: 610 (M + H) ^<+> .

[Reference Example 456] 5-Methyl-5,6-dihydro-4H-thieno [2,3-c] pyrrole-2-carboxylic acid methyl ester

4,5-bis (chloromethyl) -2-thiophenecarboxylic acid methyl ester (DJ Zwanenburg and Hans Wynberg, J. Org. Chem., 34, 333-340, (1969)) (520 mg) was added to acetonitrile ( 600 ml), methylamine (40% methanol solution, 722 μl) was added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 1: 0 → 19: 1) to obtain the title compound (176 mg).
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Reference Example 457] 2-Chloro-N- (6-chloropyridazin-3-yl) acetamide

3-Amino-6-chloropyridazine (10.4 g) was dissolved in N, N-dimethylformamide (200 ml), chloroacetyl chloride (7.48 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue. The precipitated solid was collected by filtration and washed with ethyl acetate and water to give the title compound (9.39 g).
¹ H-NMR (CDCl ₃ ) δ: 4.30 (2H, s), 7.56 (1H, d, J = 9.3 Hz), 8.51 (1H, d, J = 9.3 Hz), 9 .68 (1H, br.s).

[Reference Example 458] S- {2-[(6-chloropyridazin-3-yl) amino] -2-oxoethyl} thiosulfate sodium salt

In the same manner as in Reference Example 353, the title compound was obtained from the compound obtained in Reference Example 457.
¹ H-NMR (DMSO-d ₆ ) δ: 3.84 (2H, s), 7.87 (1H, d, J = 9.4 Hz), 8.36 (1H, d, J = 9.4 Hz) , 11.21 (1H, br.s).

[Reference Example 459] (1R, 2S, 5S) -2-({2-[(6-chloropyridazin-3-yl) amino] -2-oxoethanethioyl} amino) -5-[(dimethylamino) Carbonyl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as in the method described in Reference Example 427, the title compound was obtained from the compound obtained in Reference Example 458 and the compound obtained in Reference Example 144.
¹ H-NMR (CDCl ₃ ) δ: 1.35 to 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 = 9.0 Hz), 8.47 (1H, d, J = 9.0 Hz) ), 10.03 (1H, br.s), 11.03 (1H, s).

[Reference Example 460] (1S, 3R, 4S) -3-amino-4-({2-[(6-chloropyridazin-3-yl) amino] -2-oxoethanethiol} amino) -N, N -Dimethylcyclohexanecarboxamide hydrochloride

In the same manner as in the method described in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 459.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.53 (1H, m), 1.73-1.85 (3H, m), 2.03 to 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 = 9.3 Hz), 8.37 (1H, d, J = 9.3 Hz), 8.43 (3H, br.s), 11.11 (1H, d, J = 6.6 Hz), 11.37 (1H, s).
MS (FAB) m / z: 385 [(M + H) ⁺ , Cl ³⁵ ], 387 [(M + H) ⁺ , Cl ³⁷ ].

[Reference Example 461] 2-Chloro-N- (6-chloropyridin-3-yl) acetamide

In the same manner as in the method described in Reference Example 457, the title compound was obtained from 5-amino-2-chloropyridine.
¹ H-NMR (CDCl ₃ ) δ: 4.22 (2H, s), 7.34 (1H, d, J = 8.5 Hz), 8.14 (1H, dd, J = 8.5, 2. 7 Hz), 8.30 (1 H, br. S), 8.45 (1 H, d, J = 2.7 Hz).

[Reference Example 462] S- {2-[(6-chloropyridin-3-yl) amino] -2-oxoethyl} thiosulfate sodium salt

In the same manner as in Reference Example 353, the title compound was obtained from the compound obtained in Reference Example 461.
¹ H-NMR (DMSO-d ₆ ) δ: 3.77 (2H, s), 7.47 (1H, d, J = 8.8 Hz), 8.04 (1H, dd, J = 8.8, 2.7 Hz), 8.57 (1 H, d, J = 2.7 Hz), 10.51 (1 H, s).

[Reference Example 463] (1R, 2S, 5S) -2-({2-[(6-chloropyridin-3-yl) amino] -2-oxoethanethioyl} amino) -5-[(dimethylamino) Carbonyl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 427, the title compound was obtained from the compound obtained in Reference Example 462 and the compound obtained in Reference Example 144.
¹ H-NMR (CDCl ₃ ) 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 = 8.5 Hz), 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) ⁺ , Cl ³⁵ ], 508 [(M + Na) ⁺ , Cl ³⁷ ].

[Reference Example 464] (1S, 3R, 4S) -3-amino-4-({2-[(6-chloropyridin-3-yl) amino] -2-oxoethanethiol} amino) -N, N -Dimethylcyclohexanecarboxamide hydrochloride

In the same manner as in the method described in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 463.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.7 Hz), 8.26 (1H, dd, J = 8.7, 2.). 4 Hz), 8.38 (3 H, br. S), 8.85 (1 H, d, J = 2.4 Hz), 10.90 (1 H, d, J = 6.8 Hz), 11.07 (1 H, s).
MS (FAB) m / z: 384 [(M + H) ⁺ , Cl ³⁵ ], 386 [(M + H) ⁺ , Cl ³⁷ ].

[Reference Example 465] 2'-aminosulfonyl-1,1'-biphenyl-4-carboxylic acid

2-Bromobenzenesulfonamide (800 mg) and 4-carboxyphenyl boronic acid (563 mg) were suspended in a mixed solvent of toluene (5 ml) -water (5 ml). Tetrakis (triphenylphosphine) palladium (392 mg) and anhydrous sodium carbonate (1.08 g) were sequentially added to the reaction solution, and the mixture was heated to reflux overnight. After cooling to room temperature, diethyl ether and water were added for liquid separation, and the organic layer was extracted twice with water. The obtained aqueous layers were all combined, and 12N hydrochloric acid aqueous solution was added to this solution to make it acidic. The solution was concentrated to about 20 ml under reduced pressure, and the precipitated colorless powder was collected by filtration and dried under reduced pressure to obtain the title compound (539 mg).
MS (EI) m / z: 277 M ^<+> .

[Reference Example 466] 2-[(5-Methylpyridin-2-yl) amino] -2-oxoacetic acid methyl ester

In the same manner as in Reference Example 242, the title compound was obtained from 2-amino-5-methylpyridine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H, s), 3.98 (3H, s), 7.57 (1H, dd, J = 8.4, 2.0 Hz), 8.14 (1H, d, J = 8.4 Hz), 8.17 (1H, d, J = 2.0 Hz).
MS (ESI) m / z: 195 (M + H) ^<+> .

[Reference Example 467] 2-[(5-Methylpyridin-2-yl) amino] -2-oxoacetic acid lithium salt

In the same manner as in Reference Example 266, the title compound was obtained from the compound obtained in Reference Example 466.
¹ H-NMR (DMSO-d ₆ ) δ: 2.25 (3H, s), 7.63 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 8.2 Hz) , 8.15 (1H, s), 10.00 (1H, br. S).
MS (FAB) m / z: 181 (M-Li + 2H) ^<+> .

[Reference Example 468] 2-Oxo-2- (4-toluidino) acetic acid methyl ester

In the same manner as described in Reference Example 242, the title compound was obtained from p-toluidine and chlorooxoacetic acid methyl ester.
MS (ESI) m / z: 194 (M + H) ^<+> .

[Reference Example 469] (1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-{[2-oxo-2- (4-toluidino) acetyl] amino} cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 91, the title compound was obtained by condensing the carboxylic acid lithium salt obtained by hydrolyzing the ester described in Reference Example 468 with the compound obtained in Reference Example 144. It was.
MS (ESI) m / z: 447 (M + H) ^<+> .

[Reference Example 470] 4-Bromomethyl-3-chlorothiophene-2-carboxylic acid methyl ester

To a solution of 3-chloro-4-methyl-2-thiophenecarboxylic acid methyl ester (3.81 g) in carbon tetrachloride (40 ml) was added N-bromosuccinimide (3.56 g) and α, α′-azobisisobutyro. Nitrile (200 mg) was added and heated to reflux for 2.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19 → 1: 9) to give the title compound (2.92 g) as a yellow compound. Obtained as an oil.
¹ H-NMR (CDCl ₃ ) 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} -3-chloro-2-thiophenecarboxylic acid

To a tetrahydrofuran (30 ml) solution of methylamine (2 mol / L tetrahydrofuran solution, 27 ml), a tetrahydrofuran (50 ml) solution of the compound (2.92 g) obtained in Reference Example 470 was added dropwise over 30 minutes. After stirring at room temperature for 1 hour, the reaction solution was concentrated to about half under reduced pressure, di-tert-butyl dicarbonate (3.0 g) was added, and the mixture was stirred for 75 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was allowed to stand overnight. Water was added to separate the organic layer and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 99: 1 → 19: 1) to obtain a colorless oil (4.0 g). To a solution of this oil (4.0 g) in methanol (35 ml) were added water (5 ml) and sodium hydroxide (1.2 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, ice water was added to the residue, acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and hexane was added to crystallize to obtain the title compound (2.67 g) as a colorless powder.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.74 (3H, br. S), 4.14 (2H, br. S), 7.40 (0.5 H, br) .S), 7.48 (0.5H, br.s).

[Reference Example 472] (1R, 2S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 68, (1R, 2S) -2-aminocyclohexylcarbamic acid tert-butyl ester (WO01 / 74774) and the compound obtained in Reference Example 266 were condensed to obtain the title compound. It was.
¹ H-NMR (CDCl ₃ ) 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, 2.5 Hz), 7.90 (1H, br. S), 8 .17 (1H, dd, J = 8.8, 0.55 Hz), 8.29 (1H, dd, J = 2.5, 0.55 Hz), 9.76 (1H, br.s).
MS (ESI) m / z: 397 (M + H) ^<+> .

[Reference Example 473] 5-[(4-Methylphenyl) sulfonyl] -5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine

N, N-dimethyl of 3-bromo-1-[(4-methylphenyl) sulfonyl] -4-azepanone (J. Chem. Soc. Perkin Trans., 1995, 1 卷, 2355) (6.54 g) To a formamide (100 ml) solution, thiourea (1.44 g) was added and stirred at 60 ° C. overnight. After the solvent was distilled off under reduced pressure, methylene chloride (100 ml) and saturated aqueous sodium hydrogen carbonate solution (100 ml) were added to the residue for liquid separation. The aqueous layer was extracted with methylene chloride (100 ml), combined with the previously obtained organic layer, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ethyl acetate (100 ml) was added to the resulting residue, and the precipitated pale yellow powder was collected by filtration, and the crude product 5-[(4-methylphenyl) sulfonyl] -5,6 was collected. , 7,8-Tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylformamide (1.86 g) was obtained. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (methanol: methylene chloride = 1: 19) to give 5-[(4-methylphenyl) sulfonyl] -5,6,7,8-tetrahydro. A mixture (4.01 g) of -4H-thiazolo [5,4-c] azepin-2-ylformamide and the title compound was obtained. The mixture and the crude product were combined, suspended in dioxane (50 ml), 3N hydrochloric acid (50 ml) was added, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, methylene chloride (250 ml) and a saturated aqueous sodium carbonate solution (200 ml) were added for liquid separation, the oil layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Diisopropyl ether (100 ml) was added to the residue and the pale yellow powder precipitated was collected by filtration to obtain the title compound (4.47 g).
¹ H-NMR (CDCl ₃ ) δ: 1.75-1.87 (2H, m), 2.40 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.53 (2H, t, J = 5.7 Hz), 4.37 (2H, s), 4.73 (2H, br. S), 7.25 (2H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.5 Hz).
MS (ESI) m / z: 324 (M + H) ^<+> .

[Reference Example 474] 5,6,7,8-Tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine hydrobromide

The title compound was obtained by treating the compound obtained in Reference Example 473 in the same manner as in Reference Example 291.
¹ H-NMR (DMSO-d ₆ ) 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-tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine

The compound (2.73 g) obtained in Reference Example 474 was suspended in methanol, and triethylamine (2.30 ml), acetic acid (453 μl), 37% aqueous formaldehyde solution (668 μl) and cyanoborohydride were added to this suspension under ice cooling. Sodium (544 mg) was added. After stirring at room temperature overnight, a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added and concentrated to dryness. The residue was purified by silica gel chromatography (methanol: methylene chloride = 3: 17). Methanol (100 ml) and anhydrous sodium carbonate (20 g) were added to the resulting crude product, and the mixture was stirred at room temperature for 30 minutes, and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, methylene chloride (250 ml) and methanol (50 ml) were added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting pale yellow powder was washed with acetonitrile (100 ml) to give the title compound (1.23 g).
¹ H-NMR (CDCl ₃ ) δ: 1.70-1.85 (2H, s), 2.38 (3H, s), 2.77 (2H, t, J = 5.6 Hz), 2.97 (2H, t, J = 5.6 Hz), 3.65 (2H, s), 4.68 (2H, br. S).
MS (ESI) m / z: 184 (M + H) ^<+> .

[Reference Example 476] 2-Bromo-5-methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepine

The compound (1.13 g) obtained in Reference Example 475 was suspended in water (10 ml), 48% aqueous hydrobromic acid solution (7.0 ml) was added, and the mixture was stirred under ice-cooling. An aqueous solution (3.0 ml) containing sodium nitrite (639 mg) was carefully added dropwise to the reaction solution. After completion of the dropwise addition, this suspension was stirred overnight at room temperature. Under ice-cooling, methylene chloride (100 ml) was added to the reaction mixture, and the mixture was stirred and neutralized with a saturated aqueous sodium carbonate solution. After separation, the aqueous layer was extracted with methylene chloride (100 ml), and the organic layers were combined and dried over anhydrous sodium sulfate. Purification by silica gel chromatography (methanol: methylene chloride = 3: 47) gave the title compound (582 mg) as a pale orange oil.
¹ H-NMR (CDCl ₃ ) 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-tetrahydro-4H-thiazolo [5,4-c] azepine-2-carboxylic acid lithium salt

In the same manner as in Reference Example 10, the title compound was obtained from the compound obtained in Reference Example 476.
¹ H-NMR (DMSO-d ₆ ) 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 [3,4-d] thiazol-2-ylamine

To a solution of 1,2,2-trimethylpyrrolidin-3-one (1.00 g) in cyclohexane (5 ml), pyrrolidine (1.31 ml) and p-toluenesulfonic acid monohydrate (7.48 mg) were added in turn. Heated to reflux for days. The mixture was allowed to stand at room temperature and then concentrated under reduced pressure to obtain crude 1,2,2-trimethyl-3- (pyrrolidin-1-yl) -2,5-dihydro-1H-pyrrole (972 mg). Formamidine disulfide hydrochloride (1.20 g) was added to a solution of this in dimethylformamide (10 ml), and the mixture was stirred at room temperature for 4 days. After concentration under reduced pressure, methanol (50 ml) and anhydrous sodium carbonate (20 g) were added to the residue, and the mixture was stirred at room temperature for 1 hour. Insoluble materials were removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (methanol: methylene chloride = 1: 99 → 1: 9) to give the title compound (580 mg).
¹ H-NMR (CDCl ₃ ) 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 [3,4-d] thiazole

In the same manner as in Reference Example 476, the title compound was obtained from the compound obtained in Reference Example 478.
¹ H-NMR (CDCl ₃ ) 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 [3,4-c] pyridine-6-carboxylic acid

2-[(4-Methylphenyl) sulfonyl] -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid ethyl ester (Chem. Commun., 2001, 1102), The title compound was obtained in the same manner as in Reference Example 291.
¹ H-NMR (CDCl ₃ ) 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 [3,4-c] pyridine-6-carboxylic acid lithium salt

To a solution of the compound obtained in Reference Example 480 (1.66 g) in methanol (100 ml), thionyl chloride (3.0 ml) was added and heated under reflux overnight. After leaving to room temperature, the solvent was distilled off under reduced pressure, and methylene chloride (100 ml) and a saturated aqueous sodium hydrogen carbonate solution (100 ml) were added to the residue for liquid separation. Methylene chloride (100 ml) and di-tert-butyl dicarbonate (1.40 g) were added to the aqueous layer, and the mixture was stirred at room temperature for 2 hours. After liquid separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane (50 ml) was added to the residue and the precipitated pale yellow powder was collected by filtration to give crude 2- (tert-butoxycarbonyl) -1,3-dihydro-2H-pyrrolo [3,4-c] pyridine-6- Carboxylic acid methyl ester (602 mg) was obtained. To a solution of this crude product (564 mg) in methanol (10 ml) was added 1N aqueous lithium hydroxide solution (2.20 ml), and the mixture was stirred at room temperature overnight. Concentration to dryness under reduced pressure gave the title compound (591 mg) as a light brown solid.
¹ H-NMR (DMSO-d ₆ ) δ: 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 (1H, br.s).
MS (ESI) m / z: 265 (M-Li + 2H) ^<+> .

[Reference Example 482] 5- (Pyridin-4-yl) pyrimidine-2-carboxylic acid methyl ester

The compound obtained from pyridin-4-ylboronic acid and 5-bromopyrimidine-2-carboxylic acid was esterified with methanol and thionyl chloride by the method described in Reference Example 237 to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 4.12 (3H, s), 7.57 (2H, d, J = 6.1 Hz), 8.83 (2H, d, J = 6.1 Hz), 9 .18 (2H, s).
MS (ESI) m / z: 216 (M + H) ^<+> .

[Reference Example 483] 5- (Pyridin-4-yl) pyrimidine-2-carboxylic acid lithium salt

The title compound was obtained from the compound obtained in Reference Example 482 by a method similar to that of Reference Example 322.
¹ H-NMR (DMSO-d ₆ ) δ: 7.85 (2H, d, J = 6.0 Hz), 8.69 (2H, d, J = 6.0 Hz), 9.12 (2H, s) .
MS (ESI) m / z: 202 (M-Li + 2H) ^<+> .

[Reference Example 484] 2'-Methyl- [1,1'-biphenyl] -4-carbaldehyde

The title compound was obtained from 2-bromotoluene and 4-formylbenzeneboronic acid by the method described in Reference Example 237.
¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H, s), 7.20-7.33 (4H, m), 7.50 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 8.2 Hz), 10.07 (1H, s).
MS (ESI) m / z: 197 (M + H) ^<+> .

[Reference Example 485] 2'-methyl- [1,1'-biphenyl] -4-carboxylic acid

The compound (1.51 g) obtained in Reference Example 484 was suspended in water (100 ml). To this suspension, tert-butanol (10 ml), 2-methyl-2-butene (20 ml), sodium chlorite (3 .67 g) and sodium dihydrogen phosphate dihydrate (3.62 g) were sequentially added, and the mixture was stirred at room temperature overnight. Diisopropyl ether (200 ml) was added to the reaction solution for liquid separation, and the organic layer was washed with 3N hydrochloric acid (50 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane to give the title compound (1.43 g) as a colorless powder.
¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H, s), 7.20-7.35 (4H, m), 7.65 (2H, d, J = 8.1 Hz), 8.18 (2H, d, J = 8.1 Hz).
MS (ESI) m / z: 213 (M + H) ^<+> .

[Reference Example 486] 2'-methyl- [1,1'-biphenyl] -4-carboxylic acid methyl ester

The compound (1.42 g) obtained in Reference Example 485 was suspended in methanol, thionyl chloride (1 ml) was added to this suspension, and the mixture was heated to reflux for 2 hours. After leaving to room temperature, a saturated aqueous sodium hydrogen carbonate solution (100 ml) and methylene chloride (100 ml) were added to the reaction solution to separate the layers. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (1.51 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 2.26 (3H, s), 3.94 (3H, s), 7.20-7.35 (4H, m), 7.40 (2H, d, J = 7.8 Hz), 8.08 (2H, d, J = 7.8 Hz).
MS (ESI) m / z: 227 (M + H) ^<+> .

[Reference Example 487] 2 '-[(Dimethylamino) methyl]-[1,1'-biphenyl] -4-carboxylic acid methyl ester

The compound (663 mg) obtained in Reference Example 486 was dissolved in 1,2-dichloroethane (30 ml), and N-bromosuccinimide (521 mg) and 2,2′-azobisisobutyronitrile (48.1 mg) were dissolved in this solution. ) Was added and heated to reflux for 1 hour. After completion of the reaction, the mixture was cooled to 0 ° C., dimethylamine (40% aqueous solution, 0.99 ml) was added, and the mixture was stirred at room temperature for 3 days. Water (100 ml) and methylene chloride (100 m) were added to the mixture and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (methanol: methylene chloride = 1: 25) to give the title compound (607 mg) as a colorless oil.
¹ H-NMR (CDCl ₃ ) 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 = 8.2 Hz), 7.52 (1H, dd, J = 7.4, 1.5 Hz), 8.07 (2H, d, J = 8.2 Hz).
MS (ESI) m / z: 270 (M + H) ^<+> .

[Reference Example 488] Lithium salt of 2 ′-[(dimethylamino) methyl]-[1,1′-biphenyl] -4-carboxylic acid

The title compound was obtained from the compound obtained in Reference Example 487 in the same manner as in Reference Example 322.
¹ H-NMR (DMSO-d ₆ ) δ: 2.06 (6H, s), 3.29 (2H, s), 7.20-7.38 (5H, m), 7.49 (1H, d , J = 7.3 Hz), 7.88 (2H, d, J = 8.0).
MS (ESI) m / z: 256 (M-Li + 2H) ^<+> .

[Reference Example 489] 4- [4- (methoxycarbonyl) phenyl] -2-methyl-1-pyridine N-oxide

The title compound was obtained from 4- (2-methylpyridin-4-yl) benzoic acid methyl ester (JP 2000-143623) by the method described in Reference Example 239.
¹ H-NMR (CDCl ₃ ) δ: 2.60 (3H, s), 3.96 (3H, s), 7.42 (1H, dd, J = 6.8, 2.7 Hz), 7.53 (1H, d, J = 2.7 Hz), 7.66 (2H, d, J = 8.2 Hz), 8.14 (2H, d, J = 8.2 Hz), 8.3
3 (1H, d, J = 6.8 Hz).
MS (FAB) m / z: 244 (M + H) ^<+> .

[Reference Example 490] 4- {2-[(Acetyloxy) methyl] pyridin-4-yl} benzoic acid methyl ester

A solution of the compound obtained in Reference Example 489 (980 mg) in acetic anhydride (25 ml) was stirred at 130 ° C. for 30 minutes. After cooling to 90 ° C., methanol (50 ml) was added and stirred for 1 hour. After adding methylene chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution (150 ml) to the reaction solution, solid sodium hydrogen carbonate was added until the reaction solution became basic. After stirring for 3 hours, the layers were separated, and the aqueous layer was extracted with methylene chloride (2 × 50 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (methylene chloride: methanol = 40: 1 → 10: 1), and further medium pressure column chromatography using silica gel as a carrier (hexane: ethyl acetate = 2: 1). → 1: 1) to give the title compound (749 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 3.96 (3H, s), 5.29 (2H, s), 7.47 (1H, dd, J = 5.1) , 1.7 Hz), 7.57-7.60 (1 H, m), 7.70 (2 H, d, J = 8.5 Hz), 8.15 (2 H, d, J = 8.5 Hz), 8 .68 (1H, d, J = 5.1 Hz). MS (ESI) m / z: 286 (M + H) ^<+> .

[Reference Example 491] 4- (2-{[(tert-Butoxycarbonyl) amino] methyl} pyridin-4-yl) benzoic acid methyl ester

Water (1.0 ml) and lithium hydroxide (137 mg) were added to a solution of the compound obtained in Reference Example 490 (532 mg) in tetrahydrofuran (4.0 ml) at room temperature. After stirring for 24 hours, tetrahydrofuran was distilled off under reduced pressure, and water (4.0 ml) and 1N hydrochloric acid (5.65 ml) were added. The resulting solid was collected by filtration, washed with water and dried to give a white solid (400 mg). A part of this solid (272 mg) was suspended in tetrahydrofuran (10 ml), and methanol (2.0 ml) and trimethylsilyldiazomethane (2.0 M hexane solution, 890 μl) were added at room temperature. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Acetic acid ethyl ester (5.0 ml), trimethylamine hydrochloride (12 mg), methanesulfonyl chloride (140 μl), and triethylamine (252 μl) were added to a solution of the obtained solid methylene chloride (10 ml) at room temperature. After stirring for 3 hours, a saturated aqueous sodium hydrogen carbonate solution (20 ml) and methylene chloride (20 ml) were added for liquid separation, and the aqueous layer was extracted with methylene chloride (2 × 15 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Sodium azide (155 mg) was added to a solution of the obtained reddish purple oily substance in N, N-dimethylformamide (5.0 ml) at room temperature. After stirring for 1 hour, water (100 ml) and methylene chloride (30 ml) were added for liquid separation, and the aqueous layer was extracted with methylene chloride (3 × 20 ml). The organic layers were combined and dried over anhydrous sodium sulfate, dioxane (5.0 ml) was added, and the mixture was concentrated to about 5 ml under reduced pressure. Tetrahydrofuran (5.0 ml), di-tert-butyl dicarbonate (400 mg), and 10% palladium-carbon (100 mg) were added to the obtained brown solution, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: acetone = 20: 1) to obtain the title compound (270 mg) as a pale yellow oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 3.96 (3H, s), 4.52 (2H, d, J = 5.4 Hz), 4.94 (0.5H , Br.s), 5.59 (0.5H, br.s), 7.42 (1H, dd, J = 5.1, 1.7 Hz), 7.51 (1H, br.s), 7 .69 (2H, d, J = 8.3 Hz), 8.15 (2H, d, J = 8.3 Hz), 8.61 (1H, d, J = 5.1 Hz).
MS (ESI) m / z: 343 (M + H) ^<+> .

[Reference Example 492] 1- (Phenylsulfonyl) piperidine-4-carboxylic acid ethyl ester

Triethylamine (1.40 ml) was added to a solution of ethyl isonipecotate (1.08 ml) in tetrahydrofuran (10 ml), benzenesulfonyl chloride (1.02 ml) was further added at 0 ° C., and the mixture was stirred at room temperature for 21 hours. After adding ice and stirring for 10 minutes, ethyl acetate and 0.5 N hydrochloric acid were added to form two layers. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to obtain the title compound (1.66 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1 Hz), 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, 11.4 Hz), 3.59-3.67 (2H, m), 4.10 ( 2H, q, J = 7.1 Hz), 7.51-7.63 (3H, m), 7.74-7.78 (2H, m).
MS (ESI) m / z: 298 (M + H) ^<+> .

[Reference Example 493] 1- (Phenylsulfonyl) piperidine-4-carboxylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 492.
¹ H-NMR (CDCl ₃ ) 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-Fluorobenzoyl) piperidine-4-carboxylic acid ethyl ester

In the same manner as in Reference Example 492, the title compound was obtained from isonipecotic acid ethyl ester and p-fluorobenzoyl chloride.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz), 4.30-4.70 ( 1H, br), 7.09 (2H, t, J = 8.8 Hz), 7.41 (2H, dd, J = 8.8, 5.4 Hz).
MS (ESI) m / z: 280 (M + H) ^<+> .

[Reference Example 495] 1- (4-Fluorobenzoyl) piperidine-4-carboxylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 494.
¹ H-NMR (CDCl ₃ ) 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 = 8.5 Hz), 7.40 (2H, dd, J = 8.5, 5.4 Hz).
MS (ESI) m / z: 252 (M + H) ^<+> .

[Reference Example 496] 4- (Pyrrolidin-1-ylcarbonyl) benzoic acid methyl ester

In the same manner as in Reference Example 492, the title compound was obtained from pyrrolidine and terephthalic acid monomethyl chloride.
¹ H-NMR (CDCl ₃ ) δ: 1.85-1.93 (2H, m), 1.94-2.01 (2H, m), 3.38 (2H, t, J = 6.6 Hz) 3.66 (2H, t, J = 6.6 Hz), 3.94 (3H, s), 7.57 (2H, d, J = 8.6 Hz), 8.07 (2H, d, J = 8.6 Hz).
MS (ESI) m / z: 234 (M + H) ^<+> .

[Reference Example 497] 4- (Pyrrolidin-1-ylcarbonyl) benzoic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 496.
¹ H-NMR (CDCl ₃ ) δ: 1.85-2.03 (4H, m), 3.43 (2H, t, J = 6.6 Hz), 3.67 (2H, t, J = 6. 6 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.14 (2H, d, J = 8.6 Hz).
MS (ESI) m / z: 220 (M + H) ^<+> .

[Reference Example 498] 4- (Pyrrolidin-1-ylmethyl) benzoic acid methyl ester

The compound obtained in Reference Example 496 was treated in the same manner as in Reference Example 212 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 8.3 Hz), 7.98 (2H, d, J = 8.3 Hz).
MS (ESI) m / z: 220 (M + H) ^<+> .

[Reference Example 499] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4-[(methylamino) carbonyl] cyclohexylcarbamic acid 9H-fluoren-9-ylmethyl ester

To a solution of the compound obtained in Reference Example 436 (823 mg) in methanol (20 ml) was added 10% palladium carbon catalyst (117 mg), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The catalyst was filtered off with a glass filter, and the filtrate was concentrated under reduced pressure. To a 1,2-dimethoxyethane (15 ml) solution of the obtained colorless viscous oil (622 mg), saturated aqueous sodium hydrogen carbonate solution (5 ml), water (2 ml), fluoren-9-ylmethyl succinimidyl carbonate (867 mg). ) And stirred at room temperature for 13 hours. The reaction solution was diluted with ethyl acetate and water was added to form two layers. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with slurry by adding ethyl acetate, and the white powder was collected by filtration. The mother liquor was concentrated under reduced pressure, washed with slurry with diethyl ether, and the white powder was collected by filtration. The powder collected by filtration was dissolved in ethyl acetate and mixed, and the solvent was evaporated under reduced pressure. The residue was dried with a vacuum pump to obtain the title compound (939 mg) as a white powder.
¹ H-NMR (CDCl ₃ ) 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 = 4.9 Hz), 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 = 7.6 Hz), 7.58 (2H, br.d, J = 7.1 Hz), 7.76 (2H, d, J = 7.6 Hz).
MS (ESI) m / z: 394 (M-COOtBu) ^<+> .

[Reference Example 500] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4-[(methylamino) carbothioyl] cyclohexylcarbamic acid 9H-fluoren-9-ylmethyl ester

In the same manner as in Reference Example 443, the title compound was obtained from the compound obtained in Reference Example 499.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, br.s), 1.55-2.10 (6H, m), 2.45-2.72 (1H, br), 3.17 (3H, d, J = 4.4 Hz), 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 = 7.6 Hz), 7.42-7.53 (0.5H, br), 7.58 (2H, br. D) , J = 6.6 Hz), 7.75 (2H, d, J = 7.6 Hz), 7.80-7.90 (0.5 H, br).
MS (ESI) m / z: 410 (M-COOtBu) ^<+> .

[Reference Example 501] (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(methylamino) carbotyoyl] Cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 500 in a manner similar to that described in Reference Example 444.
¹ H-NMR (CDCl ₃ ) 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 = 4.9 Hz), 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, 2.2 Hz), 7.96-8.07 (1H, br), 8.17 (1H, d, J = 8.8 Hz), 8.30 (1H , D, J = 2.0 Hz), 9.76 (1H, s).
MS (ESI) m / z: 414 (M- ^t Bu + H) ^<+> .

[Reference Example 502] 2,2-Dichloro-N- (5-chloropyrimidin-2-yl) acetamide

To a solution of 2-amino-5-chloropyrimidine (1.30 g) in N, N-dimethylformamide (30 ml) was added dichloroacetyl chloride (1.44 ml) and sodium bicarbonate (1.26 g), and the mixture was stirred at room temperature for 1 hour. Stir. The solvent was distilled off under reduced pressure, and methylene chloride and water were added to the residue for liquid separation. The aqueous layer was extracted with methylene chloride, the organic layers were combined, washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: ethyl acetate = 1: 1) using silica gel as a carrier. The obtained white solid was slurry washed with a mixed solvent of hexane-diethyl ether (4: 1) and collected by filtration to give the title compound (1.24 g) as a white solid.
¹ H-NMR (CDCl ₃ ) 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-chloropyrimidin-2-yl) amino] -2-oxoethanethioyl} amino) -5-[(dimethylamino) Carbonyl] cyclohexylcarbamic acid tert-butyl ester

The compound (8.03 g) obtained in Reference Example 144, the compound (6.76 g) obtained in Reference Example 502, and sulfur (947 mg) were added to N, N-dimethylformamide (90 ml), heated to 120 ° C., and the mixture was mixed. Diisopropylethylamine (9.57 ml) was added to the mixture and stirred at the same temperature for 10 minutes. The solvent was distilled off under reduced pressure, methylene chloride was added to the residue, and the insoluble material was removed by Celite filtration. Water was added to the filtrate for liquid separation, and the organic layer was washed with water. The purified product obtained through flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 19: 1) was dissolved in methylene chloride, hexane was added and the solid was collected by filtration to give the title compound (940 mg) as a pale yellow solid. Got as. The filtrate was purified by silica gel column chromatography to obtain the title compound (940 mg) containing N, N-dimethylformamide as a light brown solid.
¹ H-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).

[Reference Example 504] 2-Chloro-N- (4-chloro-3-nitrophenyl) acetamide

In the same manner as in Reference Example 502, the title compound was obtained from 4-chloro-3-nitroaniline and chloroacetyl chloride.
¹ H-NMR (CDCl ₃ ) δ: 4.23 (2H, s), 7.54 (1H, d, J = 8.8 Hz), 7.74 (1H, dd, J = 8.8, 2. 4 Hz), 8.22 (1 H, d, J = 2.4 Hz), 8.39 (1 H, br. S).

[Reference Example 505] (1R, 2S, 5S) -2-{[2- (4-Chloro-3-nitroanilino) -2-oxoethanethioyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamine Acid tert-butyl ester

Sulfur (128 mg) and triethylamine (833 μl) were added to a solution of the compound (498 mg) obtained in Reference Example 504 in N, N-dimethylformamide (4 ml), and the mixture was stirred at room temperature for 1 hour. The compound (571 mg) obtained in Reference Example 144 and 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (767 mg) were added to the reaction solution, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, methylene chloride and water were added to the residue for liquid separation, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by flash column chromatography using silica gel as a support (ethyl acetate) gave the title compound (688 mg) as a yellow solid.
¹ H-NMR (CDCl ₃ ) 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 (1 H, br. S), 7.52 (1 H, d, J = 8.6 Hz), 7. 69 (1H, d, J = 8.6 Hz), 8.39 (1 H, br. S), 9.95 (1 H, br. S), 10.37 (1 H, s).
MS (ESI) m / z: 528 (M + H) ^<+> .

[Reference Example 506] (1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4-{[(7-chlorocinnolin-3-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester

In the same manner as in Reference Example 97, the compound obtained in Reference Example 96 and the compound obtained in Reference Example 298 were condensed to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.2 Hz), 1.36 (9H, s), 1.53-2.16 (6H, m), 2.48 (1H, br.s), 4.17 (2H, q, J = 7.2 Hz), 4.30-4.35 (2H, m), 4.86 (1H, br.s), 7.78 (1H, dd, J = 8.8, 2.0 Hz), 7.97 (1H, d, J = 8.8 Hz), 8.59-8.60 (1H, m), 8.64 (1H, d, J = 8.6 Hz), 8.73 (1H, s).
MS (ESI) m / z: 477 (M + H) ^<+> .

[Reference Example 507] (1S, 3R, 4S) -3-[(tert-Butoxycarbonyl) amino] -4-{[(7-chlorocinnolin-3-yl) carbothioyl] amino} cyclohexanecarboxylic acid ethyl ester

In the same manner as in Reference Example 443, the title compound was obtained from the compound obtained in Reference Example 506.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 1.37 (9H, br.s), 1.59-2.26 (6H, m), 2 .49 (1H, br.s), 4.17 (2H, q, J = 7.1 Hz), 4.54 (1H, br.s), 4.83-4.87 (2H, m), 7 .76 (1H, dd, J = 8.7, 1.8 Hz), 7.97 (1H, d, J = 8.7 Hz), 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-chlorocinnolin-3-yl) carbothioyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 251, the title compound was obtained by condensing carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 507 and dimethylamine hydrochloride.
¹ H-NMR (CDCl ₃ ) 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, 2.0 Hz), 7.97 (1H, d, J = 8.7 Hz), 8.56 (1H , S), 9.19 (1H, br. S), 10.60 (1H, d, J = 7.8 Hz).
MS (ESI) m / z: 492 (M + H) ^<+> .

[Reference Example 509] (1S, 3R, 4S) -3-Amino-4-{[(7-chlorocinnolin-3-yl) carbothioyl] amino} -N, N-dimethylcyclohexanecarboxamide

In the same manner as in Reference Example 325, the title compound was obtained from the compound obtained in Reference Example 508.
MS (ESI) m / z: 392 (M + H) ^<+> .

[Reference Example 510] (1R, 2S, 5S) -2-({[(4-chlorobenzoyl) amino] carbonyl} amino) -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

To a solution of p-chlorobenzamide (311 mg) in dichloroethane (20 ml), oxalyl chloride (435 μl) was added and heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, and a solution of the residue in acetonitrile (10 ml) was added dropwise to a solution of the compound (571 mg) obtained in Reference Example 144 in acetonitrile (20 ml) and stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure, ether was added to the residue, and the solid was collected by filtration to give the title compound (678 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) 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 = 8.3 Hz), 7.88 (2H, br.s), 8.92 (1H, d, J = 7.6 Hz), 9.78 (1H, s).
MS (ESI) m / z: 489 (M + Na) ^<+> .

[Reference Example 511] (1S, 3R, 4S) -3-Amino-4-({[(4-chlorobenzoyl) amino] carbonyl} amino) -N, N-dimethylcyclohexanecarboxamide

The title compound was obtained from the compound obtained in Reference Example 510 in a manner similar to that described in Reference Example 325.
¹ H-NMR (CDCl ₃ ) 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 = 8.5 Hz), 7.86 (2H, d, J = 8.5 Hz), 8.85 (1H, br. S), 8.93 (1H, d, J = 7.3 Hz).
MS (ESI) m / z: 367 (M + H) ^<+> .

[Reference Example 512] (E) -3- (5-Chloropyridin-2-yl) -2-acrylic acid methyl ester

To a solution of sodium hydride (60% oil, 580 mg) suspended in tetrahydrofuran (30 ml), a solution of 2- (dimethoxyphosphoryl) acetic acid methyl ester (2.35 ml) in tetrahydrofuran (30 ml) was added dropwise at −30 ° C. did. After stirring at the same temperature for 30 minutes, a solution of tetrahydrofuran (10 ml) and 5-chloropyridine-2-carboxaldehyde (J. Med. Chem. 1970, 13 卷, 1124) (1.96 g) in tetrahydrofuran (15 ml) Was added. After gradually raising the temperature to room temperature over 1 hour, water (100 ml) and diethyl ether (50 ml) were added and separated, and the aqueous layer was extracted with diethyl ether (50 ml). The organic layers were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane (30 ml) was added to the obtained white solid, stirred for 30 minutes, and then collected by filtration to obtain the title compound (1.89 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 3.82 (3H, s), 6.91 (1H, dd, J = 15.7, 0.9 Hz), 7.36 (1H, d, J = 8. 3 Hz), 7.64 (1 H, d, J = 15.7 Hz), 7.68 (1 H, ddd, J = 8.3, 2.4, 0.9 Hz), 8.59 (1 H, d, J = 2.4 Hz).
MS (ESI) m / z: 197 (M ^<+> ).

[Reference Example 513] (1R, 2S, 5S) -2-{[(E) -3- (5-chloropyridin-2-yl) acryloyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by condensing the lithium salt of the carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 512 with the compound obtained in Reference Example 144 in the same manner as in Reference Example 97. .
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.65 to 1.88 (3H, m), 1.88 to 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 = 15.4 Hz), 7. 30 (1H, d, J = 8.3 Hz), 7.54 (1H, d, J = 15.4 Hz), 7.65 (1H, dd, J = 8.3, 2.4 Hz), 8.53 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 451 (M + H) ^<+> .

[Reference Example 514] 3- (4-Chlorophenyl) -2-fluoro-3-hydroxypropionic acid ethyl ester

To a solution of 4-chlorobenzaldehyde (141 mg) in benzene (20 ml), zinc powder (1.96 g) was added, and a catalytic amount of iodine was added while heating under reflux. A benzene solution (2.5 ml) of bromofluoroacetic acid ethyl ester (185 mg) was added dropwise thereto and stirred for 2.5 hours. The reaction mixture was ice-cooled, 1N hydrochloric acid (12.5 ml) was added, and the mixture was stirred at room temperature for 1.5 hr. Water and ethyl acetate were added for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (117 mg) as a colorless oily mixture of diastereomeric mixtures.
¹ H-NMR (CDCl ₃ ) δ: 1.16 to 1.24 (3H, m), 3.35 (1H, br.d, J = 51.9 Hz), 4.15 to 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-Chlorophenyl) -2-fluoroacrylic acid ethyl ester

Pyridine (100 μl) was added to a solution of the compound (51 mg) obtained in Reference Example 514 in methylene chloride (1.0 ml), cooled to 0 ° C., thionyl chloride (20 μl) was added, and the mixture was stirred at 0 ° C. for 20 minutes. 1N Aqueous hydrochloric acid solution and ethyl acetate were added for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (2 ml), 1,8-diazabicyclo [5.4.0] undec-7-ene (34 μl) was added, and the mixture was stirred at room temperature for 3.5 hours. 1N Hydrochloric acid and methylene chloride were added for liquid separation, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (22 mg) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.2 Hz), 4.35 (2H, q, J = 7.2 Hz), 6.87 (1H, d, J = 34.9 Hz), 7.37 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz).

[Reference Example 516] (Z) -3- (4-Chlorophenyl) -2-fluoroacrylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 515.
¹ H-NMR (DMSO-d ₆ ) δ: 7.06 (1H, d, J = 36.4 Hz), 7.52 (2H, d, J = 8.2 Hz), 7.72 (2H, d, J = 8.2 Hz).
MS (ESI-negative) m / z: 198 (M-H) ^- .

[Reference Example 517] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4-[(dimethylamino) carbonyl] cyclohexylcarbamic acid 2,2,2-trichloroethyl ester

To a pyridine (175 ml) solution of the compound (10.0 g) obtained in Reference Example 144, 2,2,2-trichloroethyl chloroformate (10.6 ml) was added dropwise and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and methylene chloride and 0.5N hydrochloric acid aqueous solution were added for liquid separation, and the obtained organic layer was washed twice with 0.5N hydrochloric acid aqueous solution and then once with saturated saline. Washed. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of methylene chloride, hexane was added, and the solid was collected by filtration. This was slurry washed with diethyl ether to give the title compound (13.6 g) as a white solid.
¹ H-NMR (CDCl ₃ ) 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 = 7.3 Hz).
MS (ESI) m / z: 460 (M + H) ^<+> .

[Reference Example 518] (1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro [1,3] thiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexylcarbamic acid 2,2,2-trichloroethyl ester

In the same manner as described in Reference Example 252, the compound obtained in Reference Example 517 was treated with hydrochloric acid, deprotected, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 6.8 Hz), 7.36 (1H, br.d, J = 8.5 Hz).
MS (ESI) m / z: 540 (M + H) ^<+> .

[Reference Example 519] (1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro [1,3] thiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester

The compound (5.01 g) obtained in Reference Example 518 was dissolved in a mixed solvent of ethanol (100 ml) and water (5 ml), and zinc (6.06 g) and ammonium chloride (2.48 g) were added. Stir for 5 hours. Zinc was filtered off using celite, sodium hydrogen carbonate (7.78 g) and di-tert-butyl dicarbonate (6.08 g) were added to the filtrate, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, methylene chloride and water were added to the residue for liquid separation, and the aqueous layer was extracted twice with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography using silica gel as a carrier (ethyl acetate: methanol = 7: 3). This was purified by preparative recycle HPLC (Nippon Analytical Industry LC908-C60, column: using JAIGEL 1H-40 and 2H-40, solvent: chloroform) to obtain the title compound (2.30 g) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Reference Example 520] 2,2-Dichloro-N- (5-chloropyridin-2-yl) acetamide

The title compound was obtained from 2-amino-5-chloropyridine in the same manner as described in Reference Example 457.
¹ H-NMR (CDCl ₃ ) δ: 6.06 (1H, s), 7.73 (1H, dd, J = 8.8, 2.4 Hz), 8.15 (1H, dd, J = 9. 0, 0.5 Hz), 8.30 (1 H, dd, J = 2.5, 0.5 Hz), 8.78 (1 H, s). MS (ESI) m / z: 239 (M + H) ^<+> .

[Reference Example 521] (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[(methylamino) Carbonyl] cyclohexylcarbamic acid tert-butyl ester

To a solution of the compound (1.01 g) obtained in Reference Example 436 in methanol (50 ml) was added 10% palladium carbon catalyst (0.35 g), and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (5.0 ml), the compound (600 mg) obtained in Reference Example 520, diisopropylethylamine (5.0 ml) and sulfur (80.3 mg) were added, and the mixture was stirred at 120 ° C. for 2 hours. Stir. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted twice with methylene chloride (200 ml). The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 50: 1 → 30: 1) to obtain the title compound (812 mg) as a yellow glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.25-2.50 (7H, m), 1.46 (9H, s), 2.82 (3H, d, J = 4.9 Hz), 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, 22.4 Hz), 8.02 (1H, s), 8.10-8.23 (1H, m), 8.31 (1H, d, J = 2.4 Hz), 9.50-9.85 (0.2 H, br), 9.85-10.15 (0.8 H, br), 10.56 (1 H, s).
MS (ESI) m / z: 470 (M + H) ^<+> .

[Reference Example 522] (1S, 3R, 4S) -3-Amino-4-({2-[(5-fluoropyridin-2-yl) amino] -2-oxoethanethiol} amino) -N, N -Dimethylcyclohexanecarboxamide hydrochloride

In the same manner as in the method described in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 427.
¹ H-NMR (DMSO-d ₆ ) 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, 9.0 Hz), 8.14 (1H, dd, J = 9. 0, 4.2 Hz), 8.33 (3 H, br. S), 8.44 (1 H, d, J = 2.9 Hz), 10.64 (1 H, s), 10.97 (1 H, d, J = 7.1 Hz).
MS (ESI) m / z: 368 (M + H) ^<+> .

[Reference Example 523] 3-Amidinobenzoic acid ethyl ester hydrochloride

To a solution of 3-cyanobenzoic acid (5 g) in ethanol (100 ml), hydrochloric acid gas was blown and saturated with stirring under ice cooling. Ethanol (400 ml) was added to the resulting suspension to dissolve it, and the mixture was warmed to room temperature and sealed up and left for 18 hours. Concentrated to dryness under reduced pressure, ethanol (100 ml) was added to the resulting residue to dissolve, and ammonia gas was blown and saturated with stirring under ice cooling. After raising the temperature to room temperature, it was sealed and left for 18 hours. The residue obtained by distilling off the solvent under reduced pressure was purified with a synthetic adsorbent HP-20 (water → acetonitrile: water = 1: 4). The obtained crude product was dissolved in methanol / dichloromethane = 1/4, the insoluble material was filtered off, and further purified by silica gel chromatography (methanol: methylene chloride = 1: 4) to give the title compound (5.53 g). Obtained as a colorless powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (3H, t, J = 7.0 Hz), 4.38 (2H, q, J = 7 Hz), 7.78 (1H, t, J = 7.8 Hz), 8.11 (1H, dd, J = 7.8, 1.0 Hz), 8.27 (1H, d, J = 7.8 Hz), 8.38 (1H, d, J = 1) .5 Hz), 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) methyl] benzoic acid ethyl ester

Diisopropylethylamine (952 μl) and di-tert-butoxycarbonate (480 mg) were added to a solution of the compound (250 mg) obtained in Reference Example 523 in methanol (5.0 ml). After stirring for 3 days, the solvent was distilled off under reduced pressure, and the resulting residue was purified using medium pressure column chromatography using silica gel as a carrier (methylene chloride: methanol = 25: 1) to give the title compound (285 mg). Obtained as a white foamy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.2 Hz), 1.56 (9H, s), 4.41 (2H, q, J = 7.2 Hz), 7 .52 (1H, t, J = 7.8 Hz), 8.14 (1H, d, J = 7.8 Hz), 8.19 (1H, d, J = 7.8 Hz), 8.43 (1H, s).
MS (ESI) m / z: 293 (M + H) ^<+> .

[Reference Example 525] (1R, 2S, 5S) -2-[(3-cyanobenzoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester

Diisopropylethylamine (730 μl) was added to a solution of the compound obtained in Reference Example 144 (800 mg) and 3-cyanobenzoyl chloride (560 mg) in methylene chloride (30 ml) at room temperature. After stirring for 4 hours, water and a saturated aqueous ammonium chloride solution were added, and after liquid separation, the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (methylene chloride: acetone = 5: 1 → 1: 1) to give the title compound (1.15 g ) Was obtained as a white foamy solid.
¹ H-NMR (CDCl ₃ ) 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 = 7.9 Hz), 7.75 (1H, d) , J = 7.9 Hz), 8.06-8.16 (3H, m).
MS (ESI) m / z: 415 (M + H) ^<+> .

[Reference Example 526] 3-[[(Ethoxycarbonyl) amino] (imino) methyl] benzoic acid ethyl ester

Methylene chloride (10 ml), diisopropylethylamine (952 μl) and chloroformic acid ethyl ester (160 μl) were added to the compound (250 mg) obtained in Reference Example 523. After stirring for 8 hours, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added, the layers were separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using medium pressure column chromatography using silica gel as a carrier (methylene chloride: methanol = 25: 1). The title compound (270 mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1 Hz), 1.40 (3H, t, J = 7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 4.39 (2H, q, J = 7.1 Hz), 6.84 (1H, br.s), 7.51 (1H, t, J = 7.8 Hz), 8.10− 8.25 (2H, m), 8.45 (1H, s), 9.63 (1H, br. S).
MS (ESI) m / z: 265 (M + H) ^<+> .

[Reference Example 527] 2,2-Dichloro-N- (5-fluoropyridin-2-yl) acetamide

To a solution of 2-amino-5-fluoropyridine (250 mg) in acetic acid ethyl ester (10 ml) was added dichloroacetyl chloride (279 μl) at room temperature, followed by stirring at 60-70 ° C. for 2.5 hours. After cooling the reaction solution, saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound (438 mg).
¹ H-NMR (CDCl ₃ ) 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-fluoropyridin-2-yl) amino] -2-oxoethanethiol} Amino) cyclohexylcarbamic acid tert-butyl ester

  N, N-dimethylformamide (1.0 ml) and diisopropylethylamine (1.0 ml) were added to the compound obtained in Reference Example 527 (112 mg), the compound obtained in Reference Example 144 (143 mg) and sulfur (17 mg), and the mixture was added. Was stirred at 130 ° C. for 20 minutes. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with methylene chloride. The solution was purified by silica gel column chromatography (methylene chloride: methanol = 99: 1) and washed with diisopropyl ether to give the title compound (121 mg). The NMR data agreed with that of the compound of Reference Example 424.

[Reference Example 529] 4-morpholinobenzoic acid methyl ester

Under ice cooling, thionyl chloride (436 μl) was added dropwise to methanol (10 ml). To this solution, 4-morpholinobenzoic acid (207 mg) was added and heated under reflux for 1.5 hours, and then the solvent was distilled off under reduced pressure. Methylene chloride and water were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 3.28 (4H, t, J = 4.9 Hz), 3.84-3.87 (7H, m), 6.86 (2H, dt, J = 9. 6, 2.5 Hz), 7.94 (2H, dt, J = 9.6, 2.4 Hz).
MS (EI) m / z: 222 (M + H) ^<+> .

[Reference Example 530] 4- (3-Oxomorpholin-4-yl) benzoic acid methyl ester

Benzyltriethylammonium chloride (639 mg) and potassium permanganate (222 mg) were added to a methylene chloride (10 ml) solution of the compound (207 mg) obtained in Reference Example 529, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen sulfite solution was added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography using silica gel as a carrier (hexane: ethyl acetate = 1: 2) to obtain the title compound (41 mg).
¹ H-NMR (CDCl ₃ ) 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, 2.2 Hz), 8.08 (2H, dt, J = 9.0, 2.2 Hz).
MS (EI) m / z: 236 (M + H) ^<+> .

[Reference Example 531] 4- (3-Oxomorpholin-4-yl) benzoic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 530.
¹ H-NMR (DMSO-d ₆ ) δ: 3.78-3.82 (2H, m), 3.97-4.01 (2H, m), 4.23 (2H, s), 7.57 (2H, dt, J = 9.1, 2.2 Hz), 7.96 (2H, dt, J = 9.1, 2.2 Hz), 12.97 (1H, br.s).

[Reference Example 532] 3- (5-Chlorothien-2-yl) -2-fluoro-3-hydroxypropionic acid ethyl ester

To a benzene (200 ml) solution of 5-chlorothiophene-2-carboxaldehyde (1.07 ml), zinc powder (19.6 g) was added and heated to reflux. A catalytic amount of iodine was added thereto, and then a benzene (25 ml) solution of bromofluoroacetic acid ethyl ester (3.70 g) was added dropwise. After heating to reflux for 1.5 hours, a catalytic amount of iodine was added, and the mixture was further heated to reflux for 3.5 hours. The reaction mixture was allowed to cool, 1N aqueous hydrochloric acid solution (125 ml) was added under ice cooling, and the mixture was stirred for 1 hr. The insoluble material was filtered through Celite and washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 4: 1) to obtain the title compound (2.53 g).
¹ H-NMR (CDCl ₃ ) 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-chlorothien-2-yl) -2-fluoroacrylic acid ethyl ester

Pyridine (4.70 ml) and thionyl chloride (849 μl) were added to a solution of the compound obtained in Reference Example 532 (2.46 g) in methylene chloride (50 ml) under ice cooling, and the mixture was added at 0 ° C. for 30 minutes and at room temperature for 1 minute. Stir for hours. 1N Hydrochloric acid aqueous solution was added to the reaction solution for liquid separation, and the aqueous layer was extracted with methylene chloride. The organic layer was washed with 1N aqueous hydrochloric acid and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (150 ml), 1,8-diazabicyclo [5.4.0] undec-7-ene (1.60 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography using silica gel as a carrier (hexane: ethyl acetate = 7: 1) to obtain the title compound (1.05 g).
¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 4.34 (2H, q, J = 7.1 Hz), 6.90 (1H, dd, J = 3.9, 2.0 Hz), 7.06 (1H, d, J = 33.7 Hz), 7.08-7.10 (1H, m).
MS (FAB) m / z: 235 (M + H) ^<+> .

[Reference Example 534] (Z) -3- (5-chlorothien-2-yl) -2-fluoroacrylic acid

In the same manner as in Reference Example 274, the title compound was obtained from the compound obtained in Reference Example 533.
¹ H-NMR (DMSO-d ₆ ) δ: 7.22 (1H, dd, J = 3.9, 2.0 Hz), 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-tetrahydro-4H-thiazolo [4,5-d] azepin-2-ylamine

In the same manner as described in Reference Example 475, the title compound was obtained from 5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepin-2-ylamine (JP-A-2-45489). Got.
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Reference Example 536] 2-Bromo-6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine

In the same manner as in Reference Example 476, the title compound was obtained from the compound obtained in Reference Example 535.
¹ H-NMR (CDCl ₃ ) 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-tetrahydro-4H-thiazolo [4,5-d] azepine-2-carboxylic acid lithium salt

In the same manner as in Reference Example 10, the title compound was obtained from the compound obtained in Reference Example 536.
¹ H-NMR (DMSO-d ₆ ) 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-tetrahydro [1,6] naphthyridine-2-carbonitrile hydrochloride

4N hydrochloric acid was added to a solution of 2-cyano-7,8-dihydro-5H- [1,6] naphthyridine-6-carboxylic acid tert-butyl ester (WO00 / 09480) (3.74 g) in methylene chloride (5.0 ml). -Dioxane solution (14 ml) was added and stirred at room temperature for 65 minutes and at 40 ° C for 40 minutes. 4N Hydrochloric acid-dioxane solution (8 ml) was added to the reaction mixture, and the mixture was further stirred at 45 ° C. for 75 min. Acetic acid ethyl ester was added to the reaction mixture, and the precipitated powder was collected by filtration to give the title compound (3.20 g) as a colorless powder.
¹ H-NMR (DMSO-d ₆ ) δ: 3.14 (2H, t, J = 6.4 Hz), 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-tetrahydro [1,6] naphthyridine-2-carbonitrile

In the same manner as in Reference Example 9, the compound obtained in Reference Example 538 was reacted to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H, s), 2.81 (2H, q, J = 6.0 Hz), 3.10 (2H, t, J = 6.0 Hz), 3 .71 (2H, s), 7.44 (1H, d, J = 8.1 Hz), 7.47 (1H, d, J = 7.8 Hz).

[Reference Example 540] 6-Methyl-5,6,7,8-tetrahydro [1,6] naphthyridine-2-carboxylic acid hydrochloride

Concentrated hydrochloric acid (12 ml) was added to the compound (2.46 g) obtained in Reference Example 539 and heated at 100-110 ° C. for 5.5 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added, and the mixture was made alkaline with 1N aqueous sodium hydroxide solution. The solution was concentrated to about half, neutralized with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. Ethanol was added to the residue, the mixture was heated at 40-50 ° C., and insoluble materials were removed through celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethanol, 1N hydrochloric acid-ethanol (18 ml) was added, and the solvent was evaporated under reduced pressure. Acetic acid ethyl ester was added to the residue, and the insoluble material was collected by filtration to give the crude title compound (2.33 g).
¹ H-NMR (DMSO-d ₆ ) δ: 2.93 (3H, s), 3.16 (1H, d, J = 16.4 Hz), 3.37-3.80 (3H, m), 4 .35-4.47 (1H, m), 4.59 (1H, d, J = 16.8 Hz), 7.83 (1H, d, J = 8.1 Hz), 7.93 (1H, d, J = 8.1 Hz).

[Reference Example 541] (1S, 3R, 4S) -4-{[(Benzyloxy) carbonyl] amino} -3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid tert-butyl ester

The compound (7.15 g) obtained in Reference Example 142 was dissolved in methylene chloride (100 ml), and 2-methyl-2-propanol (4.88 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride A salt (4.89 g) and 4-dimethylaminopyridine (2.08 g) were added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with methylene chloride (200 ml), washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: acetone = 30: 1 → 20: 1) to obtain the title compound (7.07 g).
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoethane Oil} amino) cyclohexanecarboxylic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 541 (700 mg) in methanol (7.0 ml) -tetrahydrofuran (7.0 ml) was added 10% palladium carbon catalyst (wet, 350 mg), and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. did. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (10 ml), sulfur (65 mg), the compound obtained in Reference Example 520 (374 mg) and diisopropylethylamine (0.816 ml) were added, and the mixture was stirred at 120 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride was added to the residue, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 100: 1 → 50: 1) to obtain the title compound (373 mg).
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 8.19. (1H, d, J = 9.0 Hz), 8.32 (1H, d, J = 2.4 Hz), 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-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) cyclohexanecarboxylic acid tert -Butyl ester hydrochloride

To a solution of the compound obtained in Reference Example 542 (530 mg) in ethyl acetate (3.90 ml) was added 1N hydrochloric acid-ethyl acetate solution (1.30 ml), and the mixture was stirred at room temperature for 3 hours. Acetic acid ethyl ester was added to the reaction mixture, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (284 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 6.8 Hz).
MS (ESI) m / z: 413 (M + H) ^<+> .

[Reference Example 544] (1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} Amino) cyclohexanecarboxylic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 541 (1.00 g) in methanol (20 ml) -tetrahydrofuran (20 ml) was added 10% palladium carbon catalyst (wet, 500 mg), and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N, N-dimethylformamide (10 ml), and the compound (231 mg) obtained in Reference Example 266, 1-hydroxybenzotriazole was dissolved in this solution. (139 mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288 mg) were sequentially added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a 10% aqueous citric acid solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine. The oil layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (364 mg).
¹ H-NMR (CDCl ₃ ) 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, 2.6 Hz), 8.00 (1H, br.s), 8.18 (1H, d, J = 8.9 Hz), 8.31 (1H, d, J = 2.5 Hz) , 9.72 (1H, br.s).
MS (ESI) m / z: 441 (M-tBu) ^<+> .

[Reference Example 545] 2-methyl-1,2,3,4-tetrahydro-6-isoquinolinecarboxylic acid methyl ester

3,4-Dihydro (1H) isoquinoline-2,6-dicarboxylic acid 2- (tert-butyl) ester 6-methyl ester (WO00 / 09480) (344 mg) in methylene chloride (6 ml) under ice-cooling and trifluoro Acetic acid (3 ml) was added and stirred for 30 minutes. The reaction mixture was concentrated, diluted with chloroform, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform / methanol (4/1). The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 20: 1 → 1: 1) to obtain 1,2,3,4- Tetrahydroisoquinoline-6-carboxylic acid methyl ester (154 mg) was obtained. This was dissolved in methylene chloride (5 ml), and formalin (90.6 μl) was added at room temperature. After stirring for 10 minutes, acetic acid (46 μl) and sodium triacetoxyborohydride (269 mg) were added under ice cooling. After stirring at room temperature for 105 minutes, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (162 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 2.70 (2H, dd, J = 6.0 Hz), 2.96 (2H, dd, J = 6.0 Hz), 3 .62 (2H, s), 3.90 (3H, s), 7.08 (1H, d, J = 7.6 Hz), 7.78 (1H, d, J = 7.6 Hz), 7.80 (1H, s).
MS (ESI) m / z: 206 (M + H) ^<+> .

[Reference Example 546] (1S, 2R, 4S) -4- (aminocarbonyl) -2-[(tert-butoxycarbonyl) amino] cyclohexylcarbamic acid fluoren-9-ylmethyl ester

Under cooling with ice, the compound (1.92 g) obtained in Reference Example 142 was dissolved in N, N-dimethylformamide (30 ml), and ammonium chloride (523 mg), 1-hydroxybenzotriazole (661 mg), 1- (Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.41 g) and diisopropylethylamine (1.70 ml) were sequentially added, and the mixture was allowed to stand at room temperature and stirred for 3 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and 10% aqueous citric acid solution were added to the residue to separate the layers. The oil layer was washed with saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was solidified by adding hexane to crude (1R, 2S, 5S) -5- (aminocarbonyl) -2-{[(benzyl Oxy) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester (1.66 g) was obtained. A mixture of this crude product (1.65 g), 10% palladium carbon catalyst (400 mg) and methanol (150 ml) was stirred overnight at room temperature under a hydrogen atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was succinimidylcarboxylic acid 9-fluorenylmethyl ester (2.13 g), 1,2-dimethoxyethane (130 ml) and saturated carbonic acid. Aqueous sodium hydrogen solution (130 ml) was added, and the mixture was stirred overnight at room temperature. To the reaction mixture are added ethyl acetate, saturated brine and water, and the mixture is separated. The obtained organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure to give the title compound (1.99 g). It was.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.53 to 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 = 7.3 Hz), 7.53-7.61 (2H, m), 7.76 (2H, d) , J = 7.3 Hz).
MS (ESI) m / z: 502 (M + Na) ^<+> .

[Reference Example 547] (1S, 2R, 4S) -4- (aminocarbothioyl) -2-[(tert-butoxycarbonyl) amino] cyclohexylcarbamic acid fluoren-9-ylmethyl ester

The compound (1.98 g) obtained in Reference Example 546 was dissolved in tetrahydrofuran (200 ml), and Lawesson's reagent (1.22 g) was added to the solution, followed by stirring at room temperature for 4 days. Further, Lawesson's reagent (0.50 g) was added to the reaction solution and stirred overnight. Silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 2: 1). Diethyl ether was added to the obtained oil and stirred, and the precipitated powder was collected by filtration to give the title compound (1.25 g).
¹ H-NMR (CDCl ₃ ) 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 = 7.3 Hz), 7.57 (3H, br.s). ), 7.76 (2H, d, J = 7.1 Hz).
MS (ESI) m / z: 518 (M + Na) ^<+> .

[Reference Example 548] (1R, 2S, 5S) -5- (Aminocarbothioyl) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) cyclohexyl Carbamic acid tert-butyl ester and (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-cyanocyclohexylcarbamic acid tert -Butyl ester

The compound (4.64 g) obtained in Reference Example 547 was dissolved in N, N-dimethylformamide (50 ml), piperidine (2.78 ml) was added to this solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (methanol: methylene chloride = 3: 47 → 3: 17) to obtain crude (1R, 2S, 5S) -2-amino-5- (aminocarbotyoyl). ) Cyclohexylcarbamic acid tert-butyl ester (2.17 g) was obtained. This compound was dissolved in N, N-dimethylformamide (100 ml), and the compound (1.78 g), 1-hydroxybenzotriazole (1.07 g) and 1- (dimethylaminopropyl) obtained in Reference Example 266 were added to this solution. -3-Ethylcarbodiimide hydrochloride (2.28 g) was sequentially added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a 10% aqueous citric acid solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane = 2: 1) to give the title compound having a cyano group at the 5-position (427 mg) and 5 The title compound (718 mg) having an aminocarbothioyl group at the position was obtained.
5-cyano form: ¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 7.85 (1H, br.s), 8.15 (1H, d, J = 8.8 Hz), 8.31 (1H, d , J = 2.4 Hz), 9.69 (1H, br.s).
5- (aminocarbochioyl) isomer: ¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 7.98 (1H, br.s), 8.18 (1H, d, J = 8. 8 Hz), 8.31 (1 H, d, J = 2.4 Hz), 9.72 (1 H, s).
MS (ESI) m / z: 456 (M + H) ^<+> .

[Reference Example 549] (1R, 2S, 5RS) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (thiazol-2-yl) Cyclohexylcarbamic acid tert-butyl ester

The compound having an aminocarbothioyl group at the 5-position obtained in Reference Example 548 (72 mg) and bromoacetaldehyde dimethyl acetal (20.4 μl) were dissolved in N, N-dimethylformamide (5 ml) and stirred at 50 ° C. for 8 hours. did. Further, bromoacetaldehyde dimethyl acetal (80 μl) was added and stirred for 13 hours, and then allowed to stand to room temperature. Di-tert-butyl dicarbonate (34.5 mg) and anhydrous sodium hydrogen carbonate (200 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, triethylamine (97 μl) was added, and the mixture was stirred for 2 hours. To the reaction solution were added ethyl acetate and 10% aqueous citric acid solution, and the mixture was separated. The organic layer was washed with saturated brine, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 2: 1) to give the title compound (37.5 mg).
¹ H-NMR (CDCl ₃ ) 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 (0.5 H, m), 8.02-8.11 (0.5 H, m), 8.16-8.22 (1 H, m), 8.27-8.33 (1 H, m), 9.66-9.80 (1H, m).
MS (ESI) m / z: 480 (M + H) ^<+> .

[Reference Example 550] (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (1,2,4- Oxadiazol-3-yl) cyclohexylcarbamic acid tert-butyl ester

The compound having a cyano group at position 5 (427 mg) obtained in Reference Example 548 and anhydrous sodium hydrogen carbonate (84.9 mg) were suspended in ethanol, and hydroxylamine sulfate (82.9 mg) was added to this suspension. Heated to 60 ° C. and stirred for 6 days. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (methanol: methylene chloride = 1: 9) to give crude (1R, 2S, 5S) -5- [amino (hydroxyimino) methyl]. -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) cyclohexylcarbamic acid tert-butyl ester (183 mg) was obtained. To this compound, methyl orthoformate (5 ml) and boron trifluoride diethyl ether complex (1 drop) were added at room temperature, heated to 55 ° C., and stirred for 20 minutes. After leaving to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (methanol: methylene chloride = 1: 19) to obtain the title compound (57.6 mg).
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 8.04 (1H, s), 8.19 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.4 Hz), 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-1,3,4-oxadiazol-2-yl) cyclohexylcarbamate benzyl ester

The compound (4.0 g) obtained in Reference Example 142 was dissolved in N, N-dimethylformamide (100 ml), and hydrazine monohydrate (765 mg), 1-hydroxybenzotriazole (1.38 g), 1 -(Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.93 g) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and methylene chloride and an aqueous sodium hydrogen carbonate solution were added to the residue for liquid separation. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, silica gel (25 g) and methanol (15 ml) were added to the obtained filtrate and stirred, and insoluble materials were removed by filtration. The solvent was distilled off under reduced pressure to obtain crude (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4- (hydrazinocarbonyl) cyclohexylcarbamic acid benzyl ester (3.71 g). . To the obtained crude product (1.73 g), methyl orthoacetate (10 ml) and boron trifluoride diethyl ether complex (2 drops) were added and heated to 70 ° C. and stirred overnight. After leaving to room temperature, the solvent was distilled off under reduced pressure, and methylene chloride and aqueous sodium hydrogen carbonate solution were added to the resulting residue for liquid separation. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel chromatography (methanol: methylene chloride = 1: 19) gave the title compound (1.10 g).
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (5-methyl-1, 3,4-oxadiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

A mixture of the compound obtained in Reference Example 551 (1.10 g), 10% palladium carbon catalyst (300 mg) and methanol (50 ml) was stirred at room temperature for 1 hour in a hydrogen atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in N, N-dimethylformamide (50 ml). To this solution, the compound obtained in Reference Example 266 (632 mg), 1-hydroxybenzotriazole (381 mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (810 mg) were sequentially added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a 10% aqueous citric acid solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (944 mg).
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 8.02 (1H, br.s), 8.19 (1H, d, J = 8.8 Hz), 8.32 (1H , D, J = 2.4 Hz), 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-oxadiazol-2-yl) cyclohexylcarbamic acid benzyl ester

In the same manner as described in Reference Example 551, the compound obtained in Reference Example 142 was condensed with hydrazine and then subjected to a cyclization reaction using methyl orthoformate to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (1,3,4- Oxadiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 553 was deprotected and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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, 2.6 Hz), 8.00 (1H, br.s), 8.19 (1H, d, J = 8.9 Hz), 8.32 (1H, d, J = 2. 6 Hz), 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-hydroxyethyl) amino] carbonyl} cyclohexylcarbamic acid benzyl ester

In the same manner as in Reference Example 143, the compound obtained in Reference Example 142 and 2-aminoethanol were condensed to give the title compound.
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (1,3-oxazole- 2-yl) cyclohexylcarbamic acid tert-butyl ester

Dimethyl sulfoxide (3.47 ml) was added dropwise to a solution of oxalyl chloride (2.85 ml) in methylene chloride (50 ml) cooled to −60 ° C. under a nitrogen atmosphere, and then the compound (3.55 g) obtained in Reference Example 555 was obtained. Of methylene chloride (20 ml) was added dropwise over 15 minutes. After stirring at −60 ° C. for 45 minutes, triethylamine (11.4 ml) was added dropwise, and the mixture was further stirred for 30 minutes. Water was added to the reaction solution at −60 ° C. to return to room temperature, followed by extraction with chloroform and drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 50: 1 → 10: 1) to obtain a yellow solid (2.43 g). A solution of triphenylphosphine (4.41 g) in methylene chloride (25 ml) was added successively with a solution of hexachloroethane (3.32 g), triethylamine (4.69 ml) and the resulting yellow solid (2.43 g) in methylene chloride (35 ml). In addition, the mixture was stirred at room temperature for 20 hours. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was further stirred for 30 min. The reaction mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was obtained by silica gel chromatography (chloroform: methanol = 50: 1) The oxazole cyclized product was obtained as a mixture with triphenylphosphine oxide. The obtained mixture was dissolved in methanol (30 ml), 10% palladium carbon catalyst (2.08 g) was added, and the mixture was stirred at room temperature for 14 hours in a hydrogen atmosphere. A 10% palladium carbon catalyst (1.02 g) was added, and the mixture was further stirred for 6 hours under a hydrogen atmosphere. The catalyst was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 50: 1 → 1: 1), and then the obtained compound and the compound obtained in Reference Example 266 (612 mg) in N, N-dimethylformamide (15 ml) solution. 1- (Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (872 mg) and 1-hydroxybenzotriazole monohydrate (461 mg) were added at room temperature. After stirring the reaction solution for 12 hours, chloroform was added to the reaction solution, which was washed successively with water and a saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel flash column chromatography (methanol: chloroform = 50: 1) to obtain the title compound (390 mg).
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 7.98-8.11 (1H, m), 8.25 (1H, d, J = 8.8 Hz), 8 .31 (1H, d, J = 2.4 Hz), 9.75 (1H, s).
MS (ESI) m / z: 464 (M + H) ^<+> .

[Reference Example 557] (1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4-({[2- (trimethylsilyl) ethoxy] carbonyl} amino) cyclohexanecarboxylic acid

A mixture of the compound obtained in Reference Example 141 (4.20 g), 10% palladium carbon catalyst (1.0 g) and ethanol (100 ml) was stirred at room temperature for 5 hours in a hydrogen atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure. Dioxane (50 ml), water (50 ml) and triethylamine (2.09 ml) were added to the resulting residue, and the mixture was ice-cooled. To this mixture was added 1- [2- (trimethylsilyl) ethoxycarbonyloxy] pyrrolidine-2,5-dione (2.85 g), and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and 10% aqueous citric acid solution were added to the residue for liquid separation. The oil layer was washed successively with saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a pale yellow oil (4.46 g). Water (10 ml) and lithium hydroxide (479 mg) were added to a tetrahydrofuran (50 ml) solution of this oil, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and ethyl acetate and a 10% aqueous citric acid solution were added to the residue to separate the layers. The oil layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained colorless powder was washed with hexane to give the title compound (3.51 g).
¹ H-NMR (CDCl ₃ ) δ: 0.06 (9H, s), 0.97 (2H, t, J = 7.8 Hz), 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 (0.5 H, br. S), 5.18 (0.5 H, br. S), 6.42 (0.5 H, br. S).
MS (ESI) m / z: 401 (M-H) < ^- >].

[Reference Example 558] N-hydroxyacetamidine

Hydroxyamine (50% water content, 661 mg) was dissolved in acetonitrile (10 ml) and stirred at 60 ° C. overnight. The solvent was distilled off under reduced pressure, and the resulting colorless powder was washed with diethyl ether to obtain the title compound (673 mg).
¹ H-NMR (DMSO-d ₆ ) 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-1,2,4-oxadiazol-5-yl) cyclohexylcarbamic acid 2 -(Trimethylsilyl) ethyl ester

The compound (201 mg) obtained in Reference Example 557 and the compound (37 mg) obtained in Reference Example 558 were suspended in 1,2-dimethoxyethane (5 ml), and 1- (dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride (115 mg) was added and stirred at room temperature overnight. Subsequently, molecular sieve (MS-4A, powder, 1.0 g) was added to the reaction solution, and the mixture was heated to reflux overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (96.5 mg).
¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 0.98 (2H, t, J = 8.4 Hz), 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 (1 H, br. S), 5.14 (1 H, br. S).
MS (ESI) m / z: 341 (M-Boc + 2H) ^<+> .

[Reference Example 560] (1S, 2R, 4S) -4- (3-methyl-1,2,4-oxadiazol-5-yl) -2-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The compound (96.5 mg) obtained in Reference Example 559 was dissolved in ethanol (10 ml), and paratoluenesulfonic acid (45.8 mg) was added to this solution at room temperature. The reaction was heated to 60 ° C. and stirred overnight. After leaving to room temperature, the solvent was distilled off under reduced pressure to obtain a colorless powder. To this powder, the compound obtained in Reference Example 10 (67 mg) and N, N-dimethylformamide (5 ml) were added. To this solution were added 1-hydroxybenzotriazole (44.5 mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (84 mg), and the mixture was stirred overnight at room temperature. After distilling off the solvent under reduced pressure, methylene chloride and aqueous sodium hydrogen carbonate solution were added to the residue for separation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (methanol: methylene chloride = 3: 47) to obtain the title compound (110 mg).
¹ H-NMR (CDCl ₃ ) δ: 0.02 (9H, s), 0.97 (2H, dd, J = 9.9, 7.0 Hz), 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, 7.0 Hz), 4.60-4.69 (1H, m), 5.23 (1H, d, J = 7.6 Hz), 7.41 (1H, d, J = 8.3 Hz).
MS (ESI) m / z: 521 (M + H) ^<+> .

[Reference Example 561] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4- (1,3,4-thiadiazol-2-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The compound (1.0 g) obtained in Reference Example 557 was dissolved in N, N-dimethylformamide (20 ml), and formic hydrazide (149 mg), 1-hydroxybenzotriazole (335 mg) and 1- (dimethylaminopropyl) were added to this solution. ) -3-Ethylcarbodiimide hydrochloride (713 mg) was sequentially added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a 10% aqueous citric acid solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a colorless powder (1.12 g). Toluene (50 ml) and Lawesson's reagent (2.0 g) were added to this powder at room temperature, and then heated under reflux for 1 hour. The solution was allowed to stand at room temperature, silica gel was added to the solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 0: 1) to give the title compound (511 mg).
¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 0.99 (2H, t, J = 8.4 Hz), 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-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,3,4-thiadiazol-2-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

In the same manner as described in Reference Example 560, the compound obtained in Reference Example 561 was treated with paratoluenesulfonic acid, deprotected, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 0.03 (9H, s), 0.97 (2H, t, J = 8.5 Hz), 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 = 8.5 Hz), 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-fluoropyridin-2-yl) amino] -2-oxoethanethiol} amino) -N, N -Dimethylcyclohexanecarboxamide hydrochloride

To a suspension of the compound obtained in Reference Example 427 (73.3 g) in dioxane (350 ml) -methanol (200 ml), 4N hydrochloric acid-dioxane solution (350 ml) was added dropwise over 5 minutes, and the mixture was stirred for 10 minutes under ice water. The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with dioxane and tetrahydrofuran, and dried to give the title compound (76.4 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.34 to 1.55 (1H, m), 1.64 to 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 = 11.9 Hz), 10.89-10.99 (1H, m).
MS (ESI) m / z: 367 (M + H) ^<+> .

[Reference Example 564] 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid hydrochloride

1N Hydrochloric acid ethanol solution (36 ml) was added to the compound obtained in Reference Example 10 (3.00 g), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered and washed with ethanol (9 ml). The wet substance was dried under reduced pressure at room temperature to obtain the title compound (2.76 g).
¹ H-NMR (D ₂ O) δ: 4.82-4.88 (1H, d, J = 16.0 Hz), 4.51-4.57 (1H, d, J = 16.0 Hz), 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-1,3,4-thiadiazol-2-yl) cyclohexylcarbamic acid 2- ( Trimethylsilyl) ethyl ester

In the same manner as described in Reference Example 561, the compound obtained in Reference Example 557 was condensed with acetohydrazide, reacted with Lawesson's reagent, and then heated to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 0.98 (2H, t, J = 8.5 Hz), 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-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (5-Methyl-1,3,4-thiadiazol-2-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

In the same manner as described in Reference Example 560, the compound obtained in Reference Example 565 was treated with paratoluenesulfonic acid, deprotected, and condensed with the compound obtained in Reference Example 564 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 0.02 (9H, s), 0.97 (2H, t, J = 7.8 Hz), 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 = 5.5 Hz), 2.95 (2H , T, J = 5.5 Hz), 3.35-3.49 (1H, m), 3.73 (2H, br.s), 3.89 (1H, br.s), 4.14 (2H) , T, J = 7.8 Hz), 4.58-4.69 (1H, m), 5.29 (1H, br.s), 7.47 (1H, d, J = 8.1 Hz).
MS (ESI) m / z: 537 (M + H) ^<+> .

[Reference Example 567] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4- (1,3-oxazol-5-yl) cyclohexylcarbamic acid benzyl ester

N-methylformamide (0.99 ml) was added dropwise at 75 ° C. under reduced pressure to a mixture of quinoline (8.00 ml) and p-toluenesulfonyl chloride (4.84 g). The generated gas was cooled with a Liebig condenser and turned into a liquid, and recovered in an eggplant flask cooled to −78 ° C. to obtain methyl isocyanide (553 mg). To a solution of methyl isocyanide (349 mg) in tetrahydrofuran (10 ml) was added n-butyllithium (1.57 M hexane solution, 6.95 ml) at −78 ° C. in a nitrogen atmosphere, and the mixture was stirred for 15 minutes. A solution of the compound (1.02 g) obtained in Reference Example 141 in tetrahydrofuran (10 ml) was added dropwise to the reaction solution at −78 ° C., and the mixture was stirred for 30 minutes. The reaction mixture was warmed to 0 ° C. and stirred for 15 minutes, then cooled again to −78 ° C. and acetic acid (0.62 ml) was added. The reaction solution was further stirred at 0 ° C. for 45 minutes, diluted with diethyl ether, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by flash column chromatography using silica gel as a carrier (methanol: methylene chloride = 1: 49 → 3: 97) to obtain the title compound (663 mg).
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (1,3-oxazole- 5-yl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 567 was deprotected and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 7.78 (1H, s), 7.95 -8.10 (1H, m), 8.17 (1H, d, J = 8.8 Hz), 8.30 (1H, d, J = 2.4 Hz), 9.74 (1H, s).
MS (ESI) m / z: 464 (M + H) ^<+> .

[Reference Example 569] (1S, 2R, 4S) -4- (aminocarbonyl) -2-[(tert-butoxycarbonyl) amino] cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

In the same manner as in Reference Example 143, the compound obtained in Reference Example 557 was condensed with ammonium chloride to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 0.97 (2H, t, J = 8.3 Hz), 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-cyanocyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The compound (1.48 g) obtained in Reference Example 569 and triethylamine (1.04 ml) were dissolved in methylene chloride (25 ml), and trifluoroacetic anhydride (0.790 ml) was added to the solution under ice cooling. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the solution and the phases were separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue and solidified to obtain the title compound (1.18 g).
¹ H-NMR (DMSO-d ₆ ) δ: 0.01 (9H, s), 0.91 (2H, dd, J = 9.0, 7.1 Hz), 1.38 (9H, s), 1 .48-1.64 (3H, m), 1.65-1.77 (1 H, m), 1.81 (2 H, t, J = 5.9 Hz), 3.03 (1 H, br. S) 3.62 (1H, br.s), 3.78 (1H, br.s), 4.02 (2H, dd, J = 9.0, 7.1 Hz), 6.54 (1H, br.s). 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-1,2,4-oxadiazol-3-yl) cyclohexylcarbamic acid 2 -(Trimethylsilyl) ethyl ester

In the same manner as described in Reference Example 550, the compound obtained in Reference Example 570 was reacted with hydroxylamine and then subjected to a cyclization reaction using trimethyl orthoacetate to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 0.03 (9H, s), 0.98 (2H, t, J = 8.4 Hz), 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-1,2,4-oxadiazol-3-yl) -2-{[(5-methyl 1-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

In the same manner as described in Reference Example 560, the compound obtained in Reference Example 571 was treated with paratoluenesulfonic acid, deprotected, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 0.02 (9H, s), 0.96 (2H, t, J = 8.4 Hz), 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 = 8.4 Hz), 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- (trimethylsilyl) ethoxy] carbonyl} amino) cyclohexylcarbamic acid benzyl ester

Triethylamine (1.67 ml) and diphenylphosphoryl azide (2.06 ml) were added to a toluene (60 ml) solution of the compound (3.14 g) obtained in Reference Example 142, and the mixture was stirred at 80 ° C. for 2 hours. After cooling to room temperature, trimethylsilylethanol (4.59 ml) was added and stirred at 90 ° C. for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in ethyl acetate. This solution was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 1), and hexane was added to the resulting solid and collected by filtration to obtain the title compound (2.72 g).
¹ H-NMR (CDCl ₃ ) 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] cyclohexylcarbamic acid benzyl ester

To a solution of the compound (1.02 g) obtained in Reference Example 573 in tetrahydrofuran (6.0 ml) was added 1N tetrabutylammonium tetrahydrofuran solution (6.0 ml), and the mixture was stirred at room temperature for 3 days. Acetic acid ethyl ester was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol: concentrated aqueous ammonia = 100: 10: 1) to obtain the title compound (660 mg).
¹ H-NMR (CDCl ₃ ) 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-triazol-4-yl) amino] cyclohexylcarbamic acid benzyl ester

1,2-Diformylhydrazine (154 mg), triethylamine (0.464 ml) and chlorotrimethylsilane (0.952 ml) were added to a solution of the compound obtained in Reference Example 574 (182 mg) in pyridine (3.0 ml), and 80 ° The mixture was stirred at C for 6 hours. After cooling the reaction solution to room temperature, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to separate the solution, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 30: 1 → 10: 1) to give the title compound (127 mg). Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.54-1.91 (3H, m), 1.91-2.15 (2H, m), 2.21 (1H , D, J = 12.5 Hz), 2.37 (1H, d, J = 12.9 Hz), 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 = 7.6 Hz), 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (4H-1,2, 4-Triazol-4-yl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 575 was deprotected and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 8.04 (1H, br.s), 8.17 (1H, d, J = 8.8 Hz), 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-1,3,4-oxadiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

The compound (5.74 g) obtained in Reference Example 551 was dissolved in methanol (110 ml), 10% palladium carbon catalyst (1.22 g) was added, and the mixture was stirred at room temperature for 17 hours in a hydrogen atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (3.95 g).
¹ H-NMR (CDCl ₃ ) 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-Bromopyridin-2-yl) amino] -2-oxoacetic acid lithium salt

In the same manner as in the method described in Reference Example 266, the title compound was obtained from the compound obtained in Reference Example 262.
¹ H-NMR (DMSO-d ₆ ) δ: 8.03 (1H, dd, J = 8.8, 2.4 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.44 ( 1H, d, J = 2.4 Hz), 10.18 (1H, s).

[Reference Example 579] (1R, 2S, 5S) -2-({2-[(5-bromopyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (5-methyl-1, 3,4-oxadiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 577 (900 mg) in N, N-dimethylformamide (40 ml), the compound obtained in Reference Example 578 (1.24 g), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide Hydrochloride (1.17 g) and 1-hydroxybenzotriazole (205 mg) were added, and the mixture was stirred at 40 ° C. for 7 hr. Acetic acid ethyl ester and water were added to the reaction solution, and the mixture was separated. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 19: 1) to obtain the title compound (1.51 g).
¹ H-NMR (CDCl ₃ ) 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, 2.5 Hz), 8.03 (1H, d, J = 2.9 Hz), 8.14 (1H, d, J = 8.8 Hz), 8.41 (1H, d, J = 2. 5 Hz), 9.72 (1 H, s).

[Reference Example 580] (1R, 2S, 5S) -2-{[(7-chlorocinnolin-3-yl) carbonyl] amino} -5- (5-methyl-1,3,4-oxadiazole- 2-yl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 579, the title compound was obtained by condensing the carboxylic acid lithium salt obtained by hydrolyzing the compound obtained in Reference Example 297 with the compound obtained in Reference Example 577.
¹ H-NMR (CDCl ₃ ) 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, 1.8 Hz), 7.98 (1H, d, J = 8.8 Hz), 8.61 (1H, s), 8.69 (1H, d , J = 7.8 Hz), 8.74 (1H, s).
MS (ESI) m / z: 487 (M + H) ^<+> .

[Reference Example 581] (1R, 2S, 5S) -2-{[(7-chloroisoquinolin-3-yl) carbonyl] amino} -5- (5-methyl-1,3,4-oxadiazole-2 -Yl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as in Reference Example 579, the compound obtained in Reference Example 577 was condensed with the compound obtained in Reference Example 57 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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, 1.7 Hz), 7.90-7.97 (1 H, m), 8.02 (1 H, d, J = 1.7 Hz), 8.45-8.62 (2 H, 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-oxadiazol-5-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) Ethyl ester

A mixture of the compound (994 mg) obtained in Reference Example 569 and N, N-dimethylformamide dimethylacetal (10 ml) was stirred at 120 ° C. for 2 hours. After leaving to room temperature, the reaction solution was concentrated under reduced pressure, and hexane was added to the resulting residue to obtain a colorless powder. A 70% aqueous acetic acid solution (10 ml) and hydroxylamine (containing 50% water, 197 mg) were added to the powder and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the resulting residue for liquid separation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (759 mg).
¹ H-NMR (CDCl ₃ ) 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-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,2,4-oxadiazol-5-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

In the same manner as described in Reference Example 560, the compound obtained in Reference Example 583 was treated with paratoluenesulfonic acid, deprotected, and then condensed with the compound obtained in Reference Example 564 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 0.02 (9H, s), 0.97 (2H, dd, J = 9.9, 7.0 Hz), 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 = 5.6 Hz), 2.95 (2H, t, J = 5.6 Hz), 3.20-3.32 (1H, m), 3.74 (2H, s) , 3.90 (1H, br.s), 4.14 (2H, dd, J = 9.9, 7.0 Hz), 4.62-4.69 (1H, m), 5.19 (1H, br.s), 7.39 (1H, d, J = 8.1 Hz), 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) hydrazino] carbonyl} cyclohexylcarbamate benzyl ester

To a solution of the compound (4.00 g) obtained in Reference Example 142 in N, N-dimethylformamide (100 ml), hydrazine monohydrate (765 mg), 1-hydroxybenzotriazole (1.38 g), 1- (dimethylamino Propyl) -3-ethylcarbodiimide hydrochloride (2.93 g) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and methylene chloride and an aqueous sodium hydrogen carbonate solution were added to the residue for liquid separation. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, silica gel (25 g) and methanol (15 ml) were added to the obtained filtrate and stirred, and insoluble materials were removed by filtration. The solvent was distilled off under reduced pressure, and crude (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4- (hydrazinocarbonyl) cyclohexylcarbamic acid benzyl ester (3.71 g) was obtained as a colorless oil. Obtained as material.
To the obtained colorless oily substance (306 mg), methylene chloride (10 ml) and triethylamine (115 μl) were added, and trifluoroacetic anhydride (116 μl) was added to the mixture under ice cooling, followed by stirring at room temperature for 5 hours. Further, triethylamine (115 μl) and trifluoroacetic anhydride (116 μl) were added, and the mixture was stirred at room temperature for 1 hour. Methylene chloride and water were added to the reaction solution for separation, and the aqueous layer was extracted with methylene chloride. The obtained organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (methanol: methylene chloride = 1: 19) to obtain the title compound (283 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.52 to 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 = 7.3 Hz), 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-oxadiazol-2-yl] Cyclohexylcarbamic acid benzyl ester

Triphenylphosphine (392 mg) was dissolved in methylene chloride (10 ml), and this solution was dissolved in ice with hexachloroethane (296 mg), triethylamine (416 μl) and the compound obtained in Reference Example 584 (250 mg) in methylene chloride (5 ml). Were added sequentially. After stirring overnight at room temperature, methylene chloride and a 10% aqueous citric acid solution were added to the reaction solution to separate it. The organic layer was washed with saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (204 mg).
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- [5- (trifluoromethyl ) -1,3,4-oxadiazol-2-yl] cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 585 was deprotected and then condensed with the compound obtained in Reference Example 266 to give the title compound.
¹ H-NMR (CDCl ₃ ) 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 (1 H, br. S), 4.86 (1 H, br. S), 7.71 (1 H, dd, J = 8.8, 2.4 Hz), 7 .98 (1H, br.s), 8.18 (1H, d, J = 8.8 Hz), 8.32 (1H, d, J = 2.4 Hz), 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-chloroethoxy) carbonyl] amino} cyclohexylcarbamic acid benzyl ester

To a methylene chloride (30 ml) solution of the compound obtained in Reference Example 574 (872 mg), chloroethyl chloroformate (323 μl) and triethylamine (499 μl) were added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction solution for liquid separation, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography using silica gel as a carrier (hexane: ethyl acetate = 3: 2) to obtain the title compound (1.03 g).
¹ H-NMR (CDCl ₃ ) δ: 1.4-1.70 (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 = 5.5 Hz), 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-oxazolidin-3-yl) cyclohexylcarbamic acid benzyl ester

To a suspension of 60% sodium hydride (87 mg) in N, N-dimethylformamide (5.0 ml) was added a solution of the compound (926 mg) obtained in Reference Example 587 in N, N-dimethylformamide (5.0 ml). And stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was washed with water and saturated brine. The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is purified by flash column chromatography using silica gel as a carrier (hexane: ethyl acetate = 2: 3) to give the title compound (680 mg) was obtained.
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (2-oxo-1, 3-Oxazolidin-3-yl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 588 was deprotected and then condensed with the compound obtained in Reference Example 266 to give the title compound.
¹ H-NMR (CDCl ₃ ) 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, 2.5 Hz), 8.10 (1H, br.s), 8.19 (1H, dd, J = 8.8, 0.7 Hz), 8.31 (1 H, dd, J = 2.5, 0.7 Hz), 9.71 (1 H, s).
MS (ESI) m / z: 504 (M + Na) ^<+> .

[Reference Example 590] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4- (formylamino) cyclohexylcarbamic acid benzyl ester

To a solution of the compound (200 mg) obtained in Reference Example 574 in methylene chloride (5 ml), formic acid (31.1 μl), 1-hydroxybenzotriazole (108 mg), triethylamine (115 μl), 1- (3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (210 mg) was added and stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 49: 1 → 97: 3) to obtain the title compound (100 mg).
¹ H-NMR (CDCl ₃ ) 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 = 12.2 Hz), 5.10 (1H, d, J = 12.0 Hz), 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- (tetrazol-1-yl) cyclohexylcarbamic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 590 (792 mg) and pyridine (1.63 ml) in methylene chloride (10 ml) was added dropwise trichloromethyl chloroformate (268 μl) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. After returning the reaction mixture to room temperature and stirring for 15 minutes, trimethylsilyl azide (295 μl) was added and stirring was continued for 22 hours. The solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, the insoluble material was collected by filtration, and washed with water. The obtained solid was purified by silica gel column chromatography (methylene chloride: methanol = 199: 1 → 49: 1) to obtain the title compound (60 mg).
¹ H-NMR (CDCl ₃ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (tetrazol-1-yl) Cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 591 was deprotected and then condensed with the compound obtained in Reference Example 266 to give the title compound.
¹ H-NMR (CDCl ₃ ) 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, 2.4 Hz), 7.96-8.04 ( 1H, m), 8.17 (1H, d, J = 8.8 Hz), 8.32 (1H, d, J = 2.4 Hz), 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-pyrrol-1-yl) cyclohexylcarbamic acid benzyl ester

1N hydrochloric acid (550 μl) was added to a mixture of the compound obtained in Reference Example 574 (200 mg), 2,5-dimethoxytetrahydrofuran (71.3 μl), water (10 ml) and 1,2-dichloroethane (10 ml) at 80 ° C. For 2.5 hours. After leaving to room temperature, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the reaction solution to separate it. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to obtain the title compound (84 mg).
¹ H-NMR (CDCl ₃ ) 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 = 2.2 Hz), 6.70 (2H, t, J = 2.2 Hz), 7.29-7.39. (5H, m).
MS (ESI) m / z: 436 (M + Na) ^<+> .

[Reference Example 594] (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (1H-pyrrole-1- Yl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 593 was deprotected and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 2.0 Hz), 6.71 (2H, t, J = 2.0 Hz), 7.69. (1H, dd, J = 8.8, 2.2 Hz), 8.02 (1H, br.s), 8.17 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.2 Hz), 9.72 (1H, br.s).
MS (ESI) m / z: 462 (M + H) ^<+> .

[Reference Example 595] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4-({[(dimethylamino) methylidene] amino} carbonyl) cyclohexylcarbamic acid benzyl ester

To a solution of the compound (1.50 g) obtained in Reference Example 142 in N, N-dimethylformamide (100 ml), ammonium chloride (409 mg), 1-hydroxybenzotriazole (516 mg), 1- (dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride (1.03 g) and triethylamine (1.06 ml) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and 10% aqueous citric acid solution were added to the residue to separate the layers. The organic layer was washed with saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained powder was suspended in N, N-dimethylformamide dimethylacetal (30 ml) and stirred at 120 ° C. for 2 hours. After leaving to stand at room temperature, the precipitated colorless powder was collected by filtration and washed with diethyl ether to obtain the title compound (957 mg).
¹ H-NMR (CDCl ₃ ) 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 = 12.2 Hz), 5.12 (1H, d, J = 12.2 Hz), 5.30-5.45 (1 H, m), 7.28-7.37 (5 H, m), 8.40 (1 H, s).
MS (ESI) m / z: 447 (M + H) ^<+> .

[Reference Example 596] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4- (1,2,4-triazol-5-yl) cyclohexylcarbamic acid benzyl ester

To a solution of the compound (400 mg) obtained in Reference Example 595 in acetic acid (10 ml), hydrazine monohydrate (51.9 μl) was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the resulting residue for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (370 mg).
¹ H-NMR (DMSO-d ₆ ) 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (1,2,4- Triazol-5-yl) cyclohexacilcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 596 was deprotected and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.2 Hz), 8.06 (1H, d, J = 8.8 Hz), 8.39 (0.5 H, s), 8.47 (1H, d, J = 2.2 Hz), 8.56-8.69 (1H, m), 10.27 (1 H, s), 13.59-13.66 (1 H, m).
MS (ESI) m / z: 464 (M + H) ^<+> .

[Reference Example 598] (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4- (1-methyl-1H-1,2,4-triazol-5-yl) cyclohexylcarbamate benzyl ester

Methylhydrazine (56.9 μl) was added to a solution of the compound (400 mg) obtained in Reference Example 595 in acetic acid (10 ml), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the resulting residue for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (methanol: methylene chloride = 1: 19) to obtain the title compound (224 mg).
¹ H-NMR (CDCl ₃ ) 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 = 12.2 Hz), 5.12 (1H, d, J = 12.2 Hz), 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (1-methyl-1H- 1,2,4-triazol-5-yl) cyclohexylcarbamic acid tert-butyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 598 was deprotected and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 7.70 (1H, dd, J = 8.8, 2.4 Hz), 7.93 (1H, s), 8.06 (1H, br.s), 8.20 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.4 Hz), 9.74 (1H, s).
MS (ESI) m / z: 478 (M + H) ^<+> .

[Reference Example 600] (3R, 4S) -4-[(Benzyloxycarbonyl) amino] -3-[(tert-butoxycarbonyl) amino] piperidine-1-carbamic acid 2-trimethylsilanylethyl ester

To a solution of the compound obtained in Reference Example 212 (5.98 g) in dioxane (50 ml), 9% aqueous sodium hydrogen carbonate solution (150 ml) was added, cooled to 0 ° C., and 1-[(2-trimethylsilyl) ethoxycarbonyloxy]. A solution of pyrrolidine-2,5-dione (4.83 g) in dioxane (20 ml) was added, and the mixture was stirred at room temperature for 20 hours. Acetic acid ethyl ester and water were added to the reaction solution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to obtain the title compound (6.75 g).
¹ H-NMR (CDCl ₃ ) δ: 0.00 (9H, s), 0.96 (2H, t, J = 8.3 Hz), 1.36 to 1.53 (1H, m), 1.41 (9H, s), 1.82-2.00 (1H, m), 2.85 (1H, t, J = 12.1 Hz), 3.01 (1H, d, J = 13.4 Hz), 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-MS m / z: 394 (M-Boc) ⁺ .

[Reference Example 601] (3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -3-[(tert-butoxycarbonyl) amino] Piperidine-1-carbamic acid 2-trimethylsilanylethyl ester

In the same manner as described in Reference Example 552, the compound obtained in Reference Example 600 was deprotected and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 111.2 Hz), 2.84-2.98 (1H, m), 3.07 (1H, d, J = 13.9 Hz), 3.94. -4.29 (6H, m), 4.81-4.95 (1H, br), 7.70 (1H, d, J = 9.0 Hz), 8.09-8.34 (1H, br) , 8.20 (1H, d, J = 9.0 Hz), 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-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) piperidin-3-yl] carbamic acid tert-butyl ester

To a solution of the compound obtained in Reference Example 601 (6.92 g) in tetrahydrofuran (90 ml) was added 1.0 mmol / l tetrabutylammonium fluoride tetrahydrofuran solution (40 ml), and the mixture was stirred at room temperature for 5 days. Acetic acid ethyl ester and a saturated aqueous sodium chloride solution were added to the reaction solution. The aqueous layer was extracted with ethyl acetate and methylene chloride, and the combined organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1 → 20: 1 → 10: 1) to obtain a crude product (7.96 g). Acetic acid ethyl ester was added to the crude product, and the insoluble material was collected by filtration to give the title compound (466 mg). Water was added to the filtrate, and the mixture was extracted with ethyl acetate and methylene chloride, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture (4.86 g) of the title compound containing about 30% of tetrabutylammonium fluoride.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.55-1.72 (2H, m), 1.84-1.99 (1H, m), 2.71 (1H , T, J = 10.7 Hz), 2.85 (1H, d, J = 111.2 Hz), 3.03 (2H, t, J = 12.7 Hz), 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, 2.4 Hz), 8. 13 (1H, br.s), 8.21 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.4 Hz), 9.75 (1H, s).
MS (ESI) m / z: 398 (M + H) ^<+> .

[Reference Example 603] (3R, 4S)-[4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -1- (thiazol-2-yl) piperidine -3-yl] carbamic acid tert-butyl ester,

To a solution of tetrabutylammonium fluoride obtained in Reference Example 602 (401 mg) in toluene (4 ml), 2-bromothiazole (115 μl), sodium tert-butoxide (91 mg), (S)-(−)-2 , 2′-bis (diphenylphosphino) -1,1′-binaphthyl (65 mg) and tris (dibenzylideneacetone) dipalladium (0) (28 mg) were added, and the mixture was stirred at 80 ° C. for 3 days in an argon atmosphere. did. After cooling the reaction mixture, ethyl acetate was added, insolubles were filtered off through celite, and saturated aqueous sodium chloride solution was added to the filtrate. After extraction with ethyl acetate, the combined organic layers were washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to obtain the title compound (169 mg).
¹ H-NMR (CDCl ₃ ) 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, 1.7 Hz), 3.98 (1H, br.d, J = 12.9 Hz), 4.04-4. 15 (2H, m), 4.18-4.29 (1H, br), 5.04-5.34 (1H, m), 6.65 (1H, d, J = 3.7 Hz), 7. 21 (1H, d, J = 3.7 Hz), 7.70 (1H, dd, J = 8.8, 2.4 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.23 −8.33 (1H, br), 8.31 (1H, d, J = 2.4 Hz), 9.73 (1H, br. S).
MS (ESI) m / z: 481 (M + H) ^<+> .

[Example 1] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopropyl) -5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a solution of the compound obtained in Reference Example 59 (108 mg) and the compound obtained in Reference Example 10 (124 mg) in N, N-dimethylformamide (3 ml), 1-hydroxybenzotriazole monohydrate (71 mg), and 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100 mg) was added at room temperature and stirred for 8 days. The reaction mixture was concentrated under reduced pressure using a vacuum pump, water (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml) were added, and the mixture was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 10: 1). 1N Hydrochloric acid ethanol solution, methylene chloride and methanol were added to the obtained amorphous substance, and the mixture was concentrated to give the title compound (72 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.5-1.35 (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 = 15.4 Hz), 7.08 (1H, s), 7.17 (1H, dd, J = 8.6, 2.1 Hz), 7.41 (1H, d, J = 8.6 Hz), 7.70 (1H, s), 8.50 (1H, br, J = 11.0 Hz), 8.56 (1 H, br. S), 11.56 (1 H, br, J = 19.3 Hz), 11.86 (1 H, s).
MS (FAB) m / z: 430 (M + H) ^<+> .

[Example 2] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclobutyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (117 mg) obtained in Reference Example 60 was dissolved in N, N-dimethylformamide (5 ml), and the compound (136 mg) obtained in Reference Example 10 and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (255 mg), 1-hydroxybenzotriazole monohydrate (90 mg) was added, and the mixture was stirred overnight at room temperature. Then, the solvent was distilled off under reduced pressure using a vacuum pump, and the residue was methylene chloride and saturated sodium bicarbonate. Aqueous solution was added for liquid separation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 7: 93). The obtained compound was acidified by adding ethyl acetate and 1N hydrochloric acid ethanol solution, and the solvent was concentrated under reduced pressure. Acetic acid ethyl ester was added again, and the resulting precipitate was collected by filtration and dried to give the title compound (56 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.38 (1H) , D, J = 8.8 Hz), 7.71 (1H, s), 8.63 (1H, d, J = 8.3 Hz), 8.85 (1H, d, J = 8.6 Hz), 10 85-11.20 (1H, br), 11.81 (1H, s).
MS (FAB) m / z: 444 (M + H) ^<+> .

[Example 3] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (120 mg) obtained in Reference Example 62 was dissolved in N, N-dimethylformamide (5 ml), and 5-chloroindole-2-carboxylic acid (80 mg), 1- (3-dimethylaminopropyl) -3-ethyl was dissolved. Carbodiimide hydrochloride (98 mg), 1-hydroxybenzotriazole monohydrate (23 mg) and triethylamine (141 μl) were added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added to the residue for separation. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7), and methylene chloride (5 ml) and 1N hydrochloric acid ethanol solution (282 μl) were added to the obtained pale yellow solid. Acetic acid ethyl ester was added, the solvent was concentrated under reduced pressure, and the resulting precipitate was collected by filtration to give the title compound (109 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 1.5 Hz), 7 .14 (1H, dd, J = 8.5, 2.0 Hz), 7.38 (1H, d, J = 8.5 Hz), 7.68 (1H, d, J = 2.0 Hz), 8. 55 (1H, d, J = 8.5 Hz), 8.91 (1H, d, J = 8.5 Hz), 11.49 (1H, br. S), 11.76 (1 H, s).
MS (ESI) m / z: 458 (M + H) ^<+> .

[Example 4] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) sulfonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (400 mg) obtained in Reference Example 67 was suspended in methylene chloride (10 ml), triethylamine (0.514 ml) and 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (Japanese Patent Laid-Open No. 2000-119253) ( 319 mg) was added and stirred at room temperature for 15 minutes. Water was added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a pale yellow foam. This was dissolved in tetrahydrofuran (3 ml), methanol (2 ml) and 1N aqueous sodium hydroxide solution (1.5 ml) were added, and the mixture was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and methylene chloride and 1N aqueous hydrochloric acid were added to the residue to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3). 1N Hydrochloric acid (1 ml) was added to the obtained product, and the mixture was concentrated under reduced pressure to give the title compound (108 mg).
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

[Example 5] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (300 mg) obtained in Reference Example 65 was dissolved in N, N-dimethylformamide (20 ml), and 5-chloroindole-2-carboxylic acid (109 mg), 1-hydroxybenzotriazole monohydrate (9 mg), 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (321 mg) and triethylamine (0.232 ml) were added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure using a vacuum pump, and methylene chloride and water were added to the residue for liquid separation operation, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to obtain a colorless foamy substance. 1N Hydrochloric acid (1 ml) was added thereto, and the mixture was concentrated under reduced pressure to give the title compound (203 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 1.2 Hz), 7.38 (1H, d, J = 8.5 Hz), 7.64 (1 H, s), 8.28 (1 H, d, J = 8.5 Hz), 8.54 (1 H, d, J = 8.5 Hz), 11.70 (1 H, s).
MS (FAB) m / z: 472 (M + H) ^<+> .

[Example 6] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 67 and 5-chloroindole-2-carboxylic acid.
¹ H-NMR (DMSO-d ₆ ) 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. 0 Hz), 7.41 (1 H, d, J = 8.6 Hz), 7.70 (1 H, d, J = 2.0 Hz), 8.14 (1 H, br. S), 8.36-8. 48 (1H, m), 11.51 (1H, br.s), 11.86 (1H, s).
MS (FAB) m / z: 472 (M + H) ^<+> .

Example 7 N-{(1R ^* , 2S ^* )-2-[(6-Chloro-2-naphthoyl) amino] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the compound obtained in Reference Example 67 (275 mg), 6-chloronaphthalene-2-carboxylic acid (Eur. J. Chem. Chim. Ther., 1984, 19, vol. 205-214) Page) (148 mg), triethylamine (0.298 ml) and 1-hydroxybenzotriazole monohydrate (11 mg) were dissolved in N, N-dimethylformamide (20 ml) to give 1- (3-dimethylaminopropyl) -3. -Ethylcarbodiimide hydrochloride (412 mg) was added and reacted to give the title compound (186 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz), 7.90 (1H, d, J = 8.6 Hz), 7.98 (1H, d, J = 8. 3 Hz), 8.03-8.11 (2H, m), 8.25-8.58 (3H, m), 11.52 (1 H, br. S).
MS (FAB) m / z: 483 (M + H) ^<+> .

[Example 8] N-((1R ^* , 2R ^* )-2-{[(6-chloro-1-benzothiophen-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the compound (255 mg) obtained in Reference Example 65, 6-chlorobenzo [b] thiophene-2-carboxylic acid (JP 2000-119253) (141 mg), triethylamine (0.276 ml) and 1-Hydroxybenzotriazole monohydrate (10 mg) is dissolved in N, N-dimethylformamide (20 ml), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (382 mg) is added and reacted. This gave the title compound (239 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 1.7 Hz), 7.91 (1H, d, J = 8.6 Hz), 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) ^<+> .

[Example 9] N-((1R ^* , 2R ^* )-2-{[(5-fluoroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 65 and 5-fluoroindole-2-carboxylic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.38 (2H, m), 1.40-1.57 (1H, m), 1.54-1.68 (1H, m) , 1.71 (2H, d, J = 7.3 Hz), 1.88 (2H, d, J = 12.0 Hz), 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, 2.3 Hz), 7.01 (1H, s), 7.31-7.39 (2H, m), 8.26 (1H, d, J = 8.6 Hz), 8.59 (1H, d, J = 8.4 Hz), 11.21 ( 1 / 2H, br.s), 11.42 (1 / 2H, br.s), 11.60 (1H, s).
MS (ESI) m / z: 456 (M + H) ^<+> .

[Example 10] N-((1R ^* , 2R ^* )-2-{[(5-chloro-6-fluoroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 65 and the compound obtained in Reference Example 23.
¹ H-NMR (DMSO-d ₆ ) 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 = 10.0 Hz), 7.86 (1 H, d, J = 7.3 Hz), 8 .32 (1H, d, J = 8.5 Hz), 8.59 (1H, d, J = 8.5 Hz), 11.77 (1H, s).
MS (FAB) m / z: 490 (M + H) ^<+> .

[Example 11] N-((1R ^* , 2S ^* )-2-{[(5-bromoindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 67 and 5-bromoindole-2-carboxylic acid.
¹ H-NMR (DMSO-d ₆ ) 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 = 15.6 Hz), 7.14 (1H, s), 7. 28 (1H, d, J = 8.7 Hz), 7.37 (1H, d, J = 8.7 Hz), 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 ^<+> ).

[Example 12] N-((1R ^* , 2S ^* )-2-{[(5-ethynylindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

A solution of the compound obtained in Example 11 (300 mg) and triphenylphosphine (70 mg) in tetrahydrofuran (2 ml) was added to triethylamine (6 ml), N, N-dimethylformamide (5 ml), trimethylsilylacetylene (0.250 ml), and palladium acetate. (20 mg) was added at room temperature. After stirring at 90 ° C. for 2 hours, the reaction solution was allowed to cool to room temperature, and methylene chloride (20 ml) and saturated aqueous sodium hydrogen carbonate solution (30 ml) were added to separate the layers. The aqueous layer was extracted with methylene chloride (3 × 10 ml), the organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by preparative silica gel thin layer chromatography (methylene chloride: acetone: methanol = 10: 10: 1) to obtain a colorless solid. This was dissolved in methanol (6 ml), potassium carbonate (120 mg) was added and stirred for 1 hour. Methylene chloride (20 ml) and water (20 ml) were added to the reaction mixture, the phases were separated, and the aqueous layer was extracted with methylene chloride (2 × 15 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (methylene chloride: acetone: methanol = 10: 10: 1), dissolved in water-methanol-methylene chloride and concentrated to give the title compound (72 mg). Obtained.
¹ H-NMR (CDCl ₃ ) 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 = 14.1 Hz), 3.77 (1H, d, J = 14.1 Hz), 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) ^<+> .

[Example 13] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5,6-dimethyl-4,5,6,7 -Tetrahydrothiazolo [4,5-d] pyridazine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 51.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.50 (2H, m), 1.50 to 1.75 (4H, m), 1.80 to 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 = 8.8 Hz), 7.70 (1H, s), 8.12 (1H, d, J = 6.8 Hz), 8.47 (1H, d, J = 7. 6 Hz), 11.85 (1 H, s).
MS (FAB) m / z: 487 (M + H) ^<+> .

Example 14 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -6,7-dihydro-4H-pyrano [4,3 -D] thiazole-2-carboxamide

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 26.
¹ H-NMR (DMSO-d ₆ ) δ: 1.36-1.72 (6H, m), 1.90-2.10 (2H, m), 2.80-2.87 (2H, m) 3.93 (2H, t, J = 5.6 Hz), 4.20-4.32 (2H, m), 4.81 (2H, s), 7.12 (1H, s), 7.15. (1H, dd, J = 8.8, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 1.7 Hz), 8.11 ( 1H, d, J = 6.6 Hz), 8.36 (1H, d, J = 8.3 Hz), 11.78 (1H, s).
MS (FAB) m / z: 459 (M + H) ^<+> .

[Example 15] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [4,5-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 29.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz), 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) ^<+> .

[Example 16] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Oxazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 69 and the compound obtained in Reference Example 21.
¹ H-NMR (DMSO-d ₆ ) 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 = 1.5 Hz), 7.12 (1H, dd, J = 8.8, 2.0 Hz), 7.38 (1H, d, J = 8.8 Hz), 7.65 (1H, d, J = 2.0 Hz), 8.33 (1H, d, J = 8.6 Hz), 8.72 (1H , D, J = 8.6 Hz), 11.61 (1H, br.s), 11.72 (1H, s).
MS (FAB) m / z: 456 (M + H) ^<+> .

Example 17 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7-tetrahydrothieno [3 2-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 71 and 5- (tert-butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid ( WO94 / 21599) was decondensed by treatment with hydrochloric acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.23 (1H, s), 7.41 (1H, d, J = 8.8 Hz), 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) ^<+> .

[Example 18] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydro Thieno [3,2-c] pyridine-2-carboxamide hydrochloride

The compound obtained in Example 17 (171 mg) was suspended in methylene chloride (10 ml), triethylamine (0.104 ml) was added, and the mixture was stirred at room temperature for 10 minutes. Acetic acid (0.059 ml) was added to the reaction solution, 35% formalin (0.070 ml) and sodium triacetoxyborohydride (118 mg) were added, and the mixture was stirred at room temperature for 30 minutes. A 1N aqueous sodium hydroxide solution (3 ml) was added to the reaction solution, and then water was added to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 3) to obtain a colorless foamy substance. This was suspended in 1N hydrochloric acid and concentrated under reduced pressure to give the title compound (85 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz), 7.23 (1H, s), 7.40 (1H, d, J = 8.6 Hz), 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) ^<+> .

Example 19 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -6- (dimethylamino) -4,5,6 7-Tetrahydrobenzothiazole-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 31.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz) 7.69 (1 H, s), 8.11 (1 H, d, J = 5.1 Hz), 8.34 (1 H, d, J = 8.1 Hz), 10.95 (1 H, br. S) , 11.83 (1H, s).
MS (FAB) m / z: 500 (M + H) ^<+> .

[Example 20] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (pyridin-4-yl) -4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

N-Butyllithium (1.60 N hexane solution, 0.704 ml) was added dropwise at −78 ° C. to a tetrahydrofuran (3 ml) solution of the compound (204 mg) obtained in Reference Example 24, and the mixture was stirred at 0 ° C. for 30 minutes. After cooling to -78 ° C again, the temperature was raised to room temperature over 20 minutes while blowing carbon dioxide gas, and the reaction solution was concentrated under reduced pressure. To the N, N-dimethylformamide (6 ml) solution of the obtained residue, the compound obtained in Reference Example 71 (400 mg), 1-hydroxybenzotriazole monohydrate (254 mg), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (360 mg) and diisopropylamine (0.491 ml) were added at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, methylene chloride (30 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml), and water (100 ml) were added to the residue. After liquid separation, the aqueous layer was diluted with methylene chloride (4 × 15 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 10: 1), dissolved in 1N aqueous hydrochloric acid-methanol-methylene chloride and concentrated to give the title compound (245 mg). Obtained.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.32 (2H , Br.s), 7.40 (1H, d, J = 8.8 Hz), 7.68 (1H, d, J = 2.0 Hz), 8.15 (1H, br, J = 7.3 Hz) , 8.31 (2H, d, J = 5.9 Hz), 8.39 (1H, d, J = 8.1 Hz), 11.90 (1H, s), 14.03 (1H, br. S) . MS (ESI) m / z: 535 (M + H) ^<+> .

[Example 21] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cycloheptyl) -5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 74 and the compound obtained in Reference Example 10.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.39 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 2.0 Hz), 8.46 (1 H, d, J = 8.3 Hz), 8.77 (1 H, d, J = 8.3 Hz), 11.21-11.35 (1 H, m), 11. 71 (1H, s).
MS (ESI) m / z: 486 (M + H) ^<+> .

[Example 22] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclooctyl) -5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 78 and the compound obtained in Reference Example 10.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.70 (1H, s), 8.24 (1H, br. S), 8.58 (1H, d, J = 8.3 Hz), 11.43, 11.63 (1H, ech br.s), 11.80 (1H, s).
MS (ESI) m / z: 500 (M + H) ^<+> .

[Example 23] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the product obtained by the reaction of the compound obtained in Reference Example 63 and the compound obtained in Reference Example 34 was treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.40. (1H, d, J = 8.8 Hz), 7.69 (1H, s), 8.61 (1H, d, J = 8.3 Hz), 8.88 (1H, d, J = 8.3 Hz) , 10.05 (2H, br.s), 11.82 (1H, s). MS (FAB) m / z: 444 (M + H) ^<+> .

[Example 24] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5-isopropyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (30 mg) obtained in Example 23 was suspended in methylene chloride (20 ml), triethylamine (260 μl) was added, and the mixture was stirred at room temperature for 15 minutes. Acetic acid (179 μl) and acetone (920 μl) were added to the reaction solution, and the mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (796 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. A 1N aqueous sodium hydroxide solution (10 ml) was added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a colorless foamy substance. This was dissolved in methylene chloride, and 1N hydrochloric acid ethanol solution (1 ml) was added. The solution was concentrated under reduced pressure to obtain the title compound (205 mg).
¹ H-NMR (DMSO-d ₆ ) 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. 8 Hz), 7.38 (1 H, d, J = 8.8 Hz), 7.68 (1 H, s), 8.56 (1 H, d, J = 8.8 Hz), 8.90 (1 H, d, J = 8.8 Hz), 11.39 (1H, br.s), 11.76 (0.5 H, s), 11.80 (0.5 H, s).
MS (FAB) m / z: 486 (M + H) ^<+> .

[Example 25] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5-ethyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (500 mg) obtained in Example 23 was dissolved in N, N-dimethylformamide (10 ml), triethylamine (576 μl) and ethyl iodide (329 μl) were added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, water was added to the residue, and insoluble matter was collected by filtration. This was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a light brown foamy substance. This was suspended in 1N hydrochloric acid (2 ml), and the solution was concentrated under reduced pressure to give the title compound (180 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.32 (3H, t, J = 7.1 Hz), 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, 2.0 Hz), 7.39 (1H, d, J = 8.8 Hz), 7. 69 (1H, d, J = 1.5 Hz), 8.55 (1H, d, J = 8.5 Hz), 8.92 (1H, d, J = 8.5 Hz), 11.38 (1H, br .S), 11.70-11.80 (1H, m).
MS (FAB) m / z: 472 (M + H) ^<+> .

Example 26 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5- (1-methylcyclopropyl) -4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 63 and the compound obtained in Reference Example 39.
¹ H-NMR (DMSO-d ₆ ) 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 (1 H, s), 7.16 (1 H, d, J = 8.8 Hz), 7.39 (1 H, d, J = 8.8 Hz), 7.69 (1 H, s), 8 .53 (1H, d, J = 8.6 Hz), 8.85-8.95 (1H, m), 10.60-10.90 (1H, br), 11.73 (1H, br.s) .
MS (FAB) m / z: 498 (M + H) ^<+> .

Example 27 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4-methoxycyclopentyl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride (stereoisomer A and stereoisomer B)

In the same manner as in Example 2, the compound obtained in Reference Example 82 (mixture of stereoisomers at position 4) (268 mg) was condensed with the compound obtained in Reference Example 10 to give stereoisomer A of the title compound. A mixture of A and B was synthesized, separated by silica gel column chromatography, and converted to the hydrochloride salt to give stereoisomer A (75 mg) and stereoisomer B (70 mg) of the title compound.
Stereoisomer A:
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.38 (1H, d, J = 8.8 Hz), 7 .69 (1H, s), 8.56 (1H, d, J = 8.8 Hz), 8.88 (1H, d, J = 8.3 Hz), 10.96 (1H, br.s), 11 .75 (1H, br.s).
MS (FAB) m / z: 488 (M + H) ^<+> .
Stereoisomer B:
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz) 7.68 (1 H, s), 8.59 (1 H, d, J = 8.3 Hz), 8.90 (1 H, d, J = 8.5 Hz), 11.26 (1 H, br. S) 11.74 (1H, br.s).
MS (FAB) m / z: 488 (M + H) ^<+> .

[Example 28] N-[(1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4- (hydroxymethyl) cyclopentyl] -5- (1,1 -Dimethyl-2-hydroxyethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride (stereoisomer A)

1) N-((1R ^* , 2R ^* )-4-[(benzyloxy) methyl] -2 from the compound obtained in Reference Example 85 and the compound obtained in Reference Example 42 in the same manner as in Example 2. -{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -4,5 Stereoisomer A and stereoisomer B of 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide were obtained.
Stereoisomer A:
¹ H-NMR (CDCl ₃ ) δ: 1.05 (9H, s), 1.168, 1.171 (6H, each), 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 = 13.1 Hz), 4. 41-4.45 (1H, m), 4.51-4.57 (2H, m), 6.88 (1H, d, J = 1.5 Hz), 7.17 (1H, dd, J = 8) .8, 2.0 Hz), 7.23-7.43 (12H, m), 7.52 (1H, d, J = 7.6 Hz), 9.37 (1H, br.s).
Stereoisomer B:
¹ H-NMR (CDCl ₃ ) δ: 1.05 (9H, s), 1.17 (6H, s), 1.43-1.47 (1H, m), 1.85 to 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 = 13.3 Hz), 4.15-4.20 (1 H, m), 4.45-4.56 (3 H, m), 6.74 (1 H, d, J = 2.0 Hz), 7.16. (1H, dd, J = 8.8, 2.0 Hz), 7.27-7.43 (12H, m), 7.57 (1H, d, J = 2.0 Hz), 9.48 (1H, br.s).
2) The above stereoisomer A (288 mg) was suspended in methylene chloride (20 ml), dimethyl sulfide (1.15 ml) and anhydrous aluminum chloride (350 mg) were added, and the mixture was stirred at room temperature for 1 hour. 1N Aqueous sodium hydroxide solution (10 ml) was added to the reaction mixture, the mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 9: 1) to give 5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1. -Dimethylethyl) -N-[(1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4- (hydroxymethyl) cyclopentyl] -4,5,6 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer A) (184 mg) was obtained.
¹ H-NMR (CDCl ₃ ) 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 = 15.6 Hz), 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 = 1.7 Hz), 7.63 (4H, dd, J = 7.8, 1.5 Hz), 7.90-7.92 ( 2H, m), 10.13 (1H, br. S).
MS (FAB) m / z: 784 (M + H) ^<+> .
3) Stereoisomer A (180 mg) obtained in 2) above was dissolved in 1N tetrabutylammonium fluoride tetrahydrofuran solution (2 ml) and stirred overnight at room temperature. Methylene chloride, 1N aqueous sodium hydroxide solution and sodium chloride were added to the reaction solution, liquid separation operation was performed, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 19: 1). The obtained powder was dissolved in methanol, 1N hydrochloric acid ethanol solution (229 μl) was added, ethyl acetate was added, and the solvent was concentrated under reduced pressure to obtain the title compound (63 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.39 (1H, d, J = 8.6 Hz), 7.68 (1H, d, J = 2.0 Hz), 8. 53-8.56 (1H, m), 8.83 (1H, d, J = 8.3 Hz), 10.36 (1H, br.s), 11.75, 11.77 (1H, each) . MS (ESI) m / z: 546 (M + H) ^<+> .

[Example 29] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,7,8,10-tetrahydro-6H-pyrazolo [1,2-a] thiazolo [4,5-d] pyridazine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 44.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.50 (2H, m), 1.61 (4H, br.s), 1.80 to 2.00 (2H, m), 2 .27 (2H, br.s), 2.80-4.80 (10H, m), 7.14 (1H, d, J = 1.5 Hz), 7.17 (1H, dd, J = 8. 5, 2.0 Hz), 7.41 (1 H, d, J = 8.5 Hz), 7.70 (1 H, d, J = 2.0 Hz), 8.09 (1 H, d, J = 7.3 Hz) ), 8.44 (1H, br.s), 11.81 (1H, br.s).
MS (FAB) m / z: 499 (M + H) ^<+> .

[Example 30] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,6,7,8,9,11-hexa Hydropyridazino [1,2-a] thiazolo [4,5-d] pyridazine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 46 and the compound obtained in Reference Example 71.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.55 (2H, m), 1.55 to 2.10 (10H, m), 2.80 to 4.80 (10H, m) 7.10-7.25 (2H, m), 7.42 (1H, d, J = 8.8 Hz), 7.72 (1H, d, J = 1.7 Hz), 8.12 (1H, br.s), 8.41 (1H, br.s), 11.83 (1H, br.s).
MS (FAB) m / z: 513 (M + H) ^<+> .

Example 31 5-Chloro-N-{(1R ^* , 2S ^* )-2-[(5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-ylcarbonyl) amino] cyclohexyl } Indole-2-carboxamide hydrochloride

Under an argon atmosphere, the compound (171 mg) obtained in Reference Example 33 was dissolved in diethyl ether (5 ml), and n-butyllithium (1.60 N hexane solution, 385 μl) was added dropwise at −78 ° C. After stirring at −78 ° C. for 10 minutes, carbon dioxide gas was blown for 20 minutes, and then the temperature was raised to room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in N, N-dimethylformamide (10 ml) to obtain the compound obtained in Reference Example 71 (184 mg), 1-hydroxybenzotriazole monohydrate (76 mg). And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (215 mg) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated, methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3: 97). A hydrochloric acid ethanol solution (5 ml) was added to the product, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated. The obtained residue was solidified by adding ethyl acetate, and the powder was collected by filtration to give the title compound (31 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.52 (2H, m), 1.55 to 1.80 (4H, m), 1.82 to 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 = 8.6 Hz), 7.71 (1H, d, J = 1.7 Hz), 8.10 (1H, d, J = 7.1 Hz), 8 .45 (1H, d, J = 7.8 Hz), 10.10-10.50 (2H, br), 11.83 (1H, br. S). MS (FAB) m / z: 444 (M + H) ^<+> .

[Example 32] 2-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} -5,7-dihydro-6H -Pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester

The compound obtained in Reference Example 50 was hydrolyzed with lithium hydroxide and then reacted with the compound obtained in Reference Example 71 in the same manner as in Example 2 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 1.5 Hz), 7.19 (1H, dd, J = 8.8, 2.1 Hz) , 7.34 (1H, d, J = 8.8 Hz), 7.62 (1H, d, J = 2.1 Hz), 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) ^<+> .

Example 33 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -6-methyl-6,7-dihydro-5H-pyrrolo [3,4-d] pyrimidine-2-carboxamide hydrochloride

To a solution of the compound obtained in Example 32 (34.0 mg) in methylene chloride (1 ml) was added trifluoroacetic acid (1 ml) at room temperature and stirred for 1 hour. Concentrated under reduced pressure, the residue was dissolved in methylene chloride (1 ml), triethylamine (17.6 μl), acetic acid (7.21 μl), 35% formalin (8.13 μl), and sodium triacetoxyborohydride (20.1 mg) ) Was added at room temperature and stirred for 1 hour. Methylene chloride (10 ml) and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 7: 93), solidified with 1N hydrochloric acid ethanol solution and acetic acid ethyl ester, collected by filtration, and collected by filtration. 8.00 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.69 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 6.9 Hz), 8.65 (1H, d, J = 8.3 Hz), 8.93 (1H, s), 11.73 (1H, br.s), 11.82 (1H, br.s).
MS (FAB) m / z: 453 (M + H) ^<+> .

Example 34 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the product obtained by the reaction of the compound obtained in Reference Example 71 and the compound obtained in Reference Example 34 was treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.41 (1H, d, J = 8.6 Hz), 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) ^<+> .

Example 35 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (2-methoxyethyl) -4,5 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and 2-methoxyethyl bromide.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.70 (1H, d, J = 2.0 Hz) , 8.08-8.20 (1H, m), 8.36-8.48 (1H, m), 11.84 (1H, s).
MS (FAB) m / z: 516 (M + H) ^<+> .

[Example 36] 2- [2-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} -6,7- Dihydrothiazolo [5,4-c] pyridin-5 (4H) -yl] acetic acid methyl ester hydrochloride

In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and methyl bromoacetate.
¹ H-NMR (CDCl ₃ ) 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 = 15.4 Hz), 3.99 (1H, d, J = 15.4 Hz), 4.22 (1H , Br.s), 4.45 (1H, br.s), 6.86 (1H, d, J = 1.2 Hz), 7.18 (1H, dd, J = 8.8, 2.0 Hz) , 7.33 (1H, d, J = 8.8 Hz), 7.58-7.63 (2H, m), 7.87 (1H, br.s), 9.88 (1H, br.s) .
MS (FAB) m / z: 530 (M + H) ^<+> .

Example 37 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-isopropyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 24, the title compound was obtained from the compound obtained in Example 34 and acetone.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.71 ( 1H, d, J = 2.0 Hz), 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) ^<+> .

Example 38 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (tetrahydro-2H-pyran-4-yl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 24, the title compound was obtained from the compound obtained in Example 34 and tetrahydro-4H-pyran-4-one.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.41 (1H, d, J = 8.6 Hz), 7.71 (1H, d, J = 2.0 Hz), 8.14 (1H, br.s), 8.39 (1H, br.s), 11.84 (1H, s).
MS (FAB) m / z: 542 (M + H) ^<+> .

[Example 39] 2- [2-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} -6,7- Dihydrothiazolo [5,4-c] pyridin-5 (4H) -yl] ethylcarbamic acid tert-butyl ester

In the same manner as in Example 24, the title compound was obtained from the compound obtained in Example 34 and N- (tert-butoxycarbonyl) aminoacetaldehyde (J. Org. Chem., 1988, 53, 3457). .
¹ H-NMR (CDCl ₃ ) 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, 2.0 Hz), 7.33 (1H, d, J = 8) .8 Hz), 7.57-7.63 (2H, m), 7.81 (1H, br.s), 9.66 (1H, br.s).
MS (FAB) m / z: 601 (M + H) ^<+> .

Example 40 5- (2-Aminoethyl) -N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (450 mg) obtained in Example 39 was dissolved in methylene chloride (5 ml), hydrochloric acid ethanol solution (30 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated solid was collected by filtration to give the title compound (367 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.69 (1 H, d, J = 2.0 Hz), 8.12 (1 H, d, J = 6.6 Hz), 8.15-8.68 (4 H, m), 11. 85 (1H, s).
MS (FAB) m / z: 501 (M + H) ^<+> .

[Example 41] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- {2-[(methylsulfonyl) amino] ethyl } -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (110 mg) obtained in Example 40 was dissolved in pyridine (3 ml), methanesulfonyl chloride (30 μl) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and a solution of methylene chloride: methanol = 85: 15 and water were added to the residue for liquid separation operation, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a pale yellow foam. This was suspended in 1N hydrochloric acid (0.3 ml), and the solution was concentrated under reduced pressure to give the title compound (63 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz) 7.40 (1 H, d, J = 8.8 Hz), 7.41 (1 H, br. S), 7.69 (1 H, d, J = 2.0 Hz), 8.09 (1 H, br. s), 8.43 (1H, br.s), 11.18 (1H, br.s), 11.82 (1H, s).
MS (FAB) m / z: 579 (M + H) ^<+> .

[Example 42] 2- [2-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} -6,7- Dihydrothiazolo [5,4-c] pyridin-5 (4H) -yl] ethylcarbamic acid methyl ester hydrochloride

The compound (144 mg) obtained in Example 40 was dissolved in pyridine (3 ml), triethylamine (138 μl) was added, and the mixture was stirred at room temperature for 5 minutes. To this solution, a solution prepared by adding triphosgene (49 mg) to tetrahydrofuran (1 ml) containing methanol (20 μl) was added dropwise at room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methylene chloride: methanol = 9: 1, and water was added for liquid separation. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a colorless foamy substance. This was suspended in 1N hydrochloric acid (0.2 ml), and the solution was concentrated under reduced pressure to give the title compound (60 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.37 (1H, br.s), 7.40 (1H, d, J = 8.8 Hz), 7.70 (1H, s), 8.11 (1H, d, J = 6.8 Hz), 8.40 (1H, br.s), 11.05 (1H, br.s), 11.82 (1H, br.s).
MS (FAB) m / z: 559 (M + H) ^<+> .

[Example 43] 5- [2- (acetylamino) ethyl] -N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (90 mg) obtained in Example 40 was dissolved in N, N-dimethylformamide (3 ml), triethylamine (65 μl) and acetic anhydride (22 μl) were added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, methylene chloride and a 0.3 N aqueous sodium hydroxide solution were added to the residue, liquid separation was performed, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a colorless foamy substance. This was suspended in 1N hydrochloric acid (0.3 ml), and the solution was concentrated under reduced pressure to give the title compound (73 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz), 7.40 (1H, d, J = 8.6 Hz) 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) ^<+> .

Example 44 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (2-hydroxyethyl) -4,5 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and 2-bromoethanol.
¹ H-NMR (DMSO-d ₆ ) 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 = 5.4 Hz) , 7.12 (1H, s), 7.16 (1H, dd, J = 8.8, 2.0 Hz), 7.40 (1H, d, J = 8.8 Hz), 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) ^<+> .

Example 45 5-Butyl-N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and 1-bromobutane.
¹ H-NMR (DMSO-d ₆ ) δ: 0.88 (3H, t, J = 7.2 Hz), 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. 8 Hz), 7.40 (1 H, d, J = 8.8 Hz), 7.69 (1 H, s), 8.05-8.14 (1 H, m), 8.35 (1 H, br. S) , 11.81 (1H, s).
MS (FAB) m / z: 514 (M + H) ^<+> .

Example 46 5-Acetyl-N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide

The compound (100 mg) obtained in Example 34 was dissolved in N, N-dimethylformamide (3 ml), triethylamine (84 μl) and acetic anhydride (29 μl) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride and 1N hydrochloric acid were added to the residue, liquid separation was performed, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain the title compound (86 mg).
¹ H-NMR (CDCl ₃ ) 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) ^<+> .

[Example 47] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (methylsulfonyl) -4,5,6 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The compound (100 mg) obtained in Example 34 was dissolved in pyridine (3 ml), triethylamine (168 μl) and methanesulfonyl chloride (48 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, methylene chloride and 1N hydrochloric acid were added to the residue, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 1) to obtain the title compound (79 mg).
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 7.34 (1H, d, J = 8.8 Hz), 7.61 (3H, br.s), 9.91 (1H, br.s).
MS (FAB) m / z: 536 (M + H) ^<+> .

Example 48 5-Methyl-N-((1R ^* , 2S ^* )-2-{[(5-methylindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 67 and 5-methylindole-2-carboxylic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.50 (2H, m), 1.50 to 1.8
0 (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, 1.5 Hz), 7.05 (1 H, d, J = 1.5 Hz), 7.30 (1 H, d, J = 8.4 Hz), 7.38 (1 H, s), 8.00 (1 H, d, J = 7.3 Hz), 8.43 (1H, br.s), 11.45 (1H, br.s), 11.49 (1H, br.s).
MS (FAB) m / z: 452 (M + H) ^<+> .

Example 49 (1R ^* , 3S ^* , 4R ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester

The compound (1.40 g) obtained in Reference Example 91 was suspended in ethanol (8 ml), a hydrochloric acid ethanol solution (10 ml) was added at room temperature, and the mixture was stirred for 12 hours. The solvent was distilled off under reduced pressure, and (1R ^* , 3S ^* , 4R ^* )-3-amino-4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester hydrochloride (1 .25 g) was obtained.
In the same manner as in Example 2, the title compound was obtained from the above product and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1 Hz), 1.52-1.80 (2H, m), 2.03-2.37 (4H, m) , 2.53 (3H, s), 2.57-2.71 (1H, m), 3.73 and 3.78 (each 1H, each d, J = 14.4 Hz), 4.08-4. 17 (1H, m), 4.18 (2H, q, J = 7.2 Hz), 4.55-4.65 (1 H, m), 6.85 (1 H, br. S), 7.21 ( 1H, dd, J = 8.8, 2.0 Hz), 7.33 (1H, d, J = 8.8 Hz), 7.48 (1H, d, J = 7.6 Hz), 7.63 (1H , D, J = 2.0 Hz), 7.98 (1H, d, J = 7.6 Hz), 9.30 (1H, s).
MS (ESI) m / z: 544 (M + H) ^<+> .

Example 50 (1S, 3R, 4S) -4-{[(5-Chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester

The compound (4.2 g) obtained in Reference Example 97 was suspended in ethanol (25 ml), a hydrochloric acid ethanol solution (55 ml) was added at room temperature, and the mixture was stirred for 11 hours. The solvent was distilled off under reduced pressure to obtain a colorless solid (4.15 g).
The above product (4.15 g) was dissolved in N, N-dimethylformamide (40 ml), and the compound (2.86 g) obtained in Reference Example 10 and 1-hydroxybenzotriazole monohydrate (1. 72 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.15 g) were added and stirred for 39 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to obtain the title compound (1.71 g).
[Α] _D −94 ° (c = 1.0, chloroform).

[Example 51] (1R ^* , 3R ^* , 4S ^* )-3-{[(5-Chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester

The compound obtained in Reference Example 107 was treated with hydrochloric acid ethanol solution in the same manner as in Example 49, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.41 (1H, d, J = 8.5 Hz), 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) ^<+> .

[Example 52] (1R ^* , 3S ^* , 4R ^* )-3-{[(5-Chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester

The compound obtained in Reference Example 98 was treated with a hydrochloric acid ethanol solution in the same manner as in Example 49, and then condensed with 5-chloroindole-2-carboxylic acid to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1 Hz), 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, 2.0 Hz) 7.32 (1H, d, J = 8.8 Hz), 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) ^<+> .

[Example 53] (1R ^* , 3R ^* , 4S ^* )-4-{[(5-Chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester hydrochloride

The compound obtained in Reference Example 106 was treated with 4N hydrochloric acid dioxane solution in the same manner as in Example 49, and then condensed with 5-chloroindole-2-carboxylic acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 to 1.80 (3H, m), 1.80 to 2.10 (2H, m), 2.15 to 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, 1.2 Hz), 7.23 (1H, s), 7.43 (1H, d, J = 8.8 Hz), 7.73 (1H, s), 8 .03 (1H, d, J = 6.8 Hz), 8.73 (1H, d, J = 8.5 Hz), 11.15-11.38 (1H, br), 11.85 (1H, s) .
MS (FAB) m / z: 530 (M + H) ^<+> .

Example 54 (1R, 3R, 4S) -4-{[(5-Chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester

In the same manner as in Example 49, the compound obtained in Reference Example 112 was treated with 4N hydrochloric acid dioxane solution and then condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.72 (1H, s), 8.00 (1H, d, J = 6.9 Hz), 8.68 (1H, d, J = 8.6 Hz), 11 .80 (1H, s).
MS (FAB) m / z: 530 (M + H) ^<+> .

Example 55 N-((1R ^* , 2S ^* , 5S ^* )-5- (aminocarbonyl) -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

In the same manner as in Example 49, the compound obtained in Reference Example 113 was treated with 4N hydrochloric acid dioxane solution and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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, 1.6 Hz), 7.33 (1H, d, J = 8.4 Hz), 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) ^<+> .

[Example 56] (1R ^* , 3S ^* , 4R ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid

  The compound obtained in Example 49 (916 mg) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (8 ml), 1N aqueous sodium hydroxide solution (3.3 ml) was added at room temperature, and the same temperature was maintained for 12 hours. Stir. 1N Hydrochloric acid ethanol solution (3.3 ml) was added, the solvent was evaporated under reduced pressure, and the residue was washed with water and diethyl ether to give the title compound (712 mg).

[Example 57] N-{(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a chloroform suspension (10 ml) of the compound (168 mg) obtained in Example 56, triethylamine (0.25 ml), dimethylamine hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (53 mg), 1- ( 3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (75 mg) was added and stirred for 72 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7). The resulting colorless solid (135 mg) was suspended in ethanol (5 ml), and 1N hydrochloric acid ethanol. The solution (0.5 ml) was added and stirred for 2 hours. The solvent was distilled off to obtain the title compound (112 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.68 (1H, br.s), 8.32-8.47 (2H, m), 10.76. (1H, br.s).
MS (ESI) m / z: 543 (M + H) ^<+> .

Example 58 (1S, 3R, 4S) -4-{[(5-Chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid

The compound (1.6 g) obtained in Example 50 was suspended in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (15 ml), 1N aqueous sodium hydroxide solution (5.9 ml) was added at room temperature, and the mixture was heated at the same temperature. Stir for 12 hours. 1N Hydrochloric acid (5.9 ml) was added, the solvent was evaporated under reduced pressure, and the residue was washed with water and diethyl ether to give the title compound (1.19 g).
mp. 234-236 ° C.
[Α] _D −57 ° (c = 1.0, methanol).

[Example 59] N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(cyclopropylamino) carbonyl] cyclohexyl} -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and cyclopropylamine.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.68 (1H, d, J = 2.0 Hz) ), 7.86 (1H, br, J = 3.4 Hz), 8.06 (1H, br. S), 8.40 (1H, br, J = 7.6 Hz), 11.20-11.60 (1H, br), 11.79 (1H , S).
MS (FAB) m / z: 555 (M + H) ^<+> .

[Example 60] N-[(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (pyrrolidin-1-ylcarbonyl) cyclohexyl] -5 Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and pyrrolidine.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.7 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.69 (1H, s), 8.32 (1H, br, J = 7.6 Hz), 8 .38 (1H, br, J = 7.1 Hz), 11.22 (1H, br.s), 11.78 (1H, s).
MS (FAB) m / z: 569 (M + H) ^<+> .

Example 61 N-[(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (4-morpholinylcarbonyl) cyclohexyl] -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 56 and morpholine.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.67 (1 H, br. S), 8.35 (1 H, d, J = 7.6 Hz), 8.40 (1 H, d, J = 7.6 Hz), 10.79 ( 1H, br.s).
MS (ESI) m / z: 585 (M + H) ^<+> .

[Example 62] N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(ethylamino) carbonyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (150 mg) obtained in Example 58 was dissolved in N, N-dimethylformamide (3 ml), and N-ethylamine hydrochloride (119 mg), 1-hydroxybenzotriazole monohydrate (79 mg), 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (112 mg) and triethylamine (326 μl) were added, and the mixture was stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3). The obtained solid was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (171 μl) was added, and the solvent was evaporated under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to give the title compound (74 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (3H, t, J = 7.2 Hz), 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 = 2.0 Hz), 7.17 (1H, dd, J = 8.8, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.69 (1H, d, J = 2.0 Hz), 7.78-7.81 (1H M), 8.08-8.12 (1H, m), 8.40 (1 H, d, J = 8.1 Hz), 11.23 (1 H, br. S), 11.79 (1 H, br) .S). MS (FAB) m / z: 543 (M + H) ^<+> .

Example 63 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (900 mg) obtained in Example 58 was dissolved in N, N-dimethylformamide (50 ml), dimethylamine hydrochloride (304 mg,), 1-hydroxybenzotriazole monohydrate (262 mg), 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (369 mg) and diisopropylethylamine (1.83 ml) were added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3). The obtained white solid was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (1.49 ml) was added, and the solvent was evaporated under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to give the title compound (777 mg).
[Α] _D = −53.9 ° (18 ° C., c = 0.505, methanol).
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.60 (1H, m), 1.70-1.85 (3H, m), 1.90 to 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, 2.1 Hz), 7.41 (1H, d, J = 8.6 Hz), 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) ^<+> .

[Example 64] N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(2-methoxyethyl) (methyl) amino] Carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58.
¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.99 (6H, m), 2.80, 3.01 (3H, each), 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, 2.0 Hz), 7. 42 (1H, d, J = 8.8 Hz), 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) ^<+> .

[Example 65] N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(2-hydroxyethyl) (methyl) amino] Carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.68 (1 H, s), 8.34-8.40 (2 H, m), 11.47 (1 H, br. S), 11.79 (1 H, s). MS (FAB) m / z: 573 (M + H) ^<+> .

Example 66 N-((1R, 2S, 5S) -5- (1-azetidinylcarbonyl) -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5 Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and azetidine hydrochloride.
¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.55 (1H, m), 1.65-1.82 (3H, m), 1.88-2.01 (2H, m) 2.16 (2H, quint., J = 7.6 Hz), 3.17-3.67 (5H, m), 3.82 (2H, t, J = 7.6 Hz), 4.02-4 .14 (3H, m), 4.43-4.67 (3H, m), 7.06 (1H, s), 7.17 (1H, dd, J = 8.7, 1.7 Hz), 7 .41 (1H, d, J = 8.7 Hz), 7.69 (1H, br.s), 8.31 (1H, d, J = 7.6 Hz), 8.38 (1H, d, J = 7.6 Hz), 11.41 (1H, br.s), 11.80 (1H, s). MS (FAB) m / z: 555 (M + H) ^<+> .

Example 67 N-((1R, 2S, 5S) -2-{[(5-Chloroindol-2-yl) carbonyl] amino} -5-{[(3S) -3-fluoropyrrolidinyl] Carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and (S) -3-fluoropyrrolidine (Synlett., 1995, p. 55).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.3 Hz), 7.42 (1H, d, J = 8. 3 Hz), 7.68 (1H, s), 8.34-8.37 (2H, m), 11.78 (1H, s).
MS (FAB) m / z: 587 (M + H) ^<+> .

Example 68 (1R ^* , 3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid lithium salt

The compound (1.20 g) obtained in Example 51 was dissolved in tetrahydrofuran (32 ml), lithium hydroxide (60.8 mg) and water (4 ml) were successively added under ice cooling, and the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure to obtain the title compound (1.12 g).
¹ H-NMR (DMSO-d ₆ ) 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).

Example 69 N-{(1R ^* , 2S ^* , 4S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4-[(dimethylamino) carbonyl] cyclohexyl}- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 68 and dimethylamine hydrochloride.
¹ H-NMR (DMSO-d ₆ ) 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 = 1.5 Hz), 7.15 (1H, dd, J = 8.8, 2.1 Hz) , 7.41 (1H, d, J = 8.8 Hz), 7.69 (1H, d, J = 2.1 Hz), 8.05 (1H, d, J = 7.7 Hz), 8.63 ( 1H, d, J = 7.7 Hz), 11.20 (1H, br), 11.79 (1H, s).
MS (FAB) m / z: 543 (M + H) ^<+> .

[Example 70] N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(3R) -3-hydroxypyrrolidinyl] Carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

1) The compound (1.18 g) obtained in Reference Example 58 was dissolved in methanol (12 ml), 1N hydrochloric acid (240 μl) and palladium hydroxide (221 mg) were added, hydrogen was introduced, and the mixture was stirred at room temperature for 4.5 hours Pressure contact reduction was performed. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain crude (3R) -3-{[tert-butyl (diphenyl) silyl] oxy} pyrrolidine hydrochloride (984 mg).
The product obtained (249 mg), the compound obtained in Example 58 (295 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (126 mg) and 1-hydroxybenzotriazole monohydrate ( 87 mg) was dissolved in N, N-dimethylformamide (10 ml). Diisopropylethylamine (450 μl) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue. After separation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (methanol: methylene chloride = 3: 97), and N-((1R, 2S, 5S) -5-[((3R) -3-{[tert-butyl (diphenyl) silyl] ] Oxy} pyrrolidinyl) carbonyl] -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c Pyridine-2-carboxamide (248 mg) was obtained.
¹ H-NMR (CDCl ₃ ) 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 = 2.8 Hz), 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) The above product (240 mg) was dissolved in pyridine (10 ml), and hydrogen fluoride / pyridine (3.0 ml) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 4.5 hours. Under ice-cooling, ethyl acetate (80 ml) was added to the reaction solution for dilution, and the diluted reaction solution was poured onto ice. Sodium bicarbonate was added to this solution to make it alkaline, followed by liquid separation operation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 19 → 1: 9). The obtained crude product is dissolved in methylene chloride and methanol, 1N hydrochloric acid ethanol solution (225 μl) is added and dried once, and the residue is solidified by adding methanol-diethyl ether to obtain the title compound (114 mg). It was.
¹ H-NMR (DMSO-d ₆ ) 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 = 1.7 Hz). 7.16 (1H, dd, J = 8.8, 1.7 Hz), 7.42 (1H, d, J = 8.8 Hz), 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) ^<+> .

Example 71 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5,5-dimethoxycyclohexyl) -5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4,4-dimethoxycyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide Obtained in Reference Example 118 in the same manner as in Example 2. The title compound was obtained from the above compound and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) 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 = 15.6 Hz), 3.71 (1H, d, J = 15.6 Hz), 3.87-3.93 (1H M), 4.26-4.29 (1H, m), 6.85 (1H, d, J = 2.0 Hz), 7.19 (1H, dd, J = 8.5, 2.0 Hz) 7.30 (1H, d, J = 8.5 Hz), 7.62 (1H, s), 9.21 (1H, s).

Example 72 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-oxocyclohexyl) -5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4 -Oxocyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide The compound (100 mg) obtained in Example 71 was dissolved in chloroform (2 ml). , Trifluoroacetic acid (0.5 ml) and water (0.5 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 19: 1). The obtained colorless solid was dissolved in methanol (4 ml), 1N hydrochloric acid ethanol solution (0.38 ml) was added, and the solvent was evaporated under reduced pressure to give the title compound (35 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 13.0 Hz), 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 = 8.8 Hz), 7.38 (1H, d, J = 8.8 Hz), 7.69 (1H, s), 8.43 (1H, d, J = 8. 8 Hz), 8.91 (1 H, d, J = 8.8 Hz), 11.75 (1 H, s).

Example 73 N-[(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (hydroxyimino) cyclohexyl] -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-[(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino } -4- (Hydroxyimino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide The compound (133 mg) obtained in Example 72 was converted to pyridine. (8 ml) and methanol (8 ml) were dissolved in a mixed solvent, hydroxylamine hydrochloride (30 mg) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3 → 17: 3) to obtain the title compound (131 mg).
¹ H-NMR (CDCl ₃ ) 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 (total 1H, s), 7.56-7.64 (2H, m), 9.59, 9.62 (total 1 H, s).

[Example 74] N-((7R ^* , 8S ^* )-8-{[(5-chloroindol-2-yl) carbonyl] amino} -1,4-dioxaspiro [4.5] dec-7-yl ) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-((7R ^* , 8S ^* )-7-{[(5-chloroindole -2-yl) carbonyl] amino} -1,4-dioxaspiro [4.5] dec-8-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-Carboxamide In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 120 and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) 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 = 15.4 Hz), 3 .72 (1H, d, J = 15.4 Hz), 3.89-3.91 (1H, m), 3.99 (4H, s), 4.37-4.40 (1H, m), 6 .86 (1H, d, J = 2.0 Hz), 7.19 (1H, dd, J = 8.8, 2.0 Hz), 7.30 (1H, d, J = 8.8 Hz), 7. 38 (1H, d, J = 7.3 Hz), 7.62 (1H, d, J = 2.0 Hz), 9.15 (1H, s).

Example 75 N-[(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (methoxyimino) cyclohexyl] -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-[(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino } -4- (methoxyimino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide 1) Compound (2. 21 g) was dissolved in methylene chloride (30 ml), trifluoroacetic acid (6 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and dried with a vacuum pump, and then dissolved in N, N-dimethylformamide (20 ml) to give 5-chloroindole-2-carboxylic acid (500 mg), 1- (3-dimethylaminopropyl) -3. -Ethylcarbodiimide hydrochloride (593 mg), 1-hydroxybenzotriazole monohydrate (473 mg) and N-methylmorpholine (2.8 ml) were added, and the mixture was stirred at room temperature for 10 hours. Further, 5-chloroindole-2-carboxylic acid (242 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (237 mg) and 1-hydroxybenzotriazole monohydrate (189 mg) were added. Stir for hours. Saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate and a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3 → 4: 1), and N-[(1R ^* , 2S ^* )-2-amino-5- (methoxyimino) cyclohexyl] -5- Chloroindole-2-carboxamide (368 mg) and N-[(1R ^* , 2S ^* )-2-amino-4- (methoxyimino) cyclohexyl] -5-chloroindole-2-carboxamide (300 mg) were obtained.
2) One N-[(1R ^* , 2S ^* )-2-amino-5- (methoxyimino) cyclohexyl] -5-chloroindole-2-carboxamide or N-[(1R ^* ) obtained in the above reaction , 2S ^* )-2-amino-4- (methoxyimino) cyclohexyl] -5-chloroindole-2-carboxamide and the compound obtained in Reference Example 10 in the same manner as in Example 2, the title compound (methoxyimino A mixture of syn and anti isomers of the base part).
¹ H-NMR (CDCl ₃ ) δ: 1.84 to 2.00 (3H, m), 2.26 to 2.56 (3H, m), 2.46 (3H, s), 2.80-2 .83 (4H, m), 3.57 (1H, q, J = 15.4 Hz), 3.70 (1H, q, J = 15.4 Hz), 3.84, 3.85 (total 3H, s ), 4.08-4.14 (1H, m), 4.26-4.30 (1H, m), 6.84 (1H, s), 7.17 (1H, d, J = 8.8 Hz) ), 7.27 (1H, d, J = 8.8 Hz), 7.46-7.48 (2H, m), 7.56 (1H,
m), 9.42, 9.55 (total 1H, s).

[Example 76] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-hydroxycyclohexyl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer A) or N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) Carbonyl] amino} -4-hydroxycyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer A)
1) After removing the tert-butoxycarbonyl group of the (1R ^* , 2S ^* ) form (stereoisomer A) obtained in Reference Example 125 by the same method as 1) of Example 75, 5-chloroindole- N-((1R ^* , 2S ^* )-2-amino-4-{[tert-butyl (diphenyl) silyl] oxy} cyclohexyl) -5-chloroindole-2-carboxamide by reacting with 2-carboxylic acid (Stereoisomer A) and N-((1R ^* , 2S ^* )-2-amino-5-{[tert-butyl (diphenyl) silyl] oxy} cyclohexyl) -5-chloroindole-2-carboxamide (stereoisomerism Body A) was obtained.
2) N-((1R ^* , 2S ^* )-5-{[tert-butyl (diphenyl) silyl] oxy}-from the above product and the compound obtained in Reference Example 10 in the same manner as in Example 2. 2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereo Isomer A) or N-((1R ^* , 2S ^* )-4-{[tert-butyl (diphenyl) silyl] oxy} -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl ) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer A) was obtained.
¹ H-NMR (CDCl ₃ ) 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 = 7.6 Hz), 2.68-2.76 (1H, m), 3.56 (1H , S), 3.57 (1H, d, J = 15.3 Hz), 3.72 (1H, d, J = 15.3 Hz), 3.71-3.81 (1H, m), 3.88 -3.95 (1H, m), 6.78 (1H, s), 7.17 (1H, dd, J = 2.0,8.8 Hz), 7.37-7.44 (7H, m) , 7.59 (1H, s), 7.65-7.68 (6H, m), 9.30 (1H, s).
3) The title compound was obtained from the compound obtained in the above reaction by the same method as in Example 28, 3).
¹ H-NMR (DMSO-d ₆ ) δ: 1.25-1.30 (2H, m), 1.45-1.64 (2H, m), 1.86 (1H, d, J = 9. 0 Hz), 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 = 15.6 Hz), 3.62 (1 H, d, J = 15.6 Hz), 3.96-4.02 (2H, m), 4.78 (1H, d, J = 4.2 Hz), 7.00 (1H, s), 7.14 (1H, dd, J = 2.0, 8.8 Hz), 7.38 (1H, d, J = 8.8 Hz) ), 7.66 (1H, s), 8.20 (1H, d, J = 7.8 Hz), 8.54 (1H, d, J = 7.8 Hz), 11.69 (1H, s).

Example 77 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-hydroxy-5-methylcyclohexyl) -5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (isomer A1) or N-((1R ^* , 2S ^* )-2-{[(5-chloroindole-2 -Yl) carbonyl] amino} -4-hydroxy-4-methylcyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (isomer A2)
In the same manner as in Example 2, the compound obtained in Reference Example 128 was reacted with the compound obtained in Reference Example 128 to obtain the title compound.
Isomer A1:
¹ H-NMR (DMSO-d ₆ ) 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 .6 Hz), 7.38 (1 H, d, J = 8.6 Hz), 7.66 (1 H, d, J = 2.0 Hz), 8.21-8.26 (1 H, m), 8.59 (1H, d, J = 8.1 Hz), 11.73 (1H, br.s)
MS (FAB) m / z: 502 (M + H) ^<+> .
Isomer A2:
¹ H-NMR (DMSO-d ₆ ) 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 = 7.8 Hz), 7.38 (1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.29 (1H, br), 8.43 ( 1H, d, J = 9.3 Hz), 11.67 (1H, br) MS (FAB) m / z: 502 (M + H) ⁺ .

[Example 78] N-[(1R ^* , 2R ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (hydroxymethyl) cyclohexyl] -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

In the same manner as in Example 49, the compound obtained in Reference Example 129 was treated with a hydrochloric acid ethanol solution and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.23-7.35 (2H, m), 7.43 (1H, d, J = 7.2 Hz), 7.58 (1H, br.s), 9.29 (1H, s).
MS (ESI) m / z: 502 (M + H) ^<+> .

Example 79 N-[(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (methoxymethyl) cyclohexyl] -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

In the same manner as in Example 49, the compound obtained in Reference Example 135 was treated with hydrochloric acid ethanol solution and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 16.0 Hz), 3.76 (1H, d, J = 16.0 Hz), 4 .04-4.13 (1H, m), 4.53-4.62 (1H, m), 6.85 (1H, d, J = 2.0 Hz), 7.19 (1H, dd, J = 8.8, 2.0 Hz), 7.33 (1H, d, J = 8.8 Hz), 7.54 (1H, d, J = 7.2 Hz), 7.63 (1H, d, J = 2) .0Hz), 8.07 (1H, d, J = 5 .6 Hz), 9.49 (1H, br.s).

[Example 80] N-((1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(methylsulfonyl) amino] methyl} (Cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

1) The compound (437 mg) obtained in Reference Example 137 was dissolved in ethanol (5 ml), 4N hydrochloric acid dioxane solution (5 ml) was added at room temperature, and the mixture was stirred for 13 hours. The solvent was distilled off, the residue was dissolved in N, N-dimethylformamide (10 ml), triethylamine (0.7 ml), the compound obtained in Reference Example 10 (300 mg), 1-hydroxybenzotriazole monohydrate (162 mg) 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (230 mg) was added and stirred for 13 hours. The solvent was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3), and N-((1R ^* , 2S ^* , 5S ^* )-5- (azidomethyl) -2- {[(5-Chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (330 mg). Obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.15 to 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, 2.0 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 7.6 Hz), 8.44 (1 H, d, J = 7.6 Hz), 11.8 (1 H, s).
2) The compound (300 mg) obtained by the above reaction was dissolved in ethanol (8 ml), a catalytic amount of 10% palladium carbon was added, and the mixture was stirred at room temperature for 168 hours under a hydrogen stream. Insoluble matter was filtered, the solvent was distilled off, and crude N-((1R ^* , 2S ^* , 5S ^* )-5- (aminomethyl) -2-{[(5-chloroindol-2-yl) carbonyl] Amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (150 mg) was dissolved in chloroform (6 ml) and triethylamine (0 0.2 ml) and methanesulfonyl chloride (0.035 ml) were added and stirred for 13 hours. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to obtain the title compound (56 mg).
¹ H-NMR (CDCl ₃ ) 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, 2.0 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.52 (1H, d, J = 7.6 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.21 (1H, d, J = 5.6 Hz), 9.89 (1H, s).
MS (ESI) m / z: 579 (M + H) ^<+> .

[Example 81] N-{(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) methyl] cyclohexyl}- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide trifluoroacetate

In the same manner as in Example 24, the title compound was obtained from the amine obtained in 2) of Example 80.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 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) ^<+> .

Example 82 (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester (isomer B) and (3R ^* , 4S ^* )-3-{[(5-chloroindole- 2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert -Butyl ester (isomer B)

The compound (stereoisomer B) (1.79 g) obtained in Reference Example 140 was dissolved in tetrahydrofuran (36 ml), 10% palladium carbon (0.40 g) was added, and the mixture was stirred at room temperature for 20 hours under a hydrogen stream. . After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in N, N-dimethylformamide (36 ml), and 5-chloroindole-2-carboxylic acid p-nitrophenol ester (2.02 g) was added. The mixture was further stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, the insoluble material was collected by filtration, washed with ethyl acetate and crude (3R ^* , 4S ^* )-3-amino-4-{[((5- Chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester (or (3R ^* , 4S ^* )-4-amino-3-{[(5-chloroindol-2-yl) carbonyl] amino} Cyclohexylcarbamic acid tert-butyl ester) (isomer B1) (1.49 g) was obtained. The organic layer of the filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1 → 10: 1) to give (3R ^* , 4S ^* )-4-amino-3-{[(5- Chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester (or (3R ^* , 4S ^* )-3-amino-4-{[(5-chloroindol-2-yl) carbonyl] amino} Cyclohexylcarbamic acid tert-butyl ester) (isomer B2) (0.37 g) was obtained.
In the same manner as in Example 2, one of the title compounds was obtained from the above isomer B1 and the compound obtained in Reference Example 10.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.1 Hz), 7.05 (1H, s), 7.17 (1H, dd, J = 8.8, 2.2 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.69 (1H, s), 8.15 (1H, d, J = 7.8 Hz), 8 .37 (1H, d, J = 7.1 Hz), 11.78 (1H, s). MS (FAB) m / z: 587 (M + H) ^<+> .
In the same manner, the other title compound was obtained from the above isomer B2.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.3 Hz), 7.15-7.25 (2H, m), 7.43 (1H, d, J = 8.8 Hz), 7.73 (1H, d, J = 2. 0 Hz), 8.05 (1H, d, J = 6.6 Hz), 8.51 (1H, d, J = 8.8 Hz), 11.82 (1H, s).
MS (FAB) m / z: 587 (M + H) ^<+> .

Example 83 N-((1R ^* , 2S ^* )-5-amino-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (or N-((1R ^* , 2S ^* )-4-amino-2-{[(5-chloroindol-2-yl) carbonyl ] Amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide) hydrochloride (stereoisomer B)

The compound (stereoisomer B) (1.11 g) synthesized from isomer B1 in Example 82 was suspended in methylene chloride (20 ml), hydrochloric acid ethanol solution (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by gel filtration (Sephadex LH-20, methanol) to obtain the title compound (1.05 g).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.42 (1H, d, J = 8.8 Hz), 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) ^<+> .

[Example 84] N-[(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(methylsulfonyl) amino] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-[(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) Carbonyl] amino} -4-[(methylsulfonyl) amino] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer B)

The compound (0.20 g) obtained in Example 83 was suspended in methylene chloride (7 ml), triethylamine (0.16 ml) and methanesulfonyl chloride (28 μl) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with methylene chloride, washed with an aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1 → 15: 1) to obtain the title compound (67.9 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.69 (1H, s), 8.27 (1H, d, J = 7.3 Hz), 8.33 (1H , D, J = 8.1 Hz), 11.77 (1H, s).
MS (FAB) m / z: 565 (M + H) ^<+> .

Example 85 N-((1R ^* , 2S ^* )-5- (acetylamino) -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-((1R ^* , 2S ^* )-4- (acetylamino) -2-{[(5-chloroindole- 2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer B)

The compound obtained in Example 83 (stereoisomer B) (0.20 g) was suspended in methylene chloride (7 ml), triethylamine (0.16 ml) and acetic anhydride (34 μl) were added, and the mixture was stirred at room temperature for 20 hours. . Methylene chloride and aqueous sodium hydroxide solution were added to the reaction solution, and insoluble matters were collected by filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 15: 1 → 10: 1) to give the title compound ( 0.12 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 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 0.00 (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, 1.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.69 (1H, s), 7.89 (1H, d, J = 7.3 Hz) , 8.24 (1H, d, J = 8.1 Hz), 8.31 (1H, d, J = 7.3 Hz), 11.77 (1H, s).
MS (FAB) m / z: 528 (M + H) ^<+> .

[Example 86] N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[methoxy (methyl) amino] carbonyl} cyclohexyl)- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (250 mg) obtained in Example 58 was dissolved in N, N-dimethylformamide (5 ml), and N, O-dimethylhydroxylamine hydrochloride (142 mg), 1- (3-dimethylaminopropyl) -3-ethyl was dissolved. Carbodiimide hydrochloride (111 mg), 1-hydroxybenzotriazole monohydrate (89 mg) and N-methylmorpholine (213 ml) were added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3 → 23: 2) to obtain a colorless amorphous solid (179 mg). This was dissolved in methanol-tetrahydrofuran and 1N hydrochloric acid ethanol solution (960 ml) was added to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 1.5 Hz), 7.42 (1 H, d, J = 8.8 Hz), 7.70 (1 H, s), 8.33 (1 H, br. S), 8.41 (1 H , D, J = 7.8 Hz), 11.81 (1H, br.s).
MS (ESI) m / z: 559 (M + H) ^<+> .

[Example 87] N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(2,2-dimethylhydrazino) carbonyl] cyclohexyl } -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and N, N-dimethylhydrazine.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.42 (1H, d, J = 8.5 Hz), 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) ^<+> .

[Example 88] 6-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo) [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -2-quinolinecarboxamide hydrochloride

The compound obtained in Reference Example 145 was treated with a hydrochloric acid ethanol solution in the same manner as in Example 49, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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 = 8.6 Hz), 8.22 (1H, s), 8.52 (1H, d, J = 8.6 Hz), 8.72 (1H, d, J = 8.3 Hz) ), 8.89 (1H, d, J = 8.3 Hz).
MS (FAB) m / z: 555 (M + H) ^<+> .

[Example 89] N-{(1R, 2S, 5S) -2-{[(5-chloro-4-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

A compound obtained by condensing the compound obtained in Reference Example 144 and the compound obtained in Reference Example 274 in the same manner as in Reference Example 91 was treated with 4N hydrochloric acid dioxane solution, and then the compound obtained in Reference Example 10 To give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.1 Hz), 8.43 (1H, d, J = 7.6 Hz). 12.11 (1H, s). MS (FAB) m / z: 561 (M + H) ^<+> .

Example 90 7-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) isoquinoline-3-carboxamide hydrochloride

The compound obtained in Reference Example 146 was treated with hydrochloric acid ethanol solution in the same manner as in Example 49, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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 = 8.8 Hz), 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) ^<+> .

[Example 91] N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} tetrahydrofuran-3-yl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a solution of the compound (0.12 g) obtained in Reference Example 172 in N, N-dimethylformamide (20 ml), the compound (0.1 g) obtained in Reference Example 10 and 1-hydroxybenzotriazole monohydrate (78 mg) , And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.2 g) were sequentially added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated, and the resulting residue was diluted with chloroform: methanol (9: 1), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain the free base of the title compound and treated with hydrochloric acid ethanol solution to obtain the title compound (0.1 g).
¹ H-NMR (CDCl ₃ ) 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, 6.3 Hz), 3.97 (1H, dd, J = 9.7, 4.1 Hz), 4.15 (1H, dd, J = 9. 7, 5.8 Hz), 4.24 (1 H, dd, J = 9.2, 7.0 Hz), 4.75-4.89 (1 H, m), 4.92-5.03 (1 H, m ), 6.88 (1H, s), 7.20 (1H, dd, J = 8.8, 2.0 Hz), 7.33 (1H, d, J = 8.8 Hz), 7.35-7 .43 (1H, m), 7.58 (1H, d, J = 2.0 Hz), 7.64 (1H, d, J = 7.1 Hz), 9.38 (1H, s).
MS (FAB) m / z: 460 (M + H ^< + ^> ).

[Example 92] N-((3S, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} tetrahydrofuran-3-yl) -5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The title compound was obtained from the compound obtained in Reference Example 183 according to the methods of Reference Example 172 and Example 91.
¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 2.83 (2H, t, J = 5.3 Hz), 2.93 (2H, t, J = 5.3 Hz), 3 .72 (2H, s), 3.78-3.89 (2H, m), 4.31 (1H, dd, J = 9.2, 7.3 Hz), 4.41-4.56 (2H, m), 4.63-4.75 (1H, m), 6.88 (1H, s), 7.22 (1H, dd, J = 8.8, 2.0 Hz), 7.32 (1H, d, J = 8.8 Hz), 7.35-7.46 (1 H, m), 7.55 (1 H, d, J = 7.1 Hz), 7.60 (1 H, d, J = 2.0 Hz) ), 9.38 (1H, s).
MS (FAB) m / z: 460 (M + H ^< + ^> ).

[Example 93] N-((3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} tetrahydrofuran-3-yl) -5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in Reference Example 187 according to the methods of Reference Example 172 and Example 91.
¹ H-NMR and MS (FAB): consistent with enantiomer Example 92.

[Example 94] (3R, 4R) -3-{[(5-Chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo) [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 193 and the compound obtained in Reference Example 10 according to the method of Example 91.
Melting point: 190-192 ° C
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.46 (3H, s), 2.74-2.81 (4H, m), 3.24-3.37 (2H M), 3.54 to 3.70 (2H, m), 3.96 to 4.00 (1H, m), 4.15 to 4.23 (1H, m), 4.50 to 4.65. (1H, m), 4.77-4.82 (1H, m), 6.79, 6.87 (total 1H, each), 7.12-7.95 (5H, m), 9.91. , 9.97 (total 1H, each).
MS (FAB) m / z: 559 (M + H ^< + ^> ).

[Example 95] N-((3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} pyrrolidin-3-yl) -5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (170 mg) obtained in Example 94 was dissolved in methylene chloride (3 ml), trifluoroacetic acid (2 ml) was added at room temperature, and the mixture was stirred for 1 hour. After concentration, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform: methanol: water = 7: 3: 1, lower layer), and methanolic hydrochloric acid was added to the target product to obtain the hydrochloride to give the title compound (90 mg). (NMR was measured with free base).
Melting point: 248-250 ° C (decomposition).
¹ H-NMR (CDCl ₃ ) 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 = 8.5 Hz), 7.44 (1H, s), 7.89 (2H, br), 10.51 (1H, br).
MS (FAB) m / z: 459 (M + H ^< + ^> ).

Example 96 N-((3S, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -5-oxotetrahydrofuran-3-yl) -5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

After removing the tert-butoxycarbonyl group of the compound obtained in Reference Example 196 in the same manner as in Reference Example 69, the title compound was obtained by reacting with the compound obtained in Reference Example 10 in the same manner as in Example 91. .
¹ H-NMR (DMSO-d ₆ ) δ: 2.90 (3H, s), 3.02-3.17 (2H, m), 3.23-3.34 (4H, m), 4.20 (1H, t, J = 8.6 Hz), 4.61 (1H, t, J = 8.6 Hz), 4.92-5.01 (1H, m), 5.14-5.26 (1H, m), 7.09 (1H, s), 7.19 (1H, dd, J = 8.8, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.73 ( 1H, d, J = 2.0 Hz), 9.27 (1H, d, J = 6.8 Hz), 9.35 (1H, d, J = 6.8 Hz), 11.22-11.33 (1H , M), 11.89 (1H, s).
MS (FAB) m / z: 474 (M + H ^< + ^> ).

Example 97 N-((3S, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -2-oxotetrahydrofuran-3-yl) -5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

After removing the tert-butoxycarbonyl group of the compound obtained in Reference Example 197 in the same manner as in Reference Example 69, the title compound was reacted with 5-chloroindole-2-carboxylic acid in the same manner as in Example 91. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.52 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 2.91-3.00 (2H, m), 3 .73 (2H, s), 4.23 (1H, t, J = 8.6 Hz), 4.40-4.53 (1H, m), 4.96 (1H, dd, J = 10.8, 5.2 Hz), 5.16 (1H, dd, J = 9.2, 7.3 Hz), 7.01 (1H, s), 7.25 (1H, dd, J = 8.8, 2.0 Hz) ), 7.34 (1H, d, J = 8.8 Hz), 7.52 (1H, d, J = 2.0 Hz), 8.01 (1H, d, J = 5.4 Hz), 8.51 -8.63 (1H, m), 9.22 (1H, s).
MS (FAB) m / z: 474 (M + H ^< + ^> ).

[Example 98] (3S, 4R) -2- (3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -2-oxopyrrolidin-1-yl) acetic acid ethyl ester hydrochloride

The title compound was obtained from the compound obtained in Reference Example 199 and the compound obtained in Reference Example 10 in the same manner as in Example 91 (NMR was measured with a free base).
¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (3H, t, J = 7.1 Hz), 2.35 (3H, s), 2.71-2.84 (2H, m), 2 80-2.90 (2H, m), 3.40 (1H, d, J = 10.3 Hz), 3.61 (2H, d, J = 10.8 Hz), 3.
84 (1H, dd, J = 10.3, 5.6 Hz), 4.01-4.23 (4H, m), 4.80-4.94 (1H, m), 5.04 (1H, t , J = 8.6 Hz), 7.01 (1H, s), 7.16 (1H, dd, J = 8.8, 2.0 Hz), 7.40 (1H, d, J = 8.8 Hz) , 7.69 (1H, d, J = 2.0 Hz), 8.73 (1H, d, J = 8.6 Hz), 8.90 (1H, d, J = 8.8 Hz), 11.86 ( 1H, s).
MS (FAB) m / z: 559 (M + H ^< + ^> ).

[Example 99] N-((3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-methyl-5-oxopyrrolidin-3-yl) -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 201 and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H, s), 2.77-2.82 (2H, m), 2.86-2.91 (5H, m), 3.69 (2H , D, J = 1.2 Hz), 4.39-4.54 (3H, m), 4.93-4.98 (1H, m), 6.98 (1H, d, J = 1.2 Hz) 7.07.34 (3H, m), 7.63 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 7.8 Hz), 9.00 (1H, s)
MS (FAB) m / z: 487 (M + H ^< + ^> ).

Example 100 2-[((3R, 4R) -3-{[(5-Chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) sulfonyl] acetic acid methyl ester

The compound obtained in Example 95 (230 mg) and triethylamine (0.10 ml) were dissolved in methylene chloride (6.9 ml) and cooled on ice. Subsequently, methoxycarbonylmethanesulfonyl chloride (Synthesis, 321 pages, 1975) (105 mg) was added and the mixture was returned to room temperature and stirred overnight. The mixture was diluted with chloroform, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform _: methanol = 20: 1) and pulverized from methanol-water to give the title compound (150 mg).
¹ H-NMR (CDCl ₃ ) 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 ^< + ^> ).

[Example 101] 2-[((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) sulfonyl] acetic acid

The compound (100 mg) obtained in Example 100 was dissolved in tetrahydrofuran (4 ml) -water (1 ml) and cooled on ice. Subsequently, lithium hydroxide monohydrate (7.8 mg) was added, and the mixture was returned to room temperature and stirred for 4 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and concentrated. The precipitate was collected by filtration, washed with water and 50% ethanol, and dried under reduced pressure at 50 ° C. overnight to give the title compound (87 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 14.5 Hz), 4.65-4.71 (1H, m), 4.78-4.84 (1H, m), 7.14 (1H, s), 7.18 (1H, d, J = 8.8 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.72 (1H, s), 8. 87 (1H, d, J = 7.8 Hz), 9.12 (1H, d, J = 8.2 Hz), 11.83 (1H, s).

[Example 102] 2-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) acetic acid methyl ester

The compound obtained in Example 95 (230 mg) and potassium carbonate (90 mg) were dissolved in N, N-dimethylformamide (4.6 ml) and cooled on ice. Then, bromoacetic acid methyl ester (0.062 ml) was added and stirred for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform: methanol = 10: 1) and pulverized from methanol-water to give the title compound (190 mg).
¹ H-NMR (CDCl ₃ ) 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 = 6.5 Hz), 3.67 (2H, q, J = 6.5 Hz), 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 = 9.0 Hz), 7.53 (1H, s ), 7.77 (1H, d, J = 8.0 Hz), 7.87 (1H, d, J = 6.8 Hz), 10.22 (1H, s). MS (FAB) m / z: 531 (M + H ^< + ^> ).

[Example 103] 2-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) acetic acid

The title compound was obtained from the compound obtained in Example 102 in the same manner as in Example 101.
¹ H-NMR (DMSO-d ₆ ) δ: 2.42 (3H, s), 2.69-2.87 (6H, m), 3.13 (1H, t, J = 9.0 Hz), 3 .22 (1H, t, J = 9.0 Hz), 3.33 (each 1H, AB type d, J = 6.8 Hz), 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 = 8.8 Hz), 7.70 (1H) , S), 8.85 (1H, d, J = 7.5 Hz), 9.00 (1H, d, J = 8.3 Hz), 11.79 (1H, s).

[Example 104] 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) propionic acid methyl ester

The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 95 and 3-bromopropionic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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 = 9.2 Hz), 7.53 (1H, s ), 7.65-7.71 (2H, m), 10.02 (1H, s).
MS (FAB) m / z: 545 (M + H ^< + ^> ).

[Example 105] 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) propionic acid

The title compound was obtained from the compound obtained in Example 104 in the same manner as in Example 101.
¹ H-NMR (DMSO-d ₆ ) δ: 2.38 (3H, s), 2.39-2.84 (10H, m), 2.93 (1H, t, J = 8.8 Hz), 3 .05 (1H, t, J = 8.8 Hz), 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 = 8.8 Hz), 7.69 (1H, s), 8.81 (1H, d, J = 7.8 Hz) , 8.97 (1H, d, J = 8.3 Hz), 11.75 (1H, s).

[Example 106] 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) -3-oxopropionic acid ethyl ester

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 95 and ethyl malonyl chloride.
¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (3H, t, J = 7.0 Hz), 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 = 7.0 Hz), 4.61-4.84 (2H, m), 7.13 (1H, s), 7.18 (1H, dd, J = 8.5, 2.0 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.72 (1H, s), 8.73 (1H, t, J = 9.0 Hz), 9.10 (1H, d, J = 9.0 Hz), 11.79 (1H, s).

[Example 107] 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) -3-oxopropionic acid

The title compound was obtained from the compound obtained in Example 106 in the same manner as in Example 101.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.72 (1H, s), 8. 75 (1H, t, J = 8.8 Hz), 9.12 (1H, d, J = 7.8 Hz), 11.81 (1H, s).

[Example 108] 1-[((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) methyl] cyclopropanecarboxylic acid methyl ester

The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 95 and 1- (bromomethyl) cyclopropanecarboxylic acid methyl ester.
¹ H-NMR (CDCl ₃ ) 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 = 8.5 Hz), 7.54 (1 H, s), 7.69 (1 H, d, J = 8.0 Hz), 10.00 (1 H, s).
MS (ESI) m / z: 571 (M + H ^< + ^> ).

[Example 109] 1-[((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) methyl] cyclopropanecarboxylic acid

The title compound was obtained from the compound obtained in Example 108 in the same manner as in Example 101.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.70 (1H, s), 8.84 (1H, d) , J = 7.5 Hz), 9.12 (1H, d, J = 7.5 Hz), 11.77 (1H, s).

Example 110 (3R, 4R) -3-{[(5-Chloroindol-2-yl) carbonyl] amino} -4-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo) [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 193 and the compound obtained in Reference Example 148.
¹ H-NMR (CDCl ₃ ) δ: 1.12 (6H, d, J = 6.6 Hz), 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 = 8.5 Hz), 4.15-4.35 (2H, m), 4.50-4.65 (1H, m), 6.85, 6.91 (total 1H) , Each s), 7.15-7.90 (5H, m), 9.41, 9.50 (total 1H, each s).

[Example 111] N-((3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} pyrrolidin-3-yl) -5-isopropyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The title compound was obtained in the same manner as in Example 95 from the compound obtained in Example 110.
¹ H-NMR (CDCl ₃ ) δ: 1.13 (6H, d, J = 6.3 Hz), 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).

[Example 112] 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-isopropyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) propionic acid ethyl ester

The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 111 and 3-bromopropionic acid ethyl ester.
¹ H-NMR (CDCl ₃ ) δ: 1.14 (6H, d, J = 6.5 Hz), 1.26 (3H, t, J = 7.0 Hz), 2.51 (3H, t, J = 7.0 Hz), 2.63 (1H, dd, J = 9.5, 6.5 Hz), 2.73-2.91 (6H, m), 2.95-3.02 (1H, m), 3.22 (2H, q, J = 7.0 Hz), 3.81 (each 1H, AB type d, J = 14.5 Hz), 4.16 (2H, q, J = 7.0 Hz), 4. 40-4.45 (1H, m), 4.52-4.59 (1H, m), 6.88 (1H, d, J = 2.0 Hz), 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 ^< + ^> ).

[Example 113] 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-isopropyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) propionic acid

The title compound was obtained from the compound obtained in Example 112 in the same manner as in Example 101.
¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (6H, d, J = 6.6 Hz), 2.40 (2H, q, J = 7.0 Hz), 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 = 8.8 Hz), 7.68 (1 H, s), 8.78 (1 H, d, J = 7.5 Hz), 8.90 (1 H, d, J = 8.0 Hz), 11.73 ( 1H, s).

[Example 114] N-((3R, 4R) -1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} pyrrolidin-3-yl) -5-isopropyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 111 and acetic anhydride.
Melting point: 254-258 ° C (decomposition)
¹ H-NMR (DMSO-d ₆ ) 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 = 8.3 Hz), 4.45-4.82 (4H, m), 7.15 (1H, s), 7.18 (1H, d, J = 9.0 Hz), 7.41 (1H, d, J = 9.0 Hz), 7.71 (1H, s), 8.75-8.81 (1H, m), 9 .21 (1H, d, J = 8.0 Hz), 11.32 (1H, br), 11.83 (1H, d, J = 7.3 Hz).
MS (FAB) m / z: 529 (M + H ^< + ^> ).

[Example 115]
N-[(3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (methylsulfonyl) pyrrolidin-3-yl] -5-isopropyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 111 and methanesulfonyl chloride.
Melting point: 230-235 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 5.5 Hz), 7.14 (1H, s), 7.18 (1H, d, J = 8.6 Hz), 7.40 (1H, d, J = 8.6 Hz), 7.72 (1H, s), 8.82 (1H , Br), 9.20 (1H, d, J = 8.3 Hz), 11.30 (1H, br), 11.86 (1H, d, J = 7.5 Hz).
MS (FAB) m / z: 565 (M + H ^< + ^> ).

Example 116 (3R, 4R) -3-{[(5-Chloroindol-2-yl) carbonyl] amino} -4-{[(5-isopropyl-4,5,6,7-tetrahydrothiazolo) [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidine-1-carboxylic acid ethyl ester hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 111 and ethyl chloroformate.
Melting point: 225-228 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (3H, t, J = 7.0 Hz), 1.31-1.37 (6H, m), 3.33-3.45 (5H, m), 3.66-3.75 (4H, m), 4.05 (2H, q, J = 7.0 Hz), 4.45-4.77 (4H, m), 7.15 (1H, s), 7.17 (1H, dd, J = 8.8, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 2.0 Hz) ), 8.77 (1H, d, J = 7.0 Hz), 9.20 (1H, d, J = 8.0 Hz), 11.30 (1H, br), 11.83 (1H, d, J = 7.5 Hz).
MS (FAB) m / z: 559 (M + H ^< + ^> ).

[Example 117] (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 207 and the compound obtained in Reference Example 10.
Melting point: 152-154 ° C (decomposition).
¹ H-NMR (CDCl ₃ ) 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, 1.8 Hz), 7.32 (1H, d, J = 8.8 Hz), 7 .92 (1H, d, J = 1.8 Hz), 7.75 (1H, br.s), 8.21 (1H, br.s), 9.39 (1H, s).
MS (ESI) m / z: 573 (M + H) ^<+> .

[Example 118] N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride

The title compound was obtained from the compound obtained in Example 117 in the same manner as in Example 95. Melting point: 240-258 [deg.] C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz), 7.70 (1H, s), 8.50 (1H, br. D, J = 7. 8 Hz), 8.90-9.05 (2H, m), 9.27 (1 H, br. S), 11.9 (1 H, br. D, J = 13.4 Hz).
MS (ESI) m / z: 473 (M + H) ^<+> .

Example 119 (3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 208 and 5-chloroindole-2-carboxylic acid.
Melting point: 187-189 ° C (decomposition)
¹ H-NMR (CDCl ₃ ) 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 = 10.8 Hz), 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 = 1.5 Hz), 7.17 (1H, dd, J = 8.8, 1.9 Hz), 7.20-7.30 (1 H, m), 7.33 (1 H, d, J = 8.8 Hz), 7.58 (1 H, d, J = 1.9 Hz), 10. 17 (1H, s).
MS (ESI) m / z: 573 (M + H ^< + ^> ).

[Example 120] N-((3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-4-yl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride

The title compound was obtained in the same manner as in Example 95 from the compound obtained in Example 119. Melting point: 276-278 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 1.9 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.48 (1H, br.s), 7.71 (1H, d, J = 1.9 Hz), 8.66 (1H, br.s), 8.95 (1H, d, J = 8.1 Hz), 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) ^<+> .

[Example 121] (3R ^* , 4S ^* )-4-{[(5-Fluoroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 209 and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) 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, 2.7 Hz), 7.30 (1H, dd, J = 9.0, 2. 7 Hz), 7.34 (1H, dd, J = 9.0, 4.4 Hz), 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 ^< + ^> ).

[Example 122] N-((3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride

The title compound was obtained from the compound obtained in Example 121 in the same manner as in Example 95. Melting point: 236-245 [deg.] C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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) 2.4 Hz), 7.15 (1 H, br. S), 7.37-7.44 (2 H, m), 8.46 (1 H, d, J = 7.8 Hz), 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 ^< + ^> ).

[Example 123] N-((3R ^* , 4S ^* )-1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and acetic anhydride.
Melting point: 215-225 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 to 1.85 (1H, m), 1.88, 2.06 (total 3H, each), 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 = 15.6 Hz), 7.17 (1H, d, J = 8.8 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.71 (1H, s), 8.23-8.53 (2H, m), 11.20-11. 55 (1H, m), 11.85 (1H, br.d, J = 5.4 Hz).
MS (ESI) m / z: 515 (M + H ^< + ^> ).

[Example 124] N-((3R ^* , 4S ^* )-1-acetyl-3-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-4-yl) -5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 120 and acetic anhydride.
Melting point: 225-250 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 to 1.80 (1H, m), 1.81,2.05 (total 3H, each), 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 (total 1H) , Each d, J = 6.8 Hz), 8.73, 8.83 (total 1H, each d, J = 8.3 Hz), 11.20-11.50 (1H, m), 11.89 , 11.92 (total 1H, each).
MS (FAB) m / z: 515 (M + H ^< + ^> ).

Example 125 N-((3R ^* , 4S ^* )-1-acetyl-4-{[(5-fluoroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 122 and acetic anhydride.
Melting point: 202 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 1.67-1.85 (1H, m), 1.87 (1.5 H, s), 1.87-2.10 (1 H, 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 ^< + ^> ).

[Example 126] N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (methylsulfonyl) piperidin-3-yl] -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and methanesulfonyl chloride.
Melting point: 225-230 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 1.7 Hz), 7.18 (1H, dd, J = 8.7, 1.7 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.77 (1H, s), 8.02-8.20 (1 H, m), 8. 40-8.50 (1H, m), 11.00-11.60 (1H, m), 11.87 (1H, s).
MS (ESI) m / z: 551 (M + H ^< + ^> ).

[Example 127] N-[(3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (methylsulfonyl) piperidin-4-yl] -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in Example 120 and methanesulfonyl chloride in the same manner as in Example 100.
Melting point: 228-245 [deg.] C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 10.6 Hz), 3 .55-3.80 (2H, m), 4.25-4.40 (4H, m), 7.17 (1H, d, J = 1.7 Hz), 7.19 (1H, dd, J = 8.7, 2.0 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.74 (1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 6) .6 Hz), 8.78 (1H, d, J = 7.4 Hz), 10.90-11.20 (1H, br.s), 11.89 (1H, s).
MS (ESI) m / z: 551 (M + H ^< + ^> ).

[Example 128] N-[(3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1- (methylsulfonyl) piperazin-3-yl] -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 122 and methanesulfonyl chloride.
Melting point: 216-250 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 ^< + ^> ).

Example 129 (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid methyl ester hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and methyl chloroformate.
Melting point: 248-253 [deg.] C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 1.8 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 1.8 Hz), 8.29 (1H, br.s), 8.41 (1H, d, J = 8.1 Hz), 11.29 (1H, br.s), 11.85 (1H, s).
MS (ESI) m / z: 531 (M + H ^< + ^> ).

[Example 130] (3R ^* , 4S ^* )-4-{[(5-Chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid ethyl ester hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and ethyl chloroformate.
Melting point: 215-225 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 (1 H, 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, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 2.0 Hz) , 8.23 (1H, br.s), 8.45 (1H, br.d, J = 8.1 Hz), 11.50 (1H, br.s), 11.86 (1H, s).
MS (ESI) m / z: 545 (M + H ^< + ^> ).

[Example 131] (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid 2-methoxyethyl ester hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and 2-methoxyethyl chloroformate.
Melting point: 224-226 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 2.0 Hz), 8.26 (1H, br.s), 8.42 (1H, d, J = 7.8 Hz), 11.30 (1H, br.s), 11.86 (1H, s).
MS (ESI) m / z: 575 (M + H ^< + ^> ).

[Example 132] (3R ^* , 4S ^* )-3-{[(5-Chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid ethyl ester hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 120 and ethyl chloroformate.
Melting point: 213-225 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.74 (1H, s), 8.03 (1H, d, J = 5.6 Hz), 8.79 (1H, s), 11.37 (1H, s), 11.88 (1H, s).
MS (ESI) m / z: 545 (M + H ^< + ^> ).

Example 133 N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-propionylpiperidin-3-yl) -5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in Example 118 and propionyl chloride in the same manner as in Example 100.
Melting point: 214-228 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 11.0 Hz), 7.17 (1H, dd, J = 8.8, 1.2 Hz), 7.41 (1H, d, J = 8.8 Hz), 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 ^< + ^> ).

Example 134 N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-isobutyrylpiperidin-3-yl) -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and isobutyryl chloride.
Melting point: 266-272 [deg.] C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 11.0 Hz), 7.17 (1H, dd, J = 8. 8, 2.0 Hz), 7.41 (1 H, d, J = 8.8 Hz), 7.71 (1 H, s), 8.00-8.30 (1 H, m), 8.30-8. 50 (1H, m), 10.95-11.50 (1H, m), 11.86 (1H, s).
MS (ESI) m / z: 543 (M + H ^< + ^> ).

[Example 135] N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2,2-dimethylpropanoyl) piperidine-3- Yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and pivaloyl chloride.
Melting point: 250-255 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 1.9 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.69 (1H, d, J = 1.9 Hz), 8.06 (1H, br.s) , 8.38 (1H, d, J = 7.8 Hz), 11.31 (1H, br.s), 11.84 (1H, s).
MS (ESI) m / z: 557 (M + H ^< + ^> ).

Example 136 N-[(3R ^* , 4S ^* )-4-{[(5-Chloroindol-2-yl) carbonyl] amino} -1- (3,3-dimethylbutanoyl) piperidine-3- Yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and tert-butylacetyl chloride.
Melting point: 260-265 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 0.91, 1.04 (total 9H, each), 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, 1.2 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.69 (1H, d, J = 7.6 Hz), 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 ^< + ^> ).

[Example 137] N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2,2,2-trifluoroacetyl) piperidine- 3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and trifluoroacetic anhydride.
Melting point: 262-267 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 1.9 Hz), 7.41 (1H, d, J = 8.6 Hz), 7.72 (1 H, s), 8.47 (1 H, dd, J = 22.4, 7.9 Hz), 8.60 (1 H, br), 11.08 (1 H, br. s), 11.87 (1H, s).
MS (ESI) m / z: 569 (M + H ^< + ^> ).

[Example 138] N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (cyclopropylcarbonyl) piperidin-3-yl] -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and cyclopropanecarbonyl chloride.
Melting point: 280-286 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.71 (1H, s), 8.18 (1H, br.s), 8.40, 8 .48 (total 1H, each br.s), 11.11 (1H, br.s), 11.85 (1H, s).
MS (ESI) m / z: 542 (M + H ^< + ^> ).

Example 139 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (cyclobutylcarbonyl) piperidin-3-yl] -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and cyclobutanecarbonyl chloride.
Melting point: 271-275 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.39 (1H, d, J = 9.0 Hz), 7.68 (1H, d, J = 2.0 Hz), 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 ^< + ^> ).

[Example 140] N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (cyclopentylcarbonyl) piperidin-3-yl] -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and cyclopentanecarbonyl chloride.
Melting point: 254-260 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz) , 7.42 (1H, d, J = 8.7 Hz), 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 ^< + ^> ).

[Example 141] Acetic acid 2-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-1-yl) -2-oxoethyl ester

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and acetoxyacetyl chloride.
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 8.35 (1H, br.s), 9.34 , 9.45 (total 1H, each br.s).
MS (ESI) m / z: 573 (M + H ^< + ^> ).

[Example 142] N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-glycoloylpiperidin-3-yl) -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound obtained in Example 141 (301.8 mg) was dissolved in tetrahydrofuran (10 ml), 1N aqueous sodium hydroxide solution (0.53 ml) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 to 10: 1), and the solvent was distilled off under reduced pressure. This purified product was dissolved in ethanol (3 ml) and methylene chloride (2 ml), 1N hydrochloric acid ethanol solution (0.40 ml) was added, and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was solidified with diethyl ether to obtain the title compound (195 mg).
Melting point: 216-230 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 11.0 Hz), 7.17 (1H, dd, J = 8.8, 2.0 Hz), 7.42 (1 H, d, J = 8.8 Hz), 7.71 (1 H, s), 8.33 (1 H, br. S), 8.35-8.50 (1 H, m), 10.80-11.30 (1H, br.s), 11.84 (1H, br.s).

[Example 143] N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl]- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in Example 118 in the same manner as in Example 100.
Melting point: 214-228 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 9.0 Hz), 7.17 (1H, dd, J = 8.8, 1.9 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.70 (1H, d, J = 1.9 Hz), 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) ^<+> .

[Example 144] N-[(3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl]- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 122 and methoxyacetyl chloride.
Melting point: 190-208 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 2.4 Hz), 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 ^< + ^> ).

[Example 145] N-((3R ^* , 4S ^* )-1- (3-{[tert-butyl (diphenyl) silyl] oxy} -2,2-dimethylpropanoyl) -4-{[(5- Chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

To a solution of the compound obtained in Reference Example 158 (261 mg) in chloroform (10 ml) were added thionyl chloride (3.0 ml) and a catalytic amount of dimethylformamide, and the mixture was stirred at 60 ° C. overnight. The title compound (241 mg) was obtained in the same manner as in Example 100 from the yellow oil obtained by concentrating the reaction solution under reduced pressure and the compound (200 mg) obtained in Example 118.
Melting point. 153 ° C
¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.39 (6H, d, J = 3.9 Hz), 1.57 (1H, br. S), 2.26 (1H , D, J = 10.7 Hz), 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 (1 H, d, J = 13 Hz), 4.42 (1 H, br. S), 4.67 (1 H, d, J = 13 Hz), 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 = 6.8 Hz), 8.23 (1H, s), 9.10 (1H, s).

Example 146 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (3-hydroxy-2,2-dimethylpropanoyl) Piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

Tetrabutylammonium fluoride (1 molar tetrahydrofuran solution, 0.594 ml) was added to a tetrahydrofuran (30 ml) solution of the compound (241 mg) obtained in Example 145 under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in methylene chloride, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 9: 1) to give the title compound (116 mg).
Melting point: 220 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (6H, d, J = 8.3 Hz), 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 = 5.7 Hz) ), 7.10 (1H, s), 7.16-7.19 (1H, m), 7.42 (1H, d, J = 8.8 Hz), 7.69 (1H, s), 8. 11 (1H, d, J = 8.8 Hz), 8.37 (1H, d, J = 7.3 Hz), 11.8 (1H, s).
MS (FAB) m / z: 573 (M + H ^< + ^> ).

Example 147 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (3-methoxy-2,2-dimethylpropanoyl) Piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The title compound was obtained in the same manner as in Example 145 from the compound obtained in Example 118 and the compound obtained in Reference Example 160.
Melting point: 240 ° C. (decomposition).
¹ H-NMR (CDCl ₃ ) 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 = 9.3 Hz), 3.56 (1H, d, J = 9.3 Hz), 3.76 (2H, d, J = 5.9 Hz), 4.26 (1H, m), 4.44-4.53 (2H, m ), 4.82 (1H, d, J = 13.7 Hz), 6.88 (1H, d, J = 1.5 Hz), 7.20-7.23 (1H, m), 7.33 (1H) , D, J = 8.8 Hz), 7.64 (1H, d, J = 1.5 Hz), 7.90 (1H, d, J = 7.1 Hz), 8.22 (1H, d, J = 5.1 Hz), 9.18 (1H, s).
MS (FAB) m / z: 587 (M + H ^< + ^> ).

Example 148 Acetic acid 2-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-1-yl) -1,1-dimethyl-2-oxoethyl ester

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and 2-acetoxyisobutyryl chloride.
Melting point: 190 ° C. (decomposition).
¹ H-NMR (CDCl ₃ ) δ: 1.56-1.67 (8H, m), 2.08 (3H, s), 2.35 (1H, d, J = 10.5 Hz), 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 = 1.7 Hz), 7.76 (1H, d, J = 7.3 Hz), 9.11 (1H, s).
MS (FAB) m / z: 601 (M + H ^< + ^> ).

Example 149 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-hydroxy-2-methylpropanoyl) piperidine- 3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

Sodium methoxide (76.8 mg) was added to a methanol (50 ml) solution of the compound obtained in Example 148 (190 mg) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 9: 1) to give the title compound (130 mg). Melting point: 190 ° C. (decomposition).
¹ H-NMR (CDCl ₃ ) δ: 1.53 (3H, s), 1.56-1.78 (5H, m), 2.34 (1H, d, J = 10.5 Hz), 2.53 (3H, s), 2.83-2.86 (2H, m), 2.91-2.93 (2H, m), 3.30 (1H, d, J = 12.5 Hz), 3.75 (2H, s), 4.28 (1H, d, J = 5.6 Hz), 4.43 (1H, s), 4.65 (1H, d, J = 13.5 Hz), 4.95 (1H , D, J = 13.5 Hz), 6.92 (1H, d, J = 1.5 Hz), 7.20-7.23 (1H, m), 7.33 (1H, d, J = 8. 6 Hz), 7.65 (1 H, d, J = 2.0 Hz), 8.43 (1 H, d, J = 5.6 Hz), 9.14 (1 H, s).
MS (FAB) m / z: 559 (M + H ^< + ^> ).

Example 150 N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(3-hydroxycyclobutyl) carbonyl] piperidine-3 -Yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a mixed solution of the compound (117 mg) obtained in Reference Example 152 in tetrahydrofuran (20 ml), methylene chloride (3.0 ml) and N, N-dimethylformamide (2.0 ml), the compound (306 mg) obtained in Example 118, N-methylmorpholine (200 μl), 1-hydroxybenztriazole monohydrate (87 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (197 mg) were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was diluted with methylene chloride, and a saturated aqueous sodium hydrogen carbonate solution was added to form two layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to obtain the free base (207 mg) of the title compound. This free base was treated with 1N hydrochloric acid ethanol solution to obtain the title compound.
Melting point: 200 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz) , 7.42 (1H, d, J = 8.8 Hz), 7.70 (1H, d, J = 2.0 Hz), 8.05-8.28 (1H, br), 8.38 (0. 5H, br.d, J = 7.3 Hz), 8.43 (0.5H, br.d, J = 8.3 Hz), 10.80-11.25 (1H, br), 11.84 (1H , Br.s).
MS (ESI) m / z: 571 (M + H ^< + ^> ).

[Example 151] N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(methoxycyclobutyl) carbonyl] piperidin-3-yl } -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 150 from the compound obtained in Example 118 and the compound obtained in Reference Example 154.
Melting point: 191 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.4 Hz), 7.42 (1H, d, J = 8.4 Hz), 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 ^< + ^> ).

[Example 152] N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- [3-methoxy-2- (methoxymethyl) propanoyl] Piperidin-3-yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained by condensing the carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 155 and the compound obtained in Example 118 in the same manner as in Example 150.
Melting point: 178-184 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 1.69-1.82 (1H, m), 1.84 to 2.04 (1 H, 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, 2.0 Hz), 7.42 (1H, d, J = 8.8 Hz), 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 ^< + ^> ).

Example 153 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (tetrahydro-2H-pyran-4-ylcarbonyl) piperidine -3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 150 from the compound obtained in Example 118 and the compound obtained in Reference Example 156.
Melting point: 225-248 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.71 (1 H, s), 8.00-8.30 (1 H, m), 8.35-8.50 (1 H, m), 11.16 (1 H, br. S) , 11.85 (1H, s).
MS (ESI) m / z: 585 (M + H ^< + ^> ).

Example 154 N-((3R ^* , 4S ^* )-1-benzoyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and benzoyl chloride.
Melting point: 215-225 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 1.6 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 1.6 Hz), 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 ^< + ^> ).

[Example 155] (3R ^* , 4S ^* )-3-({[5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -4,5,6 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl} amino) -4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 207 and the compound obtained in Reference Example 42.
¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (9H, s), 1.12 (6H, s), 1.15 to 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 = 9.0 Hz), 7.30-7.50 (7H, m), 7. 50-7.65 (4H, m), 7.70 (1 H, s), 7.99 (1 H, d, J = 6.8 Hz), 8.45 (1 H, br. S), 11.82 ( 1H, s).
MS (ESI) m / z: 869 (M + H ^< + ^> ).

Example 156 5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -N-((3R ^* , 4S ^* )-4-{[(5-chloro Indol-2-yl) carbonyl] amino} piperidin-3-yl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride

The compound obtained in Example 155 was treated in the same manner as in Example 95 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 1.43, 1.48 (total 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, 7.8 Hz), 8. 93 (1H, br), 9.20-9.40 (2H, m), 11.30-11.50 (1H, m), 11.87, 11.92 (total 1H, each).
MS (ESI) m / z: 769 (M + H ^< + ^> ).

Example 157 5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -N-[(3R ^* , 4S ^* )-4-{[(5-chloro Indol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl] -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 156 and methoxyacetyl chloride.
¹ H-NMR (CDCl ₃ ) 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 = 1.5 Hz), 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 = 5.1 Hz), 9.28 (1H, s).
MS (ESI) m / z: 842 (M + H) ^<+> .

Example 158 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl]- 5- (2-Hydroxy-1,1-dimethylethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in Example 157 in the same manner as in Example 146.
Melting point: 221-232 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.41 (1H, d, J = 8.8 Hz), 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) ^<+> .

Example 159 (3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -3-{[(5-isopropyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 209 and the compound obtained in Reference Example 148.
¹ H-NMR (CDCl ₃ ) δ: 1.16 (6H, d, J = 6.6 Hz), 1.53 (9H, s), 1.65 to 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) ^<+> .

Example 160 N-((3R ^* , 4S ^* )-4-{[(5-Fluoroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-isopropyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride

The compound obtained in Example 159 was treated in the same manner as in Example 95 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

[Example 161] N-[(3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl]- 5-Isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 160 and methoxyacetyl chloride.
Melting point: 214-228 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 6.6 Hz).
MS (ESI) m / z: 557 (M + H) ^<+> .

[Example 162] N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(dimethylamino) carbonyl] piperidin-3-yl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and N, N-dimethylcarbamoyl chloride.
Melting point: 267-270 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 1.8 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.70 (1H, s), 8.31 (1H, br.s), 8.40 (1H) , D, J = 7.3 Hz), 11.15-11.60 (1H, m), 11.82 (1H, s).
MS (ESI) m / z: 544 (M + H) ^<+> .

[Example 163] N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(ethylamino) carbonyl] piperidin-3-yl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and ethyl isocyanate.
Melting point: 221-235 ° C. (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.1 Hz), 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 = 8.8,1.9 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.68 (1H, d, J = 1.9 Hz), 8.02 (1H, br.s), 8.35 (1H, d, J = 7.1 Hz), 11. 20-11.70 (1H, m), 11.82 (1H, s).
MS (FAB) m / z: 544 (M + H) ^<+> .

Example 164 N-((3R ^* , 4S ^* )-1-[(tert-butylamino) carbonyl] -4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidine-3- Yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and tert-butyl isocyanate.
Melting point: 236-238 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 1.9 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 6.8 Hz), 8.34 (1H, d, J = 7.3 Hz), 11.22 (1H, br.s), 11.79 (1H, s).
MS (FAB) m / z: 572 (M + H) ^<+> .

Example 165 2-((3R ^* , 4S ^* )-4-{[(5-Chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6, 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-3-yl) acetic acid methyl ester dihydrochloride

The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 118 and bromoacetic acid methyl ester.
Melting point: 253-255 [deg.] C. (decomposition).
¹ H-NMR (DMSO-d ₆ , 80 ° C.) 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 = 8.6 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.42 (1H, d, J = 7.3 Hz), 8.62 (1H, br.s), 11.82 (1H, br.s).
MS (ESI) m / z: 545 (M + H) ^<+> .

[Example 166] 2-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-3-yl) acetic acid hydrochloride

The compound obtained in Example 165 was treated in the same manner as in Example 101 to obtain the title compound.
Melting point: 234-240 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz) 7.41 (1H, d, J = 8.8 Hz), 7.66 (1H, d, J = 2.0 Hz), 8.46 (1H, br.d, J = 7.8 Hz), 8. 65 (1H, br.s), 11.60-12.70 (2H, br.s), 11.91 (1H, br.s).

Example 167 N-[(3R ^* , 4S ^* )-4-{[(5-Chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyethyl) piperidin-3-yl]- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride

The title compound was obtained from the compound obtained in Example 118 and 2-bromoethyl methyl ether in the same manner as in Example 102 (NMR was measured with a free base).
Melting point: 238-242 ° C. (decomposition).
¹ H-NMR (CDCl ₃ ) 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 type d, J = 15.5 Hz), 4.02-4.05 (1H, m), 4.40 (1H, br), 6.88 (1H, d, J = 1.5 Hz), 7.18-7.21. (1H, m), 7.31-7.33 (1H, m), 7.63 (1H, d, J = 1.5 Hz), 8.17 (1H, d, J = 5.0 Hz), 8 .26 (1H, d, J = 7.0 Hz), 9.30 (1H, br.s).
MS (FAB) m / z: 531 (M + H) ^<+> .

Example 168 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-fluoroethyl) piperidin-3-yl]- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride

The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 118 and 2-fluoroethyl bromide (NMR was measured with a free base).
Melting point: 228-233 ° C. (decomposition).
¹ H-NMR (CDCl ₃ ) δ: 1.77 (2H, dq, J = 12.5, 4.0 Hz), 2.28-2.32 (1H, m), 2.41 (1H, t, J = 12.5 Hz), 2.52 (3 H, s), 2.65 (1 H, d, J = 10.5 Hz), 2.76-2.81 (1 H, m), 2.83-2. 86 (3H, m), 2.98-3.05 (3H, m), 3.75 (each 1H, AB type d, J = 15.5 Hz), 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 = 1.5 Hz) , 7.19-7.22 (1H, m), 7.32 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 5.5 Hz), 8.20 (1H, d, J = 7.3 Hz), 9.30 (1H, br).
MS (FAB) m / z: 519 (M + H) ^<+> .

Example 169 N-((3R, 4S) -1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

A 4N hydrochloric acid dioxane solution (7.0 ml) was added to a dioxane solution (15 ml) of the compound (630 mg) obtained in Reference Example 214, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the free base (330 mg) of the title compound was obtained in the same manner as in Example 91, using the obtained yellow solid (590 mg) and the compound (379 mg) obtained in Reference Example 10. This free base was treated with hydrochloric acid ethanol solution to give the title compound (NMR measured as free base).
Melting point: 202-222 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 to 1.85 (1H, m), 1.87, 2.06 (total 3H, each), 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 (total 1H, each s), 7.18 (1H, d, J = 8.8 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.71 (1H, s), 8.16-8.22 (1H, m), 8.37, 8. 46 (total 1 , Each d, J = 7.8Hz), 11.81,11.83 (total 1H, each s).
MS (ESI) m / z: 515 (M + H) ^<+> .
[Α] _D ²⁵ = −56.0 ° (c = 0.50, methanol).

Example 170 N-((3R, 4R) -1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 169, the title compound was obtained from the compound obtained in Reference Example 219 and the compound obtained in Reference Example 10.
Melting point: 221-238 ° C.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.56 (0.5 H, m), 1.60 to 1.70 (0.5 H, m), 1.89 to 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, 2.0 Hz), 7.37 ( 1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 2.0 Hz), 8.42 (1H, d, J = 9.8 Hz), 8.67-8.78 (1H , M), 11.02-11.14 (1H, m), 1 1.72 (0.5H, s), 11.74 (0.5H, s). MS (FAB) m / z: 515 (M + H) ^<+> .
[Α] _D ²⁵ = −105.4 ° (c = 0.58, methanol).

Example 171 N-[(3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl] -5 Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 169, the title compound was obtained from the compound obtained in Reference Example 221.
Melting point: 207-220 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 9.0 Hz), 7.17 (1H, dd, J = 8.8, 1.9 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.70 (1H, d, J = 1.9 Hz), 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).

Example 172 N-[(3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl] -5 Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 169, the title compound was obtained from the compound obtained in Reference Example 223.
Melting point: 213-230 ° C.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.37 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 2.0 Hz), 8.41 (1H, d, J = 9.8 Hz), 8.74 (1H, d, J = 9.8 Hz), 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).

Example 173 N-((3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-yl) -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 169 from the low polarity compound obtained in Reference Example 176 and the compound obtained in Reference Example 10.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.22 (1H, d, J = 8.5 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.69 (1H, d, J = 2.0 Hz), 8.40-8.50 (1H, m), 11.34-11.56 (1H, m), 11. 82 (1H, s).
MS (FAB) m / z: 488 (M + H) ^<+> .

Example 174 N-((3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-yl) -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained in the same manner as in Example 169 from the highly polar compound obtained in Reference Example 176 and the compound obtained in Reference Example 10.
¹ H-NMR (DMSO-d ₆ ) 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, 7.1 Hz), 4.40-4.50 ( 1H, m), 4.56-4.78 (2H, m), 7.12 (1H, s), 7.17 (1H, dd, J = 8.8, 2.0 Hz), 7.41 ( 1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 2.0 Hz), 8.44 (1H, d, J = 8.5 Hz), 8.15 (1H, d, J = 8.5 Hz), 11.42-11.53 (1H, m), 11.79 (1H, s).
MS (FAB) m / z: 488 (M + H ^< + ^> ).

[Example 175] (3R, 4S) -5-{[tert-butyl (diphenyl) silyl] oxy} -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[( 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} valeric acid ethyl ester

The title compound was obtained in the same manner as in Example 169 from the compound obtained in Reference Example 225.
¹ H-NMR (CDCl ₃ ) δ: 1.09 (9H, s), 1.21 (3H, t, J = 7.4 Hz), 2.49 (3H, s), 2.65 (1H, dd) , J = 15.9, 5.4 Hz), 2.67-2.90 (5 H, m), 3.60 (1 H, d, J = 14.9 Hz), 3.72 (1 H, d, J = 14.9 Hz), 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, 2.0 Hz), 7.32-7.52 (m, 7H), 7. 63-7.74 (6H, m), 7.89-8.01 (1H, m), 9.18 (1H, s).

Example 176 (3R, 4S) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -5-hydroxy-4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} valeric acid ethyl ester

To a mixed solution consisting of the compound (0.54 g) obtained in Example 175, pyridine (4.0 ml), and tetrahydrofuran (10 ml) was added dropwise hydrogen fluoride / pyridine (0.4 ml) under ice-cooling, followed by reaction. The solution was stirred for 18 hours while gradually returning to room temperature. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain the title compound (0.31 g).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.4 Hz), 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, 2.0 Hz), 7.33 (1H, d, J = 8.8 Hz), 7.56 (1 H, d, J = 8.5 Hz), 7.61 (1 H, d, J = 2.0 Hz), 7.88 (1 H, d, J = 8.5 Hz), 9.29 (1H, s)

Example 177 N-((3S, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-yl) -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To the compound (0.31 g) obtained in Example 176, 4N hydrochloric acid dioxane solution (20 ml) was added and heated to reflux for 4 hours. The reaction mixture was concentrated, and the resulting residue was recrystallized from diethyl ether to obtain the title compound (0.23 g).
Melting point: 221-238 ° C. (decomposition).
¹ H-NMR and MS: consistent with enantiomer Example 174.

Example 178 N-((3R ^* , 4R ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-3- Yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The free base of the title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 227 and 5-chloroindole-2-carboxylic acid. The free base was treated with hydrochloric acid ethanol solution to give the title compound.
Melting point: 241-244 ° C.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 7.67 (1H, d, J = 4.6 Hz), 8. 39 (1H, br), 8.94 (1H, br), 11.82 (1H, br).
MS (ESI) m / z: 522 (M + H) ^<+> .

Example 179 N-((3R ^* , 4R ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-3- Yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The free base of the title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 227 and 5-fluoroindole-2-carboxylic acid. The free base was treated with hydrochloric acid ethanol solution to give the title compound.
Melting point: 243-245 ° C.
¹ H-NMR (DMSO-d ₆ ) 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 = 6.8 Hz), 11.72. (1H, br).
MS (ESI) m / z: 506 (M + H ^< + ^> ).

Example 180 N-((3R ^* , 4R ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-4- Yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The free base of the title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 229 and the compound obtained in Reference Example 10. The free base was treated with hydrochloric acid ethanol solution to give the title compound.
Melting point: 242-247 ° C.
¹ H-NMR (DMSO-d ₆ ) 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, 1.4 Hz), 7.43 (1H, d, J = 8.5 Hz), 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 ^< + ^> ).

[Example 181] N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-3- Yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The free base of the title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 231 and 5-chloroindole-2-carboxylic acid. The free base was treated with hydrochloric acid ethanol solution to give the title compound.
Melting point: 244-249 ° C.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 7.61 (1H) , D, J = 9.9 Hz), 8.52-8.56 (1H, m), 8.83-8.85 (1H, m), 11.65 (1H, d, J = 11.9 Hz) .
MS (ESI) m / z: 522 (M + H ^< + ^> ).

[Example 182] N-((3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-3- Yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The free base of the title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 231 and 5-fluoroindole-2-carboxylic acid. The free base was treated with hydrochloric acid ethanol solution to give the title compound.
Melting point: 236-241 ° C.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 8.83 (1H, d, J = 8.5 Hz), 11.59 (1H, s).
MS (ESI) m / z: 506 (M + H ^< + ^> ).

Example 183 N-((3R ^* , 4R ^* )-3-{[(5-fluoroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-4- Yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The free base of the title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 233 and the compound obtained in Reference Example 10. The free base was treated with hydrochloric acid ethanol solution to give the title compound.
Melting point: 244-249 ° C.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.0 Hz), 11.74 (1H, s).
MS (ESI) m / z: 506 (M + H ^< + ^> ).

Example 184 N-((3S, 4R) -4-{[(5-Chloroindol-2-yl) carbonyl] amino} -1-methyl-6-oxopiperidin-3-yl) -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (low polarity compound) and N-((3R, 4R) -4-{[(5-chloroindo -Lu-2-yl) carbonyl] amino} -1-methyl-6-oxopiperidin-3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-carboxamide (high polarity compound)

The title compound was obtained in the same manner as in Example 169 from the compound obtained in Reference Example 236 and the compound obtained in Reference Example 10.
Low polarity compounds :
Melting point: 189-203 ° C (decomposition).
¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 2.59 (1H, q, J = 8.8 Hz), 2.71-2.78 (2H, m), 2.89 −3.00 (2H, m), 3.03 (3H, s), 3.12 (1H, dd, J = 17.6, 5.4 Hz), 3.43 (1H, dd, J = 12. 7, 5.1 Hz), 3.70 (1 H, d, J = 15.2 Hz), 3.77 (1 H, d, J = 15.2 Hz), 3.83 (1 H, dd, J = 12.7) , 3.9 Hz), 4.55-4.67 (2H, m), 6.99 (1H, s), 7.23 (1H, dd, J = 8.8, 2.0 Hz), 7.33. (1H, d, J = 8.8 Hz), 7.65 (1H, d, J = 2.0 Hz), 8.07 (1H, d, J = 5.1 Hz), 8.16 (1H, d, J = 5.4 Hz), 9.43 (1H, s).
MS (FAB) m / z: 501 (M + H ^< + ^> ).
High polarity compounds :
Melting point: 183-195 ° C (decomposition).
¹ H-NMR (DMSO-d ₆ ) 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 = 15.4 Hz), 3.63 (1H, d, J = 15.4 Hz), 4.30-4.40 (0.5 H, m), 4.50-4.60 (0. 5H, m), 7.04 (1H, s), 7.15 (1H, dd, J = 8.8, 2.0 Hz), 7.38 (1H, d, J = 8.8 Hz), 7. 67 (1H, d, J = 2.0 Hz), 8.49 (1H, d, J = 8.5 Hz), 8.71 (1H, d, J = 8.5 Hz), 11.74 (1H, s ).
MS (FAB) m / z: 501 (M + H ^< + ^> ).

Example 185 5-Chloro-N-((1R ^* , 2S ^* )-2-{[4- (pyridin-4-yl) benzoyl] amino} cyclohexyl) indole-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 237.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.21 (1H, s), 7.40 (1H, d, J = 8.8 Hz), 7.64 (1H, d, J = 2.0 Hz), 8.06 (4H, s), 8.18 (1H, J = 7.3 Hz), 8.34-8. 42 (3H, m), 8.94 (2H, d, J = 6.9 Hz), 11.91 (1H, s).
MS (FAB) m / z: 473 (M + H) ^<+> .

[Example 186] 4- (4-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} phenyl) pyridine N- Oxide

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 240.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz), 7.66 (1H, s) , 7.80-7.87 (4H, m), 7.91 (2H, d, J = 8.3 Hz), 8.01 (1H, d, J = 7.6 Hz), 8.09 (1H, d, J = 7.3 Hz), 8.27 (2H, d, J = 6.6 Hz), 11.79 (1H, s).
MS (FAB) m / z: 489 (M + H) ^<+> .

Example 187 5-Chloro-N-((1R ^* , 2S ^* )-2-{[4- (pyridin-2-yl) benzoyl] amino} cyclohexyl) indole-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and 4- (2-pyridyl) benzoic acid (Japanese Patent Laid-Open No. 2000-119253).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.66 (1 H, d, J = 2.0 Hz), 7.87-7.90 (1 H, m), 7.92 (2 H, d, J = 8.3 Hz), 7. 98-8.11 (3H, m), 8.15 (2H, d, J = 8.3 Hz), 8.69 (1H, d, J = 4.6 Hz), 11.80 (1H, s).
MS (FAB) m / z: 473 (M + H) ^<+> .

[Example 188] 2- (4-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} phenyl) pyridine N- Oxide

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 241.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.0 Hz), 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) ^<+> .

[Example 189] 5-chloro-N-[(1R ^* , 2R ^* )-2-({[5- (4-pyridin-2-yl) thiazol-2-yl] carbonyl} amino) cyclohexyl] indole- 2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 69 and lithium 5- (4-pyridyl) thiazole-2-carboxylic acid (JP 2000-143623). ¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.69 (1H, s), 8.04-8.13 (2H, m), 8.13 (1H, d, J = 8.8 Hz), 8.59 (1H, d, J = 8.0 Hz), 8 .75-8.87 (3H, m), 11.83 (1H, s). MS (ESI) m / z: 480 (M + H) ^<+> .

Example 190 5-Chloro-N-[(1R ^* , 2S ^* )-2-({[1- (pyridin-4-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] indole-2- Carboxamide hydrochloride

1- (4-pyridyl) piperidine-4-carboxylic acid (Tetrahedron, 1998, 44, 7095) (206 mg) was suspended in methylene chloride (50 ml), and thionyl chloride (144 μl) was added under ice-cooling. Stir for minutes. Triethylamine (969 μl) was added to the reaction solution, the compound (328 mg) obtained in Reference Example 71 was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the solution was concentrated under reduced pressure, and the deposited precipitate was collected by filtration to give the title compound (310 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.30-2.00 (10H, m), 2.74 (1H, br.s), 3.18 (2H, q, J = 12.3 Hz) , 4.03 (1H, br.s), 4.10-4.25 (3H, m), 7.15-7.55 (4H, m), 7.42 (1H
, D, J = 8.8 Hz), 7.65 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 8.20-8.35 (3H, m), 11.91. (1H, s), 13.47 (1H, br. S).
MS (FAB) m / z: 480 (M + H) ^<+> .

Example 191] N ¹ - ^{(4-chlorophenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl -4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (288 mg) obtained in Reference Example 242 was dissolved in tetrahydrofuran (8.0 ml), lithium hydroxide (46 mg) and water (1.0 ml) were successively added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product (292 mg) of lithium 2- (4-chloroanilino) -2-oxoacetate as a colorless solid. This crude product and the compound obtained in Reference Example 253 were dissolved in N, N-dimethylformamide (15 ml) to give 1-hydroxybenzotriazole monohydrate (164 mg) and 1- (3-dimethylaminopropyl) -3. -Ethylcarbodiimide hydrochloride (251 mg) was added, and it stirred at room temperature for 64.5 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3). The obtained pale yellow solid was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (0.52 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to give the title compound (245 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.83 (2H, d, J = 8.8 Hz), 8.75 (1H, d, J = 7.1 Hz), 9.00-9.10 (1H, br) , 10.81 (1H, s), 11.45-11.75 (1H, m).
MS (FAB) m / z: 547 (M + H) ^<+> .

Example 192] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (240 mg) obtained in Reference Example 243 was dissolved in tetrahydrofuran (8.0 ml), lithium hydroxide (41 mg) and water (1.0 ml) were sequentially added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain lithium 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetate (249 mg).
On the other hand, 10% palladium carbon (200 mg) was added to a methanol (10 ml) solution of the compound (293 mg) obtained in Reference Example 252 and stirred at room temperature for 18 hours in a hydrogen atmosphere. After palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure, and N-{(1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6. , 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide crude product (259 mg) was obtained.
This crude product (259 mg) and the above lithium salt (249 mg) were added to N, N-dimethylformamide (15 ml), and 1-hydroxybenzotriazole monohydrate (166 mg) and 1- (3-dimethylaminopropyl) were added. ) -3-Ethylcarbodiimide hydrochloride (235 mg) was added, and the mixture was stirred at room temperature for 63.5 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue for liquid separation, and the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7). The obtained pale yellow solid was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (0.855 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to give the title compound (209 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 2.2 Hz), 8.71 (1H, d, J = 7.6 Hz), 9.10-9.30 (1H, br), 10 .26 (1H, s), 11.30-11.60 (1H, br).
MS (FAB) m / z: 548 (M + H) ^<+> .

Example 193] N ¹ - (3- ^{chlorophenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl -4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (222 mg) obtained in Reference Example 270 and 3-chloroaniline (63 μl) were dissolved in N, N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (68 mg), 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (144 mg) was added and stirred at room temperature for 40 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1). The obtained pale yellow solid was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (0.50 ml) was added, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (174 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.77 (1H, d, J = 8.3 Hz), 7.92-8.05 ( 1H, m), 8.75 (1H, d, J = 7.3 Hz), 8.95-9.20 (1H, br), 10.87 (1H, s), 11.25-11.45 ( 1H, br).

Example 194 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (4-fluorophenyl) ethanediamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 254 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.6 Hz), 8.93-9. .02 (1H, m), 10.70 (1H, s).
MS (FAB) m / z: 531 (M + H) ^<+> .

Example 195 N ^1- (4-Bromophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5, 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (152 mg) obtained in Reference Example 255 was dissolved in tetrahydrofuran (5.0 ml), 1N aqueous sodium hydroxide solution (1.20 ml) and methanol (5.0 ml) were successively added, and the mixture was stirred at room temperature for 2.5 hours. did. The reaction mixture was concentrated under reduced pressure, and methylene chloride (10 ml) and 1N hydrochloric acid (2.0 ml) were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of 2- (4-bromoanilino) -2-oxoacetic acid as a colorless solid. This crude product and the compound (280 mg) obtained in Reference Example 253 were dissolved in N, N-dimethylformamide (30 ml), and 1-hydroxybenzotriazole monohydrate (90 mg), 1- (3-dimethylaminopropyl) was dissolved. ) -3-Ethylcarbodiimide hydrochloride (226 mg) was added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3). The obtained pale yellow solid was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (191 μl) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to give the title compound (103 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.77 (2H, d, J = 8. 8 Hz), 8.75 (1 H, d, J = 7.3 Hz), 8.97-9.09 (1 H, m), 10.82 (1 H, s), 11.11 (1 H, br. S) .
MS (FAB) m / z: 591 (M + H) ^<+> .

Example 196 N ^1- (4-Chloro-2-methylphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 191, the compound obtained in Reference Example 256 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-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 = 2.5 Hz), 7.43 (1H, d, J = 8.6 Hz), 8.76 (1H, d, J = 6.6 Hz), 9.00-9.15 (1H, br ), 10.19 (1H, s).
MS (FAB) m / z: 561 (M + H) ^<+> .

Example 197 N ^1- (4-Chloro-3-methylphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 257 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.65 (1H, d, J = 8.8 Hz), 7.74 (1H, s), 8.75 (1H, d, J = 7.8 Hz), 8.96 (1H, d, J = 8.0 Hz), 10.69 (1H, s).
MS (FAB) m / z: 561 (M + H) ^<+> .

Example 198] N ¹ - ^{(4-chloro-2-fluorophenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 191, the compound obtained in Reference Example 258 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 7.52 (1H, dd, J = 10.3, 2.0 Hz), 7.61 (1H, t, J = 8.4 Hz), 8.72 (1H, d, J = 6.8 Hz), 9.00-9.20 (1H, br), 10.38 (1H, s), 11.20-11.45 (1H, br).
MS (FAB) m / z: 565 (M + H) ^<+> .

Example 199 N ^1- (2,4-Dichlorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (300 mg) obtained in Reference Example 270 was dissolved in N, N-dimethylformamide (5 ml), and 2,4-dichloroaniline (165 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (260 mg) and 1-hydroxybenzotriazole monohydrate (91 mg) were added, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3) to obtain the free base of the title compound. This was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (108 μl) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, diethyl ether was added dropwise while irradiating with ultrasonic waves, and the resulting precipitate was collected by filtration. This was washed with diethyl ether to obtain the title compound (60 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 2.4 Hz), 7.75 (1H, d, J = 2.4 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.75 (1H, d, J = 6.8 Hz), 9.21 (1H, br.s), 10.25 (1H, s), 11.55 (1H, br.s).
MS (FAB) m / z: 581 (M + H) ^<+> .

Example 200] N ¹ - ^{(3,4-dichlorophenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

3,4-Dichloroaniline (1.62 g) was dissolved in methylene chloride (20 ml), triethylamine (1.67 ml) and chlorooxoacetic acid methyl ester (1.01 ml) were successively added under ice cooling, and the mixture was stirred at room temperature for 21 hours. did. Water and methylene chloride were added to the reaction solution for liquid separation, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethanol (50 ml), water (25 ml) and lithium hydroxide monohydrate (629 mg) were successively added, and the mixture was stirred at room temperature for 12.5 hours. Further, lithium hydroxide monohydrate (629 mg) was added, and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was concentrated to dryness under reduced pressure. Water and diethyl ether were added to the residue for liquid separation, and then the aqueous layer was acidified with hydrochloric acid. The resulting solid was collected by filtration to give a crude product (1.62 g) of 2- (3,4-dichloroanilino) -2-oxoacetic acid as a colorless solid. This crude product (191 mg) and the compound (250 mg) obtained in Reference Example 253 were dissolved in N, N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (110 mg), 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (157 mg) was added, and the mixture was stirred at room temperature for 67 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue for liquid separation, and the aqueous layer was extracted three times with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5) to obtain the title compound (154 mg).
¹ H-NMR (CDCl ₃ ) 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 = 15.5 Hz), 4.08-4.13 (1H, m), 4.69-4.72 (1H, m), 7.40 (2H) , S), 7.41 (1H, d, J = 7.7 Hz), 7.90 (1H, s), 8.01 (1H, d, J = 7.7 Hz), 9.27 (1H, s) ).
MS (ESI) m / z: 581 (M + H) ^<+> .

Example 201] N ¹ - (2,4-difluorophenyl) -N ² - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - {[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

The title compound was obtained by hydrolyzing the compound obtained in Reference Example 259 and condensing with the compound obtained in Reference Example 253 in the same manner as described in Example 191.
¹ H-NMR (CDCl ₃ ) 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 = 8.5 Hz), 7.96 (1H, d, J = 7.3 Hz), 8.22-8.29 (1H, m), 9.36 (1H, br).

Example 202] N ¹ - (3,4-difluorophenyl) -N ² - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - {[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

The title compound was obtained by hydrolyzing the compound obtained in Reference Example 260 and then condensing with the compound obtained in Reference Example 253 in the same manner as described in Example 191.
¹ H-NMR (CDCl ₃ ) 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 = 8.8 Hz), 7.72 (1H, ddd, J = 12.0, 7.1, 2.6 Hz), 7.95 (1H, d, J = 7.8 Hz), 9.22 (1H, br).

Example ^{203] N 1 - ((1S} , 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl-4,5,6,7-tetrahydroisoquinoline thiazolo [5, 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (pyridin-4-yl) ethanediamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 261 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 6.8 Hz), 8.67 (1H, d) , J = 8.0 Hz), 8.71 (2H, d, J = 6.8 Hz), 9.10-9.30 (1H, br), 11.81 (1H, s).
MS (FAB) m / z: 514 (M + H) ^<+> .

Example 204 N ^1- (5-bromopyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 195, the compound obtained in Reference Example 262 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 9.0 Hz), 8.12 (1H , Dd, J = 9.0, 2.4 Hz), 8.52 (1H, d, J = 2.4 Hz), 8.70 (1H, d, J = 7.5 Hz), 9.18 (1H, d, J = 7.5 Hz), 10.25 (1H, br.s).
MS (FAB) m / z: 592 (M + H) ^<+> .

Example 205] N ¹ - (6- ^{chloropyridin-3-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (200 mg) obtained in Reference Example 263 as a crude product was dissolved in methanol (10 ml), heated to 50 ° C., 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred for 5 minutes. A 1N aqueous hydrochloric acid solution was added thereto to adjust the pH to slightly acidic, the solvent was distilled off under reduced pressure, and a residue containing 2-[(2-chloropyridin-5-yl) amino] -2-oxoacetic acid Got. N, N-dimethylformamide (5 ml) was added to the residue and the compound (250 mg) obtained in Reference Example 253, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (328 mg), 1-hydroxy was added. Benzotriazole monohydrate (46 mg) was added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue for separation. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3) to give the free base of the title compound as a pale yellow solid. Obtained. This was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (862 μl) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, and ethyl acetate and diethyl ether were added dropwise while irradiating ultrasonic waves. The resulting precipitate was collected by filtration and washed with ethyl acetate to obtain the title compound (229 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 8.23-8.25 (1H, m), 8.72-8.77 (1H, m), 8.85 (1H, s), 9.07, 9.16 (1H, each d, J = 8.1 Hz), 11.09 (1H, d, J = 8.1 Hz), 11.78 (1H, br.s).
MS (FAB) m / z: 548 (M + H) ^<+> .

Example 206] N ¹ - (6- ^{chloro-3-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 264 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 9.3 Hz), 8.26 (1H, d, J = 9.3 Hz), 8.69 (1H, d, J = 7.6 Hz), 9.20 (1H, d, J = 7.6 Hz), 11.06 (1 H, s).
MS (FAB) m / z: 549 (M + H) ^<+> .

Example 207] N ¹ - ^{(5-Chloro-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 191, the compound obtained in Reference Example 265 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.6 Hz) ), 9.14 (1H, d, J = 7.6 Hz).
MS (FAB) m / z: 554 (M + H) ^<+> .

Example 208] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (210 mg) obtained in Reference Example 266 and the compound (350 mg) obtained in Reference Example 272 were dissolved in N, N-dimethylformamide (15 ml), and 1-hydroxybenzotriazole monohydrate (205 mg), 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (290 mg) was added and stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1). The obtained pale yellow solid was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (0.46 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to give the title compound (248 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 7.6 Hz), 9.10 (1H, d, J = 8.0 Hz), 10.30 (1 H, s).
MS (FAB) m / z: 534 (M + H) ^<+> .

[Example 209] N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4, 5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (2.3 g) obtained in Reference Example 267 was dissolved in ethanol (10 ml), 1N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid aqueous solution (20 ml) was added to the reaction mixture, and the mixture was diluted with water and stirred for 30 min. The precipitated insoluble material was collected by filtration to give 2- (4-chloroanilino) acetic acid (1.05 g) as a colorless solid. This solid and the compound (0.25 g) obtained in Reference Example 253 were dissolved in N, N-dimethylformamide (10 ml) to give 1-hydroxybenzotriazole monohydrate (0.11 g), 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (0.23 g) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3). The obtained pale yellow solid was dissolved in ethanol, 1N hydrochloric acid ethanol solution was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to give the title compound (0.15 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 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 = 6.7 Hz), 6.44 (1H, d, J = 6.7 Hz), 6 .90 (1H, d, J = 6.7 Hz), 7.00 (1H, d, J = 6.7 Hz), 7.70-7.89 (1H, m), 8.35-8.42 ( 1H, m), 11.05-11.38 (1H, m ).

[Example 210] N-{(1R, 2S, 5S) -2-{[2- (4-chloro-2-fluoroanilino) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 209, the compound obtained in Reference Example 268 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.42 (1H, m), 1.55-1.78 (3H, m), 1.80 to 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 = 8.8 Hz), 6.73 (1H, dt, J = 8.8,1. 2 Hz), 7.08 (1 H, dd, J = 11.7, 1.2 Hz), 7.78-7.92 (1 H, m), 8.35-8.42 (1 H, m), 11. 18-11.50 (1H, m).

[Example 211] N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 432 and the compound obtained in Reference Example 34 were condensed in the same manner as in Example 2, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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, 2.2 Hz), 7.41 (1H , D, J = 8.8 Hz), 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) ^<+> .

[Example 212] N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5- ( 4,5-dihydro-oxazol-2-yl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The compound (250 mg) obtained in Example 211 was suspended in methylene chloride, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred well. The organic layer was separated and dried over anhydrous magnesium sulfate, triethylamine (0.5 ml) and bromoethyl isocyanate (43 μl) were added, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 22: 3) to obtain the title compound (227 mg).
¹ H-NMR (CDCl ₃ ) 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) 2.2 Hz), 7.34 (1 H, d, J = 8.8 Hz), 7.50 (1 H, br. S), 7.62 (1 H, s), 7.87 (1 H, br. S). ), 9.48 (1H, br.s).
MS (ESI) m / z: 598 (M + H) ^<+> .

[Example 213] N-{(1R, 2S, 5S) -2-{[(5-chloro-4-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (140 mg) obtained in Reference Example 144 was dissolved in N, N-dimethylformamide (10 ml), and the compound (100 mg) obtained in Reference Example 274, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Salt (140 mg) and 1-hydroxybenzotriazole monohydrate (110 mg) were added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was partitioned between water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19), and (1R, 2S, 5S) -2-{[(5-chloro-4-fluoro Indol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester (260 mg) was obtained.
The above powder was dissolved in methylene chloride (5 ml), and 4N hydrochloric acid dioxane solution (1.2 ml) was added. The reaction solution was stirred at room temperature for 3.5 hours, and then the solvent was distilled off under reduced pressure. Methylene chloride (10 ml) was added to the residue and concentrated. This operation was repeated three times, and then the residue was dried under reduced pressure to obtain crude N-{(1S, 2R, 4S) -2-amino-4- [ (Dimethylamino) carbonyl] cyclohexyl} -5-chloro-4-fluoroindole-2-carboxamide was obtained. This was dissolved in N, N-dimethylformamide (50 ml), the compound obtained in Reference Example 10 (150 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (140 mg), 1-hydroxybenzo Triazole monohydrate (110 mg) was added and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was distributed into a water-ethyl acetate-tetrahydrofuran mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to obtain the free base (270 mg) of the title compound. This was dissolved in methylene chloride (10 ml), 1N hydrochloric acid ethanol solution (0.72 ml) was added and stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration to give the title compound (200 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.1 Hz), 8.43 (1H, d, J = 7.6 Hz), 12.11 (1H, s). MS (FAB) m / z: 561 (M + H) ^<+> .

[Example 214] N-{(1R, 2S, 5S) -2-{[(5-chloro-3-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (250 mg) obtained in Reference Example 279 was dissolved in methylene chloride (60 ml), and 4N hydrochloric acid dioxane solution (1.3 ml) was added. The reaction mixture was stirred at room temperature for 5.5 hours, 4N hydrochloric acid dioxane solution (0.65 ml) was further added, and the mixture was stirred at room temperature for 1 hour. The operation of distilling off the solvent under reduced pressure, adding methylene chloride (10 ml) to the residue and concentrating again was repeated three times. The crude product obtained by drying the residue under reduced pressure was dissolved in N, N-dimethylformamide (50 ml), and the compound obtained in Reference Example 10 (160 mg), 1- (3-dimethylaminopropyl) -3. -Ethylcarbodiimide hydrochloride (150 mg) and 1-hydroxybenzotriazole monohydrate (120 mg) were added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was partitioned into a water-ethyl acetate mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified twice by silica gel column chromatography (methanol: methylene chloride = 2: 23 → 1: 9) to obtain the free base of the title compound (260 mg). This was dissolved in methylene chloride, 1N ethanolic hydrochloric acid solution (0.69 ml) was added and the mixture was stirred at room temperature for 30 minutes, and then the solvent was distilled off. The residue was dissolved in methanol and crystallized by adding diethyl ether and hexane, which was collected by filtration to give the title compound (230 mg).
¹ H-NMR (DMSO-d ₆ ) 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, 1.7 Hz), 7.40 (1H , D, J = 8.8, 1.7 Hz), 7.65 (1H, d, J = 1.7 Hz), 7.72 (1H, d, J = 5.9 Hz), 8.74 (1H, d, J = 8.0 Hz), 10.85-11.35 (1H, br), 11.71 (1H, s).
MS (FAB) m / z: 561 (M + H) ^<+> .

[Example 215] N-{(1R, 2S, 5S) -2-{[(3-bromo-5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 282 was treated with 4N hydrochloric acid dioxane solution and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 1.8 Hz), 7.45-7.49 (2H, m), 7.80 (1H, d, J = 7.6 Hz), 8.76 (1H) , D, J = 8.8 Hz), 12.31 (1H, s).
MS (FAB) m / z: 622 (M + H) ^<+> .

[Example 216] N-{(1R, 2S, 5S) -2-{[(3-chloro-5-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 284.
¹ H-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, 2.4 Hz), 7.24 (1H, dd, J = 8.8, 2) .4 Hz), 7.45 (1H, dd, J = 8.8, 4.4 Hz), 7.69 (1H, d, J = 2.5 Hz), 8.79 (1H, d, J = 2. 5 Hz), 12.10 (1 H, s).
MS (FAB) m / z: 561 (M + H) ^<+> .

[Example 217] N-{(1R, 2S, 5S) -2-{[(5-chloro-3-formylindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 286.
¹ H-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, 1.4 Hz), 7.56 (1H, d, J = 8.0 Hz), 8.21 (1H, d, J = 1.4 Hz), 8.65 (1H, t, J = 7.4 Hz), 9.92 (1H, d, J = 6.8 Hz), 10.15 (1H, t, J = 9.1 Hz), 13.00 (1H, d, J = 6.4) .
MS (FAB) m / z: 571 (M + H) ^<+> .

Example 218 5-Chloro ^{-N 2 - ((1S, 2R} , 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ³ , N ³ -dimethylindole-2,3-dicarboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 289.
¹ H-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 = 8.0 Hz), 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) ^<+> .

[Example 219] N-{(1R, 2S, 5S) -2-[(6-chloro-2-naphthoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (270 mg) obtained in Reference Example 294 was dissolved in methylene chloride (10 ml), 1N hydrochloric acid ethanol (10 ml) was added, and the mixture was stirred for 90 minutes. The residue obtained by distilling off the solvent under reduced pressure was dissolved in N, N-dimethylformamide (7 ml) to obtain the compound (110 mg) obtained in Reference Example 10, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. Hydrochloride (100 mg) and 1-hydroxybenzotriazole monohydrate (70 mg) were added, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified twice by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 10: 1), the resulting free base was dissolved in methanol, and 1N hydrochloric acid ethanol solution ( 0.30 ml) was added. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (130 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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, 2.2 Hz), 7.87 (1H , D, J = 8.5 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.02 (1H, d, J = 8.8 Hz), 8.10 (1H, d, J = 2.2 Hz), 8.33 (1 H, s), 8.43 (1 H, d, J = 8.1 Hz), 8.52 (1 H, d, J = 7.3 Hz).
MS (FAB) m / z: 554 (M + H) ^<+> .

Example 220 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo) [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide hydrochloride

In the same manner as in Example 219, the compound obtained in Reference Example 299 was treated with hydrochloric acid ethanol solution and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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, 2.0 Hz), 8.38 (1H, d, J = 8.8 Hz), 8.66 (1H, s), 8.91 (1H, s), 8.96 (1H, d, J = 7.3 Hz), 9.53 (1H, br).
MS (FAB) m / z: 556 (M + H) ^<+> .

[Example 221] N-{(1R, 2S, 5S) -2-{[(5-chlorobenzimidazol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 300 was treated with hydrochloric acid ethanol solution in the same manner as in Example 219, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.60 (1H, m), 1.60 to 1.83 (3H, m), 2.00 to 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 = 8.8 Hz), 7.62 (1H, d, J = 12.5 Hz), 7.63 (1H, s), 8.75-8 .87 (1H, m), 9.09 (1H, dd, J = 12.5, 8.8 Hz), 11.20-11.40 (1H, m).
MS (FAB) m / z: 546 (M + H) ^<+> .

Example 222 N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4 -C] pyridin-2-yl) carbonyl] amino} cyclohexyl) -7-fluoroisoquinoline-3-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 304.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.3 Hz), 9.31 (1H, s).
MS (FAB) m / z: 539 (M + H) ^<+> .

[Example 223] N-{(1R, 2S, 5S) -2-{[(7-chloro-2H-chromen-3-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound (220 mg) obtained in Reference Example 252 was dissolved in methanol (10 ml), 10% palladium carbon (180 mg) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (30 ml) and the compound (108 mg) obtained in Reference Example 306, 1-hydroxybenzotriazole monohydrate (78 mg), 1- (3-dimethylaminopropyl) -3 -Ethylcarbodiimide hydrochloride (196 mg) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue for separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a pale yellow foam. This foamy substance was dissolved in methylene chloride (2 ml), and 1N hydrochloric acid ethanol solution (363 μl) was added. The solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the deposited precipitate was collected by filtration to give the title compound (175 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 14.5 Hz), 4.89 (1H , D, J = 14.5 Hz), 6.92 (1H, s), 6.98 (1H, dd, J = 8.1, 1.7 Hz), 7.08 (1H, s), 7.17 (1H, d, J = 8.3 Hz), 8.12 (1H, d, J = 8.1 Hz), 8.34 (1H, d, J = 8.1 Hz).
MS (FAB) m / z: 558 (M + H) ^<+> .

[Example 224] N-{(1R, 2S, 5S) -2-{[(E) -3- (4-chlorophenyl) -2-propenoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 219, the compound obtained in Reference Example 307 was treated with hydrochloric acid ethanol solution and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 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 = 15.7 Hz), 7.35 (1H, d, J = 15.7 Hz), 7.44 (1H, d, J = 8.6 Hz) 7.55 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 8.1 Hz), 8.34 (1H, br.s), 11.25-11.70 ( 1H, br).
MS (ESI) m / z: 530 (M + H) ^<+> .

Example 225 6-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-oxo-1,4-dihydroquinoline-2-carboxamide hydrochloride

In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 309.
¹ H-NMR (DMSO-d ₆ ) 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 = 15.6 Hz), 6.77 (1H , Br.s), 7.73 (1H, d, J = 8.9 Hz), 7.94 (1H, d, J = 8.9 Hz), 7.97 (1H, d, J = 2.2 Hz) 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) ^<+> .

[Example 226] 2-[({(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} amino) Carbonyl] -4,6-dihydro-5H-pyrrolo [3,4-d] thiazole-5-carboxylic acid tert-butyl ester

1) The compound (1.46 g) obtained in Reference Example 310 was dissolved in methylene chloride (10 ml), a hydrochloric acid ethanol solution (10 ml) was added at room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, the solvent was distilled off, ethanol was added and the mixture was concentrated. Diisopropyl ether was added to the residue, solidified and collected by filtration, and N-{(1S, 2R, 4S) -2-amino-4-[(dimethyl Amino) carbonyl] cyclohexyl} -5-chloroindole-2-carboxamide hydrochloride was obtained.
2) This was dissolved in N, N-dimethylformamide (5 ml) at room temperature, and the compound (1.31 g) obtained in Reference Example 406, 1-hydroxybenzotriazole monohydrate (640 mg) and 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.36 g) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to obtain the title compound (1.22 g).
¹ H-NMR (CDCl ₃ ) 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 = 1.5 Hz), 7.20 (1H, dd, J = 8.8, 2.0 Hz), 7.33 (1H, d, J = 8.8 Hz), 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) ^<+> .

[Example 227] 5-Chloro-N-{(1S, 2R, 4S) -2-[[(5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino ] -4-[(Dimethylamino) carbonyl] cyclohexyl} indole-2-carboxamide hydrochloride

The compound (1.22 g) obtained in Example 226 was dissolved in methylene chloride (5 ml), a hydrochloric acid ethanol solution (10 ml) was added at room temperature, and the mixture was stirred for 1 hour. After the reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 9) to obtain the free base of the title compound (636 mg) as a colorless glassy solid. This free base (200 mg) was dissolved in 1N hydrochloric acid ethanol solution (1 ml), concentrated and then solidified by adding ethyl acetate, and the resulting colorless powder was collected by filtration and dried to give the title compound (195 mg). .
¹ H-NMR (DMSO-d ₆ ) 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 = 1.5 Hz), 7.16 (1H, dd, J = 8.7, 1.8 Hz) , 7.42 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 1.8 Hz), 8.38 (1H, d, J = 7.8 Hz), 8.42 ( 1H, d, J = 7.8 Hz), 10.45-10.65 (2H, br), 11.78 (1H, br. S).
MS (FAB) m / z: 515 (M + H) ^<+> .

[Example 228] 5-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3 , 4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) indole-2-carboxamide hydrochloride

In the same manner as in Example 18, the title compound was obtained from the compound obtained in Example 227 and formalin.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.60 (1H, m), 1.65-1.90 (3H, m), 1.90 to 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 = 1.7 Hz), 7.17 (1H, dd, J = 8.8, 2.). 1 Hz), 7.41 (1 H, d, J = 8.8 Hz), 7.68 (1 H, d, J = 2.1 Hz), 8.36 (1 H, d, J = 7.8 Hz), 8. 42 (1H, d, J = 8.1 Hz), 11.78 (1H, br.s), 12.14 (1H, br.s).
MS (FAB) m / z: 529 (M + H) ^<+> .

[Example 229] 2-{[((1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-{[(5-fluoroindol-2-yl) carbonyl] amino} cyclohexyl) amino] Carbonyl} -4,6-dihydro-5H-pyrrolo [3,4-d] thiazole-5-carboxylic acid tert-butyl ester

In the same manner as in Example 226, the title compound was obtained from the compound obtained in Reference Example 311 and the compound obtained in Reference Example 406.
¹ H-NMR (CDCl ₃ ) 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. 1 Hz), 7.25-7.30 (1 H, m), 7.34 (1 H, dd, J = 9.1, 4.3 Hz), 7.42-7.49 (1 H, m), 7. 70-7.80 (1H, m), 9.37-9.45 (1H, m).
MS (ESI) m / z: 599 (M + H) ^<+> .

Example 230 N-{(1S, 2R, 4S) -2-[[(5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino] -4- [(Dimethylamino) carbonyl] cyclohexyl} -5-fluoroindole-2-carboxamide hydrochloride

In the same manner as in Example 227, the title compound was obtained from the compound obtained in Example 229.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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 = 7.8 Hz), 8.41 (1H, d, J = 8.1 Hz), 10.53 (2H, br.s), 11.68 (1H, br.s).
MS (FAB) m / z: 499 (M + H) ^<+> .

Example 231 N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d ] Thiazol-2-yl) carbonyl] amino} cyclohexyl) -5-fluoroindole-2-carboxamide hydrochloride

In the same manner as in Example 18, the title compound was obtained from the compound obtained in Example 230 and formalin.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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 (1 H, 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 = 7.6 Hz), 8.41 (1H, d, J = 8.1 Hz), 11.67 (1H, br.s), 12.37 (1H, br.s).
MS (FAB) m / z: 513 (M + H) ^<+> .

Example 232 N-{(1R, 2S, 5S) -2-[(6-chloro-2-naphthoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-5,6 -Dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxamide hydrochloride

In the same manner as in Example 226, the title compound was obtained from the compound obtained in Reference Example 294 and the compound obtained in Reference Example 293.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 7.87 (1H, d, J = 8.8 Hz), 7.96. (1H, d, J = 8.5 Hz), 8.01 (1H, d, J = 8.8 Hz), 8.10 (1H, s), 8.32 (1H,
s), 8.45 (1H, d, J = 8.1 Hz), 8.51 (1H, d, J = 7.3 Hz).
MS (FAB) m / z: 540 (M + H) ^<+> .

Example 233 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3 , 4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide hydrochloride and 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl]- 2-{[(5-Methyl-5H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide

To a mixed suspension of the compound obtained in Reference Example 299 (330 mg) in dioxane (3.0 ml) -methylene chloride (3.0 ml), 4N hydrochloric acid dioxane solution (3.0 ml) was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting white powder was dissolved in N, N-dimethylformamide (5.0 ml) to obtain the compound (172 mg) obtained in Reference Example 293, 1-hydroxybenzotriazole monohydrate. (130 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (192 mg) were added, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1). To a solution of the obtained highly polar main product ethanol (4.0 ml) was added 1N hydrochloric acid ethanol solution (0.35 ml), and the solvent was distilled off under reduced pressure. Ethanol and diethyl ether were added to the residue, the resulting precipitate was collected by filtration, and 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -5,6-Dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide hydrochloride (184 mg) was obtained.
¹ H-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 (1 H, 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 = 8.8 Hz), 8.38 (1H, d, J = 8.8 Hz), 8.66 (1H, s), 8.91 (1H, s), 8.97 (1H, d, J = 7.1 Hz), 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, as a by-product having a low polarity in silica gel column chromatography purification, 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 5H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide (98 mg) was obtained.
¹ H-NMR (CDCl ₃ ) 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) .5 Hz), 7.19 (1 H, d, J = 1.5 Hz), 7.59 (1 H, d, J = 8.8 Hz), 7.76 (1 H, d, J = 8.8 Hz), 7 .95 (1H, d, J = 8.8 Hz), 8.53 (1H, s), 8.64 (1H, d, J = 8.0 Hz), 8.73 (1H, s).
MS (FAB) m / z: 540 (M + H) ^<+> .

Example 234 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3 , 4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) isoquinoline-3-carboxamide hydrochloride

The compound (500 mg) obtained in Reference Example 146 was dissolved in hydrochloric acid ethanol solution (5 ml) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (7 ml). The compound obtained in Reference Example 293 (299 mg), 1-hydroxybenzotriazole monohydrate (71 mg), 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (403 mg) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the residue, and the mixture was separated. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7) to obtain the free base (260 mg) of the title compound as a pale yellow solid. This was dissolved in methylene chloride, 1N hydrochloric acid ethanol solution (961 μl) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, diethyl ether was added dropwise, and the resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (260 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.56 (1H, m), 1.71-1.75 (3H, m), 1.95-1.99 (1H, m) 2.12.15 (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, 1.7 Hz), 8.24 (1H, d, J = 8.8 Hz), 8.36 (1H, d, J = 1.7 Hz), 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) ^<+> .

[Example 235] 2-[({(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} amino) Carbonyl] -6,6-dimethyl-6,7-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Under an argon atmosphere, the compound (95.4 mg) obtained in Reference Example 316 was dissolved in diethyl ether (1 ml), and tert-butyllithium (1.60 N pentane solution, 244 μl) was added dropwise at −78 ° C. After stirring at −78 ° C. for 1 hour, carbon dioxide gas was blown for 10 minutes. After raising the temperature to room temperature and concentrating the reaction solution under reduced pressure, the residue was dissolved in N, N-dimethylformamide (5 ml) to obtain the compound (178 mg) obtained in Reference Example 432, 1-hydroxybenzotriazole monohydrate. (48.0 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (136 mg) were sequentially added and stirred at room temperature overnight. The reaction mixture was concentrated, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to obtain the title compound (140 mg).
¹ H-NMR (CDCl ₃ ) 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, 1.8 Hz), 7.34 (1H, d, J = 8.8 Hz), 7.48. (1H, d, J = 7.3 Hz), 7.61-7.63 (1H, m), 7.89 (1H, br.s), 9.27 (1H, br.s).
MS (ESI) m / z: 657 (M + H) ^<+> .

[Example 236] N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -6,6 -Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in Example 235 by a method similar to that in Example 227. ¹ H-NMR (DMSO-d ₆ ) 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 = 1.7 Hz), 7.17 (1H, dd, J = 8.8, 2.0 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.68 (1H, d, J = 2.0 Hz), 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) ^<+> .

[Example 237] 2-[({(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} amino) Carbonyl] -5,7-dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester

The compound (1.27 g) obtained in Reference Example 50 was dissolved in tetrahydrofuran (48 ml), lithium hydroxide (117 mg) and water (6.0 ml) were added, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was dried under reduced pressure to obtain crude lithium carboxylic acid salt (1.24 g), and then condensed with the compound obtained in Reference Example 432 in the same manner as in Example 226-2). The title compound was obtained.
¹ H-NMR (CDCl ₃ ) 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) +.

[Example 238] N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -6-methyl -6,7-dihydro-5H-pyrrolo [3,4-d] pyrimidine-2-carboxamide hydrochloride

The compound (367 mg) obtained in Example 237 was dissolved in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. The title compound was obtained from the crude product obtained by drying the reaction solution under reduced pressure and formalin in the same manner as described in Example 18.
¹ H-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 to 4.65 (1H, m), 4.65-4.90 (4H, br), 7.06 (1H, s), 7.15 (1H, dd, J = 8.7, 2.1 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.66 (1H, d, J = 1.7 Hz), 8.35-8.45 (1H, m), 8.57 (1H, d, J = 8.1 Hz) ), 9.00 (1H, s), 11.80 (1H, s), 11.90-12.20 (1H, m).
MS (FAB) m / z: 524 (M + H) ^<+> .

[Example 239] 7-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(6-methyl-6,7-dihydrothiazolo [4,5 -D] pyrimidin-2-yl) carbonyl] amino} cyclohexyl) isoquinoline-3-carboxamide hydrochloride

In the same manner as in Example 49, the compound obtained in Reference Example 146 was treated with hydrochloric acid ethanol solution, and then condensed with the compound obtained in Reference Example 322 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 8.27 (1H, d, J = 8.8 Hz), 8.37 (1H, s) ), 8.54 (1H, s), 8.62 (1H, s), 8.79 (1H, d, J = 8.3 Hz), 8.94 (1H, d, J = 8.1 Hz), 9.32 (1H, s).
MS (ESI) m / z: 554 (M + H) ^<+> .

Example 240 7-chloro-N-((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) isoquinoline-3-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 325 and the compound obtained in Reference Example 10.
¹ H-NMR (DMSO-d ₆ ) δ: 0.98, 1.04 (3H, each, J = 7.1 Hz), 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 = 8.7 Hz), 8.26 (1H, d, J = 8.7 Hz), 8 .37 (1H, s), 8.60 (1H, s), 8.91-8.98 (2H, m), 9.32 (1H, d, J = 6.6 Hz), 11.39, 11 .53 (1H, each m).
MS (FAB) m / z: 569 (M + H) ^<+> .

[Example 241] N-{(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- [2- (dimethylamino) -2- Oxoethyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 336 and the compound obtained in Reference Example 10.
¹ H-NMR (DMSO-d ₆ ) δ: 1.13 to 1.22 (1H, m), 1.40 to 1.46 (1H, m), 1.68 to 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, 1.5 Hz), 7.42 (1H, d, J = 8) .5 Hz), 7.67 (1 H, s), 8.01 (1 H, d, J = 8.5 Hz), 8.40 (1 H, d, J = 7.8 Hz), 11.35-11.58 (1H, m), 11.76 (1H, br .S).
MS (FAB) m / z: 557 (M + H) ^<+> .

[Example 242] N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(methylsulfonyl) methyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 340 was treated with a hydrochloric acid ethanol solution in the same manner as in Example 219, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.40 (1H, m), 1.55-1.62 (1H, m), 1.70 to 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, 8.8 Hz), 7.41 ( 1H, d, J = 8.8 Hz), 7.68 (1H, s), 8.26 (1H, d, J = 7.8 Hz), 8.39 (1H, d, J = 7.8 Hz), 11.78 (1H, br.s).
MS (ESI) m / z: 564 (M + H) ^<+> .

[Example 243] N-{(1R, 2S, 5S) -2-{[(2-chloro-6H-thieno [2,3-b] pyrrol-5-yl) carbonyl] amino} -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The compound obtained in Reference Example 252 was subjected to catalytic reduction in the same manner as in Example 223, and then condensed with the compound obtained in Reference Example 345 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 7.3 Hz), 7.60 (1H, d, J = 5.8 Hz), 10.54 (1H, br). MS (ESI) m / z: 549 (M + H) ^<+> .

[Example 244] N-{(1R, 2S, 5S) -2-{[3- (4-chlorophenyl) -2-propinoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 252 was catalytically reduced in the same manner as in Example 223, and then condensed with the compound obtained in Reference Example 347 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.57 (1H, d, J = 8.8 Hz), 8.34. (1H, d, J = 8.8 Hz), 8.83 (1H, d, J = 7.8 Hz).
MS (FAB) m / z: 528 (M + H) ^<+> .

[Example 245] 6-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo) [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-oxo-1,4-dihydroquinazoline-2-carboxamide hydrochloride

The compound obtained in Reference Example 252 was catalytically reduced in the same manner as in Example 223, and then condensed with the compound obtained in Reference Example 349 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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 = 8.3 Hz), 7.90 (1H, d, J = 7.3 Hz), 8.75. -9.00 (2H, m), 11.00-11.50 (1H, br), 12.53 (1H, br.s).
MS (ESI) m / z: 573 (M + H) ^<+> .

Example 246 N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2-oxoethanethioyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The compound (184 mg) obtained in Reference Example 253 and the compound (150 mg) obtained in Reference Example 351 were dissolved in methanol (1 ml) -methylene chloride (4 ml), heated and stirred at 150 ° C., and the solvent was distilled off. Heating was continued for a minute. After allowing to cool, the product was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to give the title compound (59 mg).
¹ H-NMR (CDCl ₃ ) 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 = 15.2 Hz), 3.75 (1H, d, J = 15.7 Hz), 4.45-4, 60 (1H, m), 4.80-4 .85 (1H, m), 7.31 (2H, d, J = 8.8 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.60 (2H, d, J = 8. 8 Hz), 9.99 (1 H, d, J = 7.6 Hz), 10.15 (1 H, s).
MS (ESI) m / z: 563 (M + H) ^<+> .

Example 247 N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The compound (184 mg) obtained in Reference Example 253 and the compound (150 mg) obtained in Reference Example 353 were dissolved in methanol (0.3 ml) -methylene chloride (0.3 ml), heated and stirred at 150 ° C., and the solvent was removed. Heating was continued for 5 minutes after the distillation. After allowing to cool, the product was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to give the title compound (52 mg).
¹ H-NMR (CDCl ₃ ) 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 = 15.4 Hz), 4.45-4, 60 (1H, m), 4.75-4.85 (1H, m), 7.45 (1H) , D, J = 8.3 Hz), 7.67 (1H, dd, J = 8.8, 2.5 Hz), 8.18 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.0 Hz), 10.06 (1H, d, J = 6.3 Hz), 10.56 (1H, s).
MS (ESI) m / z: 564 (M + H) ^<+> .

Example 248 N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-thioxoacetyl} amino) -5-[(dimethyl Amino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

The compound (72 mg) obtained in Reference Example 355 and 2-amino-5-chloropyridine (100 mg) were dissolved in methanol (0.2 ml) -methylene chloride (0.2 ml), heated and stirred at 150 ° C., and the solvent Was heated for 8 minutes. After allowing to cool, the product was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 23: 2) to give the title compound (4 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.60-2.00 (3H, m), 2.00-2.20 (3H, m), 2.53 (3H, s), 2.75-3 0.00 (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 = 9.3 Hz), 7.75 (1H, dd, J = 8) .8, 2.7 Hz), 8.41 (1H, d, J = 2.7 Hz), 9.05 (1H, d, J = 8.8 Hz), 11.56 (1H, s).
MS (ESI) m / z: 564 (M + H) ^<+> .

Example 249 N ^1- (5-Chloro-2-thienyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 356 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 4.2 Hz), 6.94 (1H, d, J = 4.2 Hz), 8.72 (1H, d, J = 7.3 Hz), 9.13 (1H, br.s), 11 .21 (1H, br.s), 12.32 (1H, br.s).
MS (ESI) m / z: 553 (M + H) ^<+> .

[Example 250] N-{(1R, 2S, 5S) -2-{[(4-chloroanilino) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

Isocyanic acid 4-chlorophenyl ester (76.8 mg) was added to a solution of the compound obtained in Reference Example 253 (183 mg) in methylene chloride (20 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 10: 1), and the solvent was distilled off. The residue was dissolved in ethanol (2 ml) and methylene chloride (2 ml), 1N hydrochloric acid ethanol solution (0.4 ml) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was solidified with diethyl ether to obtain the title compound (160 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 1.50 (1H, m), 1.60 to 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 = 9.0 Hz), 7.37 (2H, d, J = 9.0 Hz), 8.53 (1H) , Br.s), 8.72 (1H, br.s), 11.35, 11.67 (total 1H, each).
MS (ESI) m / z: 519 (M + H) ^<+> .

Example 251 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ² - (5-fluoropyridin-2-yl) ethanediamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 357 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.9 Hz), 8.71 (1H, d, J = 7.7 Hz), 9.13 (1H, d, J = 7.3 Hz), 10.27 (1H, s) .
MS (FAB) m / z: 532 (M + H) ^<+> .

Example 252] N ¹ - ^{(4-chlorophenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl-5,6-dihydro -4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 191, the title compound was obtained from the compound obtained in Reference Example 242 and the compound obtained in Reference Example 272.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.81 (2H, d, J = 8.8 Hz), 8.76 (1H, d, J = 7.6 Hz), 8 .95 (1H, d, J = 8.3 Hz), 10.79 (1H, s).
MS (FAB) m / z: 533 (M + H) ^<+> .

[Example 253] N ^1- [4-chloro-2- (trifluoromethyl) phenyl] -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[( 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

Thionyl chloride (1 ml) was added to a chloroform solution (10 ml) of the compound (269 mg) obtained in Reference Example 359 and stirred at 75 ° C. for 30 minutes. The solvent was distilled off under reduced pressure and dried. To this were added a methylene chloride solution (7 ml) of the compound (286 mg) obtained in Reference Example 253 and pyridine (3 ml) under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature. A saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the reaction solution, and after the liquid separation operation, the obtained organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was subjected to silica gel column chromatography (methylene chloride: methanol = 20: 1) and LH-20 column chromatography (molecular sieve, methanol) to release the title compound. Base (90 mg) was obtained as a pale yellow amorphous solid. Methylene chloride (5 ml), ethanol (5 ml) and 1N hydrochloric acid ethanol solution (1 ml) were added thereto, and the residue was evaporated and dried under reduced pressure to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example 254] N ¹ - {4-chloro-2 - [(dimethylamino) carbonyl] ^{phenyl} -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2- { [(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 362 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.4 Hz), 7.55 (1H, dd, J = 2.4, 8.5 Hz), 8.05 (1H , D, J = 8.5 Hz), 8.75 (1H, br), 9.10-9.24 (1H, m), 10.52 (1H, s).
MS (ESI) m / z: 618 (M + H) ^<+> .

Example 255 N ^1- [4-Chloro-2- (hydroxymethyl) phenyl] -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 199, the compound obtained in Reference Example 270 and 4-chloro-2-hydroxymethylaniline were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 (0.5 H, m), 7.37 (1 H, dd, J = 2.4, 8.6 Hz), 7.42 (1 H, d, J = 2.4 Hz), 7.91 (1 H, d, J = 8.6 Hz), 8.74-8.81 (1H, m), 9.03-9.19 (1H, m), 10.79 (1H, s).
MS (ESI) m / z: 577 (M + H) ^<+> .

Example 256 N ^1- (4-Chloro-2-methoxyphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 364 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 8.06 (1H, d, J = 8.5 Hz), 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) ^<+> .

[Example 257] N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2- (hydroxyimino) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 366 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound. .
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7 .04 (1H, d, J = 8.8 Hz), 7.10 (1H, d, J = 8.8 Hz), 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) ^<+> .

Example 258] N ¹ - ^{(4-chlorophenyl) -N 2 - ((3R,} 4S) -1- (2- methoxyacetyl) -3 - {[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 367 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.83 (2H, d, J = 8.8 Hz), 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) ^<+> .

Example 259] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((3R,} 4S) -1- (2- methoxyacetyl) -3 - {[(5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 368 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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), 10.2-1-10.35 ( 1H, br), 11.30-11.70 (1H, br).
MS (ESI) m / z: 550 (M + H) ^<+> .

Example 260] N ¹ - ^{(5-bromo-2-yl) -N 2 - ((3R,} 4S) -1- (2- methoxyacetyl) -3 - {[(5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 369 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 (0.2 H, m), 7.97 (1 H, d, J = 8.8 Hz), 8.11 (1 H, dd, J = 8.8, 2.2 Hz), 8. 51 (1H, d, J = 2.2 Hz), 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) ^<+> .

Example 261] N ¹ - ^{(4-chlorophenyl) -N 3 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl -4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) malonamide hydrochloride

In the same manner as in the method described in Example 5, the compound obtained in Reference Example 371 and the compound obtained in Reference Example 253 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 8.00-8.10 (1H, m), 8 .30-8.40 (1H, m), 10.29 (1H, d, J = 12.5 Hz), 12.40 (1H, br.s)
MS (FAB) m / z: 561 (M + H) ^<+> .

Example 262] N ¹ - (3- ^{chlorophenyl) -N 3 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl -4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) malonamide hydrochloride

In the same manner as in the method described in Example 5, the compound obtained in Reference Example 373 and the compound obtained in Reference Example 253 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.31 (1H, d, J = 8.8 Hz), 7.38 (1H, t, J = 8.8 Hz) 7.79 (1 H, s), 8.00-8.10 (1 H, m), 8.30-8.40 (1 H, m), 10.28 (1 H, d, J = 12.5 Hz) , 11.67 (1H, br.s).
MS (FAB) m / z: 561 (M + H) ^<+> .

Example 263] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - {[ ethyl (methyl) amino] carbonyl} -2 - {[(5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

To a solution of the compound (0.33 g) obtained in Reference Example 404 in ethanol (20 ml) was added 10% palladium carbon (0.3 g), and the mixture was stirred under a hydrogen atmosphere for 24 hours. Insoluble material was removed by filtration through a Celite pad, and the filtrate was concentrated under reduced pressure. The obtained residue (0.37 g) was dissolved in N, N-dimethylformamide (20 ml), and the compound (0.3 g) obtained in Reference Example 266 and 1-hydroxybenzotriazole monohydrate (0. 2 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.37 g) were sequentially added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with a mixed solvent consisting of chloroform-methanol (9: 1), and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (chloroform: methanol = 95: 5), and the desired fraction was concentrated. did. 1N Hydrochloric acid ethanol solution was added to the resulting residue to make a hydrochloride, and then recrystallized from a mixed solvent of methanol and diethyl ether to obtain the title compound (0.28 g).
¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (1.5 H, t, J = 6.9 Hz), 1.42 (1.5 H, t, J = 6.9 Hz), 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 = 15.9 Hz), 8.00-8.01 (2H, m), 8.44 (1H, s) , 8.71 (1H, dd, J = 10.1, 2.2 Hz), 9.14 (0.5 H, d, J = 7.8 Hz), 9.22 (0.5 H, d, J = 8) .3 Hz), 10.24 (0.5 H, s), 1 .28 (0.5H, s), 11.48 (1H, br.s), 11.61 (1H, br.s).
MS (FAB) m / z: 562 (M + H) ^<+> .

Example 264] N ¹ - (4-chlorophenyl) -N ² - ((1S, 2R, 4S) -4 - {[ethyl (methyl) amino] carbonyl} -2 - {[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 263, the compound obtained in Reference Example 404 was converted to an amine, condensed with the compound obtained in Reference Example 374, and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (1.5 H, t, J = 6.9 Hz), 1.04 (1.5 H, t, J = 6.9 Hz), 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 = 15.9 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J = 8.8 Hz), 8.75 (1H, dd, J = 10.1, 2.2 Hz), 9.00 (0.5 H, d, J = 7.8 Hz), 9.08 (0 .5H, d, J = 8.3 Hz), 10.81 (1H, d, J = 4.9 Hz), 11.45 (1H, br.s).
MS (FAB) m / z: 561 (M + H) ^<+> .

Example 265] N ¹ - ^{(5-bromo-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - {[ ethyl (methyl) amino] carbonyl} -2 - {[(5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 263, the compound obtained in Reference Example 404 was converted to an amine, condensed with the compound obtained in Reference Example 375, and treated with hydrochloric acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (1.5 H, t, J = 6.9 Hz), 1.08 (1.5 H, t, J = 6.9 Hz), 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 = 15.9 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.17 (1H, d, J = 8.8 Hz), 8.58 ( 1H, s), 8.78 (1H, dd, J = 10.1, 2.2 Hz), 9.21 (0.5 H, d, J = 7.8 Hz), 9.29 (0.5 H, d , J = 8.3 Hz), 10.29 (0.5H , S), 10.33 (0.5 H, s), 11.53 (0.5 H, br. S), 11.65 (0.5 H, br. S).
MS (FAB) m / z: 607 (M + H) ^<+> .

Example 266 N ^1- (4-Chloro-3-fluorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 263, the compound obtained in Reference Example 252 was converted to an amine, condensed with the compound obtained in Reference Example 378, and treated with hydrochloric acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.44 to 1.52 (1H, m), 1.65-1.76 (3H, m), 2.01 to 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 = 15.9 Hz), 7.56 (1H , T, J = 8.8 Hz), 7.68 (1H, d, J = 8.8 Hz), 7.90 (1H, dd, J = 11.7, 1.5 Hz), 8.73 (1H, dd, J = 12.5, 7.3 Hz), 9.06 (1H, dd, J = 12.5, 8.1 Hz), 11.01 (1H, d, J = 5.8 Hz), 11.30 -11.42 (1H, m).
MS (FAB) m / z: 565 (M + H) ^<+> .

[Example 267] N-{(1R, 2S, 5S) -2-{[3- (4-chlorophenyl) -3-oxopropanoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

In the same manner as in Example 214, the compound obtained in Reference Example 383 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (CDCl ₃ ) (free base) 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 = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz).
MS (FAB) m / z: 546 (M + H) ^<+> .

Example 268] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1R,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 5H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

In the same manner as in Example 214, the compound obtained in Reference Example 386 was deprotected by treatment with hydrochloric acid and condensed with the compound obtained in Reference Example 293 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.0 Hz), 7.17 (1H, d , J = 2.0 Hz), 7.20-7.32 (1H, m), 7.67 (1H, dd, J = 8.8, 2.8 Hz), 7.99 (1H, d, J = 8.4 Hz), 8.21 (1 H, d, J = 8.8 Hz), 8.25 (1 H, d, J = 2.8 Hz), 9.64 (1 H, s).
HRMS (FAB) m / z: 532.1520 (M + H) ⁺ .
_{(Calc; C 23 H 27 ClN 7 O} 4 S: 532.1534).

Example 269 N ¹ -[(5-chloropyridin-2-yl) amino] -N ² -((1R, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Reference Example 253, the compound obtained in Reference Example 387 was reduced, condensed in the same manner as described in Example 208 with the compound obtained in Reference Example 266, and treated with hydrochloric acid. As a result, the title compound was obtained.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example 270] N ¹ - ^{(4-chlorophenyl) -N 2 - ((1R,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl -4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

In the same manner as in the method described in Reference Example 253, the compound obtained in Reference Example 387 was reduced, and in the same manner as in the method described in Example 191, a hydrolyzed lithium salt of the compound obtained in Reference Example 242 Condensation and treatment with hydrochloric acid gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.89 (2H, d) , J = 8.8 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.63 (1H, d, J = 8.8 Hz), 10.72 (1H, s).
MS (ESI) m / z: 547 (M + H) ^<+> .

Example ^{271] N 1 - {(1R} , 2S, 5S) -2 - {[(5- chloro-indol-2-yl) carbonyl] amino} -5 - [(dimethylamino) carbonyl] cyclohexyl} -N ² -(Pyridin-4-yl) ethanediamide hydrochloride

The compound obtained in Reference Example 310 was deprotected by treatment with hydrochloric acid, and 2-[(pyridine-4-) obtained by hydrolyzing the compound obtained in Reference Example 261 in the same manner as described in Example 191. Yl) amino] -2-oxoacetic acid After condensation with lithium salt, the title compound was obtained by treatment with hydrochloric acid.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.4 Hz), 7.64 (1H, br. S), 8.28 (2H, d, J = 6.8 Hz), 8.36 (1H) , D, J = 8.0 Hz), 8.62 (1H, d, J = 8.8 Hz), 8.72 (2H, d, J = 6.8 Hz), 11.74 (1H, s), 11 .83 (1H, s).
MS (FAB) m / z: 511 (M + H) ^<+> .

Example ^{272] N 1 - {(1R} , 2S, 5S) -2 - {[(5- chloro-indol-2-yl) carbonyl] amino} -5 - [(dimethylamino) carbonyl] cyclohexyl} -N ² -(Pyridin-3-yl) ethanediamide hydrochloride

In the same manner as described in Reference Example 242, 2-[(pyridin-3-yl) amino] -2-oxo obtained by condensing 3-aminopyridine and 2-chloro-2-oxoacetic acid methyl ester The title compound was obtained in the same manner as described in Example 271 using acetic acid methyl ester and the compound obtained in Reference Example 310 as raw materials.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.4 Hz), 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) ^<+> .

Example ^{273] N 1 - {(1R} , 2S, 5S) -2 - {[(5- chloro-indol-2-yl) carbonyl] amino} -5 - [(dimethylamino) carbonyl] cyclohexyl} -N ² -(Piperidin-4-yl) ethanediamide hydrochloride

To a solution of the compound (400 mg) obtained in Reference Example 389 in ethanol (5.0 ml) was added 4N hydrochloric acid dioxane solution (8.0 ml) at room temperature, and the mixture was stirred at the same temperature for 5 hours. The solvent was evaporated under reduced pressure, washed with methylene chloride, and the insoluble material was filtered and washed to obtain the title compound (320 mg).
¹ H-NMR (DMSO-d ₆ ) 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 (1 H, d, J = 8.8 Hz), 7.65 (1 H, s), 8.25 (1 H, d, J = 8.0 Hz), 8.34 (1 H, d , J = 7.6 Hz), 8.89 (1H, d, J = 8.4 Hz), 11.75 (1H, s).
MS (ESI) m / z: 517 (M + H) ^<+> .

Example ^{274] N 1 - {(1R} , 2S, 5S) -2 - {[(5- chloro-indol-2-yl) carbonyl] amino} -5 - [(dimethylamino) carbonyl] cyclohexyl} -N ² -(1-Methylpiperidin-4-yl) ethanediamide hydrochloride

In the same manner as in Reference Example 9, the compound obtained in Example 273 was methylated and treated with hydrochloric acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.40 (1H, d) , J = 8.8 Hz), 7.68 (1 H, d, J = 2.0 Hz), 8.25-8.35 (1 H, m), 8.37 (1 H, d, J = 7.6 Hz) , 8.90-9.02 (1H, m), 9.82 (1H, br. S), 11.78 (1H, s).
MS (ESI) m / z: 531 (M + H) ^<+> .

Example 275] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ¹ -methylethanediamide hydrochloride

In the same manner as described in Example 191, the compound obtained in Reference Example 390 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example 276 N ^1- (5-chloropyrimidin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound obtained in Reference Example 391 was hydrolyzed in the same manner as described in Example 191, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example 277 N ^1- (4-chlorophenyl) -N ² -((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[(5-methyl-5, 6-Dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound obtained in Reference Example 392 was reduced in the same manner as described in Reference Example 253, and obtained by hydrolysis of the compound obtained in Reference Example 242 in the same manner as described in Example 195. Condensation with carboxylic acid and treatment with hydrochloric acid gave the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 0.96, 1.02 (3H, each t, J = 7.0 Hz), 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 = 8.8 Hz), 7.83 (2H, d, J = 8.8 Hz), 8.74-8.80 (1H, m), 9.02 (1H, d, J = 7.3 Hz) , 10.82 (1H, s), 12.41 (1H, br. S).
MS (FAB) m / z: 547 (M + H) ^<+> .

Example 278] N ¹ - ^{(5-bromo-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - {[ ethyl (methyl) amino] carbonyl} -2 - {[(5 -Methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in the method described in Example 277, the title compound was obtained from the compound obtained in Reference Example 392 and the compound obtained in Reference Example 262.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 8.10 (1H, dd, J = 8.8, 2.4 Hz), 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) ^<+> .

Example 279] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - {[ ethyl (methyl) amino] carbonyl} -2 - {[(5 -Methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in the method described in Example 277, the title compound was obtained from the compound obtained in Reference Example 392 and the compound obtained in Reference Example 243.
¹ H-NMR (DMSO-d ₆ ) δ: [0.95 (t, J = 7.0 Hz), 1.01 (t, J = 6.8 Hz), 3H], 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) ^<+> .

Example 280 N ^1- (4-Chloro-3-methoxyphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 395 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.46 to 1.54 (1H, m), 1.67-1.77 (3H, m), 2.01 to 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 = 8.7 Hz), 7.48 (1H, dd, J = 8.7, 2.2 Hz), 7.72 (1H, d, J = 2.2 Hz) , 8.75 (1H, d, J = 7.3 Hz), 9.06 (1H, br.s), 10.77 (1H, s), 11.44 (1H, br.s).
MS (FAB) m / z: 577 (M + H) ^<+> .

[Example 281] N ^1- (4-chlorophenyl) -N ² -((1R ^* , 2R ^* )-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4 -C] pyridin-2-yl) carbonyl] amino} cyclopentyl) ethanediamide hydrochloride

In the same manner as described in Example 195, the compound obtained in Reference Example 242 was hydrolyzed, condensed with the compound obtained in Reference Example 62, and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.9 Hz), 7.84 (2H, d, J = 8.9 Hz), 8.92 (1H, d, J = 8.5 Hz), 9 .03 (1H, d, J = 8.3 Hz), 10.76 (1H, s), 11.32 (1H, br. S).
MS (FAB) m / z: 462 (M + H) ^<+> .

Example 282] N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - ((1R *} , 2R *) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclopentyl) ethanediamide hydrochloride

In the same manner as in Example 208, the compound obtained in Reference Example 62 and the compound obtained in Reference Example 266 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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), 7.9-8.06 (2H, m), 8.43-8.44 (1H, m), 8.94 (1H, d, J = 8.3 Hz) ), 9.20 (1H, d, J = 8.5 Hz), 10.20 (1H, br. S), 11.78 (1.1 H, br. S).
MS (FAB) m / z: 463 (M + H) ^<+> .

Example 283 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (4-ethynylphenyl) ethanediamide

In the same manner as in the method described in Example 263, the compound obtained in Reference Example 252 and the compound obtained in Reference Example 397 were condensed to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 15.5 Hz), 3.73 (1H, d, J = 15. 5Hz) AB pattern], 4.09-4.16 (1H, m), 4.72-4.75 (1H, m), 7.42-7.46 (3H, m), 7.58 (2H) , D, J = 8.
5 Hz), 8.02 (1 H, d, J = 8.1 Hz), 9.36 (1 H, s).
MS (FAB) m / z: 537 (M + H) ^<+> .

Example 284 N ^1- (5-chloropyrazin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Reference Example 97, the compound obtained in Reference Example 253 and the compound obtained in Reference Example 399 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.44 to 1.52 (1H, m), 1.65-1.77 (3H, m), 2.00 to 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 = 1.2 Hz), 8.70 (1 H, d, J = 7.3 Hz), 9.02 (1 H, s), 9.21 (1 H, br. S), 10.91 (1 H, br) .S), 11.50 (1H, br.s).
MS (FAB) m / z: 549 (M + H) ^<+> .

Example 285] N ¹ - ^{(4-chloro-3-nitrophenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Reference Example 97, the compound obtained in Reference Example 253 and the compound obtained in Reference Example 400 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.44 to 1.53 (1H, m), 1.66-1.73 (3H, m), 1.97 to 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 = 8.8 Hz), 8.08 (1H, d , J = 8.8 Hz), 8.59 (1H, s), 8.71 (1H, d, J = 7.3 Hz), 9.07 (1H, d, J = 8.0 Hz), 11.24 (1H, s), 11.58 (1H, br. S).
MS (FAB) m / z: 592 (M + H) ^<+> .

Example 286 N ^1- (4-Chloro-2-nitrophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 208, the compound obtained in Reference Example 253 and the compound obtained in Reference Example 401 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.46 to 1.54 (1H, m), 1.66-1.77 (3H, m), 2.03 to 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 = 9.0 Hz), 8.20-8.21 (2H, m), 8.73 (1H, d, J = 6.4 Hz), 9.28. (1H, br.s), 11.49 (1H, br.s), 11.56 (1H, s). MS (FAB) m / z: 592 (M + H) ^<+> .

Example 287] N ¹ - (3- ^{amino-4-chlorophenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (236 mg) obtained in Example 285 was dissolved in ethanol (25 ml), a catalytic amount of Raney nickel was added, and the mixture was stirred at room temperature for 17 hours under a hydrogen atmosphere. Thereafter, a catalytic amount of Raney nickel was added, and the mixture was further stirred for 7 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 23: 2) to obtain a pale yellow solid (101 mg). This was dissolved in methylene chloride, and 1N hydrochloric acid ethanol solution (360 μl) was added. The solvent was distilled off under reduced pressure, a small amount of methanol was added to the residue, and diethyl ether was added dropwise while irradiating ultrasonic waves. The resulting precipitate was collected by filtration and washed with diethyl ether to give the title compound (95 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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, 1.9 Hz), 7.14 (1H, d , J = 8.5 Hz), 7.35, 7.38 (1H, ech br.s), 8.72-8.77 (1H, m), [8.91 (d, J = 7.8 Hz) , 8.9 (d, J = 8.5 z), 1H], 10.45,10.47 (1H, each br.s), 11.74 (1H, br.s).
MS (FAB) m / z: 562 (M + H) ^<+> .

Example 288] N ¹ - ^{(2-amino-4-chlorophenyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 287, the title compound was obtained from the compound obtained in Example 286.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.8 Hz) 9.06 (d, J = 8.1 Hz), 1H], 9.98 (1H, s), 11.60 (1H, br.s).
MS (FAB) m / z: 562 (M + H) ^<+> .

Example 289 N ^1- (6-Chloro-4-methylpyridin-3-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[( 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 199, the compound obtained in Reference Example 270 and the compound obtained in Reference Example 402 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.54 (1H, m), 1.65-1.77 (3H, m), 2.02 to 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 = 7.1 Hz), 9.09 (1H, d, J = 7.3 Hz), 10.48 (1H, s), 11. 40 (0.9H, br.s).
MS (FAB) m / z: 562 (M + H) ^<+> .

[Example 290] N-{(1R, 2S, 5S) -2-({[(E) -2- (4-chlorophenyl) diazenyl] carbonyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a solution of the compound obtained in Reference Example 252 (700 mg) in tetrahydrofuran (10 ml) was added 10% palladium on carbon (200 mg), and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere of 1 atm, filtered, and the filtrate was concentrated. The compound (470 mg) obtained in Reference Example 405 was added to a solution of the obtained amine in N, N-dimethylformamide (5.0 ml), and the mixture was stirred at 95 ° C. for 18 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution (50 ml), water (50 ml) and methylene chloride (30 ml) were added, and after liquid separation, the aqueous layer was extracted with methylene chloride (2 × 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, purified using silica gel column chromatography (methylene chloride: methanol = 12: 1), and treated with 1N hydrochloric acid to give the title compound (100 mg). Obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.60 (1H, m), 1.65 to 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 = 8.7 Hz), 7.83 (2H, d, J = 8.7 Hz), 8.41 (1H, br. S), 8.68 (1H, d, J = 7) .6 Hz), 11.40-11.80 (1H, br).
MS (ESI) m / z: 532 (M + H) ^<+> .

[Example 291] N-{(1R, 2S, 5S) -2-({[2- (4-chlorophenyl) hydrazino] carbonyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the reaction described in Example 290, the title compound was obtained by changing the reaction conditions to those of stirring at 40 ° C. for 3 days.
¹ H-NMR (DMSO-d ₆ ) 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 = 12.8 Hz), 6.40-6.60 (2H, m), 6.55. -6.70 (2H, m), 6.95-7.20 (2H, m), 7.88 (1H, d, J = 11.3 Hz), 8.48-8.65 (1H, m) , 11.48-11.80 (1H, br).
MS (ESI) m / z: 534 (M + H) ^<+> .

Example 292] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(4,5, 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in the method described in Example 17, the compound obtained in Reference Example 34 and the compound obtained in Reference Example 420 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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), 8.00-8.01 (2H, m), 8.10 (1H , D, J = 7.1 Hz), 8.43-8.47 (1H, m), 9.16 (1H, d, J = 7.8 Hz), 9.43 (2H, br s), 10. 27 (1H, s).
MS (FAB) m / z: 534 (M + H) ^<+> .

[Example 293] N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(1-hydroxycyclopropyl) carbonyl] piperidine-3 -Yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in the method described in Example 150, the compound obtained in Example 118 and 1-hydroxy-1-cyclopropanecarboxylic acid were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 1.5 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.70 (1 H, d, J = 1.5 Hz), 8.14-8.29 (1 H, br), 8.41 (1 H, br d, J = 7.6 Hz), 11 .83 (1H, s).
MS (ESI) m / z: 557 (M + H) ^<+> .

[Example 294] N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(1-methoxycyclopropyl) carbonyl] piperidine-3 -Yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in the method described in Example 150, the compound obtained in Example 118 and the compound obtained in Reference Example 409 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.0 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.71 (1H, d, J = 2.0 Hz), 8.08-8. 30 (1H, br), 8.41 (1H, br d, J = 7.8 Hz), 10.60-10.80 (0.5H, br), 10.85-11.05 (0.5H, br), 11.84 (1H, s).

Example 295 7-Chloro-N-((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) -3-isoquinolinecarboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 410 is treated with 4N hydrochloric acid dioxane solution, deprotected, condensed with the compound obtained in Reference Example 10, and treated again with hydrochloric acid. Gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 8.25 (1H, d, J = 8.8 Hz), 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) ^<+> .

Example 296] N ¹ - ^{(4-chloro-3-fluorophenyl) -N 2 - ((3R,} 4S) -1- (2- methoxyacetyl) -3 - {[(5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 411 is treated with 4N hydrochloric acid dioxane solution, deprotected, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid again. Gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.70 (1H, d, J = 9.0 Hz), 7.91 (1H, dd, J = 8.8, 2.3 Hz), 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) ^<+> .

Example 297] N ¹ - ^{(5-chloro-2-thienyl) -N 2 - ((3R,} 4S) -1- (2- methoxyacetyl) -3 - {[(5-methyl-4,5, 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 412 is treated with 4N hydrochloric acid dioxane solution, deprotected, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid again. Gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 4.2 Hz), 6.93 (1H, d, J = 4.2 Hz), 8.48-8.70 ( 1H, m), 9.18-9.40 (1H, m), 12.31 (1H, s).
MS (ESI) m / z: 555 (M + H) ^<+> .

[Example 298] N-{(1R, 2S, 5S) -2-{[2- (4-chlorophenoxy) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 223, the compound obtained in Reference Example 252 was reduced, condensed with p-chlorophenoxyacetic acid, and treated with hydrochloric acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 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 = 8.5 Hz), 7.15-7. .35 (1H, br), 7.88-8.03 (1H, br), 8.46 (1H, d, J = 8.8 Hz), 11.30-11.65 (1H, br).
MS (FAB) m / z: 534 (M + H) ^<+> .

Example 299 7-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5H-pyrrolo [3,4-d] thiazole -2-yl) carbonyl] amino} cyclohexyl) -3-isoquinolinecarboxamide hydrochloride

The lithium salt of the carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 413 and the compound obtained by acid treatment and deprotection of the compound obtained in Reference Example 146 are condensed and then treated with hydrochloric acid to obtain the title compound. It was.
¹ H-NMR (DMSO-d ₆ ) 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, brd, J = 8.3 Hz), 8.24 (1H, brd, J = 8.8 Hz), 8.33 (1H, s) ), 8.59 (1H, s), 8.85 (1H, brd, J = 7.6 Hz), 9.01 (1H, brd, J = 7.8 Hz), 9.28 (1H, s) ). MS (ESI) m / z: 539 (M + H) ^<+> .

Example 300 N-{(1R, 2S, 5S) -2-{[(6-Chloro-4-oxo-4H-chromen-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 417 was treated with 4N hydrochloric acid dioxane solution and the compound obtained in Reference Example 10 were condensed and then treated with hydrochloric acid. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 4.9 Hz), 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) ^<+> .

Example 301 7-Chloro-N-((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) -3-cinnolinecarboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 418 was treated with 4N hydrochloric acid dioxane solution and the compound obtained in Reference Example 10 was condensed and then treated with hydrochloric acid. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 9.0 Hz), 7.17 (1H, dd, J = 8.8, 1.9 Hz), 7.42 (1H, d, J = 8.8 Hz), 7.70 (1H, d, J = 1.9 Hz), 8.29 (1H, br s), 8.40-8.50 (1 H, m), 11.20-11.50 (1 H, br m), 11 .85 (1H, s).
MS (ESI) m / z: 558 (M + H) ^<+> .

Example 302] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound obtained in Reference Example 421 was deprotected with hydrochloric acid, methylated in the same manner as described in Example 18, and treated with hydrochloric acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 1.6 Hz), 8.90 (1H, d , J = 8.6 Hz), 10.25 (1H, s), 11.12 (1H, br s).
MS (ESI) m / z: 547 (M + H) ^<+> .

Example 303] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-isopropyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 148 and the compound obtained in Reference Example 420 were condensed and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.8 Hz), 9.24 (1/2 H, d, J = 7.8 Hz), 10.22 (1/2 H, s), 10.26 (1/2 H, s) , 11.25 (1 / 2H, br
s), 11.44 (1/2 H, br s).
MS (FAB) m / z: 578 (M + H) ^<+> .

[Example 304] N-((1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-{[2- (4-fluoroanilino) -2-oxoethanethioyl] amino} cyclohexyl ) -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 424 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid again to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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 = 8.8 Hz), 7.77 (2H, dd, J = 9.0, 5.1 Hz), 8.80 (1H, br), 10.42 (1H, s), 10.93 (1H, br), 11.28 (1H, br ).
MS (ESI) m / z: 547 (M + H) ^<+> .

[Example 305] N-[(1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-fluoropyridin-2-yl) amino] -2-oxoethane Thioyl} amino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 427 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid again to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) 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, 3.9 Hz), 8.41 (1 H, d, J = 2.9 Hz), 8.79 (1 H, d, J = 6.6 Hz), 10.49 (1 H, s), 11.07 (1 H, br
s), 11.69 (1H, br).
MS (ESI) m / z: 548 (M + H) ^<+> .

[Example 306] N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-5H-pyrrolo [3,4-d] thiazole-2-carboxamide

In the same manner as in Example 219, the compound obtained in Reference Example 428 was treated with hydrochloric acid, deprotected, and then condensed with the compound obtained in Reference Example 293 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 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 = 1.7 Hz), 7.55 (1H, d, J = 1.7 Hz), 8.00 (1H, dd, J = 8.9, 2.4 Hz), 8.05 (1H, d, J = 8.9 Hz), 8.44 (1H, d, J = 2.4 Hz), 8.71 (1H, d, J = 7.3 Hz), 10.57 (1H, s), 11.13 ( 1H, d, J = 7.8 Hz).
MS (FAB) m / z: 548 (M + H) ^<+> .

[Example 307] N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 428 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 293 under an argon atmosphere, and again treated with hydrochloric acid. This gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.4 Hz), 8.79 (1H , T, J = 7.3 Hz), 10.54 (1 H, s), 11.04 (1 H, d, J = 7.8 Hz), 12.24 (1 H, br s).
MS (ESI) m / z: 550 (M + H) ^<+> .

Example 308] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - ({[6- (dimethyl Amino) -4,5,6,7-tetrahydrobenzothiazol-2-yl] carbonyl} amino) cyclohexyl] ethanediamide

The compound obtained in Reference Example 431 was treated with hydrochloric acid for deprotection, methylated in the same manner as described in Example 18, and treated with hydrochloric acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 8.2 Hz), 9.19 (1H, dd, J = 17.7, 8.2 Hz), 10.28 (1 H, s), 10.91 (1 H, br s).
MS (ESI) m / z: 576 (M + H) ^<+> .

[Example 309] N-{(1R, 2S, 5S) -2-[({[(4-chlorophenyl) sulfonyl] amino} carbonyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5 Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a solution of the compound obtained in Reference Example 253 (328.0 mg) in methylene chloride (10 ml) was added isocyanic acid 4-chlorophenylsulfonyl ester (148 μl), and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin layer column chromatography (methylene chloride: methanol = 9: 1). The obtained product was dissolved in ethanol (2 ml) and methylene chloride (2 ml), 1N hydrochloric acid ethanol solution (0.25 ml) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was solidified with diethyl ether to obtain the title compound (104.3 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 8.5 Hz), 7.86 (2H, d, J = 8.5 Hz), 8.50-8.82 (1 H, m), 10.64 (1 H, br) s), 11.10-11.80 (1H, br).
MS (ESI) m / z: 583 (M + H) ^<+> .

Example 310] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 435 and the compound obtained in Reference Example 10.
¹ H-NMR (CDCl ₃ ) 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) .4 Hz), 3.75 (1 H, d, J = 15.4 Hz), 4.07-4.15 (1 H, m), 4.66-4.72 (1 H, m), 7.40 (1 H , D, J = 8.8, 0.6 Hz), 7.68 (1H, dd, J = 8.8, 2.4 Hz), 8.03 (1H, d, J = 7.8 Hz), 8. 16 (1H, dd, J = 8.8, 0.6 Hz), 8.30 (1H, dd, J = 2.4, 0.6 Hz), 9.72 (1H, s).
MS (ESI) m / z: 548 (M + H) ^<+> .

Example 311] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide p-toluenesulfonate monohydrate

6.2 g of the compound obtained in Example 310 was dissolved in methylene chloride (120 ml), 1 mol / L p-toluenesulfonic acid-ethanol solution (11.28 ml) was added, and the solvent was distilled off. 15% aqueous ethanol (95 ml) was added to the residue and dissolved by stirring at 60 ° C. Then, it cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol, and dried under reduced pressure at room temperature for 2 hours to obtain the title compound (7.4 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.54 (1H, m), 1.66-1.78 (3H, m), 2.03 to 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 = 7.8 Hz), 7.46 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 1.8 Hz), 8.46 (1H, t, J = 1.8 Hz), 8.75 (1H, d, J = 6.9 Hz), 9.10-9.28 (1H, br), 10.18 (1H, br), 10 .29 (1H, s).
MS (ESI) m / z: 548 (M + H) ⁺
Elemental _{analysis: C 24 H 30 ClN 7 O} 4 S · C 7 H 8 O 3 S · H 2 O
Theoretical value: C; 50.43, H; 5.46, N; 13.28, Cl; 4.80, S; 8.69
Found: C; 50.25, H; 5.36, N; 13.32, Cl; 4.93, S; 8.79
mp (decomposition): 245-248 ° C.

Example 312] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( methylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 437 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid. A compound was obtained.
¹ H-NMR (DMSO-d ₆ ) 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 = 4.2 Hz), 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 = 7.8 Hz), 10.26 (1H, br.s), 11.48 (1H, br. s). MS (ESI) m / z: 534 [(M + H) ⁺ , Cl ³⁵ ], 535 [(M + H) ⁺ , Cl ³⁷ ].

Example 313] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((3R,} 4S) -1- (2- methoxyacetyl) -3 - {[4- (pyridin-4-yl ) Benzoyl] amino} piperidin-4-yl) ethanediamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 368 is treated with 4N hydrochloric acid dioxane solution, deprotected, condensed with the compound obtained in Reference Example 237, and treated again with hydrochloric acid. Gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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) ⁺ , Cl ³⁵ ], 553 [(M + H) ⁺ , Cl ³⁷ ].

[Example 314] N-{(1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-methylpyridin-2-yl) amino] -2-oxoethane Thioyl} amino) cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 440 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid to give the title compound. Got.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.60 (1H, m), 1.65-1.90 (3H, m), 2.00 to 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 = 8.5 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.23 (1H, s), 8.83 (1H, d, J = 7.3 Hz), 10.38 (1H, s), 11.06 (1H, d, J = 7.6 Hz), 11.49 (1H, br. S).
MS (ESI) m / z: 544 (M + H) ^<+> .

[Example 315] N-[(3R, 4S) -4-{[2- (4-Chloroanilino) -2-oxoethanethioyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl] -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 219, the compound obtained in Reference Example 441 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid to give the title compound. Got.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.77 (2H, d, J = 8.8 Hz), 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) ⁺ , Cl ³⁵ ], 567 [(M + H) ⁺ , Cl ³⁷ ].

Example 316] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbothioyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in the method described in Example 3, the compound obtained in Reference Example 445 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 6.8 Hz), 9.24 (1H, br.s) ), 10.28 (1H, s), 11.29 (1H, br. S).
MS (FAB) m / z: 564 [(M + H) ⁺ , Cl ³⁵ ], 566 [(M + H) ⁺ , Cl ³⁷ ].

Example 317] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((3R,} 4S) -1- (2- methoxyethane Chi oil) -3 - {[(5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 448 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid to give the title compound. Got.
¹ H-NMR (DMSO-d ₆ ) 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) ⁺ , Cl ³⁵ ], 568 [(M + H) ⁺ , Cl ³⁷ ].

Example 318 (1S, 3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -3-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid 2,2,2-trichloroethyl ester

The title compound was obtained by treating the compound obtained in Reference Example 453 with hydrochloric acid in the same manner as described in Example 219, deprotecting, condensing with the compound obtained in Reference Example 10, and treating with hydrochloric acid again. Got.
¹ H-NMR (CDCl ₃ ) 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 = 15.4 Hz), 3 .73 (1H, d, J = 15.4 Hz), 4.08-4.16 (1H, m), 4.66-4.71 (1H, m), 4.72 (1H, d, J = 12.0 Hz), 4.82 (1H, d, J = 12.0 Hz), 7.37 (1H, d, J = 8.8 Hz), 7.69 (1H, dd, J = 8.8, 2) .4 Hz), 8.05 (1 H, d, J = 8.1 Hz), 8.16 (1 H, d, J = 8.8 Hz), 8.30 (1 H, d, J = 2.4 Hz), 9 .69 (1H, s).
MS (ESI) m / z: 651 [(M + H) ⁺ , 3 × Cl ³⁵ ], 653 [(M + H) ⁺ , 2 × Cl ³⁵ , Cl ³⁷ ], 655 [(M + H) ⁺ , Cl ³⁵ , 2 × Cl ³⁷ ].

Example 319 (1S, 3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -3-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid

The compound (475 mg) obtained in Example 318 was dissolved in tetrahydrofuran (50 ml), zinc (2.85 g) and acetic acid (5.7 ml) were sequentially added to this solution, and the mixture was stirred at room temperature for 3 hours. Celite 545 (2.85 g) was added to the reaction mixture, the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, methylene chloride was added to the resulting residue, and 1N aqueous sodium hydroxide solution was added with stirring. The liquidity was adjusted to pH 7. After the organic layer was separated, saturated brine (50 ml) was added to the aqueous layer and the mixture was extracted with methylene chloride (10 × 50 ml). The obtained organic layers were combined and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5 → 9: 1 → 4: 1) to obtain the title compound (140 mg).
¹ H-NMR (DMSO-d ₆ ) 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 = 6.8 Hz), 9.19 (1H, d, J = 8.3 Hz), 10.27 (1H , Br.s).
MS (FAB) m / z: 521 [(M + H) ⁺ , ³⁵ Cl], 523 [(M + H) ⁺ , ³⁷ Cl].

[Example 320] N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -1-methoxyimino-2-oxoethyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl } -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Reference Example 142, the ester of the compound obtained in Reference Example 454 was hydrolyzed, condensed with 4-chloroaniline in the same manner as described in Reference Example 143, and treated with hydrochloric acid. This gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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) .8 Hz), 6.19 (0.5 H, d, J = 7.8 Hz), 7.38 (2 H, d, J = 8.8 Hz), 7.71 (2 H, d, J = 8.8 Hz) , 8.70-8.79 (1H, m), 10. 28 (1H, d, J = 11.0 Hz), 11.53 (0.5 H, br. S), 11.45 (0.5 H, br. S).
MS (FAB) m / z: 576 [(M + H) ⁺ , ³⁵ Cl], 578 [(M + H) ⁺ , ³⁷ Cl].

Example 321] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - ({[1- (pyridine -4-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] ethanediamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 420 and 1- (pyridin-4-yl) piperidine-4-carboxylic acid (WO 96/10022) are condensed and treated with hydrochloric acid. Gave the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 to 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 = 7.3 Hz), 7 .99 (2H, s), 8.10-8.23 (3H, m), 8.41 (1H, s), 8.50 (1H, d, J = 8.1 Hz), 10.19 (1H , S), 13.73 (1H, br. S).
MS (FAB) m / z: 556 [(M + H) ⁺ , ³⁵ Cl], 558 [(M + H) ⁺ , ³⁷ Cl].

Example 322 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ² - (5-ethynyl-pyridin-2-yl) ethanediamide

The compound (348 mg) obtained in Reference Example 455 was dissolved in tetrahydrofuran (14 ml), tetrabutylammonium fluoride (1N tetrahydrofuran solution, 628 μl) was added, and the mixture was stirred at room temperature for 30 minutes. Activated carbon (about 1 g) was added to the reaction solution for decolorization, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7). The residue was dissolved in methylene chloride (about 1 ml), hexane (about 10 ml) was added, and the resulting precipitate was collected by filtration to give the title compound (116 mg).
¹ H-NMR (CDCl ₃ ) 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), [AB pattern 3.71 (1H, d, J = 15.5 Hz), 3.74 (1H, d, J = 15.5 Hz)], 4.08 -4.14 (1H, m), 4.66-4.69 (1H, m), 7.41 (1H, d, J = 8.6 Hz), 7.80 (1H, dd, J = 8. 6, 2.2 Hz), 8.03 (1 H, d, J = 7.6 Hz), 8.15 (1 H, d, J = 8.6 Hz), 8.46 (1 H, d, J = 2.2 Hz) ), 9.75 (1H, s).
MS (ESI) m / z 538 (M + H) ^<+> .

Example 323] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 5,6-dihydro-4H-thieno [2,3-c] pyrrol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

The title compound was obtained by hydrolyzing the compound obtained in Reference Example 456 in the same manner as described in Example 191 and condensing with the compound obtained in Reference Example 420.
¹ H-NMR (CDCl ₃ ) 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 = 6.3 Hz), 7.31 (1H, s), 7.70 (1H, dd, J = 8.8, 2.3 Hz), 8.15-8. .18 (2H, m), 8.30 (1H, d, J = 2.3 Hz), 9.72 (1H, br.s).
MS (FAB) m / z: 533 [(M + H) ⁺ , Cl ³⁵ ], 535 [(M + H) ⁺ , Cl ³⁷ ].

[Example 324] N-{(1R, 2S, 5S) -2-({2-[(6-chloropyridazin-3-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in the method described in Example 3, the compound obtained in Reference Example 460 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 9.6 Hz), 8.32 (1H, d, J = 9.6 Hz), 8.73 (1H, d, J = 7.3 Hz) ), 11.08 (2H, br.s), 11.61-11.75 (1H, m).
MS (FAB) m / z: 565 [(M + H) ⁺ , Cl ³⁵ ], 567 [(M + H) ⁺ , Cl ³⁷ ].

[Example 325] N-{(1R, 2S, 5S) -2-({2-[(6-chloropyridin-3-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 3, the compound obtained in Reference Example 464 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz), 8.20 (1H, dd, J = 8.6, 2.6 Hz), 8.77 (1H, d, J = 7.3 Hz), 8.80 (1H, d, J = 2.6 Hz), 10.73 (1 H, s), 10.94 (1 H, br.d, J = 7.6 Hz), 11.37 (1 H, br. S).
MS (FAB) m / z: 564 [(M + H) ⁺ , Cl ³⁵ ], 566 [(M + H) ⁺ , Cl ³⁷ ].

Example ^{326] N 1 - [(3R} , 4S) -3 - ({[2 '- ( aminosulfonyl) [1,1'-biphenyl] -4-yl] carbonyl} amino) -1- (2- methoxyacetyl) piperidin-4-yl] -N ² - (5- chloropyridin-2-yl) ethanediamide

In the same manner as described in Example 219, the compound obtained in Reference Example 368 was treated with hydrochloric acid, and after deprotection, the title compound was obtained by condensation with the compound obtained in Reference Example 465.
¹ H-NMR (CDCl ₃ ) 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 = 7.1 Hz), 7.51-7.54 (3.75 H, m), 7.60 (1 H, t, J = 7.0 Hz), 7.69 ( 1H, dd, J = 8.9, 2.2 Hz), 7.94-7.96 (2H, m), 8.13-8.22 (2H, m), 8.30 (1H, d, J = 2.2 Hz), 8.91 (0.75 H, br.d, J = 5.9 Hz), 9.18 (0.25 H, br.s), 9.70 (1 H, s).
MS (FAB) m / z: 629 [(M + H) ⁺ , Cl ³⁵ ], 631 [(M + H) ⁺ , Cl ³⁷ ]

Example 327] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - {(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - [(thieno [3,2 -B] pyridin-2-ylcarbonyl) amino] cyclohexyl} ethanediamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 420 was condensed with thieno [3,2-b] pyridine-2-carboxylic acid lithium salt (Japanese Patent Laid-Open No. 2001-294572), and hydrochloric acid was added. Treatment gave the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.44 to 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 = 8.1 Hz), 8.81 (1H, br.d, J = 4.2 Hz), 9 .05 (1H, br.d, J = 7.8 Hz), 10.24 (1H, s).
MS (ESI) m / z: 529 [(M + H) +, Cl 35], 531 [(M + H) +, Cl 37].

Example 328 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ² - (5-methyl-pyridin-2-yl) ethanediamide hydrochloride

In the same manner as in Example 208, the compound obtained in Reference Example 467 and the compound obtained in Reference Example 253 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.0 Hz), 7.90-7.94. (1H, m), 8.24 (1 H, s), 8.70-8.80 (1 H, m), 9.13 (0.5 H, d, J = 7.3 Hz), 9.21 (0 .5H, d, J = 8.0 Hz), 10.06 (1H , S), 11.46 (0.5 H, br. S), 11.57 (0.5 H, br. S).
MS (FAB) m / z: 528 (M + H) ^<+> .

Example 329 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (4-methylphenyl) ethanediamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 469 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid to give the title compound. Got.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 8.72-8.80 (1H, m) 8.96 (0.5H, d, J = 7.8 Hz), 9.04 (0.5H, d, J = 8.1 Hz), 10.56 (1H, d, J = 6.6 Hz), 11.30 (1H, br.s).
MS (FAB) m / z: 527 (M + H) ^<+> .

Example 330 {4-chloro-5-[({(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(Dimethylamino) carbonyl] cyclohexyl} amino) carbonyl] -3-thienyl} methyl (methyl) carbamic acid tert-butyl ester

In the same manner as in the method described in Example 2, the compound obtained in Reference Example 471 was condensed with the compound obtained in Reference Example 420 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 (total 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 = 8.8 Hz), 7.38 (1H, br. S), 7.69 (1H, dd, J = 8.8, 2.6 Hz) , 7.99 (1H, d, J = 7.6 Hz), 8.17 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.6 Hz), 9.70 ( 1H, br.s).
MS (ESI) m / z: 655 (M + H) ^<+> .

Example 331 N ¹ -{(1S, 2R, 4S) -2-[({3-chloro-4-[(methylamino) methyl] -2-thienyl} carbonyl) amino] -4-[(dimethyl amino) carbonyl] cyclohexyl} -N ² - (5- chloropyridin-2-yl) ethanediamide

In the same manner as in Example 227, the title compound was obtained from the compound obtained in Example 330.
¹ H-NMR (CDCl ₃ ) δ: 1.55-1.70 (1H, m), 1.75-1.98 (2H, m), 2.00-2.22 (2H, m), 2 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 = 7.8 Hz), 7.52 (1H, s), 7.67 (1H, dd, J = 8.8, 2.6 Hz), 8.09 (1H, d , J = 7.6 Hz), 8.09 (1H, d, J = 7.6 Hz), 8.13 (1H, d, J = 8.8 Hz), 8.29 (1H, d, J = 2. 6Hz), 9.90-11.00 (1H, br) .
MS (ESI) m / z: 555 (M + H) ^<+> .

Example 332 N ¹ -{(1S, 2R, 4S) -2-{[(3-Chloro-4-{[4,5-dihydro-1,3-oxazol-2-yl (methyl) amino] methyl} -2-thienyl) carbonyl] amino} -4 - [(dimethylamino) carbonyl] cyclohexyl} -N ² - (5-chloropyridin-2-yl) ethanediamide hydrochloride

Triethylamine (0.735 ml) and 2-bromoethyl isocyanate (0.106 ml) were added to a suspension of the compound (590 mg) obtained in Example 331 in methylene chloride (20 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with methylene chloride and washed successively with water, 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 20: 1), and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in methylene chloride (2 ml) and ethanol (3 ml), 1N hydrochloric acid ethanol solution (0.5 ml) was added, and the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration and washed to give the title compound (197 mg) as a colorless powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.60 (1H, m), 1.60 to 1.83 (3H, m), 1.85 to 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 = 6.6 Hz), 3.95-4.05 (1H, m), 4.30-4.45 (3H, m), 6.80 (1H , T, J = 5.5 Hz), 7.51 (1H, s), 7.94-8.06 (2H, m), 8.10 (1H, d, J = 6.8 Hz), 8.42 −8.50 (1H, m), 8.97 (1H, d, J = 8.6 Hz), 10.27 (1H, s).
MS (ESI) m / z: 624 (M + H) ^<+> .

Example 333 [4-chloro-5-({[(1R, 2S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) cyclohexyl] Amino} carbonyl) -3-thienyl] methyl (methyl) carbamic acid tert-butyl ester

In the same manner as described in Example 214, the compound obtained in Reference Example 472 was treated with hydrochloric acid, deprotected, and then condensed with the compound obtained in Reference Example 471 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 8.1 Hz), 7.27-7. .32 (1H, m), 7.70 (1H, dd, J = 8.8, 2.2 Hz), 8.01 (1H, d, J = 8.3 Hz), 8.18 (1H, d, J = 8.8 Hz), 8.30 (1H, d, J = 2.6 Hz), 9.73 (1H, br.s).
MS (ESI) m / z: 584 (M + H) ^<+> .

Example ^{334] N 1 - {(1S} , 2R) -2 - [({3- chloro-4 - [(methylamino) methyl] -2-thienyl} carbonyl) amino] cyclohexyl} -N ² - (5 -Chloropyridin-2-yl) ethanediamide

In the same manner as in Example 227, the title compound was obtained from the compound obtained in Example 333.
¹ H-NMR (CDCl ₃ ) 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 (1 H, m), 7.22 (1 H, d, J = 8.1 Hz), 7.42 (1 H, s), 7.71 (1 H, dd, J = 8.8, 2.6 Hz), 8.03 (1H, d, J = 9.3 Hz), 8.19 (1H, dd, J = 8.8, 0.73 Hz), 8.31 (1H, dd, J = 2.6, 0.73 Hz).
MS (ESI) m / z: 484 (M + H) ^<+> .

Example 335 N ¹ -((1S, 2R) -2-{[(3-chloro-4-{[4,5-dihydro-1,3-oxazol-2-yl (methyl) amino] methyl} -2-thienyl) carbonyl] amino} cyclohexyl) -N ² - (5-chloropyridin-2-yl) ethanediamide

In the same manner as in Example 332, the title compound was obtained from the compound obtained in Example 334.
¹ H-NMR (CDCl ₃ ) δ: 1.50-2.00 (8H, m), 2.94 (3H, s), 3.80 (2H, t, J = 8.5 Hz), 4.17 -4.25 (1H, m), 4.32 (2H, t, J = 8.5 Hz), 4.39 (1H, d, J = 16.5 Hz), 4.41 (1H, d, J = 16.5 Hz), 4.58-4.67 (1 H, m), 7.18 (1 H, d, J = 8.3 Hz), 7.40 (1 H, s), 7.69 (1 H, dd, J = 8.8, 2.4 Hz), 8.00 (1H, d, J = 8.1 Hz), 8.17 (1H, d, J = 8.8 Hz), 8.29 (1H, d, J = 2.4 Hz), 9.73 (1H, br.s).
MS (ESI) m / z: 553 (M + H) ^<+> .

Example 336] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1R,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 5,6,7,8-Tetrahydro-4H-thiazolo [5,4-c] azepin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 477 was condensed with the compound obtained in Reference Example 420 and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.3 Hz), 9.19 (1H, d, J = 8.1 Hz), 10.29 (1 H, s), 10.64 (1 H, br. S).
MS (FAB) m / z: 562 (M + H) ^<+> .

Example 337] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(4,4, 5-Trimethyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Reference Example 10, lithium 4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxylic acid lithium salt was obtained from the compound obtained in Reference Example 479. Obtained. Then, in the same manner as in Example 2, this lithium salt was condensed with the compound obtained in Reference Example 420 and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.55 (4H, m), 1.60 to 1.85 (6H, m), 1.85 to 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 (0.5 H, d, J = 7.6 Hz), 8.68 (0.5 H, d, J = 7.6 Hz), 9.07-9.20 (1 H, m), 10.29 (0. 5H, s), 10.26 (0.5 H, s), 11.83 (0.5 H, br. S), 11.76 (0.5 H, br. S).
MS (FAB) m / z: 562 (M + H) ^<+> .

Example 338 6-[({(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} amino) carbonyl] -1,3-dihydro-2H-pyrrolo [3,4-c] pyridine-2-carboxylic acid tert-butyl ester

In the same manner as in the method described in Example 2, the compound obtained in Reference Example 481 was condensed with the compound obtained in Reference Example 420 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.53 (4.5 H, s), 1.61 (4.5 H, s), 1.54-2.20 (6 H, 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, 2.3 Hz), 8.10-8.23 (3H, m), 8.30 (1H, d, J = 2.3 Hz), 8.30-8.40 (1H, m), 8.45 (0.5 H, br. S), 8.49 (0.5 H, br. S), 9.72 (1 H, br. S).
MS (ESI) m / z: 614 (M + H) ^<+> .

Example 339] N ¹ - (5- ^{chloro-2-pyridinyl) -N 2 - {(1S,} 2R, 4S) -2 - [(2,3- dihydro -1H- pyrrolo [3,4-c] Pyridin-6-ylcarbonyl) amino] -4-[(dimethylamino) carbonyl] cyclohexyl} ethanediamide hydrochloride

In the same manner as in Example 227, the title compound was obtained from the compound obtained in Example 338.
¹ H-NMR (DMSO-d ₆ ) 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 = 1.5 Hz), 8.67 (1H, d, J = 7.6 Hz), 8.75 (1H, s), 9.19 (1H, d, J = 8.3 Hz), 10.11 (2H) , Br.s), 10.26 (1H, br.s).
MS (FAB) m / z: 514 (M + H) ^<+> .

Example 340] N ¹ - ^{(5-chloro-2-pyridinyl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(2-methyl-2 , 3-Dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 18, the title compound was obtained from the compound obtained in Example 339 and formalin.
¹ H-NMR (DMSO-d ₆ ) 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 = 1.5 Hz), 8.60-8.70 (1H, m), 8.75 (1H, s), 9.18 (1H, d, J = 7.8 Hz), 10.25 (0.5H, s), 10.28 (0.5H, s) ), 11.95 (0.5 H, s), 12.02 (0 .5H, s).
MS (FAB) m / z: 528 (M + H) ^<+> .

Example 341] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - {(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - [(5,6,7 , 8-Tetrahydro [1,6] naphthyridin-2-ylcarbonyl) amino] cyclohexyl} ethanediamide hydrochloride

In the same manner as in Example 2, 6- (tert-butoxycarbonyl) -5,6,7,8-tetrahydro [1,6] naphthyridine-2-carboxylic acid methyl ester (JP 2000-119253) was hydrolyzed. The lithium salt of carboxylic acid obtained above and the compound obtained in Reference Example 420 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 1.5 Hz), 8.51 (1H, d, J = 8.3 Hz), 9.16 (1H , D, J = 7.8 Hz), 9.85 (1H, br.s), 10.02 (1H, br.s), 10.27 (1H, br.s).
MS (FAB) m / z: 528 (M + H) ^<+> .

Example 342] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(6-methyl - 5,6,7,8-tetrahydro [1,6] naphthyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 18, the title compound was obtained from the compound obtained in Example 341 and formalin.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.0 Hz), 7.89 (1H, J = 8.0 Hz), 8.00 (2H, br.s), 8.40-8.55 (2H, m), 9 .07 (0.4 H, d, J = 7.6 Hz), 9.19 (0.6 H, d, J = 8.1 Hz), 10.24 (0.6 H, s), 10.28 (0. 4H, s), 11.42-11.80 (1 H, br).
MS (FAB) m / z: 542 (M + H) ^<+> .

Example 343] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - ({[5- (pyridin -4-yl) pyrimidin-2-yl] carbonyl} amino) cyclohexyl] ethanediamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 420 and the compound obtained in Reference Example 483 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 5.6 Hz), 8.44-8.47 (1H, m), 8.79 (1H, d, J = 7.6 Hz), 8.99 (2H, d, J = 5.6 Hz), 9.08 (1H, d, J = 8.3 Hz), 9.54 (2H, s) , 10.31 (1H, s).
MS (FAB) m / z: 551 (M + H) ^<+> .

Example 344] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - {(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - [({2 '- [ (Dimethylamino) methyl] [1,1′-biphenyl] -4-yl} carbonyl) amino] cyclohexyl} ethanediamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 420 and the compound obtained in Reference Example 488 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.56 (1H, m), 1.60 to 1.85 (3H, m), 1.85 to 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 = 8.3 Hz), 7.50-7.58 (2H, m), 7.84-7.90 (1H, m), 7.95-8.05 (4H, m) 8.15 (1H, d, J = 7.3 Hz), 8.46 (1 H, br. S), 9.20 (1 H, d, J = 8.3 Hz), 10.15-10.29 ( 1H, br), 10.30 (1H, br.s ).
MS (FAB) m / z: 605 (M + H) ^<+> .

Example 345] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - ({4- [2- (Hydroxymethyl) pyridin-4-yl] benzoyl} amino) cyclohexyl] ethanediamide hydrochloride

In the same manner as in Example 2, the lithium salt of carboxylic acid obtained by hydrolyzing the compound of Reference Example 490 and the compound obtained in Reference Example 420 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.44 to 1.58 (1H, m), 1.63-1.81 (3H, m), 1.89 to 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 = 6.3 Hz), 8.24 (1H, d, J = 7.3 Hz), 7.29 (1H, s), 8.44-8.46 (1H, m), 8.80 (1H, d, J = 5.9 Hz), 9.01 (1H, d, J = 8.3 Hz), 10.27 (1H, s).
MS (ESI) m / z: 579 (M + H) ^<+> .

Example ^{346] N 1 - {(1S} , 2R, 4S) -2 - ({4- [2- ( aminomethyl) pyridin-4-yl] benzoyl} amino) -4 - [(dimethylamino) carbonyl] cyclohexyl} -N ² - (5- chloropyridin-2-yl) ethanediamide hydrochloride

In the same manner as in Example 2, the lithium salt of carboxylic acid obtained by hydrolyzing the compound of Reference Example 491 and the compound obtained in Reference Example 420 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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. 6 Hz), 7.90-8.06 (7 H, m), 8.18 (1 H, d, J = 7.6 Hz), 8.43-8.46 (1 H, m), 8.50 (3 H, br.s), 8.70 (1H, d, J = 5.2 Hz), 9.01 (1H, d, J = 8.5 Hz), 10.27 (1H, s).
MS (ESI) m / z: 578 (M + H) ^<+> .

Example 347] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - ({[1- (phenyl Sulfonyl) piperidin-4-yl] carbonyl} amino) cyclohexyl] ethanediamide

In the same manner as in the method described in Example 2, the compound obtained in Reference Example 420 and the compound obtained in Reference Example 493 were condensed to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.60-2.10 (10H, m), 2.12-2.21 (1H, m), 2.40 (2H, br.t, J = 1.11. 2 Hz), 2.65-2.77 (1 H, m), 2.92 (3 H, s), 2.99 (3 H, s), 3.77 (2 H, br. D, J = 11.7 Hz) , 3.92-4.05 (1H, m), 4.42-4.53 (1H, m), 6.31 (1H, br.d, J = 7.3 Hz), 7.53 (2H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.67-7.78 (3H, m), 8.01 (1H, brd, J = 7.3 Hz) ), 8.16 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.2 Hz), 9.72 (1H, s).
MS (ESI) m / z: 619 (M + H) ^<+> .

Example 348] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - ({[1- (4 -Fluorobenzoyl) piperidin-4-yl] carbonyl} amino) cyclohexyl] ethanediamide D22-5792

In the same manner as described in Example 2, the compound obtained in Reference Example 420 and the compound obtained in Reference Example 495 were condensed to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 7.1 Hz), 7.09 (2H, t, J = 8.5 Hz) 7.40 (2H, dd, J = 8.5, 5.4 Hz), 7.71 (1H, dd, J = 8.8, 2.4 Hz), 8.04 (1H, br.d, J = 7.6 Hz), 8.15 (1H, d, J = 8.8 Hz), 8.30 (1H, d, J = 2.4 Hz), 9.71 (1H, s).
MS (ESI) m / z: 601 (M + H) ^<+> .

Example 349] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[4- (pyrrolidin - 1-ylcarbonyl) benzoyl] amino} cyclohexyl) ethanediamide

In the same manner as in the method described in Example 2, the compound obtained in Reference Example 420 and the compound obtained in Reference Example 497 were condensed to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.68-2.23 (9H, m), 2.33 (1H, br.d, J = 7.4 Hz), 2.85-3.02 (1H, m), 2.92 (3H, s), 2.98 (3H, s), 3.31 (2H, t, J = 6.8 Hz), 3.61 (2H, t, J = 6.8 Hz) 4, 13-4.22 (1H, m), 4.54-4.63 (1H, m), 7.28 (2H, d, J = 8.1 Hz), 7.63-7.69 ( 1H, m), 7.66 (2H, d, J = 8.1 Hz) 7.95 (1H, br.d, J = 5.6 Hz), 8.05 (1H, d, J = 8.8 Hz) , 8.30 (1H, d, J = 2.4 Hz), 8.54 (1H, brd, J = 8.3 Hz), 9.76 (1H, s).
MS (ESI) m / z: 569 (M + H) ^<+> .

Example 350] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[4- (pyrrolidin - 1-ylmethyl) benzoyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 2, the lithium salt of carboxylic acid obtained by hydrolysis of the compound described in Reference Example 498 and the compound obtained in Reference Example 420 were condensed and treated with hydrochloric acid to obtain the title compound. .
¹ H-NMR (DMSO-d ₆ ) 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 = 8.1 Hz), 7.92 (2H, d, J = 8.1 Hz), 7.99 (2H, s), 8.09 (1H, br.d, J = 7.6 Hz), 8.44 (1H, s), 8.99 (1H, br.d, J = 8.3 Hz), 10.27 (1H, s), 10 65-10.80 (1H, br).
MS (ESI) m / z: 555 (M + H) ^<+> .

Example 351] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( methylamino) carbothioyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 501 was treated with 4N hydrochloric acid dioxane solution, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid. This gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.8 Hz), 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) ^<+> .

[Example 352] N-{(1R, 2S, 5S) -2-{[(4-chloroanilino) sulfonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5 6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a solution of 4-chloroaniline (255 mg) in methylene chloride (15 ml) was added chlorosulfuric acid (146 μl) at 0 ° C. After stirring at the same temperature for 1 hour, the mixture was stirred at room temperature for 2 hours. Phosphorus pentachloride (458 mg) was added to the reaction solution, and the mixture was heated to reflux for 2 hours. The temperature was returned to room temperature, the compound (731 mg) obtained in Reference Example 253 was added, and triethylamine was added to adjust the pH to neutral. After stirring at room temperature for 17 hours, water was added to the reaction solution to separate it. The aqueous layer was extracted with methylene chloride, and the combined organic layer was washed twice with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 93: 7) and then by preparative thin layer chromatography (methylene chloride: methanol = 9: 1). Purification was performed once to obtain a pale yellow solid (46 mg). This was dissolved in methylene chloride, and 1N hydrochloric acid ethanol solution (83 μl) was added. The solvent was evaporated under reduced pressure, a small amount of methanol and ether were added to the residue, and the resulting precipitate was collected by filtration to give the title compound (34 mg) as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

[Example 353] N-{(1R, 2S, 5S) -2-({2-[(5-chloropyrimidin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 219, the compound obtained in Reference Example 503 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid to give the title compound. Got.
¹ H-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 = 7.1 Hz), 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) ^<+> .

Example 354 N-{(1R, 2S, 5S) -2-{[2- (4-Chloro-3-nitroanilino) -2-oxoethanethioyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 505 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid to give the title compound. Got.
¹ H-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 = 8.8 Hz), 8.05 (1H, dd, J = 8.8, 1.4 Hz), 8. 59 (1H, d, J = 1.4 Hz), 8.75 (1H, d, J = 7.6 Hz), 10.89-10.92 (2H, m), 11.43 (1H, br.s) ).
MS (ESI) m / z: 608 (M + H) ^<+> .

Example 355 N-{(1R, 2S, 5S) -2-{[2- (3-amino-4-chloroanilino) -2-oxoethanethioyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a solution of the compound obtained in Example 354 (458 mg) in ethanol (30 ml) was added 10% palladium carbon (1.00 g), and the mixture was stirred at room temperature for 3 days. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 94: 6). The obtained yellow solid (137 mg) was dissolved in methylene chloride (5 ml), and 1N hydrochloric acid ethanol (474 μl) was added. added. Further diethyl ether (20 ml) was added and the solid was collected by filtration and washed with ether to give the title compound (144 mg) as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) 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, 2.3 Hz), 7.18 (1H, d, J = 8) .6 Hz), 7.31 (0.5 H, s), 7.33 (0.5 H, s) 8.74-8.80 (1 H, m), 10.18 (1 H, d, J = 9. 8 Hz), 10.83 (0.5 H, d, J = 7. 6 Hz), 10.89 (0.5 H, d, J = 8.0 Hz), 11.79 (0.5 H, br. S), 11.87 (0.5 H, br. S).
MS (ESI) m / z: 578 (M + H) ^<+> .

[Example 356] 6-[({(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} amino) carbonyl] -1,3-dihydro-2H-pyrrolo [3,4-c] pyridine-2-carboxylic acid tert-butyl ester

In the same manner as in Example 219, the title compound was obtained by treating the compound obtained in Reference Example 428 with hydrochloric acid, deprotecting, and then condensing with the compound obtained in Reference Example 481.
¹ H-NMR (CDCl ₃ ) 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 (1H, dd, J = 8.8, 2.4 Hz), 8.18 (0.5 H, br. S), 8.18 (1 H, d, J = 8.8 Hz), 8.23 (0.5 H, br. S), 8.31 (1H, d, J = 2.4 Hz), 8.40-8.52 (2H, m), 10.29 (1H, br.s), 10.60 (1H, br.s). MS (ESI) m / z: 630 (M + H) ^<+> .

[Example 357] N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -2-methyl-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxamide hydrochloride

The compound obtained in Example 356 was treated with hydrochloric acid, deprotected, methylated in the same manner as described in Example 18, and treated again with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, b
r. s), 11.99 (0.5 H, br. s).
MS (FAB) m / z: 544 (M + H) ^<+> .

Example 358 N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -1- (pyridin-4-yl) -4-piperidinecarboxamide hydrochloride

The compound obtained in Reference Example 428 was treated with hydrochloric acid in the same manner as described in Example 219, and after deprotection, 1- (pyridin-4-yl) -4-piperidinecarboxylic acid (Tetrahedron, 1998) , 44 卷, page 7095) and treated with hydrochloric acid again to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 6.8 Hz), 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 = 7.3 Hz), 13 .48 (1H, br.s).
MS (ESI) m / z: 572 (M + H) ^<+> .

[Example 359] N-{(1R, 2S, 5S) -2-{[(7-chlorocinnolin-3-yl) carbothioyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5 Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in the method described in Example 2, the compound obtained in Reference Example 509 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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). s), 8.00 (1H, d, J = 8.8 Hz), 8.41 (1H, d, J = 8.8 Hz), 8.65 (1H, s), 9.06 (1H, br. s), 9.20 (1H, s), 11.4 4 (1H, br.s), 11.66 (1H, br.s).
MS (ESI) m / z: 572 (M + H) ^<+> .

Example 360 N-{(1R, 2S, 5S) -2-({[(4-chlorobenzoyl) amino] carbonyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in the method described in Example 2, the compound obtained in Reference Example 511 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.6 Hz), 7.86-7.88 (2H, m), 8.68 (1H, br.s), 8.83 (1H, br.s).
MS (FAB) m / z: 547 (M + H) ^<+> .

[Example 361] N-{(1R, 2S, 5S) -2-{[(E) -3- (5-chloropyridin-2-yl) acryloyl] amino} -5-[(dimethylamino) carbonyl] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 219, the compound obtained in Reference Example 513 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid to give the title compound. Got.
¹ H-NMR (DMSO-d ₆ ) 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 = 16.2 Hz), 7.08 (1H, d, J = 15.4 Hz), 7.38 (1H, dd, J = 15.4, 3.9 Hz), 7.60 (1 H, d, J = 8.4 Hz), 7.94 (1 H, d, J = 8.4 Hz), 8.28 (1 H, d, J = 7.1 Hz), 8.35 (1H, d, J = 9.8 Hz ), 8.59 (1H, s), 11.72 (0.5, br. S), 11.88 (0.5 H, br. S).
MS (ESI) m / z: 531 (M + H) ^<+> .

Example 362 N-{(1R, 2S, 5S) -2-{[(Z) -3- (4-chlorophenyl) -2-fluoroacryloyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl } -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 49, the compound obtained in Reference Example 519 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 516, and again treated with hydrochloric acid to give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 38.6 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.52-8.56 (2H, m), 11.36 (1H, br.s).
MS (EI) m / z: 547 (M ^<+> ).

[Example 363] N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Methylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 521 was treated with 4N hydrochloric acid dioxane solution, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid. This gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 4.4 Hz), 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, 2.4 Hz), 8.05 (1H, d, J = 9.0 Hz), 8.43 ( 1H, d, J = 2.4 Hz), 8.51-8.58 (1H, m), 10.55 (1H, s), 11.13 (1H, d, J = 7.8 Hz).
MS (ESI) m / z: 550 (M + H) ^<+> .

Example 364 N-[(1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-fluoropyridin-2-yl) amino] -2-oxoethane Thioyl} amino) cyclohexyl] -5-methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepine-2-carboxamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 522 and the compound obtained in Reference Example 477 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 9.0 Hz), 8. 05-8.27 (1H, m), 8.43 (1H, d, J = 2.9 Hz), 8.70-8.82 (1H, m), 10.54 (1H, s), 11. 05-11.30 (2H, m).
MS (FAB) m / z: 562 (M + H) ^<+> .

[Example 365] (3-{[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} phenyl) (imino) methylcarbamic acid tert-butyl ester

Water (1.0 ml) and lithium hydroxide (20.5 mg) were added to a solution of the compound (250 mg) obtained in Reference Example 524 in tetrahydrofuran (3.0 ml) at room temperature. After stirring for 15 hours, the mixture was concentrated under reduced pressure. 1-Hydroxybenzotriazole (140 mg) and 1- [3- (dimethylamino) were added to a solution of the obtained solid and the compound (464 mg) obtained in Reference Example 253 in N, N-dimethylformamide (5.0 ml) at room temperature. Propyl] -3-ethylcarbodiimide hydrochloride (330 mg) was added. After stirring at the same temperature for 21 hours, the solvent was distilled off under reduced pressure, methylene chloride, water and a saturated aqueous sodium hydrogen carbonate solution were added to separate the solution, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using medium pressure column chromatography (methylene chloride: methanol = 10: 1) using silica gel as a carrier. The title compound (213 mg) was obtained as a light brown foamy solid.
¹ H-NMR (CDCl ₃ ) 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 = 15.5 Hz), 3.73 (1H, d, J = 15.5 Hz), 4.15-4.23 (1H, m), 4.58-4.64 (1H, m), 7.43-7.57 (2H) M), 7.91 (1H, d, J = 6.1 Hz), 7.98 (1H, d, J = 6.6 Hz), 8.12 (1H, d, J = 7.8 Hz), 8 .23 (1H, s), 9.30-10.00 (2H, br). MS (ESI) m / z: 612 (M + H) ^<+> .

Example 366 N-{(1R, 2S, 5S) -2-({3- [amino (imino) methyl] benzoyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

To a solution of the compound obtained in Example 365 (210 mg) in methylene chloride (4.0 ml) was added 4N hydrochloric acid dioxane solution (4.0 ml) at room temperature. After stirring for 1 hour, saturated hydrochloric acid ethanol solution (20 ml) was added. After stirring overnight, the solvent was distilled off under reduced pressure. Water (4.0 ml) was added to the obtained residue, the solvent was distilled off under reduced pressure, and the residue was dried to give the title compound (210 mg) as a pale brown solid.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

[Example 367] N-{(1R, 2S, 5S) -2-[(3-cyanobenzoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6 7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

In the same manner as in Example 214, the compound obtained in Reference Example 525 was treated with 4N hydrochloric acid dioxane solution, and after deprotection, the title compound was obtained by condensation with the compound obtained in Reference Example 10. It was.
¹ H-NMR (CDCl ₃ ) δ: 1.50-1.66 (1H, m), 1.74-1.88 (1H, m), 1.90-2.07 (2H, m), 2 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 = 15.4 Hz), 3.74 (1H, d, J = 15.4 Hz), 4.13-4 .21 (1H, m), 4.58-4.64 (1H, m), 7.47 (1H, d, J = 7.1 Hz), 7.55 (1H, t, J = 7.8 Hz) , 7.74 (1H, d, J = 7.8 Hz), 8.03 (1H, d, J = 5.6 Hz), 8.06 (1H, d, J = 7.8 Hz), 8.12 ( 1H, s).
MS (ESI) m / z: 494 (M ^<+> ).

Example 368 N-{(1R, 2S, 5S) -2-({3- [amino (hydroxyimino) methyl] benzoyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

Ethanol (5.0 ml) and tetrahydrofuran (2.0 ml) were added to the compound (270 mg) obtained in Example 367 for dissolution, and hydroxylamine hydrochloride (114 mg) and triethylamine (230 μl) were added at room temperature. After heating under reflux for 3 hours, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added, and after separation, the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using silica gel as a carrier (methylene chloride: methanol = 7: 1), Sephadex column (methanol), and reverse phase high performance liquid chromatography (acetonitrile-water-formic acid system) for fractionation. After purification using 1N hydrochloric acid, the product was converted to a hydrochloride, and purified again using a Sephadex column (methanol) in order to obtain the title compound (175 mg) as a white solid.
¹ H-NMR (CD ₃ OD) 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 = 7.8 Hz), 7.72 (1H, d, J = 7.8 Hz), 7.94 (1 H, d, J = 7.8 Hz), 8.01 (1 H, s), 8.08 (1 H, d, J = 9.1 Hz), 8.45 (1 H, d, J = 7.6 Hz).
MS (ESI) m / z: 528 (M + H) ^<+> .

[Example 369] (3-{[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} phenyl) (imino) methylcarbamic acid ethyl ester

In the same manner as in Example 365, the title compound was obtained by condensing the carboxylic acid lithium salt obtained by hydrolyzing the compound described in Reference Example 526 with the compound obtained in Reference Example 253.
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1 Hz), 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 = 6.1 Hz), 8.03 (1H, d, J = 7.8 Hz), 8.16 (1H, d, J = 7.8 Hz), 8.27 (1 H, s), 9.68 (1 H, br. S).
MS (ESI) m / z: 584 (M + H) ^<+> .

Example 370 N-[(1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({3- [imino (methylamino) methyl] benzoyl} amino) cyclohexyl] -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide formate D22-9226

To the compound described in Example 367 (400 mg), a saturated hydrochloric acid ethanol solution (30 ml) was added at room temperature. After stirring for 2 days, the mixture was concentrated under reduced pressure to obtain a white solid. This solid was dissolved in methanol (10 ml), and methylamine (2.0 M tetrahydrofuran solution) (30 ml) was added at room temperature. After stirring for 2 hours, the mixture was concentrated under reduced pressure, and the residue was purified using preparative reverse phase high performance liquid chromatography (acetonitrile-water-formic acid system) and Sephadex column (methanol) in order to give the title compound (152 mg). Obtained as a white solid.
¹ H-NMR (DMSO-d ₆ ) 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 = 5.6 Hz), 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 = 7.8 Hz) ), 7.81 (1H, d, J = 7.8 Hz), 7.96 (1H, d, J = 7.8 Hz), 8.15 (1H, s), 8.34-8.47 (2H) , M), 8.89 (1H, d, J = 7.6 Hz) ).
MS (ESI) m / z: 526 (M + H) ^<+> .

Example 371 N-{(1R, 2S, 5S) -2-({3- [amino (methoxyimino) methyl] benzoyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

A saturated hydrochloric acid ethanol solution (30 ml) was added to the compound described in Example 367 (300 mg) at room temperature. After stirring for 2 days, the mixture was concentrated under reduced pressure to obtain a pale yellow solid. After this solid was dissolved in methanol (10 ml), O-methylhydroxylamine hydrochloride (1.01 g) and triethylamine (1.69 ml) were added at room temperature. After stirring for 2 hours, methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added to separate the solution, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was successively used by medium pressure chromatography using silica gel as a carrier (methylene chloride: methanol = 20: 1 → 7: 1) and preparative reverse phase high performance liquid chromatography (acetonitrile-water-formic acid system). After purification, the title compound (51.8 mg) was obtained as a white solid by treatment with 1N hydrochloric acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.44 to 1.57 (1H, m), 1.63-1.88 (3H, m), 1.88 to 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 = 7.8 Hz), 7.75 (2H, d, J = 7.8 Hz), 7.99 (1H, s), 8. 33-8.50 (2H, m), 11.20-11.60 (1H, br).
MS (ESI) m / z: 542 (M + H) ^<+> .

Example 372] N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[4- (3- Oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) ethanediamide

In the same manner as in the method described in Example 2, the compound obtained in Reference Example 531 and the compound obtained in Reference Example 420 were condensed to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 6.9 Hz), 7.38 (2H, dt, J = 8.6, 2.2 Hz), 7.70 (1H, dd, J = 8.8, 2.5 Hz), 7.78 (2H, dt, J = 8.6, 2.2 Hz), 8.16 (1H, d, J = 8.8 Hz), 8.28-8.31 (2H, m ), 9.73 (1H, s).
MS (FAB) m / z: 571 (M + H) ^<+> .

Example 373 N-{(1R, 2S, 5S) -2-{[(Z) -3- (5-chlorothien-2-yl) -2-fluoro-2-propenoyl] amino} -5- [ (Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride

In the same manner as in Example 49, the compound obtained in Reference Example 519 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 534, and treated again with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 1.7 Hz), 7.22. (1H, d, J = 37.6 Hz), 7.37 (1H, d, J = 3.9 Hz), 8.50 (1H, d, J = 7.3 Hz), 8.57 (1H, br. s), 11.38-11.53 (1H, m).
MS (FAB) m / z: 554 (M + H) ^<+> .

Example 374 N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-d] azepine-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 428 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 537, and treated again with hydrochloric acid to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.44 to 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, 2.4 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.4 Hz), 8.59-8.68 (1H, m), 10.56 (1H, d, J = 4.0 Hz), 10.85 (1H, br.s), 11.00-11.09 (1H, m ).
MS m / z: 578 (M + H) ^<+> .

Example 375] N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - {(1S,} 2R, 4S) -2 - [(6,7- dihydro -4H- pyrano [4,3-d ] Thiazol-2-ylcarbonyl) amino] -4-[(dimethylamino) carbonyl] cyclohexyl} ethanediamide

In the same manner as in the method described in Example 2, the compound obtained in Reference Example 26 and the compound obtained in Reference Example 420 were condensed to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.3 Hz), 9.22 (1H , D, J = 8.1 Hz), 10.25 (1H, br.s).
MS (FAB) m / z: 535 (M + H) ^<+> .

[Example 376] N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethiol} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -6-methyl-5,6,7,8-tetrahydro [1,6] naphthyridine-2-carboxamide

In the same manner as described in Example 219, the compound obtained in Reference Example 428 was treated with hydrochloric acid, deprotected, and then condensed with the compound obtained in Reference Example 540 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 7.8 Hz), 7.67 (1H, dd, J = 8.8, 2.4 Hz), 8.05 (1H, d, J = 7.8 Hz), 8 .21 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.7 Hz), 8.50 (1H, d, J = 7.5 Hz), 10.49 (1H, d, J = 7.3 Hz), 10.60 (1H , S).
MS (ESI) m / z: 558 (M + H) ^<+> .

Example 377 (1S, 3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanthioyl} amino) -3-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid tert-butyl ester

In the same manner as described in Example 2, the compound obtained in Reference Example 543 was condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 8.3 Hz), 7.68. (1H, dd, J = 8.8, 2.4 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.4 Hz), 10.13 ( 1H, d, J = 7.6 Hz), 10.55 (1H, s).
MS (ESI) m / z: 593 (M + H) ^<+> .

[Example 378] (1S, 3R, 4S) -4-({2-[(5-chloro-2-pyridinyl) amino] -2-oxoethanethioyl} amino) -3-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid hydrochloride

To a dioxane (8.0 ml) solution of the compound (293 mg) obtained in Example 377 was added 4N hydrochloric acid-dioxane solution (10 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was suspended in diisopropyl ether and collected by filtration. The obtained powder was dissolved in water and neutralized with saturated aqueous sodium hydrogen carbonate. The aqueous solution was extracted with methylene chloride, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 1N Hydrochloric acid-ethanol solution (0.50 ml) was added to the residue and the mixture was concentrated under reduced pressure. The residue was dissolved in water and lyophilized to give the title compound (242 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.64 (1H, m), 1.6-1.86 (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, 2.7 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.7 Hz), 8.73 (1H, br.s), 10.57 (1H, s), 10.94-11. 45 (2H, m).
MS (ESI) m / z: 537 (M + H) ^<+> .

Example 379 (1S, 3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -3-[(6,7-dihydro -4H-pyrano [4,3-d] thiazol-2-ylcarbonyl) amino] cyclohexanecarboxylic acid tert-butyl ester

1N Hydrochloric acid-acetic acid ethyl ester solution (3.09 ml) was added to the compound (307 mg) obtained in Reference Example 544, and the resulting suspension was stirred at room temperature for 7 hours. Further, 2N hydrochloric acid-ethyl acetate solution (40 ml) was added to this suspension, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration and dried under reduced pressure. This solid was dissolved in N, N-dimethylformamide (10 ml), and the compound obtained in Reference Example 26 (191 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288 mg) and 1-Hydroxybenzotriazole (135 mg) was added and stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue for liquid separation, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol: methylene chloride = 1: 49) using silica gel as a carrier to obtain the title compound (124 mg).
¹ H-NMR (CDCl ₃ ) 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 = 5.6 Hz), 3.99-4.14 (3H, m), 4.62-4.71 (1H, m), 4 .88 (2H, br.s), 7.35 (1H, d, J = 8.8 Hz), 7.69 (1H, dd, J = 8.8, 2.7 Hz), 7.99 (1H, d, J = 8.1 Hz), 8.17 (1H, d, J = 8.8 Hz), 8.30 (1H, d, J = 2.7 Hz), 9.70 (1H, br.s).
MS (ESI) m / z: 564 (M + H) ^<+> .

Example 380 (1S, 3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -3-[(6,7-dihydro -4H-pyrano [4,3-d] thiazol-2-ylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Example 378, the title compound was obtained from the compound obtained in Example 379.
¹ H-NMR (DMSO-d ₆ ) δ: 1.4-1.80 (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 = 2.2 Hz), 8.59 (1H, d, J = 7. 4 Hz), 9.19 (1 H, d, J = 8.1 Hz), 10.27 (1 H, s), 12.23 (1 H, s).
MS (FAB) m / z: 508 (M + H) ^<+> .

Example ^381] N 1 - ^{(5-chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(2-methyl - 1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 2, the lithium salt of carboxylic acid obtained by hydrolyzing the compound of Reference Example 545 and the compound obtained in Reference Example 420 were condensed and treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.0 Hz), 7.62 (1H, d, J = 8.0 Hz), 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) ^<+> .

Example ^382] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4R) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (thiazol-2-yl) cyclohexyl] ethanediamide hydrochloride and N ^1- (5-chloropyridin-2-yl)- ^{N 2 - [(1S, 2R} , 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} - 4- (Thiazol-2-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 549 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and the resulting two stereoisomers. Was treated again with hydrochloric acid to give the title compound.
Low polarity compound: ¹ H-NMR (DMSO-d ₆ ) 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 = 3.2 Hz), 7.75 ( 1H, d, J = 3.2 Hz), 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) ^<+> .
High polar compound: ¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example ^383] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,2,4-oxadiazol-3-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 550 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 10, and again treated with hydrochloric acid to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) 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 = 7.1 Hz), 9.21 (1H, br.s), 9.51 (1H, s), 10.28 (1H, s).
MS (FAB) m / z: 545 (M + H) ^<+> .

Example 384] N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (5-methyl-1,3,4-oxadiazol-2-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as described in Example 214, the title compound was obtained by treating the compound obtained in Reference Example 552 with hydrochloric acid, deprotecting, condensing with the compound obtained in Reference Example 10 and treating with hydrochloric acid again. Got.
¹ H-NMR (DMSO-d ₆ ) 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), 7.9-8.08 (2H, m), 8.44-8.48 (1H, m), 8.84 (1H, d, J = 6.8 Hz) , 9.22 (1H, br.s), 10.30 (1H, s), 10.96-11.25 (1H, m).
MS (EI) m / z: 558 (M ^<+> ).

Example ^385] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4
S) -2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,3,4- Oxadiazol-2-yl) cyclohexyl] ethanediamide

In the same manner as described in Example 214, the compound obtained in Reference Example 554 was treated with hydrochloric acid, deprotected, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 8.3 Hz), 7.70 (1H, dd, J = 8.8, 2.5 Hz), 8.14 (1H, d, J = 7.8 Hz), 8. 18 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 2.5 Hz), 8.38 (1 H, s), 9.72 (1 H, s).
MS (FAB) m / z: 545 (M + H) ^<+> .

Example 386] N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,3-oxazol-2-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 556 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 to 1.82 (2H, m), 1.85 to 2.00 (1H, m), 2.01 to 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) ^<+> .

Example 387] N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4- (5- methyl-1,3,4-oxadiazol-2 Yl) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

The compound (110 mg) obtained in Reference Example 560 was dissolved in methylene chloride (5 ml), 4N hydrochloric acid-dioxane solution (5 ml) was added to this solution, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting yellow solid was dissolved in N, N-dimethylformamide (5 ml). To this solution, the compound (71.1 mg) obtained in Reference Example 266, 1-hydroxybenzotriazole (42 0.7 mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (80.9 mg) were sequentially added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, methylene chloride and aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (methanol: methylene chloride = 1: 19). 1N Hydrochloric acid ethanol solution was added to the resulting free form and concentrated. Diethyl ether was added and the precipitated colorless powder was collected by filtration to give the title compound (69.8 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 to 1.85 (2H, m), 1.89 to 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) ^<+> .

Example 388] N ¹ - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,3,4-thiadiazol-2-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as described in Example 387, the compound obtained in Reference Example 562 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 266, and treated again with hydrochloric acid to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example 389 N-[(1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-fluoropyridin-2-yl) amino] -2-oxoethane Thioyl} amino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide

To a solution of the compound (76.3 g) obtained in Reference Example 563 in N, N-dimethylformamide (1.0 L), the compound (38.4 g) obtained in Reference Example 10 and 1-hydroxybenzotriazole monohydrate ( 28.8 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (37.6 g) and diisopropylethylamine (35 ml) were added, and the mixture was stirred at room temperature for 63 hours. The reaction solution was concentrated under reduced pressure, and methylene chloride (1.2 L) and saturated aqueous sodium hydrogen carbonate solution (500 ml) were added to the residue. The aqueous layer was extracted with methylene chloride, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 1 → 10: 1), the obtained powder (77.2 g) was dissolved in methylene chloride (500 ml), and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. Methylene chloride (250 ml) was added again, diethyl ether (1 L) was added dropwise, and the mixture was stirred at 0 ° C. for 30 min and collected by filtration to give the title compound (71.5 g).
¹ H-NMR (CDCl ₃ ) 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) .4 Hz), 3.75 (1H, d, J = 15.6 Hz), 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, 4.8 Hz), 10.06 (1H, br.d, J = 7.6 Hz), 10.55 (1H, br.s).
MS (ESI) m / z: 548 (M + H) ^<+> .

Example 390 N-[(1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-fluoropyridin-2-yl) amino] -2-oxoethane Thioyl} amino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide citric acid monohydrate

The compound (6.26 g) obtained in Example 389 was suspended in 100 ml of 20% aqueous ethanol, and 11.4 ml of 1M aqueous citric acid solution was added. While stirring at 60 ° C., 20% aqueous ethanol was gradually added and dissolved. After hot filtration, the mixture was allowed to cool to room temperature with stirring and left for 1 day. Precipitated crystals were collected by filtration, dried under reduced pressure at room temperature for 2 hours, and allowed to stand for 1 day to give the title compound (6.95 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.44 to 1.56 (1H, m), 1.64 to 1.72 (1H, m), 1.74 to 1.84 (2H, m) , 2.05 (1H, d, J = 14.2 Hz), 2.21-2.32 (1H, m), 2.47-2.53 (1H, m), 2.50 (3H, s) , 2.71 (2H, d, J = 15.1 Hz), 2.62 (2H, d, J = 15.6 Hz), 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 = 8.2 Hz), 8.10 (1H, dd, J = 9.2, 3.7 Hz), 8.42 (1H, d, J = 2.7 Hz), 8.72 (1H, d, J = 6.9 Hz), 10.53 (1H, s), 11.11 (1H, d, J = 7.8 Hz).
Elemental _{analysis: C 24 H 30 FN 7 O} 3 S 2 · C 6 H 8 O 7 · H 2 O
Theoretical: C; 47.55, H; 5.32, N; 12.94, F; 2.51, S; 8.46 Found: C; 47.48, H; 5.10, N; .05, F; 2.55, S; 8.61 mp (decomposition): 176-179 ° C

Example ^391] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (5-methyl-1,3,4-thiadiazol-2-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as described in Example 387, the compound obtained in Reference Example 566 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 266, and treated with hydrochloric acid again to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example ^392] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,3-oxazol-5-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 568 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example ^393] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4- (5- methyl-1,2,4-oxadiazol-3 Yl) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 387, the compound obtained in Reference Example 572 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 266, and treated again with hydrochloric acid to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.4 Hz), 8 .79 (1H, d, J = 6.8 Hz), 9.23 (1H, d, J = 8.0 Hz), 10.31 (1H, s).
MS (ESI) m / z: 559 (M + H) ^<+> .

Example ^394] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (4H-1,2,4-triazol-4-yl) cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 576 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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), 7.9-8.05 (2H, m), 8.45-8.47 (1H, m), 8.65 (2H, s), 8.69 -8.76 (1H, m), 9.39 (1H, d, J = 8.1 Hz), 10.29 (1H, s), 11.49 (1H, br.s).
MS (ESI) m / z: 544 (M + H) ^<+> .

Example ^395] N 1 - (5- ^{chloro-2-thienyl) -N 2 - ((1S,} 2R, 4S) -4- (5- methyl-1,3,4-oxadiazol-2-yl ) -2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide citrate

To a solution of the carboxylic acid lithium salt (249 mg) obtained by hydrolysis of the compound of Reference Example 356 and the compound (317 mg) of Reference Example 577 in N, N-dimethylformamide (8 ml), 1- (dimethylaminopropyl) was added. ) -3-Ethylcarbodiimide hydrochloride (308 mg) and 1-hydroxybenzotriazole (159 mg) were added at 0 ° C., and the mixture was stirred at room temperature for 11 hours. The reaction solution was diluted with ethyl acetate, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solid obtained by concentration under reduced pressure was dissolved in methylene chloride (10 ml), 4N hydrochloric acid-dioxane solution (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in N, N-dimethylformamide (8 ml), and the compound obtained in Reference Example 10 (262 mg), 1-hydroxybenzotriazole (174 mg), 1- (dimethylaminopropyl) was obtained. ) -3-Ethylcarbodiimide hydrochloride (308 mg) and triethylamine (149 μl) were added at room temperature. The reaction solution was stirred for 19 hours, diluted with methylene chloride, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 10: 1). The obtained compound was dissolved in ethanol, hexane was added, and the precipitated solid was collected by filtration. Ethanol (15 ml) and citric acid monohydrate (138 mg) were added to the obtained solid (371 mg) and dissolved, concentrated under reduced pressure, water was added and azeotroped three times, and then dried to dry the title compound ( 503 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) 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 = 15.4 Hz), 2.75 (2H, d, J = 15.4 Hz) ), 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 = 7.6 Hz), 9.22 (1H, d, J = 8.4 Hz), 12.34 (1H, s).
MS (ESI) m / z: 564 (M + H) ^<+> .

Example ^396] N 1 - (5- ^{bromo-2-pyridinyl) -N 2 - ((1S,} 2R, 4S) -4- (5- methyl-1,3,4-oxadiazol-2-yl ) -2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 579 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 8.13 (1H, dd) , J = 8.8, 2.5 Hz), 8.53 (1H, d, J = 2.5 Hz), 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) ^<+> .

Example ^397] N 1 - (4- ^{chlorophenyl) -N 2 - ((1S,} 2R, 4S) -4- (5- methyl-1,3,4-oxadiazol-2-yl) -2- {[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide citrate

In the same manner as described in Example 395, the compound obtained in Reference Example 577 was condensed with the compound obtained in Reference Example 374, deprotected by hydrochloric acid treatment, condensed with the compound obtained in Reference Example 10, and then citric acid. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 15.4 Hz), 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 = 8.8 Hz), 7.84 (2H, d, J = 8.8 Hz), 8.78 (1H, d, J = 7.3 Hz), 9.13 (1H, d, J = 8.1 Hz), 10.83 (1H, s).
MS (ESI) m / z: 558 (M + H) ^<+> .

Example ^398] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4- (5- methyl-1,3,4-oxadiazol-2 Yl) -2-{[(6-methyl-5,6,7,8-tetrahydro [1,6] naphthyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide citrate

In the same manner as described in Example 395, the compound obtained in Reference Example 577 was condensed with the compound obtained in Reference Example 266, deprotected by hydrochloric acid treatment, condensed with the compound obtained in Reference Example 540, and then citric acid. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 15.4 Hz), 2.71 (2H, d, J = 15.4 Hz), 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 = 8.1 Hz), 7.84 (1H, d, J = 8.1 Hz), 7.98-8.07 (2H, m), 8.44-8. 48 (1H, m), 8.59 (1H, d, J = 8.1 Hz), 9.21 (1H, d, J = 7.8 Hz), 10.31 (1H, s).
MS (ESI) m / z: 553 (M + H) ^<+> .

Example 399 N-[(1R, 2S, 5S) -2-{[(5-chloro-1H-indol-2-yl) carbonyl] amino} -5- (5-methyl-1,3,4 -Oxadiazol-2-yl) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide citrate

In the same manner as described in Example 395, the compound obtained in Reference Example 577 was condensed with 5-chloroindole-2-carboxylic acid, then deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then. Treatment with citric acid gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 15.2 Hz), 2.72 (2H, d, J = 15.2 Hz), 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. 6 Hz), 7.19 (1 H, dd, J = 8.8, 2.0 Hz), 7.44 (1 H, d, J = 8.8 Hz), 7.70 (1 H, d, J = 2.0 Hz) ), 8.40 (1H, d, J = 7.6 Hz), 8.44 (1H, d, J = 7.6 Hz), 11.79 (1H, s).
MS (ESI) m / z: 554 (M + H) ^<+> .

Example ^400] N 1 - (5- ^{chloro-2-thienyl) -N 2 - ((1S,} 2R, 4S) -4- (5- methyl-1,3,4-oxadiazol-2-yl ) -2-{[(6-Methyl-5,6,7,8-tetrahydro [1,6] naphthyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide citrate

In the same manner as described in Example 395, the lithium salt of the carboxylic acid obtained by hydrolyzing the compound of Reference Example 356 and the compound obtained in Reference Example 577 were condensed and then deprotected by treatment with hydrochloric acid. Reference Example Condensation with the compound obtained at 540 followed by treatment with citric acid gave the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 15.4 Hz), 2.71 (2H, d, J = 15.4 Hz), 2 .98-3.95 (7H, m), 4.09-4.19 (1H, m), 4.47-4.56 (1H, m), 6.90 (1H, d, J = 4. 2 Hz), 6.95 (1 H, d, J = 4.2 Hz), 7.74 (1 H, d, J = 7.8 Hz), 7.83 (1 H, d, J = 7.8 Hz), 8. 58 (1H, d, J = 8.0 Hz), 9.15 (1H, d, J = 8.0 Hz), 12.32 (1H, s).
MS (ESI) m / z: 558 (M + H) ^<+> .

Example ^{401] N 1 - ((1S} , 2R, 4S) -4- (5- methyl-1,3,4-oxadiazol-2-yl) -2 - {[(5-methyl-4, 5,6,7-tetrahydronaphthalene thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} ^{cyclohexyl) -N 2 - {5- [2-} ( trimethylsilyl) ethynyl] pyridin-2-yl} ethanediamide

In the same manner as in the method described in Reference Example 455, the title compound was obtained from the compound obtained in Example 396.
¹ H-NMR (CDCl ₃ ) 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 = 8.4 Hz), 7.78. (1H, dd, J = 8.4, 2.3 Hz), 8.11-8.17 (2H, m), 8.44 (1H, d, J = 2.3 Hz), 9.73 (1H, s).
MS (FAB) m / z: 621 (M + H) ^<+> .

Example ^402] N 1 - (5- ^{ethynyl-pyridin-2-yl) -N 2 - ((1S,} 2R, 4S) -4- (5- methyl-1,3,4-oxadiazol-2 Yl) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide

To a solution of the compound obtained in Example 401 (617 mg) in methanol (30 ml), potassium fluoride (116 mg) was added and stirred at room temperature for 7 hours. The solvent was distilled off under reduced pressure, and methylene chloride and water were added to the residue for liquid separation. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (methylene chloride: methanol = 93: 7). The obtained solid was dissolved in methanol, water was added, and the solvent was evaporated under reduced pressure to obtain the title compound (287 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.81-1.96 (2H, m), 2.07-2.19 (2H, m), 2.27 (1H, br. S), 2.41 (1H, d, J = 13.2 Hz), 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 = 8.3 Hz), 7.79 (1H, d, J = 8.3 Hz), 8.14 (1H, d, J = 8.3 Hz), 8.23 (1H, d , J = 7.4 Hz), 8.45 (1H, s), 9.81 (1H, s).
MS (FAB) m / z: 549 (M + H) ^<+> .

Example 403 7-chloro-N-((1S, 2R, 4S) -4- (5-methyl-1,3,4-oxadiazol-2-yl) -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -3-cinnolinecarboxamide citrate

In the same manner as in Example 214, the compound obtained in Reference Example 580 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with citric acid to obtain the title compound. .
¹ H-NMR (DMSO-d ₆ ) 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 = 15.4 Hz), 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, 2.0 Hz), 8.39 (1H, dd, J = 8.8, 1.6 Hz), 8.65-8.70 (1H, m), 8.90-8.94. (1H, m), 9.00 (1H, d, J = 6.8 Hz), 9.66 (1H, d, J = 8.4 Hz).
MS (ESI) m / z: 567 (M + H) ^<+> .

[Example 404] N-[(1R, 2S, 5S) -2-{[(Z) -3- (4-chlorophenyl) -2-fluoroacryloyl] amino} -5- (5-methyl-1,3 , 4-oxadiazol-2-yl) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide citrate

In the same manner as described in Example 395, the compound obtained in Reference Example 577 was condensed with the compound obtained in Reference Example 516, deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then citric acid. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.66 to 1.80 (2H, m), 1.85 to 1.96 (1 H, m), 2.00 to 2.16 (2H, m) , 2.30-2.41 (1H, m), 2.46 (3H, s), 2.63 (2H, d, J = 15.6 Hz), 2.72 (2H, d, J = 15.5. 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 = 38.8 Hz), 7.51 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8.4 Hz), 8.54 ( 1H, d, J = 7.2 Hz), 8.62 (1H, d, J = 7.6 Hz).
MS (ESI) m / z: 559 (M + H) ^<+> .

[Example 405] 7-chloro-N-((1S, 2R, 4S) -4- (5-methyl-1,3,4-oxadiazol-2-yl) -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -3-isoquinolinecarboxamide citrate

In the same manner as in Example 214, the compound obtained in Reference Example 581 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with citric acid to obtain the title compound. .
¹ H-NMR (DMSO-d ₆ ) 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 = 15.4 Hz) , 2.72 (2H, d, J = 15.4 Hz), 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, 2.2 Hz), 8.27 ( 1H, d, J = 8.8 Hz), 8.37-8.41 (1 H, m), 8.61 (1 H, s), 8.95 (1 H, d, J = 7.3 Hz), 9. 08 (1H, d, J = 8.3 Hz), 9 36 (1H, s).
MS (ESI) m / z: 566 (M + H) ^<+> .

[Example 406] 6-chloro-N-((1S, 2R, 4S) -4- (5-methyl-1,3,4-oxadiazol-2-yl) -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-oxo-1,4-dihydro-2-quinazolinecarboxamide citrate

In the same manner as in Example 395, the compound obtained in Reference Example 577 was condensed with the compound obtained in Reference Example 349, deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then citric acid. To give the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 = 15.4 Hz), 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 = 8.8 Hz), 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) ^<+> .

Example ^407] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,2,4-oxadiazol-5-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as described in Example 387, the compound obtained in Reference Example 583 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 266, and treated again with hydrochloric acid to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 to 1.85 (2H, m), 1.92 to 2.05 (1H, m), 2.09 to 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) ^<+> .

Example ^408] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - {(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- [5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl] cyclohexyl} ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 586 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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), 7.9-8.08 (2H, m), 8.46 (1H, br.s), 8.86 (1H, d, J = 7.1 Hz), 9.24 (1H, br.s), 10.30 (1H, s), 11.48 (1H, br.s).
MS (ESI) m / z: 613 (M + H) ^<+> .

Example ^409] N 1 - (5- ^{chloro-2-thienyl) -N 2 - ((1S,} 2R, 4S) -4- (3- methyl-1,2,4-oxadiazol-5-yl ) -2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 387, the compound obtained in Reference Example 560 was treated with hydrochloric acid, and after deprotection, the compound of Reference Example 356 was condensed with a lithium salt of carboxylic acid obtained by hydrolysis. The title compound was obtained by treatment with hydrochloric acid again.
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 to 1.82 (2H, m), 1.90 to 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 = 4.2 Hz), 6.94 (1H, d, J = 4.2 Hz), 8.83 (1H, d, J = 6.9 Hz), 9 .15 (1H, br.s), 11.43 (1H, br.s), 12.31 (1H, s).
MS (FAB) m / z: 564 (M + H) ^<+> .

Example ^410] N 1 - (6- ^{chloro-3-yl) -N 2 - ((1S,} 2R, 4S) -4- (3- methyl-1,2,4-oxadiazol-5 Yl) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride

In the same manner as described in Example 387, the compound obtained in Reference Example 560 was treated with hydrochloric acid, and after deprotection, the compound of Reference Example 264 was hydrolyzed and condensed with a lithium salt of carboxylic acid. The title compound was obtained by treatment with hydrochloric acid again.
¹ H-NMR (DMSO-d ₆ ) 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 = 9.2 Hz), 8.29 (1H, d, J = 9.2 Hz), 8.79 (1 H, d, J = 7.1 Hz), 9.27 (1 H, d, J = 7.8 Hz), 11.06 (1 H, s).
MS (FAB) m / z: 560 (M + H) ^<+> .

Example ^411] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (2-oxo-1,3-oxazolidine-3-yl) cyclohexyl] ethanediamide

To a solution of the compound obtained in Reference Example 589 (696 mg) in methanol (70 ml), p-toluenesulfonic acid monohydrate (301 mg) was added and heated to reflux overnight. P-Toluenesulfonic acid monohydrate (82 mg) was added to the reaction solution, and the mixture was further heated under reflux for 2 hours, and then the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (50 ml), the compound (338 mg) obtained in Reference Example 564, 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (552 mg), 1-hydroxybenzotriazole (97 mg) was added and stirred at room temperature overnight. Triethylamine (599 μl) was added to the reaction mixture, and the mixture was stirred at 45 ° C. overnight. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by flash column chromatography (methylene chloride: methanol = 93: 7) using silica gel as a carrier. The desired product portion was concentrated, diethyl ether was added, and the resulting solid was filtered to obtain the title compound (83 mg).
¹ H-NMR (CDCl ₃ ) d: 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, 2.5 Hz), 8.10 (1H, br.s), 8.19 (1H, dd, J = 8.8, 0.7 Hz), 8.31 (1 H, dd, J = 2.5, 0.7 Hz), 9.71 (1 H, s).
MS (ESI) m / z: 562 (M + H) ^<+> .

Example ^412] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (tetrazol-1-yl) cyclohexyl] ethanediamide

In the same manner as in Example 214, the compound obtained in Reference Example 592 was deprotected by treatment with hydrochloric acid and condensed with the compound obtained in Reference Example 10 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) 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 = 8.1 Hz) , 7.70 (1H, dd, J = 8.9, 2.6 Hz), 8.05 (1H, d, J = 7.6 Hz), 8.16 (1H, dd, J = 8.9, 0) .6 Hz), 8.32 (1 H, dd, J = 2.6, 0.6 Hz), 8.72 (1 H, s), 9.72 (1 H, s).
MS (ESI) m / z: 545 (M + H) ^<+> .

Example ^413] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1H-pyrrol-1-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 594 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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) ^<+> .

Example ^414] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1,2,4-triazol-5-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 597 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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, 2.3 Hz), 8.05 (1 H, d, J = 8.9 Hz), 8.46 (1 H, d, J = 2.3 Hz), 8.74 (1 H, 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) ^<+> .

Example ^415] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1-methyl-1H-1,2,4-triazol-5-yl) cyclohexyl] ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 599 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 (1 H, s), 8.44 (1 H, br. S), 8.71 (1 H, d, J = 6.8 Hz), 9.14-9.26 (1 H, m), 10.27 (1H, s).
MS (FAB) m / z: 558 (M + H) ^<+> .
MS (FAB) m / z: 544 (M + H) ^<+> .

[Example 416] 7-chloro-N-((1S, 2R, 4S) -4- (3-methyl-1,2,4-oxadiazol-5-yl) -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -3-cinnolinecarboxamide hydrochloride

In the same manner as described in Example 387, the compound obtained in Reference Example 560 was treated with hydrochloric acid, deprotected, condensed with the compound obtained in Reference Example 298, and treated again with hydrochloric acid to give the title compound. Obtained.
¹ H-NMR (DMSO-d ₆ ) 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. 7 Hz), 8.38 (1 H, d, J = 9.1 Hz), 8.67 (1 H, s), 8.91 (1 H, s), 9.06 (1 H, d, J = 6.9 Hz) , 9.64 (1H, d, J = 7.8 Hz).
MS (ESI) m / z: 567 (M + H) ^<+> .

Example ^417] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - ((3R,} 4S) -3 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline thiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} -1- (thiazol-2-yl) piperidin-4-yl) ethanediamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 603 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) 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 (total 1H, each d, J = 7.8 Hz), 10.28,10.33 (total 1H, each br.s), 11.30-11.64 (1H, br).
MS (ESI) m / z: 561 (M + H) ^<+> .

[Test Example 1] Measurement of human FXa inhibitory action (IC ₅₀ value) In each well of a 96-well (well) microplate, 10 μl of a sample 5% DMSO solution in which the concentration was set stepwise, Tris buffer (100 mM Tris, After adding 10 μl of 200 mM potassium chloride, 0.2% BSA, pH 7.4) 40 μl, 0.0625 U / ml human FXa (Enzyme Research Laboratories, Inc., dissolved and diluted in Tris buffer), 750 μM S- 40 μl of 2222 aqueous solution (Chromogenix) was added, and the absorbance at 405 nm was measured at room temperature for 10 minutes to determine the increase in absorbance (ΔOD / min). As a control, Tris buffer was used instead of the specimen.
The inhibition rate (%) at each final concentration of the sample obtained by the following formula was plotted on the vertical axis of the logarithmic probability paper, and the final concentration of the sample was plotted on the horizontal axis to obtain a 50% inhibition concentration (IC ₅₀ value). .
Inhibition rate (%) = (1−sample ΔOD / min ÷ control ΔOD / min) × 100 (result) Table 1 shows that the compound of the present invention has a potent FXa inhibitory action.

[Test Example 2] Measurement of anti-FXa activity in rat plasma after oral administration (A) Administration and blood collection A drug solution (1 mg / ml) in which 10 mg of a sample is dissolved or suspended in 0.5% methylcellulose (MC) is given to rats. Orally administered (10 ml / kg). 0.5, 1, 2, 4 hours after drug administration, 0.5 ml of blood was cervixed using a syringe infused with 50 μl of 3.13% (w / v) aqueous solution of trisodium citrate dihydrate. It was collected from a vein (collected blood volume: 0.45 ml). Rats in the control group were administered 0.5% MC solution and then blood was collected as described above. Each blood sample was centrifuged at 4 ° C. and 1500 × g for 10 minutes to separate plasma, and then stored at −40 ° C. until used for measurement of plasma anti-FXa activity described below.
(B) Measurement of plasma FXa inhibitory activity Plasma anti-FXa activity was measured using S-2222 as a substrate. 5456 μl of Tris buffer (100 mM Tris, 200 mM potassium chloride, 0.2% BSA, pH 7.4), 44 μl of human FXa (2.5 U / ml) and 550 μl of water were mixed. The obtained human FXa solution was used for the following tests.
Immediately after adding 5 μl of rat plasma obtained in the above operation (A) to each well of a 96-well microplate, and subsequently adding 55 μl of the above human FXa solution and 40 μl of 750 μM S-2222 aqueous solution, The absorbance at 405 nm was measured at room temperature using a total of SPECTRAmax 340 or 190 (Molecular Devices Co., USA), and the reaction rate (ΔOD / min) was determined.
The anti-FXa activity, that is, the inhibition rate (%) was calculated by the following formula.
Inhibition rate (%) = [1− (ΔOD / min of sample ÷ ΔOD / min of control group)] × 100
(Results) The compounds described in Examples 63, 191, 192, 194 and 204 exhibited strong plasma FXa inhibitory activity of 62% to 96% after oral administration of 10 mg / kg.

Claims (17)

General formula (1)

(Wherein R ¹ and R ² each independently represents a hydrogen atom;
Q ¹ is a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, a substituent A saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent Show;
Q ² represents a single bond;
Q ³ is the following group

(Wherein Q ⁵ represents an alkylene group having 4 carbon atoms);
R ³ represents a hydrogen atom, R ⁴ represents a 5-membered heterocyclic group which may have a substituent;
Q ⁴ represents an aryl group which may have a substituent, a heteroaryl group which may have a substituent, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may have a substituent, A saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have a substituent;
T ^O represents a carbonyl group or a thiocarbonyl group;
T ¹ is a group —C (═O) —C (═O) —N (R ′) —, a group —C (═S) —C (═O) —N (R ′) —, a group —C ( = O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(in the group, R 'represents a hydrogen atom.) Indicates. ), A salt thereof, or a solvate thereof. R ⁴ may have a thiazolyl group that may have a substituent, a thiadiazolyl group that may have a substituent, an oxazolyl group that may have a substituent, an oxadiazolyl group that may have a substituent, or a substituent. The compound according to claim 1, a salt thereof, or a solvate thereof, which is a triazolyl group, a tetrazolyl group that may have a substituent, or a pyrrolyl group that may have a substituent. R ⁴ may have a thiazolyl group that may have a substituent, a 1,3,4-thiadiazolyl group that may have a substituent, a 1,3-oxazolyl group that may have a substituent, or a substituent. The compound according to claim 1 or 2, a salt thereof, or a solvate thereof, which is a 1,2,4-oxadiazolyl group or a 1,3,4-oxadiazolyl group which may have a substituent. Q ¹ is a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group that may have a substituent, or a saturated or unsaturated bicyclic or tricyclic that may have a substituent. It is a condensed heterocyclic group, The compound of any one of Claims 1-3, its salt, or those solvates. Q ¹ is a thienopyridyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent, a thiazopyridyl group which may have a substituent, or a tetrahydrothiazolopyridyl group which may have a substituent A thiazolopyridazinyl group which may have a substituent, a tetrahydrothiazolopyridazinyl group which may have a substituent, a pyranothiazolyl group which may have a substituent, a dihydro which may have a substituent Pyranothiazolyl group, optionally substituted furopyridyl group, optionally substituted tetrahydrofuropyridyl group, optionally substituted oxazolopyridyl group, optionally substituted tetrahydrooxazolo Pyridyl group, pyrrolopyridyl group that may have a substituent, may have a substituent Dihydropyrrolopyridyl group, tetrahydropyrrolopyridyl group which may have a substituent, pyrrolopyrimidinyl group which may have a substituent, dihydropyrrolopyrimidinyl group which may have a substituent, oxazolo which may have a substituent Pyridazinyl group, tetrahydrooxazolopyridazinyl group which may have a substituent, pyrrolothiazolyl group which may have a substituent, dihydropyrrolothiazolyl group which may have a substituent, which has a substituent A pyrrolooxazolyl group, a dihydropyrrolooxazolyl group that may have a substituent, a benzothiazolyl group that may have a substituent, a tetrahydrobenzothiazolyl group that may have a substituent, a substituent Thiazolopyrimidinyl group, which may have Drothiazolopyrimidinyl group, benzoazepinyl group which may have a substituent, tetrahydrobenzoazepinyl group which may have a substituent, thiazoloazepinyl group which may have a substituent, may have a substituent Tetrahydrothiazoloazepinyl group, Thienoazepinyl group which may have a substituent, Tetrahydrothienoazepinyl group which may have a substituent, 4,5,6,7-Tetrahydro-5 which may have a substituent A 6-tetramethylenethiazolopyridazinyl group or a 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may have a substituent. The compound of any one, its salt, or those solvates. Substituents on group Q ¹ are hydroxyl, halogen, halogenoalkyl, amino, cyano, amidino, hydroxyamidino, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl C ₁ -C. ₆ alkyl group, hydroxy C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, carboxyl group, C ₂ -C ₆ carboxyalkyl group, C _2- C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group, amidino group substituted by C ₂ -C ₆ alkoxycarbonyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkoxycarbonyl group , amino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl group, di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkoxycarbonyl amino ₁ -C ₆ alkyl group, C ₁ -C ₆ alkanoyl group, C ₁ -C ₆ alkanoylamino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ alkylsulfonylamino C ₁ - C ₆ alkyl group, a carbamoyl group, C ₁ -C ₆ alkylcarbamoyl group, N, N-di (C ₁ -C ₆ alkyl) carbamoyl group, C ₁ -C ₆ alkylamino group, di (C ₁ -C ₆ alkyl ) amino group, aminosulfonyl group, an arylsulfonyl group, an arylcarbonyl group which may a halogen atom is substituted, C ₂ -C ₆ alkoxycarbonyl (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl groups, C _1- C ₆ alkylsulfonyl C ₁ -C ₆ alkyl group or 5-6 membered heterocyclic group containing 2 nitrogen, oxygen or sulfur atoms of the same or different kind, 5-6 membered heterocyclic group -C ₁ -C ₄ alkyl group, 5- to 6-membered heterocyclic group - carbonyl group, 5- to 6-membered heterocyclic group - amino -C ₁ -C ₄ alkyl, 5-6 membered heterocyclic group - amino group, 5- to 6-membered heterocyclic group - oxy group, 3- to 6-membered heterocyclic group - carbonyl -C ₁ -C ₄ alkyl group and 5- to 6-membered heterocyclic group (C ₁ -C ₆ alkyl) amino -C ₁ -C ₄ compound according to any one of claims 1 to 5 is one to three chosen from an alkyl group, a salt or solvate thereof. Q ⁴ may have a phenyl group that may have a substituent, a pyridyl group that may have a substituent, a pyridazinyl group that may have a substituent, a pyrazinyl group that may have a substituent, or a substituent A furyl group, a thienyl group that may have a substituent, a pyrrolyl group that may have a substituent, a thiazolyl group that may have a substituent, an oxazolyl group that may have a substituent, or a substituent The compound, salt thereof, or solvate thereof according to any one of claims 1 to 6, which is a group selected from a pyrimidinyl group and a tetrazolyl group which may have a substituent. The substituent on Q ⁴ is a hydroxyl group, halogen atom, halogenoalkyl group, amino group, cyano group, aminoalkyl group, nitro group, hydroxyalkyl group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonylalkyl group, Acyl group, amidino group, hydroxyamidino group, linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, linear chain An amidino group substituted with a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched or cyclic amidino group substituted with a alkoxy group having 1 to 6 carbon atoms, a linear form, Amidino group, linear, branched or cyclic alkenyl group having 2 to 6 carbon atoms substituted by a branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms Linear or branched alkynyl group having 2 to 6 carbon atoms, linear, branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms, carbamoyl group, linear or branched on nitrogen atom A mono- or dialkylcarbamoyl group substituted with a linear or branched alkyl group having 1 to 6 carbon atoms, a mono- or dialkylamino group substituted with a linear, branched or cyclic alkyl group with 1 to 6 carbon atoms and 5 The compound according to any one of claims 1 to 7, a salt thereof, or a solvate thereof, which is selected from 1 to 6 members selected from a -6-membered nitrogen-containing heterocyclic group. Q ⁴ is phenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4-ethynylphenyl group, 3-chlorophenyl group, 3-fluorophenyl group, 3-bromophenyl group, 3-ethynyl. Phenyl group, 3-chloro-4-fluorophenyl group, 4-chloro-3-fluorophenyl group, 4-chloro-2-fluorophenyl group, 2-chloro-4-fluorophenyl group, 4-bromo-2-fluoro Phenyl group, 2-bromo-4-fluorophenyl group, 2,4-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dibromophenyl group, 4-chloro-3-methylphenyl group, 4-fluoro- 3-methylphenyl group, 4-bromo-3-methylphenyl group, 4-chloro-2-methylphenyl group, 4-fluoro-2-methyl Phenyl group, 4-bromo-2-methylphenyl group, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dibromophenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group 4-chloro-2-pyridyl group, 4-fluoro-2-pyridyl group, 4-bromo-2-pyridyl group, 4-ethynyl-2-pyridyl group, 4-chloro-3-pyridyl group, 4-fluoro- 3-pyridyl group, 4-bromo-3-pyridyl group, 4-ethynyl-3-pyridyl group, 5-chloro-2-pyridyl group, 5-fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5-ethynyl-2-pyridyl group, 4-chloro-5-fluoro-2-pyridyl group, 5-chloro-4-fluoro-2-pyridyl group, 5-chloro-3-pyridyl group, 5-fluoro-3- Pyridyl Group, 5-bromo-3-pyridyl group, 5-ethynyl-3-pyridyl group, 6-chloro-3-pyridazinyl group, 6-fluoro-3-pyridazinyl group, 6-bromo-3-pyridazinyl group, 6-ethynyl It is a -3-pyridazinyl group, a 5-chloro-2-thiazolyl group, a 5-fluoro-2-thiazolyl group, a 5-bromo-2-thiazolyl group or a 5-ethynyl-2-thiazolyl group. Or a salt thereof, or a solvate thereof. The compound, salt or solvate thereof according to claim 1, which is any one of the following compounds, salts thereof or solvates thereof.

The compound, salt or solvate thereof according to claim 1, which is any one of the following compounds, salts thereof or solvates thereof.

  The pharmaceutical containing the compound of any one of Claims 1-11, its salt, or those solvates.   The activated blood coagulation factor X inhibitor containing the compound of any one of Claims 1-11, its salt, or those solvates.   The blood coagulation inhibitor containing the compound of any one of Claims 1-11, its salt, or those solvates.   A prophylactic and / or therapeutic agent for a thrombus or embolus, comprising the compound according to any one of claims 1 to 11, a salt thereof, or a solvate thereof.   A cerebral infarction, a cerebral embolism, a myocardial infarction, an angina pectoris, a pulmonary infarction, a pulmonary embolism, a Buerger disease, or a deep part containing the compound according to any one of claims 1 to 11, a salt thereof, or a solvate thereof. Venous thrombosis, generalized intravascular coagulation syndrome, thrombus formation after prosthetic valve / joint replacement, thrombus formation and reocclusion after revascularization, systemic inflammatory response syndrome (SIRS), multiple organ failure (MODS), extracorporeal A prophylactic and / or therapeutic agent for thrombus formation during circulation or blood coagulation during blood collection.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.